bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2020‒01‒26
1752 papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Metformin Mitigates Nickel-Elicited Angiopoietin-Like Protein 4 Expression via HIF-1α for Lung Tumorigenesis.
  2. Preclinical safety and antitumor activity of the arginine-degrading therapeutic enzyme pegzilarginase, a PEGylated, cobalt-substituted recombinant human arginase 1.
  3. Flumethasone enhances the efficacy of chemotherapeutic drugs in lung cancer by inhibiting Nrf2 signaling pathway.
  4. Requirement for epithelial p38α in KRAS-driven lung tumor progression.
  5. Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo.
  6. Actin-like protein 8 promotes cell proliferation, colony-formation, proangiogenesis, migration and invasion in lung adenocarcinoma cells.
  7. FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1α-PINK1-Parkin pathway.
  8. Psoas muscle mass in patients undergoing lung cancer surgery: a prognostic difference between squamous cell carcinoma and adenocarcinoma.
  9. SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner.
  10. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in non-small cell lung cancer.
  11. Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.
  12. NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter.
  13. The association of physical function and quality of life on physical activity for non-small cell lung cancer survivors.
  14. Influx rate constant of 18F-FDG increases in metastatic lymph nodes of non-small cell lung cancer patients.
  15. Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer.
  16. Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity.
  17. Pre-Disease and Pre-Surgery BMI, Weight Loss and Sarcopenia Impact Survival of Resected Lung Cancer Independently of Tumor Stage.
  18. Preliminary data on circulating tumor cells in metastatic NSCLC patients candidate to immunotherapy.
  19. COPD and lung cancer incidence in the Women's Health Initiative Observational Study: A brief report.
  20. O-GlcNAc Transferase Regulates Cancer Stem-like Potential of Breast Cancer Cells.
  21. The MEK5-ERK5 kinase axis controls lipid metabolism in small cell lung cancer.
  22. New Paradigms to Assess Consequences of Long-Term, Low-Dose Curcumin Exposure in Lung Cancer Cells.
  23. Improved workflow for mass spectrometry-based metabolomics analysis of the heart.
  24. Co-delivery of 2-Deoxyglucose and a Glutamine Metabolism Inhibitor V9302 via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer.
  25. Naesohwangryeon-tang Induced Apoptosis and Autophagy in A549 Human Lung Cancer Cells.
  26. Activation of AMPK pathway compromises Rab11 downregulation-mediated inhibition of Schwann cell proliferation in a Glut1 and Glut3-dependent manner.
  27. Carotid body Type I cells engage flavoprotein and Pin1 for oxygen sensing.
  28. Centromere protein F and Forkhead box M1 correlation with prognosis of non-small cell lung cancer.
  29. Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma.
  30. Neoplastic meningitis in solid tumours: Updated review of diagnosis, prognosis, therapeutic management, and future directions.
  31. Overexpression of molecule GRP94 favors tumor progression in lung adenocarcinoma by interaction with regulatory T cells.
  32. TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.
  33. Is it possible to achieve more accurate mediastinal nodal radiotherapy planning for NSCLC with PET/CT?
  34. Nicotinic-nAChR signaling mediates drug resistance in lung cancer.
  35. HIF1α-dependent upregulation of ATAD2 promotes proliferation and migration of stomach cancer cells in response to hypoxia.
  36. Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges.
  37. Polyphyllin VII induces apoptotic cell death via inhibition of the PI3K/Akt and NF‑κB pathways in A549 human lung cancer cells.
  38. Amino acids in cancer.
  39. Correlation between glucose metabolism and serum steroid hormones in patients with polycystic ovary syndrome.
  40. TRIM67 Promotes the Proliferation, Migration, and Invasion of Non-Small-Cell Lung Cancer by Positively Regulating the Notch Pathway.
  41. TRIM59 as a novel molecular biomarker to predict the prognosis of patients with NSCLC.
  42. Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy in EGFR / ALK wild-type advanced non-small cell lung cancer.
  43. p62 promotes bladder cancer cell growth by activating KEAP1/NRF2-dependent antioxidative response.
  44. Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth.
  45. Inactivation of RB1 and histological transformation in EGFR-mutant lung adenocarcinoma.
  46. MicroRNA-425-5p Inhibits Lung Cancer Cell Growth in Vitro and in Vivo by Downregulating TFIIB-Related Factor 2.
  47. hsa_circ_0062389 promotes the progression of non-small cell lung cancer by sponging miR-103a-3p to mediate CCNE1 expression.
  48. PAS kinase deficiency reduces aging effects in mice.
  49. Exosomal miR-106b serves as a novel marker for lung cancer and promotes cancer metastasis via targeting PTEN.
  50. Successful lung Cancer EGFR sequencing from DNA extracted from TTF-1 immunohistochemistry slides: a new means to extend insufficient tissue.
  51. N-acetyl cysteine protects against chlorine-induced tissue damage in an ex vivo model.
  52. Endothelial cell sprouting driven by RhoJ directly activated by a membrane-anchored Intersectin 1 (ITSN1) RhoGEF module.
  53. MTAP-deficiency could predict better treatment response in advanced lung adenocarcinoma patients initially treated with pemetrexed-platinum chemotherapy and bevacizumab.
  54. Melatonin inhibits Warburg-dependent cancer by redirecting glucose oxidation to the mitochondria: a mechanistic hypothesis.
  55. Multikinase Inhibitor Crizotinib Is Active in MET Exon 14-Altered Lung Cancer.
  56. Stanford type IV venous collateral blood flow following complete chronic occlusion of the superior vena cava in a patient with lung cancer.
  57. Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma.
  58. Extracellular volatilomic alterations induced by hypoxia in breast cancer cells.
  59. Development of a lateral flow aptamer assay strip for facile identification of theranostic exosomes isolated from human lung carcinoma cells.
  60. Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.
  61. Inhibition mechanism of lung cancer cell metastasis through targeted regulation of Smad3 by miR-15a.
  62. Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities.
  63. A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis.
  64. A new abietane diterpenoid from Ajuga ovalifolia var. calantha induces human lung epithelial A549 cell apoptosis by inhibiting SHP2.
  65. Radiomics predicts survival of patients with advanced non-small cell lung cancer undergoing PD-1 blockade using Nivolumab.
  66. Great debate: surgery versus stereotactic radiotherapy for early-stage non-small cell lung cancer.
  67. NCX and EAAT transporters in ischemia: At the crossroad between glutamate metabolism and cell survival.
  68. The endemic and endangered Maugean Skate (Zearaja maugeana) exhibits short-term severe hypoxia tolerance.
  69. Population morbidity in elderly lung cancer patients from Poland with specific trends in elderly women.
  70. Down-regulation of tissue factor inhibits invasion and metastasis of non-small cell lung cancer.
  71. Bone decalcification to assess programmed cell death ligand 1 expression in bone metastases of non-small cell lung cancers.
  72. Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis.
  73. MDMA hepatotoxicity under heat stress condition: novel insights from in vitro metabolomic studies.
  74. Elaboration of a multimodal MRI-based radiomics signature for the preoperative prediction of the histological subtype in patients with non-small-cell lung cancer.
  75. Integrative metabolic pathway analysis reveals novel therapeutic targets in osteoarthritis.
  76. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan.
  77. Erratum: Long non-coding RNA transcribed from pseudogene PPIAP43 is associated with radiation sensitivity of small cell lung cancer cells.
  78. Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification.
  79. Nicotine Upregulates the Level of Mcl-1 through STAT3 in H1299 Cells.
  80. Delineating cell behavior and metabolism of non-melanoma skin cancer in vitro.
  81. Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy.
  82. Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines.
  83. Negative reactions of BRAF mutation-specific immunohistochemistry to non-V600E mutations of BRAF.
  84. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes.
  85. Modified Liujunzi Decoction () Alleviates Chemotherapy-Induced Anorexia in Advanced Non-Small Cell Lung Cancer: A Propensity Score Matched Case-Control Study.
  86. Exploratory analysis of front-line therapies in REVEL: a randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy.
  87. Patient-reported Outcomes After the Treatment of Early Stage Non-small-cell Lung Cancer With Stereotactic Body Radiotherapy Compared With Surgery.
  88. Systematic impacts of chronic unpredictable mild stress on metabolomics in rats.
  89. Tumor-node-metastasis staging and treatment patterns of 73,167 patients with lung cancer in Brazil.
  90. Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer.
  91. Transmission of Functional, Wild-Type Mitochondria and the Fittest mtDNA to the Next Generation: Bottleneck Phenomenon, Balbiani Body, and Mitophagy.
  92. Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells.
  93. Sequential blinded treatment decisions in ALK-positive non-small cell lung cancers in the era of precision medicine.
  94. Target Alpha Therapy with Thorium-227.
  95. Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.
  96. Chromosome arm aneuploidies shape tumour evolution and drug response.
  97. DNAH10 mutation correlates with cisplatin sensitivity and tumor mutation burden in small-cell lung cancer.
  98. Restoration of Mal overcomes the defects of apoptosis in lung cancer cells.
  99. Thrombin-mediated activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease.
  100. A rare case of hyperprogression of nonsmall cell lung cancer in a patient on atezolizumab therapy.
  101. Association between COMT gene Val108/158Met and antidepressive treatment response: a meta-analysis.
  102. Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway.
  103. The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.
  104. Role of Interleukin-34 in Cancer.
  105. Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma.
  106. The optimal sequence of bronchial brushing and washing for diagnosing peripheral lung cancer using non-guided flexible bronchoscopy.
  107. PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice.
  108. Not everything is what it seems: malignant pleural mesothelioma mimicking lung cancer.
  109. 18F-FDG PET/CT Evaluation of Crizotinib and Lorlatinib Therapy in Metastatic ROS-1-Positive Non-Small Cell Lung Cancer.
  110. Relevance and prognostic ability of Twist, Slug and tumor spread through air spaces in lung adenocarcinoma.
  111. Stereotactic Body Radiation Therapy for Extracranial Oligometastatic Non-small-cell Lung Cancer: A Systematic Review.
  112. Systematic analyses of genetic variants in chromatin interaction regions identified four novel lung cancer susceptibility loci.
  113. Association Between Diet, Physical Activity and Body Mass Index, Fat Mass Index and Bone Mineral Density of Soldiers of the Polish Air Cavalry Units.
  114. Characterization of Arsenic-Induced Cancer Stem-Like Cells.
  115. Acanthamoeba castellanii phosphate transporter (AcPHS) is important to maintain inorganic phosphate influx and is related to trophozoite metabolic processes.
  116. Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.
  117. The role of vascular function on exercise capacity in health and disease.
  118. Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation.
  119. Choroidal metastasis as the initial presentation of lung adenocarcinoma: A case report.
  120. Effect of lung volume on helical radiotherapy in esophageal cancer: are there predictive factors to achieve acceptable lung doses?
  121. Nivolumab-Induced Psoriatic Arthritis in a Patient With Advanced Small Cell Lung Cancer.
  122. Gold nanoparticle based double-labeling of melanoma extracellular vesicles to determine the specificity of uptake by cells and preferential accumulation in small metastatic lung tumors.
  123. A prognostic analysis method for non-small cell lung cancer based on the computed tomography radiomics.
  124. Neuroprotective effect of Annona muricata-derived polysaccharides in neuronal HT22 cell damage induced by hydrogen peroxide.
  125. Lipid profiling of serum and lipoprotein fractions in response to pitavastatin using an animal model of familial hypercholesterolemia.
  126. Hyperbaric oxygen activates visfatin expression and angiogenesis via angiotensin II and JNK pathway in hypoxic human coronary artery endothelial cells.
  127. Identifying drug targets in tissues and whole blood with thermal-shift profiling.
  128. rs622342A>C in SLC22A1 is associated with metformin pharmacokinetics and glycemic response.
  129. Berberine induces dose-dependent quiescence and apoptosis in A549 cancer cells by modulating cell cyclins and inflammation independent of mTOR pathway.
  130. Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis.
  131. Autophagy decreases alveolar epithelial cell injury by regulating the release of inflammatory mediators.
  132. Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent.
  133. Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review.
  134. Genetic variants in the folate metabolic pathway genes predict melanoma-specific survival.
  135. Tumor Microenvironment-Responsive Theranostic Nanoplatform for in situ Self-Boosting Combined Phototherapy through Intracellular Reassembly.
  136. Upregulation of 6-phosphofructo-2-kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex.
  137. Treatment patterns and survival after 18F-fluorodeoxyglucose positron emission tomography/computed tomography-guided local consolidation therapy for oligometastatic non-small cell lung cancer: a two-center propensity score-matched analysis.
  138. The signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type Ia.
  139. LncRNA NNT-AS1 regulates the progression of lung cancer through the NNT-AS1/miR-3666/E2F2 axis.
  140. Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma and Paraganglioma.
  141. Lung cancer surgery for patients on hemodialysis: A decade of experience at multicenter institutions.
  142. Assessment of robustness against setup uncertainties using probabilistic scenarios in lung cancer: a comparison of proton with photon therapy.
  143. Rhegmatogenous retinal detachment secondary to isolated retinal metastasis from small cell lung carcinoma: An uncommon complication.
  144. Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer.
  145. Investigation of the EIL/EIN3 Transcription Factor Gene Family Members and Their Expression Levels in the Early Stage of Cotton Fiber Development.
  146. Letter from Jordan.
  147. The Glycosyltransferase Gene OsUGT90A1 Helps Protect Plasma Membranes During Chilling Stress in Rice.
  148. Lung cancer mortality among smokers and never-smokers in the United States.
  149. Potential predictors for chemotherapeutic response and prognosis in epithelial ovarian, fallopian tube and primary peritoneal cancer patients treated with platinum-based chemotherapy.
  150. Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle.
  151. Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer.
  152. Endoscopic ultrasound-guided ascites aspiration in the hands of the chest physician using the EBUS endoscope in the oesophagus.
  153. Metformin Attenuates Liver Fat Content: Finding from Schizophrenia Patients with Olanzapine-induced Weight Gain.
  154. The stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival.
  155. Correlation between serum leptin level and Body mass index (BMI) in patients with type 2 diabetes Mellitus.
  156. Correlation Between Equilibrium Constant and Stabilization Energy: A Combined Approach Based on Chemical Thermodynamics, Statistical Thermodynamics and Density Functional Reactivity Theory.
  157. D-dimer and diffusion-weighted imaging pattern as two diagnostic indicators for cancer-related stroke: A case-control study based on the STROBE guidelines.
  158. Metabolic disparities of different oxidative stress‑inducing conditions in HTR8/SVneo cells.
  159. PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.
  160. Cell Electropermeabilisation Enhancement by Non-Thermal-Plasma-Treated PBS.
  161. Spinal cord neurodegeneration after inorganic mercury long-term exposure in adult rats: Ultrastructural, proteomic and biochemical damages associated with reduced neuronal density.
  162. Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes.
  163. Is surgical resection of primary tumour superior to exploratory thoracotomy without resection in treating lung cancer patients with unexpected pleural metastasis detected during operation?
  164. Therapeutic IDOL reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice.
  165. MicroRNA-519 inhibits hypoxia-induced tumorigenesis of pancreatic cancer by regulating immune checkpoint PD-L1.
  166. Epidemiology of Lung Cancer.
  167. BLOOD PLASMA METABOLOMICS PREDICTS PREGNANCY IN HOLSTEIN CATTLE TRANSFERRED WITH FRESH AND VITRIFIED/WARMED EMBRYOS PRODUCED IN VITRO.
  168. Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) for PD-L1 testing in triple-negative breast cancer: a translational assay compared with conventional IHC.
  169. Impact of Sarcopenia on Surgical Outcomes in Non-small Cell Lung Cancer.
  170. Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy.
  171. Nocardial brain abscess mimicking lung cancer metastasis in immunocompetent patient with pulmonary nocardiasis: a case report.
  172. Glycolysis-Based Genes Associated with the Clinical Outcome of Pancreatic Ductal Adenocarcinoma Identified by The Cancer Genome Atlas Data Analysis.
  173. The emergence of preclinical studies on the role of the microbiome in lung development and experimental animal models of bronchopulmonary dysplasia.
  174. High fat diet incorporated with meat proteins changes biomarkers of lipid metabolism, antioxidant activities, and the serum metabolomic profile in Glrx1-/- mice.
  175. Autophagy and autophagy-related proteins in cancer.
  176. Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements.
  177. Critical review of the evidence for a causal association between exposure to asbestos and esophageal cancer.
  178. Effects of hub genes on the clinicopathological and prognostic features of lung adenocarcinoma.
  179. An exceptional response to olaparib in relapsed and refractory BRCA2 mutated non-small cell lung cancer in hereditary breast-ovarian cancer syndrome.
  180. Metabolism and Disposition of Ataluren following Oral Administration to Mice, Rats, Dogs, and Humans.
  181. Cadmium-Related Effects on Cellular Immunity Comprises Altered Metabolism in Earthworm Coelomocytes.
  182. Environmental arginine controls multinuclear giant cell metabolism and formation.
  183. Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response.
  184. Metformin upregulates mitophagy in patients with T2DM: A randomized placebo-controlled study.
  185. Untargeted metabolic fingerprinting reveals impact of growth stage and location on composition of sea buckthorn (Hippophaë rhamnoides) leaves.
  186. IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα- BCa and AR- PCa cells and promotes cell survival.
  187. Insights into the regulation of molecular mechanisms involved in energy shortage in detached citrus fruit.
  188. Targeting glutamine metabolism slows soft tissue sarcoma growth.
  189. Hypoxic environment may enhance migration/penetration of endocrine resistant MCF7- derived breast cancer cells through monolayers of other non-invasive cancer cells in vitro.
  190. MnO2@Ce6-loaded mesenchymal stem cells as an "oxygen-laden guided-missile" for the enhanced photodynamic therapy on lung cancer.
  191. Uncertainty and certain death: the role of clinical trials in terminal cancer care.
  192. A novel technique for robotic-assisted lobectomy for lung cancer: the anterior approach.
  193. Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells.
  194. Alterations in α-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons.
  195. Commentary: The role of low-dose computed tomography for lung cancer screening among the nonsmoking Asian population.
  196. Exogenous Ubiquitin Attenuates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via the Involvement of CXCR4 and Modulation of Mitochondrial Homeostasis.
  197. Short-term Efficacy of Different First-Line Chemotherapy Regimens for Advanced Non-Small Cell Lung Cancer: A Network Meta-Analysis.
  198. Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells.
  199. Advanced nanotechnology for hypoxia-associated antitumor therapy.
  200. LIFESTYLE RISK FACTORS AND BONE MASS IN RECURRENT STONE-FORMING PATIENTS: A CROSS-SECTIONAL STUDY IN 144 SUBJECTS.
  201. Close Encounters of the Cell Kind: The Impact of Contact Inhibition on Tumour Growth and Cancer Models.
  202. p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis.
  203. Lung Cancer Screening: How We do It and Why.
  204. Resveratrol Attenuates Intermittent Hypoxia-Induced Lung Injury by Activating the Nrf2/ARE Pathway.
  205. DMD carrier model with mosaic dystrophin expression in the heart reveals complex vulnerability to myocardial injury.
  206. Lycopene attenuates body weight gain through induction of browning via regulation of peroxisome proliferator-activated receptor γ in high-fat diet-induced obese mice.
  207. A robust TDP-43 knock-in mouse model of ALS.
  208. Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance.
  209. [Pericardial Fenestration and Multidisciplinary Treatment to Improve the Prognosis of the Malignant Pericarditis Due to Lung Cancer].
  210. Bifidobacterium longum-fermented rice bran and rice bran supplementation affects the gut microbiome and metabolome.
  211. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue.
  212. A panel of autoantibodies against tumor-associated antigens in the early immunodiagnosis of lung cancer.
  213. A Mouse Homolog of a Human TP53 Germline Mutation Reveals a Lipolytic Activity of p53.
  214. Dexmedetomidine alleviates hepatic injury via the inhibition of oxidative stress and activation of the Nrf2/HO-1 signaling pathway.
  215. The endoplasmic reticulum stress and related signal pathway mediated the glyphosate-induced testosterone synthesis inhibition in TM3 cells.
  216. Commentary: The A, C, G, and Ts of differentiating stage I and stage IV lung cancer.
  217. High ubiquitin conjugating enzyme E2 T mRNA expression and its prognostic significance in lung adenocarcinoma: A study based on the TCGA database.
  218. Glycine transporter type 1 (GlyT1) inhibition improves conspecific-provoked immobility in Balb/c mice: Analysis of corticosterone response and glucocorticoid gene expression in cortex and hippocampus.
  219. A CRISPR/Cas9 genome editing pipeline in the EndoC-βH1 cell line to study genes implicated in beta cell function.
  220. Associations between nutritional factors and chemotherapy toxicity in older adults with solid tumors.
  221. Reconstructing kinase network topologies from phosphoproteomics data reveals cancer-associated rewiring.
  222. Benefits and Challenges of Diabetes Technology Use in Older Adults.
  223. Effects of Birth Weight and Postnatal Nutritional Restriction on Skeletal Muscle Development, Myofiber Maturation, and Metabolic Status of Early-Weaned Piglets.
  224. Comment on 'volatile biomarker in breath predicts lung cancer and pulmonary nodules'.
  225. Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.
  226. Controlled release of H2S and NO gases through CO2-stimulated anion exchange.
  227. Salinomycin and dichloroacetate synergistically inhibit Lewis lung carcinoma cell proliferation, tumor growth and metastasis.
  228. Metabolism of Estrogens: Turnover Differs Between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells.
  229. Statistical Analysis of the Heart and Lung Mass in Forensic Anatomical Cases and Its Forensic Significance.
  230. Evaluation of heavy metals and metabolites in the urine of patients with breast cancer.
  231. Recommendation for the diagnosis and management of immune checkpoint inhibitor related infections.
  232. The Russian Radiobiological Human Tissue Repository: Characteristics of biological specimens donated by nuclear workers with lung cancer.
  233. Advances in Lung Cancer Imaging.
  234. Proteomic Analysis of Saccharomyces cerevisiae Response to Oxidative Stress Mediated by Cocoa Polyphenols Extract.
  235. Potential Metabolite Biomarkers for Acute Versus Chronic Stage of Ischemic Stroke: A Pilot Study.
  236. Regulation of Autophagy Is a Novel Tumorigenesis-Related Activity of Multifunctional Translationally Controlled Tumor Protein.
  237. Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo.
  238. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.
  239. Melanoma - time to fast or time to feast? An interplay between PPARs, metabolism and immunity.
  240. DLEU1: A functional long noncoding RNA in tumorigenesis.
  241. Acetoacetate Enhances Oxidative Metabolism and Response to Toxicants of Cultured Kidney Cells.
  242. Can gallic acid potentiate the antihyperglycemic effect of acarbose and metformin? Evidence from streptozotocin-induced diabetic rat model.
  243. Striving to Reduce Radon-Induced Lung Cancer in Wisconsin.
  244. Circ0021205 aggravates the progression of non-small cell lung cancer by targeting miRNA-16-5p/VEGFA.
  245. Identification of a Sixteen-gene Prognostic Biomarker for Lung Adenocarcinoma Using a Machine Learning Method.
  246. L-type Calcium Channel Blocker Enhances Cellular Delivery and Gene Silencing Potency of Cell-Penetrating Asymmetric siRNAs.
  247. GORK Channel: A Master Switch of Plant Metabolism?
  248. First in man study of [18F]fluoro-PEG-folate PET: a novel macrophage imaging technique to visualize rheumatoid arthritis.
  249. Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar development.
  250. When histones are under glucose starvation.
  251. Does progress achieved in the treatment of patients with metastatic non-small-cell lung cancer reach the elderly population? A cohort study from a cancer centre from Eastern Switzerland.
  252. Evidence of a Role for One-Carbon Metabolism in Blood Pressure: Can B Vitamin Intervention Address the Genetic Risk of Hypertension Owing to a Common Folate Polymorphism?
  253. A MSN-based tumor-targeted nanoplatform to interfere with lactate metabolism to induce tumor cell acidosis for tumor suppression and anti-metastasis.
  254. Relationship between epidermal growth factor receptor mutations and skin rash in non-small cell lung cancer patients.
  255. Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.
  256. Reply to Comment on 'Volatile biomarker in breath predicts lung cancer and pulmonary nodules'.
  257. Neuronal GDPGP1 and glycogen metabolism: friend or foe?
  258. Cardiac left ventricular ejection fraction in men and women with schizophrenia on long-term antipsychotic treatment.
  259. The mitochondrial epilepsies.
  260. Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3.
  261. UBAP2L Forms Distinct Cores that Act in Nucleating Stress Granules Upstream of G3BP1.
  262. Identification and implementation of hemolysis interference thresholds in serum ionized calcium measurement.
  263. Reactive oxygen species-activatable camptothecin polyprodrug based dextran enhances chemotherapy efficacy by damaging mitochondria.
  264. Diabetes Technology Use in Adults with Type 1 and Type 2 Diabetes.
  265. Metabolic changes related to the IDH1 mutation in gliomas preserve TCA-cycle activity: An investigation at the protein level.
  266. Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer.
  267. Macrophage activation as an archetype of mitochondrial repurposing.
  268. Glucose metabolism in brown adipose tissue determined by deuterium metabolic imaging in rats.
  269. Potential effect of non-thermal plasma for the inhibition of scar formation: a preliminary report.
  270. P-selectin-deficient mice to study pathophysiology of sickle cell disease.
  271. Identification of a selective DDX3X inhibitor with newly developed quantitative high-throughput RNA helicase assays.
  272. Loss of HSPA9 induces peroxisomal degradation by increasing pexophagy.
  273. Non-targeted urine metabolomics analysis the protective and therapeutic effects of Citri Reticulatae Chachiensis Pericarpium on high-fat feed induced hyperlipidemia in rats.
  274. Zinc Finger Transcription Factor MZF1-A Specific Regulator of Cancer Invasion.
  275. Discriminant Analysis of Lung Cancer using Nonlinear Clustering of Copy Numbers.
  276. Assessment of cancer-related fatigue among Jordanian patients: a cross-sectional survey.
  277. Disparate Phenotypes Resulting from Mutations of a Single Histidine in Switch II of Geobacillus stearothermophilus Translation Initiation Factor IF2.
  278. Reducing stigma around smoking would encourage more early lung cancer screening.
  279. Vitamin B6 inhibits macrophage activation to prevent lipopolysaccharide-induced acute pneumonia in mice.
  280. Temporal changes in the spinal cord transcriptome after peripheral nerve injury.
  281. Effects of lncRNA SNHG20 on proliferation and apoptosis of non-small cell lung cancer cells through Wnt/β-catenin signaling pathway.
  282. VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake.
  283. FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle.
  284. Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery.
  285. A Rare Pancreatic Tail Metastasis from Squamous Cell Lung Carcinoma Diagnosed by EUS-FNB and a Small Review of the Literature.
  286. The Brazilian TP53 mutation (R337H) and sarcomas.
  287. Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer.
  288. Micro-RNA and the Features of Metabolic Syndrome: A Narrative Review.
  289. Chemoradiation and granulocyte-or granulocyte macrophage-colony stimulating factors (G-CSF or GM-CSF): Time to think out of the box?
  290. The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease.
  291. Retraction: Immunoglobulin G Expression in Lung Cancer and Its Effects on Metastasis.
  292. An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder.
  293. Role of Cresp® in the management of chemotherapy-induced anemia in cancer patients: A real-world clinical practice audit.
  294. Terminal Alkynes as Raman Probes of α-Synuclein in Solution and in Cells.
  295. Pain, fatigue and depression symptom cluster in survivors of prostate cancer.
  296. Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.
  297. YAP1 and TAZ negatively control bone angiogenesis by limiting hypoxia-inducible factor signaling in endothelial cells.
  298. Atg11 is required for initiation of glucose starvation-induced autophagy.
  299. Novel associations of serum adropin and lipopolysaccharide-binding protein versus lipid profiles in childhood obesity.
  300. Metabolic analysis of salicylic acid-induced chilling tolerance of banana using NMR.
  301. Scutellarin Prevents Angiogenesis in Diabetic Retinopathy by Downregulating VEGF/ERK/FAK/Src Pathway Signaling.
  302. Mitophagy and its contribution to metabolic and aging associated disorders.
  303. Transcriptomic and epigenetic mechanisms underlying myeloid diversity in the lung.
  304. The pro- and anti-cancer effects of oxycodone are associated with epithelial growth factor receptor level in cancer cells.
  305. Postruminal infusions of amino acids or glucose affect metabolisms of splanchnic, mammary, and other peripheral tissues and drive amino acid use in dairy cows.
  306. Author Correction: Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells.
  307. Is biological therapy in systemic sclerosis the answer?
  308. Resistance to MET/VEGFR2 Inhibition by Cabozantinib Is Mediated by YAP/TBX5-Dependent Induction of FGFR1 in Castration-Resistant Prostate Cancer.
  309. Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells.
  310. Association of Serum Ferritin Levels with Smoking and Lung Function in COPD Patients of Tertiary Care Center: Mysuru.
  311. Genetic basis of oxygen sensing in the carotid body: HIF2α and an isoform switch in cytochrome c oxidase subunit 4.
  312. Glucocorticoid Signalling Drives Reduced Versican Levels in the Fetal Mouse Lung.
  313. Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells.
  314. Cytoprotective Effects of Delphinidin for Human Chondrocytes against Oxidative Stress through Activation of Autophagy.
  315. Overexpression of transcription factor Foxa1 and target genes remediates therapeutic protein production bottlenecks in Chinese hamster ovary cells.
  316. The Effects of Carob (Ceratonia siliqua L.) on Emotional Behavior Impairment and Metabolic Disorders Induced by Estrogen Deficiency in Rats.
  317. Salvianolic acid B protects against oxLDL-induced endothelial dysfunction under high-glucose conditions by downregulating ROCK1-mediated mitophagy and apoptosis.
  318. Systemic Evaluation on the Pharmacokinetics of Platinum-Based Anticancer Drugs From Animal to Cell Level: Based on Total Platinum and Intact Drugs.
  319. Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency.
  320. A Complex Interplay between Nitric Oxide, Quorum Sensing, and the Unique Secondary Metabolite Tundrenone Constitutes the Hypoxia Response in Methylobacter.
  321. Targeting MEK5 impairs nonhomologous end-joining repair and sensitizes prostate cancer to DNA damaging agents.
  322. Cell senescence and fibrotic lung diseases.
  323. Cost-effectiveness of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.
  324. Search for non-acidic ALR2 inhibitors: Evaluation of flavones as targeted agents for the management of diabetic complications.
  325. SNHG3 Functions as miRNA Sponge to Promote Breast Cancer Cells Growth Through the Metabolic Reprogramming.
  326. The impact of COPD on polyneuropathy: results from the German COPD cohort COSYCONET.
  327. Relation of Plasma Xanthine Oxidoreductase Activity to Coronary Lipid Core Plaques Assessed by Near-Infrared Spectroscopy Intravascular Ultrasound in Patients With Stable Coronary Artery Disease.
  328. Association between trace elements in serum from bipolar disorder and schizophrenia patients considering treatment effects.
  329. Pazopanib Selectively Inhibits Choroidal Vascular Endothelial Cell Proliferation and Promotes Apoptosis.
  330. Meta-analysis of modified Stoppa approach and ilioinguinal approach in anterior pelvic ring and acetabular fractures.
  331. Dissection of flag leaf metabolic shifts and their relationship with those occurring simultaneously in developing seed by application of non-targeted metabolomics.
  332. Environmental pollutants damage airway epithelial cell cilia: Implications for the prevention of obstructive lung diseases.
  333. Superoxide induced inhibition of death receptor signaling is mediated via induced expression of apoptosis inhibitory protein cFLIP.
  334. Trehalose and alginate oligosaccharides increase the stability of muscle proteins in frozen shrimp (Litopenaeus vannamei).
  335. Hyper-coagulability in obese patients accurately identified by combinations of global coagulation assay parameters.
  336. An octopus-mimic PEGylated peptide as a specific integrin αvβ3 inhibitor for preventing tumor progression.
  337. BISPHOSPHONATES FOR THE TREATMENT OF CALCITRIOL-INDUCED HYPERCALCEMIA.
  338. Multi-lineage Lung Regeneration by Stem Cell Transplantation across Major Genetic Barriers.
  339. Preoperative platelet-lymphocyte ratio is a superior prognostic biomarker to other systemic inflammatory response markers in non-small cell lung cancer.
  340. Gene expression profiling of cells of origin of squamous cell carcinomas in head-and-neck, esophagus, and lung.
  341. Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial.
  342. Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study.
  343. Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration.
  344. Impact of Maternal Smoking Associated Lyso-phosphatidylcholine 20:3 on Offspring Brain Development.
  345. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.
  346. Patient-derived organoids of non-small cells lung cancer and their application for drug screening.
  347. ROS-augmented and tumor-microenvironment responsive biodegradable nanoplatform for enhancing chemo-sonodynamic therapy.
  348. Enoyl Coenzyme A Hydratase 1 Combats Obesity and Related Metabolic Disorders by Promoting Adipose Tissue Browning.
  349. Profiling of human lymphocytes reveals a specific network of protein kinases modulated by endurance training status.
  350. Brief Education and a Conjoint Valuation Survey May Reduce Decisional Conflict Regarding Lung Cancer Screening.
  351. The Occurrence of Lung Cancer and Non-Pulmonary Malignancies After Pleural Infections.
  352. Molecular and cellular insights into the role of SND1 in lipid metabolism.
  353. Plasma-polymerized phlorotannins and their enhanced biological activities.
  354. Blood contains circulating cell-free respiratory competent mitochondria.
  355. Spatially-guided non-local mean approach for denoising of PET images.
  356. The effect of lncRNA-ARAP1-AS2/ARAP1 on high glucose-induced cytoskeleton rearrangement and epithelial-mesenchymal transition in human renal tubular epithelial cells.
  357. Evolution of Diabetes Technology.
  358. Pathway analysis of glutamate-mediated, calcium-related signaling in glioma progression.
  359. Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.
  360. Design, synthesis and biological evaluation of erythrina derivatives bearing a 1,2,3-triazole moiety as PARP-1 inhibitors.
  361. Novel roles of phosphoinositides in signaling, lipid transport, and disease.
  362. A review on osteoclast diseases and osteoclastogenesis inhibitors recently developed from natural resources.
  363. New directions in antimalarial target validation.
  364. Vagal sensory neurons drive mucous cell metaplasia.
  365. Altered growth trajectory in children born to mothers with gestational diabetes mellitus and preeclampsia.
  366. Energy conversion processes and related gene expression in a sunflower mutant with altered salicylic acid metabolism.
  367. E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer.
  368. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.
  369. Immunological axis of berberine in managing inflammation underlying chronic respiratory inflammatory diseases.
  370. Mechanical stretch activates glycometabolism-related enzymes via estrogen in C2 C12 myoblasts.
  371. Hypoxia-induced changes in intragenic DNA methylation correlate with alternative splicing in breast cancer.
  372. The regulation of p53, p38 MAPK, JNK and XBP-1s by sphingosine kinases in human embryonic kidney cells.
  373. Arginine, ornithine and citrulline supplementation in rainbow trout: Free amino acid dynamics and gene expression responses to bacterial infection.
  374. Mesenchymal stem cell-derived exosomes ameliorate cardiomyocyte apoptosis in hypoxic conditions through microRNA144 by targeting the PTEN/AKT pathway.
  375. Balance disorder, falling risks and fear of falling in obese individuals: cross-sectional clinical research in Isparta.
  376. Photo-controlled delivery of very long chain fatty acids to cell membranes and modulation of membrane protein function.
  377. PRMT2 inhibits the formation of foam cell induced by ox-LDL in RAW 264.7 macrophage involving ABCA1 mediated cholesterol efflux.
  378. Dietary thymol supplementation promotes skeletal muscle fibre type switch in longissimus dorsi of finishing pigs.
  379. Nazartinib in EGFR Thr790Met-mutant non-small-cell lung cancer.
  380. Lorlatinib in anaplastic lymphoma kinase-positive non-small cell lung cancer: Indian experience.
  381. Letter From the Guest Editor: Lung Cancer-From Diagnosis to Imaging to Management.
  382. A LIGHTning Strike to the Metastatic Niche.
  383. Neutrophils do not impact viral load or the peak of disease severity during RSV infection.
  384. Chaperone mediated detection of small molecule target binding in cells.
  385. Zinc induces iron egress from intestinal Caco-2 cells via induction of Hephaestin: A role for PI3K in intestinal iron absorption.
  386. Retinoic Acid: A Key Regulator of Lung Development.
  387. The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes.
  388. Effect of antioxidants on the H2O2-induced premature senescence of human fibroblasts.
  389. Tumour infiltrating lymphocytes and correlation with response to intensified platinum-based chemotherapy in BRCA-like tumours.
  390. Early Age at Natural Menopause Is Related to Lower Post-Bronchodilator Lung Function: A Longitudinal Population-based Study.
  391. Lung metastases, triple receptor negativity, multiple organ metastases and no adjuvant radiotherapy as predictors of poorer survival after palliative mastectomy.
  392. Long-term alkaline conditions inhibit the relative abundances of tetracycline resistance genes in saline 4-chlorophenol wastewater treatment.
  393. Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers.
  394. Postischemic supplementation of folic acid improves neuronal survival and regeneration in vitro.
  395. Low-dose 18F-FDG TOF-PET/MR for accurate quantification of brown adipose tissue in healthy volunteers.
  396. MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress.
  397. Dexamethasone-Induced Perturbations in Tissue Metabolomics Revealed by Chemical Isotope Labeling LC-MS analysis.
  398. A combination of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol stabilizes hypoxic inducible factor 1 alpha and improves hair density in female volunteers.
  399. Imaging breast cancer using hyperpolarized carbon-13 MRI.
  400. How Patient Perceptions Shape Responses and Outcomes in Inherited Cardiac Conditions.
  401. Treatment with the Ketone Body D-β-hydroxybutyrate Attenuates Autophagy Activated by NMDA and Reduces Excitotoxic Neuronal Damage in the Rat Striatum in Vivo.
  402. Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency.
  403. Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur.
  404. Serum metabolomics reveals metabolic profiling for women with hyperandrogenism and insulin resistance in polycystic ovary syndrome.
  405. Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAFV600E by synergistically decreasing global trimethylation of H3K27.
  406. Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation.
  407. Corrigendum to 'Inhibition of HDACs-EphA2 signaling axis with WW437 demonstrates promising preclinical antitumor activity in breast cancer' [EBioMedicine 31 (2018) 276-286].
  408. Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma).
  409. New grapefruit cultivars exhibit low cytochrome P4503A4-Inhibition activity.
  410. Quantitative proteomic analysis identifies novel regulators of methotrexate resistance in choriocarcinoma.
  411. Von Hippel-Lindau tumor suppressor (VHL) stimulates TOR signaling by interacting with phosphoinositide 3-kinase (PI3K).
  412. Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake.
  413. Falsely Accused? Insufficient Evidence to Conclude that Sitagliptin is a Cause of Chronic Cough.
  414. Preclinical models for neuroblastoma: Advances and challenges.
  415. Long non-coding RNA XIST expedites lung adenocarcinoma progression through upregulating MDM2 expression via binding to miR-363-3p.
  416. Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice.
  417. Impact of Hyperglycemia on Long-Term Outcome in Patients With ST-Segment Elevation Myocardial Infarction.
  418. A negative energy balance during the peri-implantational period reduces dam IGF-1 but does not alter progesterone or pregnancy-specific protein B (PSPB) or fertility in suckled cows.
  419. CPF impedes cell cycle re-entry of quiescent lung cancer cells through transcriptional suppression of FACT and c-MYC.
  420. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis.
  421. Generalized parametric cure models for relative survival.
  422. Tannic acid inhibits lipid metabolism and induce ROS in prostate cancer cells.
  423. N6-Methyladenosine: A Potential Breakthrough for Human Cancer.
  424. Coordination of host and symbiont gene expression reveals a metabolic tug-of-war between aphids and Buchnera.
  425. Isoalantolactone restores the sensitivity of gram-negative Enterobacteriaceae carrying MCR-1 to carbapenems.
  426. Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes.
  427. LncRNA CASC2 inhibits astrocytic activation and adenosine metabolism by regulating PTEN in pentylenetetrazol-induced epilepsy model.
  428. RNA N6-methyladenosine modification in solid tumors: new therapeutic frontiers.
  429. In silico MS/MS spectra for identifying unknowns: a critical examination using CFM-ID algorithms and ENTACT mixture samples.
  430. Exploring molecular evolution of Rubisco in C3 and CAM Orchidaceae and Bromeliaceae.
  431. The lung microbiota: role in maintaining pulmonary immune homeostasis and its implications in cancer development and therapy.
  432. Transcriptomic profiles reveal differences between the right and left ventricle in normoxia and hypoxia.
  433. A novel trifluoromethyl 2-phosphonopyrrole analogue inhibits human cancer cell migration and growth by cell cycle arrest at G1 phase and apoptosis.
  434. [Primary Pulmonary Tumor in an Adolescent].
  435. Direct and indirect healthcare costs of lung cancer CT screening in Denmark: a registry study.
  436. HLA class II allele analyses implicate common genetic components in type 1 and non-insulin treated type 2 diabetes.
  437. Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone.
  438. Assessing seasonal demographic covariation to understand environmental-change impacts on a hibernating mammal.
  439. Amplitude effects allow short jetlags and large seasonal phase shifts in minimal clock models.
  440. Understanding the impact of chronic obstructive pulmonary disease exacerbations on patient health and quality of life.
  441. Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement.
  442. Association between phospholipid metabolism in plasma and spontaneous preterm birth: a discovery lipidomic analysis in the cork pregnancy cohort.
  443. miR-210 is induced by hypoxia and regulates neural cell adhesion molecule in prostate cells.
  444. [Effect of progesterone on the pathogenesis and development of hemangioma in nude mice].
  445. Radiation metabolomics in the quest of cardiotoxicity biomarkers: the review.
  446. Extracellular domains I-II of cell-surface glycoprotein CD44 mediate its trans-homophilic dimerization and tumor cluster aggregation.
  447. Imaging of cerebral venous thrombosis.
  448. A four-chemokine signature is associated with a T cell-inflamed phenotype in primary and metastatic pancreatic cancer.
  449. Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency.
  450. Diagnostic Yield and Safety of Pleural Cryobiopsy during Medical Thoracoscopy to Diagnose Pleural Effusion. A Systematic Review and Meta-Analysis.
  451. Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects.
  452. Development and Survival of MYC-driven Lymphomas Requires MYC-Antagonist MNT to Curb MYC-induced Apoptosis.
  453. Integrating circulating miRNA analysis in the clinical management of lung cancer: Present or future?
  454. Identification of Parthenolide Dimers as Activators of Pyruvate Ki-nase M2 in Xenograft of Glioblastoma Multiforme in vivo.
  455. Bregmannian consensus clustering for cancer subtypes analysis.
  456. An Examination of Child and Adolescent Neurodevelopment Through National Institutes of Health Studies.
  457. Qualitative and quantitative analysis of glenoid bone stock and glenoid version: inter-reader analysis and correlation with rotator cuff tendinopathy and atrophy in patients with shoulder osteoarthritis.
  458. Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer.
  459. Effects of curative-intent lung cancer therapy on functional exercise capacity and patient-reported outcomes.
  460. Insights into the expression profiles and functions of circRNAs in a newborn hyperoxia-induced rat bronchopulmonary dysplasia model.
  461. AXIN2 gene silencing reduces apoptosis through regulating mitochondria-associated apoptosis signaling pathway and enhances proliferation of ESCs by modulating Wnt/β-catenin signaling pathway.
  462. Dual Chalcogen-Chalcogen Bonding Catalysis.
  463. CircTIMELESS regulates the proliferation and invasion of lung squamous cell carcinoma cells via the miR-136-5p/ROCK1 axis.
  464. In Situ Light-Initiated Ligands Crosslinking Enables Efficient All-Solution-Processed Perovskite Light-Emitting Diodes.
  465. The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia.
  466. Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma.
  467. Pulmonary hypertension in chronic obstructive pulmonary disease.
  468. Glucose-6-phosphate transporter mediates macrophage proliferation and functions by regulating glycolysis and mitochondrial respiration.
  469. Adjustable and Versatile 3D Tumor Spheroid Culture Platform with Interfacial Elastomeric Wells.
  470. A Zeaxanthin-Producing Bacterium Isolated from the Algal Phycosphere Protects Coral Endosymbionts from Environmental Stress.
  471. Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for transfusion.
  472. Early inoculation with caecal fermentation broth alters small intestine morphology, gene expression of tight junction proteins in the ileum, and the caecal metabolomic profiling of broilers.
  473. Circulating tumor cells are associated with recurrent disease in patients with early stage non-small cell lung cancer treated with stereotactic body radiation therapy.
  474. Comparative Evaluation of the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes and Platelet-Rich Plasma: An In Vitro Analysis.
  475. Modulatory effects of TGF-β1 and BMP6 on thecal angiogenesis and steroidogenesis in the bovine ovary.
  476. Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function.
  477. Exchange protein directly activated by cAMP (Epac) 1 plays an essential role in stress-induced exercise capacity by regulating PGC-1α and fatty acid metabolism in skeletal muscle.
  478. Essential Amino Acid Supplement Lowers Intrahepatic Lipid despite Excess Alcohol Consumption.
  479. Corrigendum to "Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis" [Lung Cancer 68 (1) (2010) 27-38].
  480. Identification and Distribution of Novel Metabolites of Lolitrem B in Mice by High-Resolution Mass Spectrometry.
  481. Combination of melatonin and irisin ameliorates lipopolysaccharide-induced cardiac dysfunction through suppressing the Mst1-JNK pathways.
  482. Evidence for auxiliary anaerobic metabolism in obligately aerobic Zetaproteobacteria.
  483. A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review.
  484. Exogenous lipoid pneumonia induced by nasal instillation of paraffin oil.
  485. Circular RNA circABCC4 regulates lung adenocarcinoma progression via miR-3186-3p/TNRC6B axis.
  486. Comparison of cisplatin-induced nephrotoxicity when using conventional versus short hydration in gastric cancer-a retrospective study.
  487. Expression levels of ARHI and Beclin1 in thyroid cancer and their relationship with clinical pathology and prognosis.
  488. High-throughput identification of protein functional similarities using a gene-expression-based siRNA screen.
  489. Pre-Operative Lung Function in Children with EOS.
  490. Metabolomics Analysis of the Peels of Different Colored Citrus Fruits (Citrus reticulata cv. 'Shatangju') During the Maturation Period Based on UHPLC-QQQ-MS.
  491. Hypoxia-inducible factors in metabolic reprogramming during sepsis.
  492. Regulation of breast cancer resistance protein and P-glycoprotein by ezrin, radixin and moesin in lung, intestinal and renal cancer cell lines.
  493. The corrosion inhibition of stainless steel by ferrocene-polyoxometalate hybrid molecular materials - experimental and first principles studies.
  494. YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.
  495. Effects of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury.
  496. The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.
  497. CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells.
  498. Effects of yolkin on the immune response of mice and its plausible mechanism of action.
  499. Pharmacological strategies for insulin sensitivity: thiazolidinediones and metformin.
  500. Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib.
  501. Calcium channel CNGC19 mediates basal defense signaling to balance colonization of Piriformospora indica on Arabidopsis roots.
  502. Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study.
  503. High-Risk and Hepatitis C-Positive Organ Donors: Current Practice in Heart, Lung, and Liver Transplantation.
  504. Observational Study of Treatment Patterns in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer After First-Line EGFR-Tyrosine Kinase Inhibitors.
  505. Isolated diaphragmatic metastasis originating from early endometrial cancer.
  506. Regulation of Skeletal Muscle Function by Amino Acids.
  507. Effects of prenatal nicotine exposure on hepatic glucose and lipid metabolism in offspring rats and its hereditability.
  508. Time-restricted feeding improves markers of cardiometabolic health in physically active college-age men: a 4-week randomized pre-post pilot study.
  509. The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.
  510. Relationship of asthma control test scores with pulmonary function tests, quality of life and adiposity in asthmatic children.
  511. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors.
  512. Ubiquinol-10 delays postovulatory oocyte aging by improving mitochondrial renewal in pigs.
  513. Metabolic disturbance in Korean red ginseng-induced "Shanghuo" (excessive heat).
  514. Comparative analysis of lung and blood transcriptomes in mice exposed to multi-walled carbon nanotubes.
  515. Mu-Xiang-You-Fang protects PC12 cells against OGD/R-induced autophagy via the AMPK/mTOR signaling pathway.
  516. miR-19a/19b improves the therapeutic potential of mesenchymal stem cells in a mouse model of myocardial infarction.
  517. Low-intensity pulsed ultrasound affects growth, differentiation, migration, and epithelial-to-mesenchymal transition of colorectal cancer cells.
  518. Potential of vibrational spectroscopy for rapid and accurate determination of the hydrogen peroxide treatment of plant leaves.
  519. Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer's Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study.
  520. Golgi organization is regulated by proteasomal degradation.
  521. Effect of SKF‑96365 on cardiomyocyte hypertrophy induced by angiotensin II.
  522. Quantification of glyphosate and AMPA from microbiome reactor fluids.
  523. Quantitative Mitochondrial Proteomics Reveals ANXA7 as a Crucial Factor in Mitophagy.
  524. Mief1 augments thyroid cell dysfunction and apoptosis through inhibiting AMPK-PTEN signaling pathway.
  525. Inhibition of the SIRT1 signaling pathway exacerbates endoplasmic reticulum stress induced by renal ischemia/reperfusion injury in type 1 diabetic rats.
  526. Ligand-installed anti-VEGF genomic nanocarriers for effective gene therapy of primary and metastatic tumors.
  527. The USP21/YY1/SNHG16 axis contributes to tumor proliferation, migration, and invasion of non-small-cell lung cancer.
  528. Derivation of LIF-Independent Embryonic Stem Cells Using Inducible OCT4 Expression.
  529. Metabolic impairment in response to early induction of C/EBPβ leads to compromised cardiac function during pathological hypertrophy.
  530. [18F]FDDNP PET binding predicts change in executive function in a pilot clinical trial of geriatric depression.
  531. The effect of topical xylometazoline on Eustachian tube function.
  532. Protein kinase C promotes choline transporter‑like protein 1 function via improved cell surface expression in immortalized human hepatic cells.
  533. Pathogenic Carboxyl Ester Lipase (CEL) Variants Interact with the Normal CEL Protein in Pancreatic Cells.
  534. Lung ultrasound-a new diagnostic modality in persistent tachypnea of infancy.
  535. Sarcopenia in relation to nutrition and lifestyle factors among middle-aged and older Korean adults with obesity.
  536. A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors.
  537. Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica.
  538. Micronuclei frequency in peripheral blood lymphocytes of healthy subjects living in turin (North-Italy): contribution of body mass index, age and sex.
  539. Can a better understanding of frailty improve the quality of life of patients with fibrotic interstitial lung diseases?
  540. A Multimodal Ca(II) Responsive Near IR-MR Contrast Agent Exhibiting High Cellular Uptake.
  541. Long non-coding RNA FTX alleviates hypoxia/reoxygenation-induced cardiomyocyte injury via miR-410-3p/Fmr1 axis.
  542. Alterations to dual stream connectivity predicts response to aphasia therapy following stroke.
  543. The molecular targets of diclofenac differs from ibuprofen to induce apoptosis and epithelial mesenchymal transition due to alternation on oxidative stress management p53 independently in PC3 prostate cancer cells.
  544. Spinal AMP Kinase Activity Differentially Regulates Phrenic Motor Plasticity.
  545. Elevated Expression of Lumican in Lung Cancer Cells Promotes Bone Metastasis through an Autocrine Regulatory Mechanism.
  546. Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival.
  547. Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.
  548. The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension.
  549. Hyperglycemia-induced endothelial dysfunction is alleviated by thioredoxin mimetic peptides through the restoration of VEGFR-2-induced responses and improved cell survival.
  550. ΜicroRNA‑421 participates in vitiligo development through regulating human melanocyte survival by targeting receptor‑interacting serine/threonine kinase 1.
  551. Repeatability of arterial input functions and kinetic parameters in muscle obtained by dynamic contrast enhanced MR imaging of the head and neck.
  552. Whole-genome mapping of small-molecule targets for cancer medicine.
  553. Correction: Schwann cells support oncogenic potential of pancreatic cancer cells through TGFβ signaling.
  554. Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.
  555. Engineering Shelf-Stable Coating for Microfluidic Organ-on-a-Chip using Bioinspired Catecholamine Polymers.
  556. OSU-A9 induced-reactive oxygen species cause cytotoxicity in duodenal and gastric cancer cells by decreasing phosphorylated nuclear pyruvate kinase M2 protein levels.
  557. Metabolic Profiling-Based Evaluation of the Fermentative Behavior of Aspergillus oryzae and Bacillus subtilis for Soybean Residues Treated at Different Temperatures.
  558. Multiple Pulmonary Resections for Synchronous and Metachronous Lung Cancer at Two Chinese Centers (Commentary).
  559. miR-23b-3p acts as a counter-response against skeletal muscle atrophy.
  560. The prognostic role of platelet-to-lymphocyte ratio on overall survival in gastric cancer: a systematic review and meta-analysis.
  561. Development of novel phosphodiesterase 5 inhibitors for the therapy of alzheimer's disease.
  562. Increased mitochondrial content and function by resveratrol and select flavonoids protects against benzo[a]pyrene-induced bioenergetic dysfunction and ROS generation in a cell model of neoplastic transformation.
  563. Commentary: Ex vivo lung perfusion plus solute adsorption: An exorcism of evil humors?
  564. High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma.
  565. bHLH121 Functions as A Direct Link that Facilitates the Activation of FIT by bHLH IVc Transcription Factors for Maintaining Fe Homeostasis in Arabidopsis.
  566. Family accommodation of anxiety in a community sample of children on the autism spectrum.
  567. Effects of Starvation on Antioxidant-Related Signaling Molecules, Oxidative Stress, and Autophagy in Juvenile Chinese Perch Skeletal Muscle.
  568. Achieving postprandial glucose control with lixisenatide improves glycemic control in patients with type 2 diabetes on basal insulin: a post-hoc analysis of pooled data.
  569. Hydrogen sulfide (H2S) and nitric oxide (NO) alleviate cobalt toxicity in wheat (Triticum aestivum L.) by modulating photosynthesis, chloroplastic redox and antioxidant capacity.
  570. Review on 2D and 3D MRI Image Segmentation Techniques.
  571. Treatment outcome and clinical characteristics of HER2 mutated advanced non-small cell lung cancer patients in China.
  572. Mining histone methyltransferases and demethylases from whole genome sequence.
  573. Compassionate Care in Behavior Analytic Treatment: Can Outcomes be Enhanced by Attending to Relationships with Caregivers?
  574. Effects of low salinity on gill and liver glycogen metabolism of great blue-spotted mudskippers (Boleophthalmus pectinirostris).
  575. The role of steroids in severe CAP.
  576. Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1.
  577. Correction to: Caveolin-1 Expression Together with VEGF can be a Predictor for Lung Metastasis and Poor Prognosis in Osteosarcoma.
  578. Direct prospective comparison of 18F-FDG PET and arterial spin labelling MR using simultaneous PET/MR in patients referred for diagnosis of dementia.
  579. Flavonoids from Houttuynia cordata attenuate H1N1-induced acute lung injury in mice via inhibition of influenza virus and Toll-like receptor signalling.
  580. Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer.
  581. NADPH oxidase and neurodegenerative diseases: mechanisms and therapy.
  582. A new energy setup strategy for intact N-glycopeptides characterization using higher-energy collisional dissociation.
  583. ASIC1a Channels Regulate Mitochondrial Ion Signaling and Energy Homeostasis in Neurons.
  584. Determinants of vitamin D supplementation among older adults and its effect on 25(OH)D levels according to bone mineral density status.
  585. BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways are involved in mitochondria-mediated neuronal apoptosis in dorsal root ganglia after sciatic nerve transection.
  586. Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions.
  587. Quantitative Proteomics of the Cancer Cell Line Encyclopedia.
  588. Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma: a report of two cases.
  589. Pancreatic Enzyme Replacement Therapy in Pancreatic Cancer.
  590. Use of Diabetes Technology in Children: Role of Structured Education for Young People with Diabetes and Families.
  591. Imatinib mesylate affects extracellular ATP catabolism and expression of NTPDases in a chronic myeloid leukemia cell line.
  592. Docosahexaenoic Acid Attenuates Mitochondrial Alterations and Oxidative Stress Leading to Cell Death Induced by Very Long-Chain Fatty Acids in a Mouse Oligodendrocyte Model.
  593. 18F- FDG PET/CT-derived parameters predict clinical stage and prognosis of esophageal cancer.
  594. Measurement of electron affinity of iridium atom and photoelectron angular distributions of iridium anion.
  595. Natural heat shock protein 90 inhibitors in cancer and inflammation.
  596. Luteolin prevents irinotecan-induced intestinal mucositis in mice through antioxidant and anti-inflammatory properties.
  597. Anti-apoptotic activity of Chlamydia trachomatis Pgp3 protein involves activation of the ERK1/2 pathway mediated by up-regulation of DJ-1 protein.
  598. Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis.
  599. Evaluation of the integration of P recovery, polyhydroxyalkanoate production and short cut nitrogen removal in a mainstream wastewater treatment process.
  600. Human induced pluripotent stem cell-derived GABAergic interneuron transplants attenuate neuropathic pain.
  601. Integration of omics data sources to inform mechanistic modelling of immune-oncology therapies: a tutorial for clinical pharmacologists.
  602. In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs.
  603. Mechanisms of nitrous oxide emission during photoelectrotrophic denitrification by self-photosensitized Thiobacillus denitrificans.
  604. Hypoxia in autumn of the East China Sea.
  605. Longxuetongluo capsule alleviates LPS-induced neuro-inflammation by regulating multiple signaling pathways in BV2 microglia cells.
  606. Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase.
  607. Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation.
  608. DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG.
  609. Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.
  610. The Relationship between Plasma Serotonin and Kynurenine Pathway Metabolite Levels and the Treatment Response to Escitalopram and Desvenlafaxine.
  611. Prevalence of Vitamin B12 Defi ciency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes Mellitus Patients.
  612. Ranolazine Induced Bradycardia, Renal Failure, and Hyperkalemia: A BRASH Syndrome Variant.
  613. Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy.
  614. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans.
  615. The Effect of Processing Medium on The 2 H/1 H of Carbon-Bound Hydrogen in α-Cellulose Extracted from Higher Plants.
  616. The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing.
  617. 15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism.
  618. Simultaneous determination of a promising anti-brain tumor agent CAT3 and its two major metabolites in mouse plasma and brain by a LC-MS/MS method.
  619. Highly Reduced Genomes of Protist Endosymbionts Show Evolutionary Convergence.
  620. Lung Function before and after Spine fusion in Children with EOS Treated Previously with Distraction-based Devices.
  621. Electrophysiological biomarkers of antidepressant response to ketamine in treatment-resistant depression: Gamma power and long-term potentiation.
  622. Downregulation of long non-coding RNA NR2F2-AS1 inhibits proliferation and induces apoptosis of nasopharyngeal carcinoma cells by upregulating the expression of PTEN.
  623. Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis.
  624. DNA epigenetic marks are linked to embryo aberrations in amphipods.
  625. Rate of change in maximum 18F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.
  626. "Hot Lung" Sign in Pulmonary Intravascular Large B-Cell Lymphoma on 18F-FDG PET/CT.
  627. Transmissible gastroenteritis virus targets Paneth cells to inhibit the self-renewal and differentiation of Lgr5 intestinal stem cells via Notch signaling.
  628. Calixarene-Based Supramolecular AIE Dots with Highly Inhibited Nonradiative Decay and Intersystem Crossing for Ultrasensitive Fluorescence Image-Guided Cancer Surgery.
  629. Familial pneumothoraces - Birt-Hogg-Dubé syndrome. Differentiation with other cystic lung diseases.
  630. Identification of hub genes and key pathways of dietary advanced glycation end products‑induced non‑alcoholic fatty liver disease by bioinformatics analysis and animal experiments.
  631. Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells.
  632. High-Fidelity Single Molecule Quantification in a Flow Cytometer Using Multiparametric Optical Analysis.
  633. A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.
  634. Lipophilic Metabolic Efficiency (LipMetE) and Drug Efficiency Indices to Explore the Metabolic Properties of the Substrates of Selected Cytochrome P450 Isoforms.
  635. Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming.
  636. Nucleoside-modified AdoMet analogues for differential methyltransferase targeting.
  637. ABPA - Presenting as Total Lung Collapse.
  638. Whole grain consumption and human health: an umbrella review of observational studies.
  639. Dietary polyunsaturated fatty acids affect volume and metabolism of Drosophila melanogaster sperm.
  640. Wegner Granulomatosis -Great Masquiderer of Lung Malignancy.
  641. Selection of the Reference Gene for Expression Normalization in Papaver somniferum L. under Abiotic Stress and Hormone Treatment.
  642. Experimental measurement of ionization chamber angular response and associated magnetic field correction factors in MR-linac.
  643. A normalized drug response metric improves accuracy and consistency of anticancer drug sensitivity quantification in cell-based screening.
  644. Alterations in energy system contribution following upper body sprint interval training.
  645. AIFM2 blocks ferroptosis independent of ubiquinol metabolism.
  646. Atypical manifestations of granulomatosis with polyangiitis: the diagnostic challenge for pulmonologists.
  647. Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease.
  648. Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis.
  649. Characterization of human cardiac mesenchymal stromal cells and their extracellular vesicles comparing with human bone marrow derived mesenchymal stem cells.
  650. Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity.
  651. The performance of the single-walled carbon nanotube covalently modified with polyethylene glycol to delivery of Gemcitabine anticancer drug in the aqueous environment.
  652. Physical activity attenuates metabolic risk of adolescents with overweight or obesity: the ICAD multi-country study.
  653. [89Zr]Zr-rituximab PET/CT activity in patients with therapy refractory interstitial pneumonitis: a feasibility study.
  654. Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression.
  655. Metal bioaccessibility, particle size distribution and polydispersity of playground dust in synthetic lysosomal fluids.
  656. Surveillance Imaging After Curative Intent Therapy for Lung Cancer.
  657. LC-MS untargeted approach showed that methyl jasmonate application on Vitis labrusca L. grapes increases phenolics at subtropical Brazilian regions.
  658. Metabolic disturbances and cardiovascular risk factors in obese children with vitamin D deficiency.
  659. An atypical bronchogenic cyst with yeast over-infection.
  660. Multifunctional Nanocarriers for Lung Drug Delivery.
  661. A self-calibrating and multiplexed electrochemical lab-on-a-chip for cell culture analysis and high-resolution imaging.
  662. GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
  663. Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network.
  664. Role of oxysterol-binding protein-related proteins in malignant human tumours.
  665. Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes.
  666. Using personalized immune-humanized xenograft mouse models to predict immune checkpoint responses in malignant melanoma: potential and hurdles.
  667. Autophagy as a cellular stress response mechanism in the nervous system.
  668. Dihydropyridines as potential α-amylase and α-glucosidase inhibitors: Synthesis, in vitro and in silico studies.
  669. Phototropin- and photosynthesis-dependent mitochondrial positioning in Arabidopsis thaliana mesophyll cells.
  670. Studies of mice deleted for Sox3 and uc482: relevance to X-linked hypoparathyroidism.
  671. A new strategy to improve the water solubility of an organic fluorescent probe using silicon nanodots and fabricate two-photon SiND-ANPA-N3 for visualizing hydrogen sulfide in living cells and onion tissues.
  672. Striatal iron content is linked to reduced fronto-striatal brain function under working memory load.
  673. Guts and gastrulation: Emergence and convergence of endoderm in the mouse embryo.
  674. [Neoadjuvant treatment of primarily resectable and borderline resectable pancreatic cancer].
  675. Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin.
  676. Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.
  677. Functions of reactive oxygen species in apoptosis and ganoderic acid biosynthesis in Ganoderma lucidum.
  678. Ambient Condition Mg2+-Doping Producing Highly Luminescent Green and Violet Emitting Perovskite Nanocrystals with Reduced Toxicity and Enhanced Stability.
  679. Synthesis and Preclinical Evaluation of an 18F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [18F]SynVesT-2.
  680. Single-Atom-Enzyme as Efficient Multiple Reactive Oxygen and Nitrogen Species Scavenger for Sepsis Management.
  681. Expression of estrogen receptor α variants and c-Fos in rat mammary gland and tumors.
  682. Degradation of antibiotic ciprofloxacin by different AOP systems using electrochemically generated hydrogen peroxide.
  683. Study of Lipoprotein (A) and Lipid Profi le in Type 2 Diabetes Mellitus and their Relationship with Glycemic Control.
  684. Mechanical stimulation in Brachypodium distachyon: implications for fitness, productivity and cell wall properties.
  685. Inflammatory Myofibroblastic Tumor of the Lung: An Extremely Rare Condition in Adults.
  686. Resibufogenin (RB) Inhibited Colorectal Cancer Cell Growth and Tumorigenesis through Triggering Ferroptosis and ROS Production Mediated by GPX4 Inactivation.
  687. Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.
  688. Transcriptome analysis of potato shoots, roots and stolons under nitrogen stress.
  689. Benzene exposure induces gut microbiota dysbiosis and metabolic disorder in mice.
  690. Dual functions of iridium(III) 2-phenylpyridine complexes: Metastasis inhibition and lysosomal damage.
  691. Metabolic memory and diabetic nephropathy: beneficial effects of natural epigenetic modifiers.
  692. Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors.
  693. History of withdrawal modulates drug- and food-cue reactivity in cocaine dependent participants.
  694. P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head.
  695. Enzyme-assist-interference-free Strategy for Raman Selective Determination of Sialic Acid.
  696. Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer.
  697. Redox-coupled proton pumping drives carbon concentration in the photosynthetic complex I.
  698. Genome-wide analysis and expression profiles of the StR2R3-MYB transcription factor superfamily in potato (Solanum tuberosum L.).
  699. Mechanisms of Nickel-Induced Cell Damage in Allergic Contact Dermatitis and Nutritional Intervention Strategies.
  700. Automated Flow Synthesis of Tumor Neoantigen Peptides for Personalized Immunotherapy.
  701. Glycogen synthase kinase 3β inhibitor- CHIR 99021 augments the differentiation potential of mesenchymal stem cells.
  702. Differential visible spectral influence on carbon metabolism in heterotrophic marine flavobacteria.
  703. Human papillomavirus Oncogene Manipulation Using Clustered Regularly Interspersed Short Palindromic Repeats/Cas9 Delivered by pH-Sensitive Cationic Liposomes.
  704. Small Peptide-Doxorubicin Co-Assembly for Synergistic Cancer Therapy.
  705. FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.
  706. Development of functional liposomes by modification of stimuli-responsive materials and their biomedical applications.
  707. Self-Management Behaviors of Patients with Type 1 Diabetes: Comparing Two Sources of Patient-Generated Data.
  708. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects.
  709. Prolyl hydroxylase 3 controls the intestine goblet cell generation through stabilizing ATOH1.
  710. Graphene Oxide-Grafted Magnetic Nanorings Mediated Magnetothermodynamic Therapy Favoring Reactive Oxygen Species-Related Immune Response for Enhanced Antitumor Efficacy.
  711. In the Wrong Place at the Wrong Time: Microbial Misplacement and ARDS.
  712. High-Intensity Training and Saffron: Effects on Breast Cancer-related Gene Expression.
  713. VEGFC-Mediated Lymphatic Drainage Increases Brain Tumor Immunogenicity.
  714. Cell Biology: Tight Junctions as Biomolecular Condensates.
  715. Metabolic choreography of gene expression: nutrient transactions with the epigenome.
  716. Comparative Sacral Morphology in Spondylolisthesis Patients.
  717. Placental Accumulation of Triacylglycerols in Gestational Diabetes Mellitus and Its Association with Altered Fetal Growth are Related to the Differential Expressions of Proteins of Lipid Metabolism.
  718. Association between vascular endothelial growth factor gene polymorphisms and PCOS risk: A meta-analysis.
  719. The roles of strawberry and honey phytochemicals on human health: A possible clue on the molecular mechanisms involved in the prevention of oxidative stress and inflammation.
  720. Incidence of Intraspinal and Extraspinal MRI Abnormalities in Patients With Adolescent Idiopathic Scoliosis.
  721. Correction to: Health-related quality of life and its socio-economic and cultural predictors among advanced cancer patients: evidence from the APPROACH cross-sectional survey in Hyderabad-India.
  722. Metabolic response assessment and PET-guided treatment of esophageal cancer.
  723. An Intense, But Ecologically Valid, Resistance Exercise Session Does Not Alter Growth Factors Associated With Cognitive Health.
  724. Interrogation of enhancer function by enhancer-targeting CRISPR epigenetic editing.
  725. Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality.
  726. Population-level impact of human papillomavirus vaccination.
  727. Modifiable Lifestyle Behaviours Impact the Health-Related Quality of Life of Bladder Cancer Survivors.
  728. Developing a circumpolar programme for the monitoring of Arctic terrestrial biodiversity.
  729. Lysine acetylation of the housekeeping sigma factor enhances the activity of the RNA polymerase holoenzyme.
  730. Avapritinib Approved for GIST Subgroup.
  731. Genomic, metabolic and phenotypic variability shapes ecological differentiation and intraspecies interactions of Alteromonas macleodii.
  732. Systematic Understanding of the Mechanisms of Flos Chrysanthemi Indici-mediated Eeffects on Hypertension via Computational Target Fishing.
  733. Sodium-Glucose Cotransporter 2 Inhibitor-Associated Prolonged Euglycemic Diabetic Ketoacidosis in Type 2 Diabetes: A Case Report and Literature Review.
  734. Advances in histone demethylase KDM4 as cancer therapeutic targets.
  735. Identification of key genes by integrating DNA methylation and next-generation transcriptome sequencing for esophageal squamous cell carcinoma.
  736. Study of Serum Magnesium Level in Type 2 Diabetes Mellitus Patients with Special Emphasis on Microvascular Macrovascular Complications.
  737. IMPACT OF STRUCTURED INSULIN ORDER SETS ON INPATIENT HYPOGLYCEMIA AND GLYCEMIC CONTROL.
  738. Association of Lactate Dehydrogenase with In-Hospital Mortality in Patients with Acute Aortic Dissection: A Retrospective Observational Study.
  739. Cell-free synthesis of functionally active HSPB5.
  740. Vaccination with Ectoparasite Proteins Involved in Midgut Function and Blood Digestion Reduces Salmon Louse Infestations.
  741. Study Protocol for the Evaluation of "SuperFIT", a Multicomponent Nutrition and Physical Activity Intervention Approach for Preschools and Families.
  742. Geriatric Conditions Predict Discontinuation of Anticoagulation in Long-Term Care Residents With Atrial Fibrillation.
  743. Distribution of allele frequencies for genes associated with physical activity and/or physical capacity in a homogenous Norwegian cohort- a cross-sectional study.
  744. Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer.
  745. Pulmonary Sarcoidosis Presenting with Miliary Opacities.
  746. Liquid Biopsy: A Tool for the Diagnostic and Prognostic Evaluation of Cancers.
  747. Diabeto-theranostics.
  748. Targeted metabolomics of pellicle and saliva in children with different caries activity.
  749. Evolutionary perspective on the hematopoietic system through a colonial chordate: allogeneic immunity and hematopoiesis.
  750. TSLP and IL-33 reciprocally promote each other's lung protein expression and ILC2 receptor expression to enhance innate type-2 airway inflammation.
  751. Standard Gibbs energy of metabolic reactions: V. enolase reaction.
  752. Combined Kinetin and Spermidine Treatments Ameliorate Growth and Photosynthetic Inhibition in Vigna angularis by Up-Regulating Antioxidant and Nitrogen Metabolism under Cadmium Stress.
  753. Hypofractionated radiation therapy with versus without immune checkpoint inhibitors in patients with brain metastases: A meta-analysis.
  754. Melatonin Inhibits Formation of Mitochondrial Permeability Transition Pores and Improves Oxidative Phosphorylation of Frozen-Thawed Ram Sperm.
  755. Injury Occurrence in Male Handball Players and its Impact on Physical Constitution.
  756. Squeezing lipids: NMR characterization of lipoprotein particles under pressure.
  757. Optimization of nucleotide sugar supply for polysaccharide formation via thermodynamic buffering.
  758. Ultrasound-assisted synthesis of clover-shaped nano-titania functionalized covalent organic frameworks for the dispersive solid phase extraction of N-nitrosamines in drinking water.
  759. Toxicological responses, bioaccumulation, and metabolic fate of triclosan in Chlamydomonas reinhardtii.
  760. Etomidate in the management of severe Cushing's disease and MRSA bacteraemia in a district general hospital in the United Kingdom.
  761. Metastatic small cell neuroendocrine carcinoma of the submandibular gland from the lung: A case report.
  762. The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis.
  763. Inhibitory potential of plant secondary metabolites on anti-Parkinsonian drug targets: Relevance to pathophysiology, and motor and non-motor behavioural abnormalities.
  764. TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching.
  765. MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis.
  766. Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia.
  767. Papillary syringocystadenoma in an uncommon location: a case report.
  768. Metabolomic Profiling of the Synergistic Effects of Ginsenoside Rg1 in Combination with Neural Stem Cell Transplantation in Ischemic Stroke Rats.
  769. The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model.
  770. Hexose transport in Torulaspora delbrueckii: identification of Igt1, a new dual-affinity transporter.
  771. NRF-2 and nonalcoholic fatty liver disease.
  772. Transcompp: Understanding phenotypic plasticity by estimating Markov transition rates for cell state transitions.
  773. High Serum Levels of Cholesterol Increase Anti-tumor Functions of Nature Killer Cells and Reduce Growth of Liver Tumors in Mice.
  774. In-vivo full-field measurement of microcirculatory blood flow velocity based on intelligent object identification.
  775. Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome.
  776. Using a dyadic approach to explore parental support for physical activity among young cancer survivors.
  777. Functional inter-relationships between carbohydrate and lipid storage, and mitochondrial activity during sporulation in S. cerevisiae.
  778. Supplementation of dietary nitrate attenuated oxidative stress and endothelial dysfunction in diabetic vasculature through inhibition of NADPH oxidase.
  779. Frequency-dependent changes in mitochondrial number and generation of reactive oxygen species in a rat model of vibration-induced injury.
  780. Describing the fecal metabolome in cryogenically collected samples from healthy participants.
  781. Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis.
  782. The circular RNA HIPK3 reduces hydrogen peroxide-induced injury of PC-12 cells by upregulation of miR-455.
  783. Predictors for unsuccessful weaning from venoarterial extracorporeal membrane oxygenation in patients undergoing coronary artery bypass grafting.
  784. Pan-cancer analysis of RNA methyltransferases identifies FTSJ3 as a potential regulator of breast cancer progression.
  785. The combined association of depressive symptoms and C-reactive protein for incident disease risk up to 12 years later. Findings from the English Longitudinal of Ageing (ELSA).
  786. NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons.
  787. Mbov_0503 Encodes a Novel Cytoadhesin that Facilitates Mycoplasma bovis Interaction with Tight Junctions.
  788. Active analyte import improves dynamic range and sensitivity of a Vitamin B12 biosensor.
  789. Changes in physical activity, diet, and body weight across the education and employment transitions of early adulthood: A systematic review and meta-analysis.
  790. Molecular Entrapment by RNA: An Emerging Tool for Disrupting Protein-RNA Interactions in vivo.
  791. Effect of ER stress on sphingolipid levels and apoptotic pathways in retinal pigment epithelial cells.
  792. B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression.
  793. [Lung ultrasound in a patient with dyspnoea and fever in primary care].
  794. Effect of lifestyle on blood pressure in patients under antihypertensive medication: An analysis from the Portuguese Health Examination Survey.
  795. Electrocautery ablation of anal high-grade squamous intraepithelial lesions: Effectiveness and key factors associated with outcomes.
  796. Protein kinase A accelerates the rate of early stage differentiation of pluripotent stem cells.
  797. Identification of sesamol byproducts produced by plasma treatment with inhibition of advanced glycation endproducts formation and ONOO- scavenging activities.
  798. Single-cell analysis on stromal fibroblasts in the microenvironment of solid tumours.
  799. Regulation of mTORC1 by Small GTPases in Response to Nutrients.
  800. Do perceived norms of social media users' eating habits and preferences predict our own food consumption and BMI?
  801. Cathepsin B overexpression induces degradation of perilipin 1 to cause lipid metabolism dysfunction in adipocytes.
  802. Proneural and mesenchymal glioma stem cells display major differences in splicing and lncRNA profiles.
  803. Influence of Sex on Urinary Organic Acids: A Cross-Sectional Study in Children.
  804. Importance of diet in reducing cancer incidence in Poland: a review
  805. Acute Cardiovascular Responses to Vagus Nerve Stimulation Following Experimental Spinal Cord Injury.
  806. Protein complexes including PGRMC1 and actin-associated proteins are disrupted by AG-205.
  807. Greasing the Wheels of Regeneration.
  808. The Adaptive and Innate Immune Cell Landscape of Uterine Leiomyosarcomas.
  809. Optimization and multiomic basis of phenyllactic acid overproduction by Lactobacillus plantarum.
  810. Metabolomics in multiple sclerosis disease course and progression.
  811. Retinoblastoma binding protein 7 is involved in Kiss1 mRNA upregulation in rodents.
  812. Technological Advances in Management of Diabetes Mellitus.
  813. It's That Time of Year Again.
  814. Is visceral abdominal fat area a better indicator for hyperglycemic risk? Results from the Pinggu Metabolic Disease Study.
  815. Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice.
  816. STVNa Attenuates Isoproterenol-Induced Cardiac Hypertrophy Response through the HDAC4 and Prdx2/ROS/Trx1 Pathways.
  817. Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response.
  818. Artesunate targets oral tongue squamous cell carcinoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition.
  819. Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing.
  820. Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes.
  821. Continuous variation in herkogamy enhances the reproductive response of Lonicera implexa to spatial variation in pollinator assemblages.
  822. Universal and Specific Predictors of Chinese Children With Dyslexia - Exploring the Cognitive Deficits and Subtypes.
  823. Correction to: Status and trends of circumpolar peregrine falcon and gyrfalcon populations.
  824. Treatment of hypoxia-dependent cardiovascular diseases by myo-inositol trispyrophosphate (ITPP)-enhancement of oxygen delivery by red blood cells.
  825. Associations between age and dyslipidemia are differed by education level: The Cardiovascular and Metabolic Diseases Etiology Research Center (CMERC) cohort.
  826. Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia.
  827. CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint.
  828. Mass spectrometry-based metabolomics approach in the isolation of bioactive natural products.
  829. Fenoxycarb and methoxyfenozide (RH-2485) affected development and chitin synthesis through disturbing glycometabolism in Lymantria dispar larvae.
  830. The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences.
  831. Correlation Study of Apolipoprotein'a' with Diabetic Retinopathy in Patients of Type 2 Diabetes Mellitus with Retinopathy.
  832. Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.
  833. Proteasome activity and expression of mammalian target of rapamycin signaling factors in skeletal muscle of dairy cows supplemented with conjugated linoleic acids during early lactation.
  834. Enolate-forming compounds provide protection from platinum neurotoxicity.
  835. Biofilm formation displays intrinsic offensive and defensive features of Bacillus cereus.
  836. The relationship between hypoglycaemia, body mass index and quality of life among patients with type 1 diabetes: observations from the DEPICT clinical trial programme.
  837. Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors.
  838. Associations between Physical Activity and Comorbidities in People with COPD Residing in Spain: A Cross-Sectional Analysis.
  839. A multilevel hypernetworks approach to capture properties of team synergies at higher complexity levels.
  840. Age-dependent remarkable regenerative potential of the dentate gyrus provided by intrinsic stem cells.
  841. Binocular Encoding in the Damselfly Pre-motor Target Tracking System.
  842. Cross-sectional phenotyping of small airway dysfunction in preschool asthma using the Impulse Oscillometry System.
  843. TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma.
  844. Sensitivity and specificity of Interleukin 29 in patients with rheumatoid arthritis and other rheumatic diseases.
  845. Metabolic regulation of epigenetic remodeling in immune cells.
  846. Differential basal expression of immune genes confers Crassostrea gigas resistance to Pacific oyster mortality syndrome.
  847. OptFill: A Tool for Infeasible Cycle-Free Gapfilling of Stoichiometric Metabolic Models.
  848. Test-retest repeatability of [18F]MC225-PET in rodents: A tracer for imaging of P-gp function.
  849. Quantitative evaluation of postintervention foot blood supply in patients with peripheral artery disease by computed tomography perfusion.
  850. GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer.
  851. Biointerface: A nano-modulated way for biological transportation.
  852. The Ionization Energy of Liquid Water Revisited.
  853. Glycemic control and FEV1 recovery during pulmonary exacerbations in pediatric cystic fibrosis-related diabetes.
  854. HbA1c: The Glucose Management Indicator, Time in Range, and Standardization of Continuous Glucose Monitoring Reports in Clinical Practice.
  855. Drug-loaded implantable surgical cavity-adaptive hydrogels for prevention of local tumor recurrence.
  856. Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia.
  857. Ab Initio molecular dynamics and high dimensional neural network potential study of VZrNbHfTa melt.
  858. Associations between catechol-O-methyltransferase (COMT) genotypes at rs4818 and rs4680 and gene expression in human dorsolateral prefrontal cortex.
  859. Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases.
  860. Cysteine Toxicity Drives Age-Related Mitochondrial Decline by Altering Iron Homeostasis.
  861. Enhancement of pullulanase production from recombinant Bacillus subtilis by optimization of feeding strategy and fermentation conditions.
  862. Model reduction of rigid-body molecular dynamics via generalized multipole potentials.
  863. White Matter and Neuroprotection in Alzheimer's Dementia.
  864. Re: A Prospective Head-to-Head Comparison of 18F-Fluciclovine With 68Ga-PSMA-11 in Biochemical Recurrence of Prostate Cancer in PET/CT.
  865. Sclerostin antibody treatment rescues the osteopenic bone phenotype of TGFβ inducible early gene-1 knockout female mice.
  866. Toward an MRI-Based Mesoscale Connectome of the Squid Brain.
  867. Fluid resuscitation following rib fractures.
  868. Comparison of Capillary Blood Glucose Versus Arterial Blood Glucose in Diabetic Patients Admitted in ICU on Vasopressor Support.
  869. Bespoken nanoceria: A new effective treatment in experimental hepatocellular carcinoma.
  870. MiR-7a ameliorates spinal cord injury by inhibiting neuronal apoptosis and oxidative stress.
  871. The Use of Arm Span as a Substitute for Height in Calculating Body Mass Index (BMI) for Spine Deformity Patients.
  872. miR-885 mediated cardioprotection against hypoxia/reoxygenation-induced apoptosis in human cardiomyocytes via inhibition of PTEN and BCL2L11 and modulation of AKT/mTOR signaling.
  873. Is Laguncularia racemosa more invasive than Sonneratia apetala in northern Fujian, China in terms of leaf energetic cost?
  874. Hot Electron Cooling in Silicon Nanoclusters via Landau-Zener Non-Adiabatic Molecular Dynamics: Size Dependence and Role of Surface Termination.
  875. Comparison of different images in gross target volume delineating on VX2 nasopharyngeal transplantation tumor models.
  876. The role of Self Nano Emulsifying drug delivery systems of CDODA-Me in sensitizing Erlotinib resistant Nonsmall cell lung cancer.
  877. Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids.
  878. Harnessing ecological and evolutionary principles to guide the design of microbial production consortia.
  879. Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation.
  880. Consequences of mutations in the genes of the ER export machinery COPII in vertebrates.
  881. Dysfunctional pain perception and modulation among torture survivors: The role of pain personification.
  882. Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies.
  883. piRNAs: biogenesis and their potential roles in cancer.
  884. HIV, aging, and adherence: an update and future directions.
  885. Sedimentary phosphorus cycling and budget in the seasonally hypoxic coastal area of Changjiang Estuary.
  886. Amino Acid Sensing: Architecture of mTORC1 on the Lysosome Surface.
  887. Low-dose curcumin reduced TNBS-associated mucin depleted foci in mice by scavenging superoxide anion and lipid peroxides, rebalancing matrix NO synthase and aconitase activities, and recoupling mitochondria.
  888. Dysregulation of magnesium transport protects Bacillus subtilis against manganese and cobalt intoxication.
  889. Mapping the spectrum of psychological and behavioural responses to low-dose CT lung cancer screening offered within a Lung Health Check.
  890. Commentary: Taking matters into your own hands: Venoarterial extracorporeal membrane oxygenation for controlled reperfusion during lung transplantation.
  891. The Who, What, Why, When, Where, and How of Team-Based Interdisciplinary Cancer Rehabilitation.
  892. Analysis of hypoxia-associated dendritic cells in colitic mice and effects of probiotics on IL-10 production in inflammatory dendritic-cells under hypoxia.
  893. Profiles of prognostic alternative splicing signature in hepatocellular carcinoma.
  894. Acid and heat fastness in microsporidia: How acid fast are acid fast microsporidium?
  895. Gli1 interacts with YAP1 to promote tumorigenesis in esophageal squamous cell carcinoma.
  896. Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases.
  897. ROCK-TAZ signaling axis regulates mechanical tension-induced osteogenic differentiation of rat cranial sagittal suture mesenchymal stem cells.
  898. Effect of Nutritional Anaemia on HbA1c Levels in Type 2 Diabates.
  899. Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells.
  900. Mechanisms underlying suppression of noradrenaline-induced contraction by prolonged treatment with advanced glycation end-products in organ-cultured rat carotid artery.
  901. CUPRA-ZYME: An assay for measuring carbohydrate-active enzyme activities, pathways and substrate specificities.
  902. Vesicular Dysfunction and the Pathogenesis of Parkinson's Disease: Clues From Genetic Studies.
  903. Causes of death among cancer patients in the era of cancer survivorship in Korea: Attention to the suicide and cardiovascular mortality.
  904. The differential effect of treadmill exercise intensity on hippocampal soluble aβ and lipid metabolism in APP/PS1 mice.
  905. Effects of treatment with a microRNA mimic or inhibitor on the developmental competence, quality, epigenetic status and gene expression of buffalo (Bubalus bubalis) somatic cell nuclear transfer embryos.
  906. mRNA levels of drug-metabolizing enzymes in 11 brain regions of cynomolgus macaques.
  907. Validation of predictive equations for resting energy expenditure in treatment-seeking adults with overweight and obesity: Measured versus estimated.
  908. Small-sized copolymeric nanoparticles for tumor penetration and intracellular drug release.
  909. Circular RNA VRK1 correlates with favourable prognosis, inhibits cell proliferation but promotes apoptosis in breast cancer.
  910. A highly sensitive red-emitting probe for the detection of viscosity changes in living cells, zebrafish, and human blood samples.
  911. Ubiquitin-specific protease 14 promotes prostate cancer progression through deubiquitinating the transcriptional factor ATF2.
  912. Advances in percutaneous lung tumor therapy: 2019 update.
  913. HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA.
  914. Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy.
  915. Mechanisms of lung toxicity induced by biomass burning aerosols.
  916. Antitumor activity of celastrol by inhibition of proliferation, invasion, and migration in cholangiocarcinoma via PTEN/PI3K/Akt pathway.
  917. Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis.
  918. Research on Target Deviation Measurement of Projectile Based on Shadow Imaging Method in Laser Screen Velocity Measuring System.
  919. Effect of Drought Stress during Soybean R2-R6 Growth Stages on Sucrose Metabolism in Leaf and Seed.
  920. Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model.
  921. Molecular design strategy towards high-redox-potential and low soluble n-type phenazine derivatives as cathode materials for lithium batteries.
  922. Correlation of chemotherapy costs with quality of life in nasopharyngeal cancer patients.
  923. Mendelian randomization study of obesity and cerebrovascular disease.
  924. [Research progress on the effects of plateau hypoxia on blood-brain barrier structure and drug permeability].
  925. Mechanical stretch regulates the expression of specific miRNA in extracellular vesicles released from lung epithelial cells.
  926. Structural characterization and in-silico analysis of Momordica charantia 7S globulin for stability and ACE inhibition.
  927. TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency.
  928. A Multi-Omics Analysis of Bone Morphogenetic Protein 5 (BMP5) mRNA Expression and Clinical Prognostic Outcomes in Different Cancers Using Bioinformatics Approaches.
  929. Reactivity of Metabolic Intermediates and Cofactor Stability under Model Early Earth Conditions.
  930. Duloxetine and pregabalin in neuropathic pain of lung cancer patients.
  931. Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice.
  932. The effect of prednisolone on endometrial VGEF concentrations, Gene polymorphisms and pregnancy outcome in women with polycystic ovary syndrome: A retrospective cohort study.
  933. The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction.
  934. The paradox between the environmental appeal of bio-based plastic packaging for consumers and their disposal behaviour.
  935. Metabolic manipulation by Pseudomonas fluorescens: a powerful stratagem against oxidative and metal stress.
  936. Novel invasion indices quantify the feed-forward facilitation of tumor invasion by macrophages.
  937. Prediction of triptolide targets in rheumatoid arthritis using network pharmacology and molecular docking.
  938. Role of thyroid hormones in craniofacial development.
  939. Differential work-function enabled bifunctional switching in strontium titanate flexible resistive memories.
  940. Discriminating Between Non-Specific Interstitial Pneumonia and Idiopathic Pulmonary Fibrosis at Early Stages: When CPET is Enough?
  941. LncRNA H19 is involved in myocardial ischemic preconditioning via increasing the stability of nucleolin protein.
  942. An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases.
  943. Simvastatin alleviated diabetes mellitus-induced erectile dysfunction in rats by enhancing AMPK pathway-induced autophagy.
  944. Relation of Hypocholesterolemia With Diabetes Mellitus in Patients With Coronary Artery Disease.
  945. The Role of General Parenting Style in Child Diet and Obesity Risk.
  946. Treatment of recurrent epithelial ovarian cancer.
  947. In Vivo Assessment of Thoracic Vertebral Shape From MRI Data Using a Shape Model.
  948. Atrial fibrillation and remote monitoring through cardiac implantable electronic devices in heart failure patients.
  949. Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy.
  950. Anatomical considerations in Pecs blocks.
  951. 3,4-Dihydroisocoumarins, Interesting Natural Products: Isolation, Organic Syntheses and Biological Activities.
  952. Type 2 diabetes mellitus in women with polycystic ovary syndrome during a 24-year period: importance of obesity and abdominal fat distribution.
  953. Pulmonary Mucormycosis: A Case Report of a Rare Infection with Potential Diagnostic Problems.
  954. Synchronization of Delayed Neural Networks via Integral-Based Event-Triggered Scheme.
  955. Carbonic Anhydrase XII Expression Is Modulated during Epithelial Mesenchymal Transition and Regulated through Protein Kinase C Signaling.
  956. Nanoscale Surface-induced Unfolding of Single Fibronectin is Restricted by Serum Albumin Crowding.
  957. Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma.
  958. A 7 Tesla fMRI investigation of human tinnitus percept in cortical and subcortical auditory areas.
  959. The role of circadian clock gene BMAL1 in vascular proliferation.
  960. Classification and Imaging Findings of Lung Neoplasms.
  961. Impact of Malnutrition on Outcomes Following Transcatheter Aortic Valve Implantation (from a National Cohort).
  962. A Method for the Evaluation of Site-Specific Nephrotoxic Injury in the Intact Rat Kidney.
  963. Fatigue in new registered nurses: A 12-month cross-lagged analysis of its association with work motivation, engagement, sickness absence, and turnover intention.
  964. SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function.
  965. De novo Sequencing, Assembly and Annotation of the Transcriptome for the Free-Living Testate Amoeba Arcella intermedia.
  966. S-Equol ameliorates insulin secretion failure through Chrebp/Txnip signaling via modulating PKA/PP2A activities.
  967. A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane.
  968. MicroRNA Biomarker hsa-miR-195-5p for Detecting the Risk of Lung Cancer.
  969. Difficulties in recognizing granulomatosis with polyangiitis (GPA) in elderly patients undergoing diagnostic thoracotomy twice - a report of two cases.
  970. Occupational performance in multiple sclerosis and its relationship with quality of life and fatigue.
  971. A reference library for assigning protein subcellular localizations by image-based machine learning.
  972. Pharmacodynamics of current and emerging PD-1 and PD-L1 inhibitors for the treatment of non-small cell lung cancer.
  973. A Small Compound Targeting Prohibitin with Potential Interest for Cognitive Deficit Rescue in Aging mice and Tau Pathology Treatment.
  974. A symptom combination predicting treatment-resistant schizophrenia - A strategy for real-world clinical practice.
  975. Identification and characterisation of chronic lung allograft dysfunction patients with mixed phenotype: A single center study.
  976. Cellular environment controls the dynamics of histone H3 lysine 56 acetylation in response to DNA damage in mammalian cells.
  977. HWL-088, a new highly potent FFAR1 agonist, improves glucolipid metabolism and acts additively with Metformin in ob/ob diabetic mice.
  978. New entry to the enantioselective formation of substituted cyclohexenes bearing an all-carbon quaternary stereogenic center.
  979. Slug, a Cancer-Related Transcription Factor, is Involved in Vascular Smooth Muscle Cell Transdifferentiation Induced by Platelet-Derived Growth Factor-BB During Atherosclerosis.
  980. Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice.
  981. Combined analysis of whole-exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity.
  982. Osteoprotegerin promotes intimal hyperplasia and contributes to in-stent restenosis: Role of an αVβ3/FAK dependent YAP pathway.
  983. Substrate specificity of plastid phosphate transporters in a non-photosynthetic diatom and its implication in evolution of red alga-derived complex plastids.
  984. A facile microwave assisted synthesis and structure elucidation of (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones by crystallographic, spectroscopic and DFT studies.
  985. Psyllium husk intake and risk of type 2 diabetes: an evidence-based scientific and regulatory review of a qualified health claim conducted by the US Food and Drug Administration.
  986. Sulforaphane attenuates angiotensin II-induced human umbilical vein endothelial cell injury by modulating ROS-mediated mitochondrial signaling.
  987. N-H Chirality in Folded Peptide LK7β Is Governed by the Cα-H Chirality.
  988. Advances in Cellular Target Engagement and Target Deconvolution.
  989. New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management.
  990. Processing and Analyzing Multiple Genomes Alignments with MafFilter.
  991. Preclinical evaluation of the combination of AZD1775 and irinotecan against selected pediatric solid tumors: A Pediatric Preclinical Testing Consortium report.
  992. Effects and Mechanism of Action of PX-478 in Oxygen-Induced Retinopathy in Mice.
  993. Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection.
  994. Controlling Single Molecule Conductance by Chemical Reaction.
  995. Low expression of vascular endothelial growth factor and high serum level of cyclic guanine monophosphate as the risk factors of femoral head osteonecrosis in alcohol-exposed Wistar rat.
  996. Uterine and placental blood flow indexes and antinuclear autoantibodies in unexplained recurrent pregnancy loss: should they be investigated in pregnancy as correlated potential factors? A retrospective study.
  997. Spirometric Analysis in Type 2 Diabetes Mellitus.
  998. Multivisceral Transplant, The Prince Charles Experience.
  999. A crucial RNA-binding lysine residue in the Nab3 RRM domain undergoes SET1 and SET3-responsive methylation.
  1000. [Lung Cancer Accompanied by Sarcoidosis with Mediastinal and Bilateral Hilar Lymphadenopathy;Report of a Case].
  1001. Vibrational Spectroscopy and Morphological Studies on Protein-Capped Biosynthesized Silver Nanoparticles.
  1002. Physiological and transcriptional response of Xanthomonas oryzae pv. oryzae to berberine, an emerging chemical control.
  1003. Factors associated with early sexual initiation and unsafe sex in adolescents: Substance use and parenting style.
  1004. Nanomedicine in osteosarcoma therapy: micelleplexes for delivery of nucleic acids and drugs for osteosarcoma-targeted therapy.
  1005. Drug Metabolite Identification using UHPLC UV Spectroscopy and Parallelized Scans on a Tribrid Orbitrap Mass Spectrometer.
  1006. Oral tyrosine kinase inhibitors in OMFS: a review.
  1007. Prognostic Value of 18F-FDG PET Using Texture Analysis in Cardiac Sarcoidosis.
  1008. 'I wanted my child dead' - Physical, social, cognitive, emotional and spiritual life stories of Turkish parents who give care to their children with schizophrenia: A qualitative analysis based on empowerment approach.
  1009. Hepatic proteomic analysis of selenoprotein F knockout mice by iTRAQ: An implication for the roles of selenoprotein F in metabolism and diseases.
  1010. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells.
  1011. Challenges of pancreas transplantation in developing countries, exploring the Turkey example.
  1012. Circulating miR-330-3p in Late Pregnancy is Associated with Pregnancy Outcomes Among Lean Women with GDM.
  1013. Metabolic and cardiorespiratory effects of decreasing lung hyperinflation with budesonide/formoterol in COPD: a randomized, double-crossover, placebo-controlled, multicenter trial.
  1014. Synthesis of a 1,2,3-bistriazole derivative of embelin and evaluation of its effect on high-fat diet fed-streptozotocin-induced type 2 diabetes in rats and molecular docking studies.
  1015. Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-Apoptotic Mcl-1 and Bfl-1 Proteins.
  1016. "Napoleon Hat" Sign: A Distinctive Cytologic Clue to Reactive Pneumocytes.
  1017. Cationic polyelectrolyte/graphene oxide as an efficient sorbent for the extraction and analysis of trace acidic herbicides in vegetables.
  1018. Gαi2+ vomeronasal neurons govern the initial outcome of an acute social competition.
  1019. Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids.
  1020. Mean Platelet Volume (MPV) is a Measure of Glycemic Control in Diabetes Mellitus 2.
  1021. Parkin overexpression attenuates Aβ-induced mitochondrial dysfunction in HEK293 cells by restoring impaired mitophagy.
  1022. Molecular Mechanisms Driving mRNA Degradation by m6A Modification.
  1023. Childhood cancer: unique opportunities and inherent challenges.
  1024. Chimeric Interaction of Nitrogenase-like Reductases with the MoFe Protein of Nitrogenase.
  1025. Influences of different iron forms activated peroxydisulfate on volatile fatty acids production during waste activated sludge anaerobic fermentation.
  1026. Structural and Functional Characterization of the Dominant Negative P-Loop Lysine Mutation in the Dynamin Superfamily Protein Vps1.
  1027. Modulators of Fam210a and Roles of Fam210a in the Function of Myoblasts.
  1028. Effects of Lactobacillus plantarum Q180 on Postprandial Lipid Levels and Intestinal Environment: A Double-Blind, Randomized, Placebo-Controlled, Parallel Trial.
  1029. Decreased markers of bone turnover in children and adolescents with type 1 diabetes.
  1030. Insulin pumps use in Greece: efficacy and safety data from 140 patients with type 1 diabetes mellitus.
  1031. Diabetes Technology in the Inpatient Setting for Management of Hyperglycemia.
  1032. Diabetes Technology and Exercise.
  1033. Commentary: Double, double, toil, and trouble: Removing evil humours during ex vivo lung perfusion.
  1034. Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization.
  1035. Molecular Imaging of Newly Diagnosed Prostate Cancer.
  1036. Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.
  1037. Rhipicephalus (Boophilus) microplus (Ixodida: Ixodidae) Larvae Collected From Vegetation in the Coastal Wildlife Corridor of Southern Texas and Research Solutions for Integrated Eradication.
  1038. Current developments in LC-MS for pharmaceutical analysis.
  1039. Determination of complex small molecule structures using molecular alignment simulation.
  1040. In Vitro Characterization of Dental Pulp Stem Cells Cultured in Two Microsphere-Forming Culture Plates.
  1041. Carboxyl terminal activating region 3 of latent membrane protein 1 encoded by the Epstein‑Barr virus regulates cell proliferation and protein expression in NP69 cells.
  1042. Metabolic Role of PTEN in Insulin Signaling and Resistance.
  1043. Quantitative Color Doppler Ultrasonography Measurement of Thyroid Blood Flow in Patients with Graves' Disease.
  1044. Growing up gator: a proteomic perspective on cardiac maturation in an oviparous reptile, the American alligator (Alligator mississippiensis).
  1045. Demographics and Outcomes of Eccrine Porocarcinoma: Results from the National Cancer Database.
  1046. Multimorbidity in COPD, does sleep matter?
  1047. Mutational landscape screening of methylene tetrahydrofolate reductase to predict homocystinuria associated variants: An integrative computational approach.
  1048. Treatment duration and disease recurrence after the successful treatment of patients with Mycobacterium avium complex lung disease.
  1049. Inhibition of protein FAK enhances 5-FU chemosensitivity to gastric carcinoma via p53 signaling pathways.
  1050. Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor.
  1051. The curcumin analogue WZ35 affects glycolysis inhibition of gastric cancer cells through ROS-YAP-JNK pathway.
  1052. Comparison of activity, expression and S-nitrosylation of glycolytic enzymes between pale, soft and exudative and red, firm and non-exudative pork during post-mortem aging.
  1053. Pt-O bond as an active site superior to Pt0 in hydrogen evolution reaction.
  1054. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.
  1055. Champ4life Study Protocol: A One-Year Randomized Controlled Trial of a Lifestyle Intervention for Inactive Former Elite Athletes with Overweight/Obesity.
  1056. Auxin Canalization and Vascular Tissue Formation by TIR1/AFB-Mediated Auxin Signaling in Arabidopsis.
  1057. Association of dietary intake of fruit and green Vegetables with PTEN and P53 mRNA gene expression in visceral and subcutaneous adipose tissues of obese and non-obese adults.
  1058. Technetium retention by gamma alumina nanoparticles and the effect of sorbed Fe2.
  1059. Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study.
  1060. Dual Modality FeS Nanoparticles with Reactive Oxygen Species-Induced and Photothermal Toxicity toward Pathogenic Bacteria.
  1061. Influence of cytoskeleton organization on recombinant protein expression by CHO cells.
  1062. Angiotensin Receptor Blockers and the Risk of Suicide: An Exercise in the Critical Examination of a Case-Control Study.
  1063. Preliminary study on the clinical significance of kinesin Kif18a in nonsmall cell lung cancer: An analysis of 100 cases.
  1064. Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells.
  1065. VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy.
  1066. AMPA receptor-mTORC1 signaling activation is required for neuroplastic effects of LY341495 in rat hippocampal neurons.
  1067. Antibody targeted PET Imaging of 64Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA positive tumors.
  1068. MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses.
  1069. Offsetting anthropogenic carbon emissions from biomass waste and mineralised carbon dioxide.
  1070. Prolidase deficiency: a new genetic cause of combined pulmonary fibrosis and emphysema syndrome in the adult.
  1071. Antimicrobials for food and feed; a bacteriocin perspective.
  1072. Expression of SIRT5 protein in gastric cancer cells.
  1073. Role of HIF-1α in Cold Ischemia Injury of Rat Donor Heart Via the miR-21/PDCD4 Pathway.
  1074. A prospective study examining the impact of uniportal video-assisted thoracic surgery on the short-term quality of life in patients with lung cancer.
  1075. Growth effects of N-acylethanolamines on gut bacteria reflect altered bacterial abundances in inflammatory bowel disease.
  1076. Biomedical Application of Manganese Dioxide Nanomaterials.
  1077. Vascular uptake on 18F-sodium fluoride positron emission tomography: precursor of vascular calcification?
  1078. Structural and Thermophysical Anomalies of Liquid Water: A Tale of Molecules in the Instantaneous Low and High-Density Regions.
  1079. The Rhinella arenarum transcriptome: de novo assembly, annotation and gene prediction.
  1080. A recoded view on the F9 p.Cys178Ter pathogenic mechanism.
  1081. Should Patients Choose Lung Transplantation or Optimal Drug Therapy?　- The Clinical Situation in the Treatment of Pulmonary Arterial Hypertension in Japan.
  1082. Volatile organic compound breath signatures of children with cystic fibrosis by real-time SESI-HRMS.
  1083. A Structural Study on the Listeria Monocytogenes Internalin A-Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations.
  1084. Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis.
  1085. Anti-tumor immune response varies among individuals: A gene expression profiling of mouse melanoma.
  1086. Structures of Type III Secretion System Needle Filaments.
  1087. The metal transporter CrNRAMP1 is involved in zinc and cobalt transports in Chlamydomonas reinhardtii.
  1088. Identification of potential therapeutic targets in Neisseria gonorrhoeae by an in-silico approach.
  1089. In situ localization of alkaline phosphatase activity in tumor cells by an aggregation-induced emission fluorophore-based probes.
  1090. Co-expression of glycosylated aquaporin-1 and transcription factor NFAT5 contributes to aortic stiffness in diabetic and atherosclerosis-prone mice.
  1091. The occurrence of polybrominated diphenyl ethers and their metabolites in Portuguese river biota.
  1092. Evaluation of the impact of chlorophyll removal techniques on polyphenols in rosemary and thyme by-products.
  1093. Association between Serum Uric Acid Levels and Metabolic Syndrome.
  1094. Experimental and computational evidence for C=O π-bonding in [CH2OH]+ and related oxonium ions.
  1095. Textural analysis of hybrid DOTATOC-PET/MRI and its association with histological grading in patients with liver metastases from neuroendocrine tumors.
  1096. Understanding the Lipid and Protein Corona Formation on Different Sized Polymeric Nanoparticles.
  1097. Low-frequency Ultrasound with Short Application Time Improves Cellulase Activity and Reducing Sugars Release.
  1098. Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation.
  1099. Identification of MMP1 as a Potential Prognostic Biomarker and Correlating with Immune Infiltrates in Cervical Squamous Cell Carcinoma.
  1100. DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis.
  1101. Repurposing of Streptomyces antibiotics as adenosine deaminase inhibitors by pharmacophore modeling, docking, molecular dynamics, and in vitro studies.
  1102. Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation.
  1103. Study of Blood Glucose and White Blood Cell Count Combination in Predicting Short Term Outcome of Acute Ischemic Stroke.
  1104. CuS@PDA-FA nanocomposites: a dual stimuli-responsive DOX delivery vehicle with ultrahigh loading level for synergistic photothermal-chemotherapies on breast cancer.
  1105. Lower Levels of 25-Hydroxyvitamin D3 are Associated with a Higher Prevalance of Diabetic Retinopathy in Type 2 Diabetes.
  1106. Targeting chondroitinase ABC to axons enhances the ability of chondroitinase to promote neurite outgrowth and sprouting.
  1107. Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.
  1108. Single-Shot Near-Field Volumetric Imaging System for Optical Ultrasound and Photoacoustics Using Capacitive Micromachined Ultrasonic Transducer Without Transmission Mode.
  1109. A descriptive analysis of functional impairments and patho-anatomical findings in eight powerlifters.
  1110. Sex-specific association between the gut microbiome and high-fat diet-induced metabolic disorders in mice.
  1111. Anti-inflammatory effect of octyl gallate in alveolar macrophages cells and mice with acute lung injury.
  1112. BAL biomarkers' panel for differential diagnosis of interstitial lung diseases.
  1113. Insulinoma-associated protein 1 (INSM1) is a robust marker for identifying and grading pancreatic neuroendocrine tumors.
  1114. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation.
  1115. LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway.
  1116. Quantifi cation and Correlation of Serum Cortisol Levels with Diff erent Parameters of Metabolic Syndrome.
  1117. Bioremediation of cadmium polluted soil using a novel cadmium immobilizing plant growth promotion strain Bacillus sp. TZ5 loaded on biochar.
  1118. Substrate interaction with the EssC coupling protein of the Type VIIb secretion system.
  1119. Monoclonal antibodies carried in drug delivery nanosystems as a strategy for cancer treatment.
  1120. New treatments in spinal muscular atrophy: an overview of currently available data.
  1121. Maternal Selenium Deficiency in Mice Alters Offspring Glucose Metabolism and Thyroid Status in a Sexually Dimorphic Manner.
  1122. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies.
  1123. The discovery and maturation of peptide biologics targeting the small G protein Cdc42: a bioblockade for Ras-driven signalling.
  1124. Liver ChREBP Protects Against Fructose-induced Glycogenic Hepatotoxicity by Regulating L-type Pyruvate Kinase.
  1125. Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions.
  1126. TSPO PET Identifies Different Anti-inflammatory Minocycline Treatment Response in Two Rodent Models of Epileptogenesis.
  1127. Sustained effects of resistant starch on the expression of genes related to carbohydrate digestion/absorption in the small intestine.
  1128. PHOSPHATURIC MESENCHYMAL HEEL TUMOR PRESENTING WITH TUMOR-INDUCED OSTEOMALACIA.
  1129. New regulatory mechanism-based inhibitors of aspartate transcarbamoylase for potential anticancer drug development.
  1130. Early and current physical activity: cross-sectional associations with overweight among adults.
  1131. Is Better Sleep Beneficial for Metabolic Outcomes in Obese Female Adolescents with Polycystic Ovarian Syndrome?
  1132. Endodontic therapy and incident cardiovascular disease: The Atherosclerosis Risk in Communities (ARIC) study.
  1133. Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment.
  1134. Corrigendum: Competitive sorption of Pb(II), Cu(II) and Ni(II) on carbonaceous nanofibers: A spectroscopic and modeling approach.
  1135. Predictive clinical factors of chronic peripheral neuropathy induced by oxaliplatin.
  1136. A Core-Shell Layered Oxide Cathode for High-Performance Sodium-Ion Batteries.
  1137. Genomic differences between Listeria monocytogenes EGDe isolates reveals crucial roles for SigB and wall rhamnosylation in biofilm formation.
  1138. INTRAMEDULLARY SPINAL CORD METASTASIS AS THE PRESENTING FEATURE OF PAPILLARY THYROID CARCINOMA.
  1139. Activated Hgf-Met signaling cooperates with oncogenic Braf to drive primary cutaneous melanomas and angiotropic lung metastases in mice.
  1140. A novel radiomic nomogram for predicting epidermal growth factor receptor mutation in peripheral lung adenocarcinoma.
  1141. Association Between Electronic Cigarette Use and Levels of High-Sensitivity C-Reactive Protein and Uric Acid.
  1142. NGS reveals relevant resistance mutations.
  1143. Butyrate alleviates oxidative stress by regulating NRF2 nuclear accumulation and H3K9/14 acetylation via GPR109A in bovine mammary epithelial cells and mammary glands.
  1144. Sleep Apnea, Obesity, and Disturbed Glucose Homeostasis: Epidemiologic Evidence, Biologic Insights, and Therapeutic Strategies.
  1145. Effects of Huang-Lian-Jie-Du Decoction on Oxidative Stress and AMPK-SIRT1 Pathway in Alzheimer's Disease Rat.
  1146. Radon-222: environmental behavior and impact to (human and non-human) biota.
  1147. Bacteriophage Prevents Alcoholic Liver Disease.
  1148. Mechanical stress triggers nuclear remodeling and the formation of Transmembrane Actin Nuclear lines with associated Nuclear Pore Complexes.
  1149. Multifunctional compounds Lithium Chloride and Methylene Blue attenuate the negative effects of diisopropylfluorophosphate on axonal transport in rat cortical neurons.
  1150. Therapeutic efficacy and safety of initial triple combination of metformin, sitagliptin, and lobeglitazone in drug-naïve patients with type 2 diabetes: initial triple study.
  1151. Metformin Delays the Development of Atherosclerosis in Type 1 Diabetes Mellitus Via the Methylglyoxal Pathway.
  1152. Cell Death in Cells Overlying Lateral Root Primordia Facilitates Organ Growth in Arabidopsis.
  1153. Endocannabinoid modulating drugs improve anxiety but not the expression of conditioned fear in a rodent model of post-traumatic stress disorder.
  1154. Conformationally rigid pyrazoloquinazoline α-amino acids: one- and two-photon induced fluorescence.
  1155. Comparing MEG and high-density EEG for intrinsic functional connectivity mapping.
  1156. Precision therapy in RAS mutant colorectal cancer.
  1157. Do microplastics affect the zoanthid Zoanthus sociatus?
  1158. Role of Nuclear Medicine in Imaging.
  1159. Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH.
  1160. Relaxin Positively Influences Ischemia-Reperfusion Injury in Solid Organ Transplantation: A Comprehensive Review.
  1161. Electrical-driven Release and Migration of Herbicide Using a Gel-based Nanocomposite.
  1162. Probing two PESIN-indocyanine-dye-conjugates: significance of the used fluorophore.
  1163. Female Specific Association of Low Insulin-Like Growth Factor 1 (IGF1) Levels with Increased Risk of Premature Mortality in Renal Transplant Recipients.
  1164. Modulation of Nqo1 Activity Intercepts Anoikis Resistance and Reduces Metastatic Potential of Hepatocellular Carcinoma.
  1165. Pathophysiological mechanisms underlying the beneficial effects of physical activity in hypertension.
  1166. Neuroimaging methods in Epilepsy of Temporal Origin.
  1167. Normal imaging findings after aortic valve implantation on 18F-Fluorodeoxyglucose positron emission tomography with computed tomography.
  1168. In silico, in-vitro and in vivo screening of biological activities of citral.
  1169. Health Literacy and Outcomes of a Community-Based Self-Help Intervention: A Case of Korean Americans with Type 2 Diabetes.
  1170. Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer.
  1171. Nano Hydroxyapatite Particle Brushes via Direct Initiator Tethering and Surface Initiated ATRP for Dual Responsive Pickering Emulsion.
  1172. Migrating from partial least squares discriminant analysis to artificial neural networks: a comparison of functionally equivalent visualisation and feature contribution tools using jupyter notebooks.
  1173. Do micronutrient deficiencies contribute to mitochondrial failure in critical illness?
  1174. The Effect of Transcription Factor MYB14 on Defense Mechanisms in Vitis quinquangularis-Pingyi.
  1175. Drug resistance mechanisms in Japanese ALK positive NSCLC and the clinical responses based on the resistant mechanisms.
  1176. Steric Effects Control Dry Friction of H- and F-Terminated Carbon Surfaces.
  1177. Shortened Leukocyte Telomere Length Associates with an Increased Prevalence of Chronic Health Conditions among Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort.
  1178. Biodegradability of Dental Care Antimicrobial Agents Chlorhexidine and Octenidine by Ligninolytic Fungi.
  1179. Inhibition of tRNA Synthetases Induces Persistence in Chlamydia.
  1180. Application of Quantitative Analysis of Diatoms in Lung Tissue for the Diagnosis of Drowning of Experimental Animals.
  1181. Competing Mortality in Patients With Neuroendocrine Tumors: Erratum.
  1182. The role of bone-derived PDGF-AA in age-related pancreatic β cell proliferation and function.
  1183. Single-cell genomics of uncultured bacteria reveals dietary fiber responders in the mouse gut microbiota.
  1184. Identification of a Master Regulator of Differentiation in Toxoplasma.
  1185. Myeloid atg5 deletion impairs n-3 PUFA-mediated atheroprotection.
  1186. Inhibition of miR-200b-3p alleviates hypoxia-ischemic brain damage via targeting Slit2 in neonatal rats.
  1187. Multi-center, randomized, double-blind, placebo-controlled, exploratory study to evaluate the efficacy and safety of HAD-B1 for dose-finding in EGFR positive and locally advanced or metastatic NSCLC subjects who need Afatinib therapy: Study protocol clinical trial (SPIRIT Compliant).
  1188. Multiple electrolyte imbalances and mixed acid-base disorder posing a diagnostic dilemma: a case report.
  1189. A new perspective of enzyme inhibition by organophosphates.
  1190. New Concerns About Military Recruits with Metabolic Obesity but Normal Weight ("Skinny Fat").
  1191. Chitooligosaccharides Modulate Glucose-Lipid Metabolism by Suppressing SMYD3 Pathways and Regulating Gut Microflora.
  1192. HPV vaccination: Strong messages from a meta-analysis, a report and a press-release.
  1193. Utilizing Peers to Support Academic Learning for Children With Autism Spectrum Disorder.
  1194. Hypoxia and Innate Immunity: Keeping Up with the HIFsters.
  1195. Re: Cutaneous Manifestation of Sarcoidosis in Lower-Back Tattoo With Increased Uptake of 18F-FDG.
  1196. Nutrition intake in the post-ICU hospitalization period.
  1197. Ivermectin-induced programmed cell death and disruption of mitochondrial membrane potential in bovine mammary gland epithelial cells.
  1198. Inhibitory mechanism of lactoferrin on antibacterial activity of oenothein B: isothermal titration calorimetry and computational docking simulation.
  1199. Short communication: Milk microbiota profiling on water buffalo with full-length 16S rRNA using nanopore sequencing.
  1200. Crab vs. Mushroom: A Review of Crustacean and Fungal Chitin in Wound Treatment.
  1201. Negative regulation by transcription factor VvWRKY13 in drought stress of Vitis vinifera L.
  1202. Anatomical analysis of the pelvis to identify any predisposing anatomical factors for ischiofemoral space pathology: a retrospective study.
  1203. Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination.
  1204. ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer.
  1205. Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma-like lung disease in mice.
  1206. A high-fat high-calorie diet induces fibre-specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle.
  1207. The value of avian gross pathology in identifying endocrine disrupting properties.
  1208. Massive Hematemesis: An Uncommon Presentation of an Unusual Diagnosis.
  1209. Stress, anxiety, harassment: huge survey reveals pressures of scientists' working lives.
  1210. Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index.
  1211. Impacts of polystyrene microplastics on Daphnia magna: A laboratory and a mesocosm study.
  1212. Commentary: Tis the season to filter your perfusate.
  1213. Characterization of the active components of the multimerized sTNFRII-adiponectin fusion protein showing both TNFα-antagonizing and glucose uptake-promoting activities.
  1214. Science that Inspires.
  1215. Gas-Phase Formation of Fulvenallene (C7H6) via the Jahn-Teller Distorted Tropyl (C7H7) Radical Intermediate under Single-Collision Conditions.
  1216. Improved Tetanic Force and Mitochondrial Calcium Homeostasis by Astaxanthin Treatment in Mouse Skeletal Muscle.
  1217. The choice and definition of summary measure for meta-analysis of clinical studies with binary outcomes: Effect on clinical interpretation.
  1218. Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity.
  1219. Inhibition of C-Fos protein and mRNA expression in the brain of adjuvant-induced arthritic rats following treatment with N-(2-hydroxy phenyl) acetamide.
  1220. Effect of a magnetic pulse on orientation behavior in rainbow trout (Oncorhynchus mykiss).
  1221. Functional and physicochemical properties of flours and starches from different tuber crops.
  1222. Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype.
  1223. Fluorescence Signal Amplification by Using β-Galactosidase for Flow Cytometry; Advantages of an Endogenous Activity-free Enzyme.
  1224. A Lever-Type Method of Strain Exposure for Disk F-Shaped Torque Sensor Design.
  1225. Astrocytic glutamate transporters reduce the neuronal and physiological influence of metabotropic glutamate receptors in nucleus tractus solitarii.
  1226. Expression of lncRNA-ANRIL in patients with coronary heart disease before and after treatment and its short-term prognosis predictive value.
  1227. Multirate control strategies for avoiding sample losses. Application to UGV path tracking.
  1228. Caveolin: A New Link Between Diabetes and AD.
  1229. Clinical & Lab Marker Predicting Early Molecular Response Inpatient of CML Chronic Phase Treated With Imatinib.
  1230. Role of the treatment environment in the effects of aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice.
  1231. Research on embryo-like structures struggles to win US government funding.
  1232. GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons.
  1233. Prioritisation of research topics for head and neck cancer in Africa - Report of the International Collaboration On Improving Cancer outcomes in low and middle income countries - ICOnIC Africa.
  1234. Advances in molecular simulations of protein mechanical properties and function.
  1235. Microarray Expression Profiling and Raman Spectroscopy Reveal Anti-Fatty Liver Action of Berberine in a Diet-Induced Larval Zebrafish Model.
  1236. Supporting clinical decision making in advanced melanoma by preclinical testing in personalized immune-humanized xenograft mouse models.
  1237. Defining lncRNAs Correlated with CHO Cell Growth and IgG Productivity by RNA-Seq.
  1238. Relevance and Regulation of Cell Density.
  1239. Helix Shape Power-Dependent Properties of Single Upconversion Nanoparticles.
  1240. Circulating adiposity-related microRNAs as predictors of the response to a low-fat diet in subjects with obesity.
  1241. Integration of Diabetes Technology in Clinical Practice.
  1242. Curcumin reduces LPS-induced septic acute kidney injury through suppression of lncRNA PVT1 in mice.
  1243. Cerebellar Neurodynamics Predict Decision Timing and Outcome on the Single-Trial Level.
  1244. Synthetic biology of hypoxia.
  1245. Surface charge-dependent bioaccumulation dynamics of silver nanoparticles in freshwater algae.
  1246. The velvet Regulator VosA Governs Survival and Secondary Metabolism of Sexual Spores in Aspergillus nidulans.
  1247. Controlling the Rotational Barrier of Single Porphyrin Rotors on Surfaces.
  1248. Presacral Anastomotic Sinus After Low Anterior Resection Mimicking Recurrent Rectal Cancer.
  1249. Probing Biological Mechanisms with Chemical Tools.
  1250. Expression of MiR-140 and MiR-199 in Synovia and its Correlation with the Progression of Knee Osteoarthritis.
  1251. Dynamic monitoring of STAT3 activation in live cells using a novel STAT3 Phospho-BRET sensor.
  1252. A new life for self-reactive T cell precursors.
  1253. Micropapillary pattern is associated with the development of brain metastases and the reduction of survival time in EGFR-mutation lung adenocarcinoma patients with surgery.
  1254. Natural variation and CRISPR/Cas9-mediated mutation in GmPRR37 affect photoperiodic flowering and contribute to regional adaptation of soybean.
  1255. Fast Track to Discover Novel Promoters in Rice.
  1256. Measuring the link between cardiac mechanical function and metabolism during hyperpolarized 13C-pyruvate magnetic resonance experiments.
  1257. Slice-selective learning for Alzheimer's disease classification using a generative adversarial network: a feasibility study of external validation.
  1258. Mental-health disparities between heterosexual and sexual-minority adolescents: Examining the role of informant discrepancies.
  1259. Airway wall thickness and airflow limitations in asthma assessed in quantitative computed tomography.
  1260. "Old Roads-New Connections" SSIEM 2018 Annual Symposium in Athens.
  1261. A network pharmacology approach to explore the potential targets underlying the effect of sinomenine on rheumatoid arthritis.
  1262. Lifecycle management in pharmaceutical analysis: How to establish an efficient and relevant continued performance monitoring program.
  1263. Relative Activity Factor (RAF)-Based Scaling of Uptake Clearance Mediated by Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3 in Human Hepatocytes.
  1264. Roflupram exerts neuroprotection via activation of CREB/PGC-1α signaling in experimental models of Parkinson's disease.
  1265. Depressed sympathovagal modulation indicates sepsis in patients with suspected infection.
  1266. The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model.
  1267. Plasma steroid profiles before and after ACTH stimulation test in healthy horses.
  1268. Hydrostatic Pressure-Induced Spectral Variation of Reichardt's Dye: A Polarity/Pressure Dual Indicator.
  1269. The Endocannabinoid System: A Target for Cancer Treatment.
  1270. Building confidence in digital health through metrology.
  1271. Q&A: Christina Curtis on Computational and Systems Biology.
  1272. Mangiferin: A promising natural xanthone from Mangifera indica for the control of acyclovir - resistant herpes simplex virus 1 infection.
  1273. Narrative of a versatile and adept species Pseudomonas putida.
  1274. A work of FiCTION.
  1275. Spontaneous Curvature, Differential Stress, and Bending Modulus of Asymmetric Lipid Membranes.
  1276. GRK2 enforces androgen receptor dependence in the prostate and prostate tumors.
  1277. AON-induced splice-switching and DMPK pre-mRNA degradation as potential therapeutic approaches for Myotonic Dystrophy type 1.
  1278. Effect of scrotal insulation on sperm quality and seminal plasma proteome of Brangus bulls.
  1279. Emerging prospects of mixotrophic microalgae: Way forward to sustainable bioprocess for environmental remediation and cost-effective biofuels.
  1280. Biostimulant Effect and Biochemical Response in Lettuce Seedlings Treated with A Scenedesmus quadricauda Extract.
  1281. Dual diagnosis: A systematic review of the organization of community health services.
  1282. Steroidal glycoalkaloids from Solanum lyratum inhibit the pro-angiogenic activity of A549-derived exosomes.
  1283. Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition.
  1284. Whole-fornix endoscopic submucosal dissection for gastric mucosal adenocarcinoma.
  1285. Proteomic analysis of Sporothrix schenckii cell wall reveals proteins involved in oxidative stress response induced by menadione.
  1286. Autologous stem cell transplantation following high-dose chemotherapy in children with high-risk neuroblastoma: Practicality in resource-limited countries.
  1287. Pulmonary haemorrhage following thrombolysis with streptokinase in myocardial infarction.
  1288. Gene of the month: GLI-1.
  1289. Ability of the Global Alignment and Proportion Score to Predict Mechanical Failure Following Adult Spinal Deformity Surgery-Validation in 149 Patients With Two-Year Follow-up.
  1290. Gene signatures of breast cancer development and the potential for novel targeted treatments.
  1291. A self-assembled pH/enzyme dual-responsive prodrug with PEG deshielding for multidrug-resistant tumor therapy.
  1292. Prenatal betamethasone exposure increases corticotropin-releasing hormone expression along with increased hippocampal slice excitability in the developing hippocampus.
  1293. Relationship between immune parameters during a severe exacerbation in allergic asthmatic children and asthma outcomes in the following year.
  1294. Interactive Alternative Splicing Analysis of Human Stem Cells Using psichomics.
  1295. Effect of Cultivar on Chlorophyll Meter and Canopy Reflectance Measurements in Cucumber.
  1296. New aspects of monoamine oxidase B inhibitors: the key role of halogens to open the golden door.
  1297. Cord Blood Hemopoietic Cell Receptor Expression is Associated with Early Life Atopic Risk and Lung Function.
  1298. Microfluidics-based Single-Cell Protrusion Analysis for Rapid Screening Drugs Targeting Subcellular Mitochondrial Trafficking in Cancer Progression.
  1299. Publisher Correction: The glycogen synthase kinase MoGsk1, regulated by Mps1 MAP kinase, is required for fungal development and pathogenicity in Magnaporthe oryzae.
  1300. Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss.
  1301. High-Efficiency Flexible Perovskite Solar Cells Enabled by Ultrafast Room-Temperature Reactive Ion Etching Process.
  1302. Redox-Channeling Polydopamine-Ferrocene (PDA-Fc) Coating to Confer Context-Dependent and Photothermal Antimicrobial Activities.
  1303. Association of body mass index, cardiorespiratory fitness, and their correlates among female physiotherapy students in Nawabshah.
  1304. Clickable Galactose Analogs for Imaging Glycans in Developing Zebrafish.
  1305. Physiological and transcriptomic analyses of cadmium stress response in Dendrobium officinale seedling.
  1306. Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice.
  1307. Core-shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts.
  1308. Cystic lung disease in an adult non-smoker.
  1309. Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.
  1310. Dysbiosis in Parkinson's disease might be triggered by certain antibiotics.
  1311. Advent of New perioperative care for fluid management after cardiovascular surgery: A review of current evidence.
  1312. Tobacco manufacturer lobbying to undercut minimum price laws: an analysis of internal industry documents.
  1313. NADPH biosensor-based identification of an alcohol dehydrogenase variant with improved catalytic properties caused by a single charge reversal at the protein surface.
  1314. E35 ablates acute leukemia stem and progenitor cells in vitro and in vivo.
  1315. Integrated modelling to assess N pollution swapping in slurry amended soils.
  1316. Association between On-Treatment Haemoglobin A1c and All-Cause Mortality in Individuals with Type 2 Diabetes: Importance of Personalized Goals and Type of Anti-Hyperglycaemic Treatment.
  1317. Physical activity and mortality: what is the dose response and how big is the effect?
  1318. Natural drivers of multidecadal Arctic sea ice variability over the last millennium.
  1319. The SAMPL6 challenge on predicting octanol-water partition coefficients from EC-RISM theory.
  1320. Optimization of FLIM imaging, fitting and analysis for auto-fluorescent NAD(P)H and FAD in cells and tissues.
  1321. Scenarios of Genes-to-Terpenoids Network Led to the Identification of a Novel α/β-Farnesene/β-Ocimene Synthase in Camellia sinensis.
  1322. [DRUG-INDUCED INTERSTITIAL LUNG DISEASE DURING COMBINED ANDROGEN BLOCKADE WITH BICALUTAMIDE AND LEUPRORELIN ACETATE FOR PROSTATE CANCER].
  1323. Exercise in neuromuscular disorders: a promising intervention.
  1324. Live cell single molecule tracking and localization microscopy of bioorthogonally labeled plasma membrane proteins.
  1325. Axial alignment of carbon nanotubes on fibers to enable highly conductive fabrics for electromagnetic interference shielding.
  1326. Orchid conservation and research: An analysis of gaps and priorities for globally Red Listed species.
  1327. Extraction of Nonlinear Synergies for Proportional and Simultaneous Estimation of Finger Kinematics.
  1328. Targeting selective autophagy by AUTAC degraders.
  1329. Radiotherapy to the Primary Tumour for Patients with Metastatic Prostate Cancer: Practice-Changing Results from STAMPEDE.
  1330. [Anaesthesia in Electrochemotherapy].
  1331. [6. Handling of Personal Information].
  1332. Assessment and Management of Endocarditis Among People Who Inject Drugs in the General Hospital Setting.
  1333. Benzenesulfonamide Derivatives as Calcium/Calmodulin-Dependent Protein Kinase Inhibitors and Antiviral Agents Against Dengue and Zika Virus Infections.
  1334. Pharmacokinetic and pharmacodynamic considerations in developing a response to the opioid epidemic.
  1335. Health-related quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndrome: an Australian cross-sectional study.
  1336. Commentary: Age is just an element of the quality of life puzzle following aortic valve replacement.
  1337. Profiling Cell Type Abundance and Expression in Bulk Tissues with CIBERSORTx.
  1338. Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure.
  1339. Monoacylglycerol lipase alpha inhibition alters prefrontal cortex excitability and blunts the consequences of traumatic stress in rat.
  1340. Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways.
  1341. Physiological and metabolic responses of a novel Dunaliella salina strain to Myo-inositol.
  1342. Correlation between Mean Platelet Volume and Glycosylated Haemoglobin in Patients with Type 2 Diabetes Mellitus.
  1343. Effect of cereal soaking and carbohydrase supplementation on growth, nutrient digestibility and intestinal microbiota in liquid-fed grow-finishing pigs.
  1344. Evolution of cellular stress response mechanisms.
  1345. Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies.
  1346. Reporter gene imaging and its role in imaging-based drug development.
  1347. The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms.
  1348. A new analytical workflow using HPLC with drift-tube ion-mobility quadrupole time-of-flight/mass spectrometry for the detection of drug-related metabolites in plants.
  1349. The role of α-cells in islet function and glucose homeostasis in health and type 2 diabetes.
  1350. A Study of Metabolic Associations with Psoriasis.
  1351. Lung Volume Reduction Surgery: Re-interpreted With Longitudinal Data Analyses Methodology (Commentary).
  1352. Diabetic neuropathy: what does the future hold?
  1353. Clinical research informatics: a growing subspecialization of biomedical informatics.
  1354. A Study of Correlation between Total Serum Adiponectin and Risk of Peripheral Vascular Disease in patients of Type 2 Diabetes Mellitus.
  1355. Publisher Correction: A reference collection of patient-derived cell line and xenograft models of proneural, classical and mesenchymal glioblastoma.
  1356. Salicylic Acid Targets Protein Phosphatase 2A to Attenuate Growth in Plants.
  1357. Deep Learning Approach for Generating MRA Images From 3D Quantitative Synthetic MRI Without Additional Scans.
  1358. A flexible 3-dimensional microelectrode array for in vitro brain models.
  1359. Pericardial diseases in patients with cancer: contemporary prevalence, management and outcomes.
  1360. Linking Small-Scale Flight Manoeuvers and Density Profiles to the Vertical Movement of Insects in the Nocturnal Stable Boundary Layer.
  1361. Crosstalk between ROS-dependent apoptotic and autophagic signaling pathways in Zn(II) phthalocyanine photodynamic therapy of melanoma.
  1362. Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz.
  1363. Glucocorticoids are active players and therapeutic targets in atherosclerotic cardiovascular disease.
  1364. Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.
  1365. Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces.
  1366. Disease progression model of 4T1 metastatic breast cancer.
  1367. Retraction notice to "Trends in bromide wet deposition concentrations in the contiguous United States, 2001-2016" [Environ. Pollut. 233 (2018) 168-179].
  1368. Synthetic Pesticides and Health in Vulnerable Populations: Agricultural Workers.
  1369. INCREASED SYSTEMIC HEPARANASE IN RETINAL VEIN OCCLUSION IS ASSOCIATED WITH ACTIVATION OF INFLAMMATION AND THROMBOPHILIA.
  1370. Real-time 4D-MRI-based internal target volume definition for moving lung tumors.
  1371. Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload.
  1372. Genome-scale CRISPR screening for potential targets of ginsenoside compound K.
  1373. Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging.
  1374. Convergent extension in the amphibian, Xenopus laevis.
  1375. Characterisation of patients with acute myocardial infarction complicated by left ventricular thrombus.
  1376. Arogenate dehydratases can modulate the levels of phenylacetic acid in Arabidopsis.
  1377. Use of rapid diagnostics to manage pediatric bloodstream infections? You bet your ASP!
  1378. USE OF A CONTINUOUS GLUCOSE MONITOR FOR PREOPERATIVE MONITORING AND TREATMENT OF HYPOGLYCEMIA IN A CASE OF PANCREATIC NEUROENDOCRINE TUMOR.
  1379. Biphasic exocytosis of herpesvirus from hippocampal neurons and mechanistic implication to membrane fusion.
  1380. Good wolf! Wild canines play ball with people.
  1381. Machine learning with autophagy-related proteins for discriminating renal cell carcinoma subtypes.
  1382. Association between non-alcoholic fatty liver disease and coronary calcification depending on sex and obesity.
  1383. Epitope and Fc-mediated Crosslinking, but not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity.
  1384. A helitron-induced RabGDIα variant causes quantitative recessive resistance to maize rough dwarf disease.
  1385. Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling.
  1386. Correlation between equi-partition of aminoacyl-tRNA synthetases and amino-acid biosynthesis pathways.
  1387. JAK inhibition prevents bleomycin-induced fibrosis in mice and is effective in morphea patients.
  1388. Sepsis: Symptoms, Assessment, Diagnosis, and the Hour-1 Bundle in Patients With Cancer.
  1389. The Brain-Heart Connection in Sympathetically Triggered Inherited Arrhythmia Syndromes.
  1390. Three's company: A woman with rash, uterine mass and cystic lungs.
  1391. A design rule for two-dimensional van der Waals heterostructures with unconventional band alignments.
  1392. Grape seed proanthocyanidins suppressed macrophage foam cell formation by miRNA-9 via targeting ACAT1 in THP-1 cells.
  1393. Effects of the vat pasteurization process and refrigerated storage on the bovine milk metabolome.
  1394. Long noncoding RNA PVT1 acts as an oncogenic driver in human pan-cancer.
  1395. Vitamin D suppresses proangiogenic factors in patients with ulcerative colitis: A randomized double blind placebo controlled clinical trial.
  1396. Novel ADAM-17 inhibitor ZLDI-8 inhibits the metastasis of hepatocellular carcinoma by reversing epithelial-mesenchymal transition in vitro and in vivo.
  1397. High-performance Ag-modified Bi0.5Sb1.5Te3 films for the flexible thermoelectric generator.
  1398. PI3K inhibitors curtail MYC-dependent mutant p53 gain-of-function in head and neck squamous cell carcinoma.
  1399. Differential Abundance Analysis with Bayes Shrinkage Estimation of Variance (DASEV) for Zero-Inflated Proteomic and Metabolomic Data.
  1400. Proteomic Analysis of Beef Tenderloin and Flank Assessed Using an Isobaric Tag for Relative and Absolute Quantitation (iTRAQ).
  1401. Synthesis of Polyhedral Borane Cluster Fused Heterocycles via Transition Metal Catalyzed B-H Activation.
  1402. ERRATUM.
  1403. [Research progress on mechanism in adaptation of hemoglobin to plateau hypoxia].
  1404. Human papillomavirus infection maybe not associated with primary lung cancer in the Fujian population of China.
  1405. Hebbian-Type Primary Motor Cortex Stimulation: A Potential Treatment of Impaired Hand Function in Chronic Stroke Patients.
  1406. Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity but Develop Fewer Tumors Following Chronic Liver Injury.
  1407. Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis.
  1408. PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network.
  1409. Probabilistic Approach for Virtual Screening Based on Multiple Pharmacophores.
  1410. Myalgic Encephalomyelitis - Time to repent.
  1411. Sugar levels drop in yoghurts.
  1412. Plasmonic ternary hybrid photocatalyst based on polymeric g-C3N4 towards visible light hydrogen generation.
  1413. Crizotinib versus chemotherapy: a real-world cost-effectiveness study in China.
  1414. Hederagenin protects mice against ovariectomy-induced bone loss by inhibiting RANKL-induced osteoclastogenesis and bone resorption.
  1415. Biological Functions and Analytical Strategies of Sialic Acids in Tumor.
  1416. Skin pigmentation in a patient with vitamin B12 deficiency presented with subacute combined degeneration of spinal cord.
  1417. Thin-Layer Potentiometry for Creatinine Detection in Undiluted Human Urine using Ion-Exchange Membranes as Barriers for Charged Interferences.
  1418. Thiopeptide Defense by an Ant's Bacterial Symbiont.
  1419. Disrupted inhibition may give clues in understanding neurodevelopmental disorders.
  1420. A Study of Association of XBAI GLUT1 Gene Polymorphism in Patients of Type 2 Diabetes Mellitus with Diabetic Nephropathy.
  1421. Thermochemical formation of dioxins promoted by chromium chloride: In situ Cr- and Cl-XAFS analysis.
  1422. Proactive Rehabilitation for Chemotherapy-Induced Peripheral Neuropathy.
  1423. Metabolic Adaptations to Infections at the Organismal Level.
  1424. A PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD Lipid.
  1425. CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition.
  1426. Comparing Maximal Mean and Critical Speed and Metabolic Powers in Elite and Sub-Elite Soccer.
  1427. Predictors of distant metastasis in acinic cell carcinoma of the parotid gland.
  1428. Toll-like receptor 5 signaling ameliorates liver fibrosis by inducing interferon β-modulated interleukin-1 receptor antagonist in mice.
  1429. Reduced scale model qualification of 5L & 250 mL bioreactors using multivariant visualization & Bayesian inferential methods.
  1430. Pembrolizumab - emerging treatment of pulmonary sarcomatoid carcinoma: A case report.
  1431. Numerical analysis of apparent decitabine uptake in HCT116 cells: Incorporation of a bidirectional first-order kinetic parameter for ENT1 transport and Michaelis-Menten parameters for subsequent phosphorylation.
  1432. Preparation and characterization of copper and zinc adsorbed cetylpyridinium and N-lauroylsarcosinate intercalated montmorillonites and their antibacterial activity.
  1433. Non-targeted metabolomics analysis reveals dynamic changes of volatile and non-volatile metabolites during oolong tea manufacture.
  1434. Phenotypic variation in spatially structured microbial communities: ecological origins and consequences.
  1435. Cell-type-specific drug-inducible protein synthesis inhibition demonstrates that memory consolidation requires rapid neuronal translation.
  1436. A primer on model selection using the Akaike Information Criterion.
  1437. Understanding the role of active site residues in CotB2 catalysis using a cluster model.
  1438. Dynamic mapping of the corticospinal tract in open cordotomy and myelomeningocele surgery.
  1439. Plasma Apelin, Visfatin and Resistin Levels in Patients with First Episode Psychosis and Chronic Schizophrenia.
  1440. Circular RNA hsa_circRNA_002178 silencing retards breast cancer progression via microRNA-328-3p-mediated inhibition of COL1A1.
  1441. Dual Imaging Gold Nanoplatforms for Targeted Radiotheranostics.
  1442. Immunogenic cell death: A link between gut microbiota and anticancer effects.
  1443. C-type natriuretic peptide restores growth impairment under enzyme replacement in mice with mucopolysaccharidosis VII.
  1444. Mesothelioma: Hippo pathway as a target, lessons from COMMAND.
  1445. Routine Use of Cardiovascular Magnetic Resonance in the Work-Up of Patients With Ventricular Arrhythmias?
  1446. Is time elapsed between cannabis use and sleep start time associated with sleep continuity? An experience sampling method.
  1447. The Journal Impact Factor- Does it reflect the quality of a journal?
  1448. A link between mitochondrial gene expression and life stage morphologies in Trypanosoma cruzi.
  1449. In the literature: December 2019.
  1450. Phase separation provides a mechanism to reduce noise in cells.
  1451. Dual NDP52 Function in Persistent CSFV Infection.
  1452. Development of an in vitro system and model-based translational framework to assess haemolysis risk following intravenous abuse of medications containing polyethylene oxide.
  1453. Identification of a nomogram based on long non-coding RNA to improve prognosis prediction of esophageal squamous cell carcinoma.
  1454. Effect of rosiglitazone on myocardial injury in septic rats through NF-κB pathway.
  1455. Evaluation of cardiovascular risk related to a monoclonal antibody mediated increase in vascular endothelial growth factor in conscious normal rats.
  1456. Bariatric surgery-induced weight loss in patients with and without type 2 diabetes mellitus.
  1457. Transcriptional Programming of Human Mechanosensory Neuron Subtypes from Pluripotent Stem Cells.
  1458. Quantitative Interpretation of Hydration Dynamics Enabled the Fabrication of Zwitterionic Antifouling Surface.
  1459. A Special Amino-Acid Formula Tailored to Boosting Cell Respiration Prevents Mitochondrial Dysfunction and Oxidative Stress Caused by Doxorubicin in Mouse Cardiomyocytes.
  1460. Wild primates copy higher-ranked individuals in a social transmission experiment.
  1461. Inter-Individual Nectar Chemistry Changes of Field Scabious, Knautia arvensis.
  1462. US cancer centre leaders secretly worked for China, internal report finds.
  1463. Shining a spotlight on somatic mutations in ulcerative colitis.
  1464. Consciousness & Brain Functional Complexity in Propofol Anaesthesia.
  1465. Efficient Spin-Orbit Torque Switching with Non-Epitaxial Chalcogenide Heterostructures.
  1466. Short communication: Clostridial spore counts in vat milk of Alpine dairies-A status quo report.
  1467. Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model.
  1468. Diagnosis of inherited metabolic disorders by selective metabolite testing: three years' experience at a tertiary care center in Rawalpindi.
  1469. Psychosocial Aspects of Diabetes Technology Use: The Child and Family Perspective.
  1470. Silicosis: An ancient disease in need of a dose of modern medicine.
  1471. Patellofemoral contact pressure for medial patellofemoral ligament reconstruction using suture tape varies with the knee flexion angle: A biomechanical evaluation.
  1472. Fermented Morinda citrifolia (Noni) Alleviates DNCB-Induced Atopic Dermatitis in NC/Nga Mice through Modulating Immune Balance and Skin Barrier Function.
  1473. Dynamics of Auxilin 1 and GAK in clathrin-mediated traffic.
  1474. Yogurt as an Alternative Ingredient to Improve the Functional and Nutritional Properties of Gluten-Free Breads.
  1475. Post-traumatic stress disorder in a population of 2008 Wenchuan earthquake survivors with disabilities: the role of environmental barriers.
  1476. Photocatalytically Active Graphitic Carbon Nitride as an Effective and Safe 2D Material for In Vitro and In Vivo Photodynamic Therapy.
  1477. New Roles for the Heterochronic Transcription Factor LIN-29 in Cuticle Maintenance and Lipid Metabolism at the Larval-to-Adult Transition in Caenorhabditis elegans.
  1478. The effects of hydrodynamics on the three-dimensional downstream migratory movement of Atlantic salmon.
  1479. JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages.
  1480. Scientific and Regulatory Approach to Botanical Drug Development: A U.S. FDA Perspective.
  1481. The association of preoperative thyroid-stimulating hormone level and the risk of differentiated thyroid cancer in patients with thyroid nodules: A systematic review and meta-analysis.
  1482. Technical and nidus-specific factors associated with adequacy of intraprocedural biopsy samples preceding radiofrequency ablation of osteoid osteoma.
  1483. Endocrine disrupting chemicals associated with dry eye syndrome.
  1484. Lipid hijacking.
  1485. Intraoperative Correction of Liver Deformation Using Sparse Surface and Vascular Features via Linearized Iterative Boundary Reconstruction.
  1486. Optimization induced by stability and the role of limited control near a steady state.
  1487. Comparison of Lowenstein-Jensen medium and MGIT culture system for recovery of Mycobacterium tuberculosis from abscess samples.
  1488. What can seasonal models teach us about energy balance?
  1489. Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma.
  1490. Cross-talk between autophagy and apoptosis regulates testicular injury/recovery induced by cadmium via PI3K with mTOR-independent pathway.
  1491. Editorial Comment.
  1492. Performance of WO3-Incorporated Carbon Electrodes for Ambient Mesoscopic Perovskite Solar Cells.
  1493. The Importance of Fatty Acids as Nutrients during Post-Exercise Recovery.
  1494. pH-sensitive MOF integrated with glucose oxidase for glucose-responsive insulin delivery.
  1495. CRISPR/Cas9-mediated precise genome modification by a long ssDNA template in zebrafish.
  1496. Time-course transcriptomic alterations reflect the pathophysiology of polyhexamethylene guanidine phosphate-induced lung injury in rats.
  1497. Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase-independent cell death pathway: Central role of apoptosis-inducing factor.
  1498. Closed Loop.
  1499. Symplasmic Isolation Marks Cell Fate Changes During Somatic Embryogenesis.
  1500. Differential roles of exogenous protein disulfide isomerase A3 on proliferating cell and neuroblast numbers in the normal and ischemic gerbils.
  1501. Recent progress in perovskite solar cells: the perovskite layer.
  1502. Global discovery the PstP interactions using Mtb proteome microarray and revealing novel connections with EthR.
  1503. Treatment of Acute Exacerbation of IPF - A Call to Arms.
  1504. Comprehensive transcriptome analysis provides insights into metabolic and gene regulatory networks in trichomes of Nicotiana tabacum.
  1505. Preparation, characterization, and application of magnetic activated carbon for treatment of biologically treated papermaking wastewater.
  1506. Sulfate Radical Scavenging by Mineral Surfaces in Persulfate-Driven Oxidation Systems: Reaction Rate Constants and Implications.
  1507. Bridging Behavioral Science with Cancer Prevention and Control: Contributions of an NCI Working Group (2009-2019).
  1508. Single-molecule resonance Raman effect in a plasmonic nanocavity.
  1509. High Protein Diet Accelerates Diabetes and Kidney Disease in the BTBRob/ob Mouse.
  1510. Stabilization of Gaze during Early Xenopus Development by Swimming-Related Utricular Signals.
  1511. Microglial depletion and repopulation in brain slice culture normalizes sensitized proinflammatory signaling.
  1512. Upper bound on angular momentum transport in Taylor-Couette flow.
  1513. Correlation of Serum Prolactin Level with Child Pugh Scoring System in Cirrhosis of Liver.
  1514. Different carbon sources result in differential activation of sigma B and stress resistance in Listeria monocytogenes.
  1515. Stereoselective synthesis of trifluoromethyl-substituted 2H-furan-amines from enaminones.
  1516. Interaction of nitrofurantoin with lipid langmuir monolayers as cellular membrane models distinguished with tensiometry and infrared spectroscopy.
  1517. Universal health care: Can Indian ophthalmologist community set an example?
  1518. Effects of hair dye ingredients on the oxidative stress response: modulation of the mRNA expressions of NRF2, HO-1 and FOS in HaCaT keratinocytes.
  1519. Study of Right Ventricular Dysfunction in Type 2 Diabetes Mellitus Patients Attending Medicine OPD in Dr. Bram Hospital, Raipur.
  1520. Precision medicine in sodium channelopathies - Moving beyond seizure control towards disease modification.
  1521. Signalling architectures can prevent cancer evolution.
  1522. Association of serum bicarbonate level in predicting short term mortality in patients presenting with shock.
  1523. AI outperforms radiologists in mammographic screening.
  1524. Structural equilibrium underlying ligand-dependent activation of β2-adrenoreceptor.
  1525. Manganese-mediated Growth of ZnS Shell on KMnF3:Yb,Er Cores towards Enhanced Up/downconversion Luminescence.
  1526. Effects of a foot strengthening program on foot muscle morphology and running mechanics: A proof-of-concept, single-blind randomized controlled trial.
  1527. Suppression of Leaf Blade Development by BLADE-ON-PETIOLE Orthologs Is a Common Strategy for Underground Rhizome Growth.
  1528. Anal cancer prevention: Solving the puzzle piece by piece.
  1529. The mechanism of propofol in cancer development: An updated review.
  1530. Commentary: Mitochondria to the rescue?
  1531. Duration of one-lung ventilation as a risk factor for postoperative pulmonary complications after McKeown esophagectomy.
  1532. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.
  1533. Survey of Radon Testing and Mitigation by Wisconsin Residents, Landlords, and School Districts.
  1534. Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.
  1535. Mitochondrial Rieske iron-sulfur protein in pulmonary artery smooth muscle: A key primary signaling molecule in pulmonary hypertension.
  1536. A Study of Serum Free Testosterone Level in Type 2 Diabetes Mellitus Male Patients at Tertiary Care Hospital: A Case Control Study.
  1537. Maximum Phonation Time in People with Obesity Not Submitted or Submitted to Bariatric Surgery.
  1538. Methodological approach to microscopic colitis diagnosis: reply.
  1539. Therapeutic effects of forced exercise cycling in individuals with Parkinson's disease.
  1540. Spin-flip methods in quantum chemistry.
  1541. Characterization of E 472 food emulsifiers by high-performance thin-layer chromatography with fluorescence detection and mass spectrometry.
  1542. Nematicidal activity of 5-iodoindole against root-knot nematodes.
  1543. Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B.
  1544. Long-term outcomes of Sleeping Beauty generated CD19specific CAR T-cell therapy for relapsed-refractory B-cell lymphomas.
  1545. An iconic structure in London moonlights as a scientific tool.
  1546. Marrow outside marrow: imaging of extramedullary haematopoiesis.
  1547. Quantifying the effects of absorbed dose from radioembolisation on healthy liver function with [99mTc]TcMebrofenin.
  1548. TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice.
  1549. Impact of Short-Term Continuous and Interval Exercise Training on Endothelial Function and Glucose Metabolism in Prediabetes.
  1550. RNA-DNA hybrid nanoshapes that self-assemble dependent on ligand binding.
  1551. Volume of tidal gas movement in the nonventilated lung during one-lung ventilation and its relevant factors.
  1552. Efficient identification of novel anti-glioma lead compounds by machine learning models.
  1553. Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.
  1554. Perfluoroalkyl chemicals in neurological health and disease: Human concerns and animal models.
  1555. Synthesis of Novel Structural Hybrids between Aza-Heterocycles and Azelaic Acid Moiety with a Specific Activity on Osteosarcoma Cells.
  1556. Exendin-4 enhances the sensitivity of prostate cancer to enzalutamide by targeting Akt activation.
  1557. Cultural specialization and genetic diversity: killer whales and beyond.
  1558. α-Mangostin attenuates stemness and enhances cisplatin-induced cell death in cervical cancer stem-like cells through induction of mitochondrial-mediated apoptosis.
  1559. Posterior primary progressive prosopagnosia: Structural and molecular imaging.
  1560. Phytohormones-induced senescence efficiently promotes the transport of cadmium from roots into shoots of plants: A novel strategy for strengthening of phytoremediation.
  1561. Dracorhodin perchlorate inhibits osteoclastogenesis through repressing RANKL-stimulated NFATc1 activity.
  1562. Structural insights into NS5B protein of novel equine hepaciviruses and pegiviruses complexed with polymerase inhibitors.
  1563. Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma.
  1564. In This Issue of the Journal.
  1565. Fluorescence Spectroscopy Analysis of the Bacteria-Mineral Interface: Adsorption of lipopolysaccharides to Silica and Alumina.
  1566. Chemotyping and identification of protected Dalbergiatimber using gas chromatography quadrupole time of flight mass spectrometry.
  1567. Paris taught me how to do what is necessary to combat climate change.
  1568. Data on the recovery of glycinergic neurons after spinal cord injury in lampreys.
  1569. How hummingbirds garb themselves in rainbow hues.
  1570. FGF13 promotes metastasis of triple-negative breast cancer.
  1571. A Digital Signal Processor Based Acoustic Sensor for Outdoor Noise Monitoring in Smart Cities.
  1572. Complex pathophysiology of non-ketotic hyperglycemic chorea-ballism with atypical findings on brain magnetic resonance imaging.
  1573. Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells.
  1574. Perioperative Outcomes of Spinal Cord Stimulator Placement in Patients with Complex Regional Pain Syndrome (CRPS) Compared to Patients Without CRPS.
  1575. Sarah Joyce O'Malley, Irish anaesthetist (1896-1959).
  1576. Squamous cell carcinoma (SCC) of the Pyriform sinus with multiple metachronous brain metastases, a case report.
  1577. Exploring the impact of lymphoedema on individuals and if lymphatic venous anastomosis surgery effects perceptions on quality of life: A qualitative study.
  1578. Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics.
  1579. Trans-Mucosal Efficacy of Non-Thermal Plasma Treatment on Cervical Cancer Tissue and Human Cervix Uteri by a Next Generation Electrosurgical Argon Plasma Device.
  1580. Effects of jugular infused methionine, lysine, and histidine as a group or leucine and isoleucine as a group on production and metabolism in lactating dairy cows.
  1581. GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress.
  1582. Smoothed empirical likelihood inference for ROC curve in the presence of missing biomarker values.
  1583. Poly(peptide): Synthesis, Structure, and Function of Peptide-Polymer Amphiphiles and Protein-like Polymers.
  1584. Cloning and tissue expression of cytochrome P450 2S1, 4V2, 7A1, 7B1, 8B1, 24A1, 26A1, 26C1, 27A1, 39A1, and 51A1 in marmosets.
  1585. Correction to: Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC).
  1586. Radiation induced Wallerian degeneration of corticospinal tract in a case of brain tumour.
  1587. Genome based safety assessment for Bacillus coagulans strain LBSC (DSM 17654) for probiotic application.
  1588. Expression of Oatp2 in the Brain and Liver of Alzheimer Disease Mouse Model.
  1589. Emergence of chirality and structural complexity in single crystals at the molecular and morphological levels.
  1590. Association Between the Microsatellite Instability Status and the Efficacy of Postoperative Adjuvant Chemoradiotherapy in Patients With Gastric Cancer.
  1591. Use of eye tracking in girls with Rett syndrome.
  1592. Urban Egyptian Women Aged 19-30 Years Display Nutrition Transition-Like Dietary Patterns, with High Energy and Sodium Intakes, and Insufficient Iron, Vitamin D, and Folate Intakes.
  1593. Social Work in Action: How the Hawai'i CARES Program Aims to Strengthen Addiction Treatment Through a Social Work Lens.
  1594. Identification and Characterization of Non-Saccharomyces Species Isolated from Port Wine Spontaneous Fermentations.
  1595. Interpolation and extrapolation of global potential energy surfaces for polyatomic systems by Gaussian processes with composite kernels.
  1596. Rolipram treatment during consolidation ameliorates long-term object location memory in aged male mice.
  1597. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma.
  1598. IFN-γ/mTORC1 decreased Rab11 in Schwann cells of diabetic peripheral neuropathy, inhibiting cell proliferation via GLUT1 downregulation.
  1599. Dual-functional conjugates improving cancer immunochemotherapy by inhibiting tubulin polymerization and indoleamine-2,3-dioxygenase.
  1600. Thermotolerance and plasticity of camel somatic cells exposed to acute and chronic heat stress.
  1601. Early tranexamic acid in traumatic brain injury: Evidence for an effective therapy.
  1602. Compartment and hub definitions tune metabolic networks for metabolomic interpretations.
  1603. Automated Insulin Delivery in Children with Type 1 Diabetes.
  1604. Treatment of Human Lens Epithelium with High Levels of Nanoceria Leads to Reactive Oxygen Species Mediated Apoptosis.
  1605. Ensembles of Metastable States Govern Heterogeneous Catalysis on Dynamic Interfaces.
  1606. Unique conference to focus on FtP.
  1607. Artificial intelligence and the cardiologist: what you need to know for 2020.
  1608. Three differentially expressed miRNAs as potential biomarkers for lung adenocarcinoma prognosis.
  1609. Development and implementation strategies of a nurse-led symptom self-management program in outpatient cancer centres: The Symptom Navi© Programme.
  1610. OcUGT1-Catalyzing Glycodiversification of Steroids through Glucosylation and Transglucosylation Actions.
  1611. Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array.
  1612. T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumor immunity.
  1613. tec-1 kinase negatively regulates regenerative neurogenesis in planarians.
  1614. High mobility group AT-hook 2 and c-MYC as potential prognostic factors in pancreatic ductal adenocarcinoma.
  1615. Astaxanthin supplementation impacts the cellular HSP expression profile during passive heating.
  1616. Proposal of a New Treatment-Oriented Classification System for Spinal Deformity in Ankylosing Spondylitis.
  1617. Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat.
  1618. Epistaxis and atorvastatin: is there an association and are clinicians aware? A retrospective audit of 100 patients.
  1619. Median Nerve Injury In Children Aged 2-11 Years Presenting With Closed Supracondylar Fracture Of Humerus.
  1620. Leishmania Dual Specificity Tyrosine Regulated Kinase 1 (DYRK1) is required for sustaining Leishmania stationary phase phenotype.
  1621. The crucial role of metabolic regulation in differential hepatotoxicity induced by furanoids in Dioscorea bulbifera.
  1622. Corrigendum re "Periurethral Injection of Autologous Adipose-Derived Stem Cells with Controlled-Release Nerve Growth Factor for the Treatment of Stress Urinary Incontinence in a Rat Model" [Eur Urol 2011;59:155-63].
  1623. Susana Godinho: Placing cell biology at the center of cancer research.
  1624. Differential role of LXRα and LXRβ in the regulation of UDP-glucuronosyltransferase 1A1 in humanized UGT1 mice.
  1625. Eff ectiveness of Teneligliptin as an Add-on in T2DM Patients not Controlled on Metformin and Glimepiride.
  1626. AN INCIDENTAL COLLISION TUMOR OF THE SELLA TURCICA.
  1627. Does the video head impulse test replace caloric testing?
  1628. The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans.
  1629. Noise reduction.
  1630. Indirect effect of parental depression on school victimization through adolescent depression.
  1631. Pexophagy: A Model for Selective Autophagy.
  1632. α-Lipoic acid prevents the ionizing radiation-induced epithelial-mesenchymal transition and enhances the radiosensitivity in breast cancer cells.
  1633. Theobromine alleviates diet-induced obesity in mice via phosphodiesterase-4 inhibition.
  1634. Joint measurements of NDVI and crop production data-set related to combination of management zones delineation and nitrogen fertilisation levels.
  1635. Teratological cases of the antennae in the family Aradidae (Hemiptera: Heteroptera).
  1636. Construction of yeast producing patchoulol by global metabolic engineering strategy.
  1637. Associations of Prenatal and Childhood Antibiotic Exposure With Obesity at Age 4 Years.
  1638. Gene Therapy Untangles the Problem of Chronic Traumatic Encephalopathy.
  1639. Attributes, Performance, and Gaps in Current & Emerging Breast Cancer Screening Technologies.
  1640. Effects of propofol and sevoflurane on blood glucose, hemodynamics, and inflammatory factors of patients with type 2 diabetes mellitus and gastric cancer.
  1641. Cultural Humility in the Practice of Applied Behavior Analysis.
  1642. Topological Magnetic Phase in the Candidate Weyl Semimetal CeAlGe.
  1643. [2019 scientific breakthroughs in ambulatory general internal medicine].
  1644. A New Paradigm in the Treatment of Advanced Periocular Basal Cell Carcinoma?
  1645. Cuscuta, the Merchant of Proteins.
  1646. Nociceptors in antimicrobial defense.
  1647. Rigidity-Controlled Crossover: From Spinodal to Critical Failure.
  1648. Hydroxyethyl Starch for Fluid Replacement Therapy in High-Risk Surgical Patients: Context and Caution.
  1649. Self-Organizing 3D Human Trunk Neuromuscular Organoids.
  1650. Lethal methemoglobinemia in the invasive brown treesnake after acetaminophen ingestion.
  1651. Cell Type-Specific Transcriptomics in the Plant Embryo Using an Adapted INTACT Protocol.
  1652. The Pathway Less Traveled: Engineering Biosynthesis of Nonstandard Functional Groups.
  1653. MXene Titanium Carbide-based Biosensor: Strong Dependence of Exfoliation Method on Performance.
  1654. Soluble (pro)renin receptor increased by hypoxia maintains oxidative metabolism in trophoblasts.
  1655. Mitochondrial DNA Haplotypes Influence Energy Metabolism across Chicken Transmitochondrial Cybrids.
  1656. Role of primary retroperitoneal lymph node dissection in stage I and low-volume metastatic germ cell tumors.
  1657. The Relationship between Clinical and Quantitative Measures of Pain Sensitization in Knee Osteoarthritis.
  1658. Recruitment and retention.
  1659. Differential calcium channel-mediated dopaminergic modulation in the subthalamonigral synapse.
  1660. Crassulacean acid metabolism.
  1661. Competency-Based Assessment of Interventional Cardiology Fellows' Abilities in Intracoronary Physiology and Imaging.
  1662. NPC1b as a novel target in controlling the cotton bollworm, Helicoverpa armigera.
  1663. p-p Heterojunction Sensors of p-Cu3Mo2O9 Micro/Nanorods Vertically Grown on p-CuO Layers for Room Temperature Ultrasensitive and Fast-Recoverable Detection of NO2.
  1664. Uptake of atenolol, carbamazepine and triclosan by crops irrigated with reclaimed water in a Mediterranean scenario.
  1665. Addressing mental health in Aboriginal young people in Australia.
  1666. Chemerin-9-induced contraction was enhanced through the upregulation of smooth muscle chemokine-like receptor 1 in isolated pulmonary artery of pulmonary arterial hypertensive rats.
  1667. Disparities in exposure to surrounding greenness related to proportion of the population that were immigrants to the United States.
  1668. Effect of Trapped Solvent on the Interphase between PS-b-PMMA Thin Film and P(S-r-MMA) Brush Layer.
  1669. Phenols fragment of Veronica ciliata Fisch. Ameliorate free radical-induced nonalcoholic fatty liver disease by mediating PI3K/Akt signaling pathway.
  1670. Leaf hydraulic conductance is linked to leaf symmetry in bifacial, amphistomatic leaves of Sunflower.
  1671. AMH as a predictor of the final menstrual period.
  1672. Human Papillomavirus and carcinogenesis: Novel mechanisms of cell communication involving extracellular vesicles.
  1673. Treatment of oligometastatic lung cancer with brain metastases using stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT).
  1674. Smart motors and cargo steering drive kinesin-mediated selective transport.
  1675. Identifying Missing Biosynthesis Enzymes of Plant Natural Products.
  1676. The importance of transporters and cell polarization for the evaluation of human stem cell-derived hepatic cells.
  1677. Risk Factors Associated with Outcomes of Recombinant Tissue Plasminogen Activator Therapy in Patients with Acute Ischemic Stroke.
  1678. Follicular Regulatory T Cells Can Access the Germinal Center Independently of CXCR5.
  1679. Propensity score matched mortality comparisons of peritoneal and in-centre haemodialysis: systematic review and meta-analysis.
  1680. Gross and Histopathological Findings in the First Reported Vaping-Induced Lung Injury Death in the United States.
  1681. Management of Adolescent Substance Use Disorders, With an Emphasis on Cannabis Use Disorders.
  1682. shRNA-mediated inhibition of PhosphoGlycerate Kinase 1 (PGK1) enhances cytotoxicity of intraperitoneal chemotherapy in peritoneal metastasis of gastric origin.
  1683. 2019 List of Reviewers.
  1684. BRCA1-BRCA2 mutation analysis results in 910 individuals: Mutation distribution and 8 novel mutations.
  1685. Maxillary mesenchymal chondrosarcoma leading to a diagnosis of Li-Fraumeni syndrome.
  1686. Stingless bee honey reduces anxiety and improves memory of the metabolic disease-induced rats.
  1687. The diagnostic use of magnetic resonance imaging for acute abdominal and pelvic pain in pregnancy.
  1688. Synthetic Rewiring of Plant CO2 Sequestration Galvanizes Plant Biomass Production.
  1689. Mechanical forces induce an asthma gene signature in healthy airway epithelial cells.
  1690. Single cell analysis of human lung development: knowing what mesenchymal cells are and what they may be.
  1691. LIMITATIONS OF BASAL CORTISOL IN THE DIAGNOSIS OF CUSHING SYNDROME.
  1692. Author Correction: The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation.
  1693. In silico-based approach to investigate the ability of PEGylated rapamycin to inhibit Galectin-3.
  1694. Regorafenib and ginsenoside combination therapy: inhibition of HepG2 cell growth through modulating survivin and caspase-3 gene expression.
  1695. THE UTILITY OF ANTHOPOMETRIC INDICATORS TO IDENTIFY CARDIOVASCULAR RISK FACTORS IN VIETNAMESE CHILDREN.
  1696. Psoralea corylifolia L. Seed Extract Attenuates Methylglyoxal-Induced Insulin Resistance by Inhibition of Advanced Glycation End Product Formation.
  1697. Tailored communication for older patients with cancer: Using cluster analysis to identify patient profiles based on information needs.
  1698. Implications of the Hemoglobin Glycation Index on the Diagnosis of Prediabetes and Diabetes.
  1699. Dietary addition of zinc-methionine influenced eggshell quality by affecting calcium deposition in eggshell formation of laying hens - CORRIGENDUM.
  1700. Polymorphisms in IL-1A are associated with endometrial cancer susceptibility among Chinese Han population: A case-control study.
  1701. Between gang talk and prohibition: The transfer of blame for County Lines.
  1702. Insulin resistance in transfusion dependent adult beta thalassemia major subjects with metabolic syndrome.
  1703. Tumor-infiltrating M2 macrophage in pretreatment biopsy sample predicts response to chemotherapy and survival in esophageal cancer.
  1704. Capillary electrophoresis-based immuno- and aptamer assays: A review.
  1705. Haemostatic Nanoparticles-Derived Bioactivity of from Selaginella tamariscina Carbonisata.
  1706. Advances in Therapy for Relapsed or Refractory Hodgkin Lymphoma.
  1707. Bicentennial of the discovery of selenium commemorated at the Museum of Natural History in Athens.
  1708. Increased activity of the sterol branch of the mevalonate pathway elevates glycosylation of secretory proteins and improves antifungal properties of Trichoderma atroviride.
  1709. A numerical modeling strategy for passive electro-acoustic transducers.
  1710. Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors.
  1711. Transcatheter Aortic Valve Replacement for Failed Surgical Aortic Bioprosthetic Valves: Is the Panacea Approaching?
  1712. Somatostatin analogues and the risk of post-operative pancreatic fistulas after pancreatic resection - A systematic review & meta-analysis.
  1713. This Month in AJP.
  1714. Interconnection and damping assignment control based on modified actor-critic algorithm with wavelet function approximation.
  1715. GC-MS based metabolomic profiling of lung tissue couple with network pharmacology revealed the possible protection mechanism of Pudilan Xiaoyan Oral Liquid in LPS-induced lung injury of mice.
  1716. Letter to the Editor: One Perspective on Diversity in ABA.
  1717. White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer's disease rat model.
  1718. A Comparison of Functional Networks Derived From Representational Similarity, Functional Connectivity, and Univariate Analyses.
  1719. The application of helix fusion methods in structural biology.
  1720. Biomarkers of exposure, effect, and susceptibility in occupational exposure to traffic-related air pollution: A review.
  1721. Real-time Malaria Parasite Screening in Thick Blood Smears for Low-Resource Setting.
  1722. Optimizing b-values for accurate depiction of pancreatic cancer with tumor-associated pancreatitis on computed diffusion-weighted imaging.
  1723. CuBr2/EDTA-mediated ATRP for ultrasensitive fluorescence detection of lung cancer DNA.
  1724. Patient-centered outreach treatment toward micro-elimination of hepatitis C virus infection in hemodialysis patients.
  1725. Hypertensive Mediated Organ Damage and Hypertension Management. How to Assess Beneficial Effects of Antihypertensive Treatments?
  1726. Transcatheter Aortic Valve Replacement Like a PRO: Years in the Making.
  1727. A concept analysis of psychological distress in parents related to diabetes management in children and adolescents.
  1728. Human Breathomics Database.
  1729. Accelerated charge transfer in water-layered peptide assemblies.
  1730. Brazilian consensus on the diagnosis and treatment of extremities soft tissue sarcomas.
  1731. Salivary human beta-defensins and cathelicidin levels in relation to periodontitis and type 2 diabetes mellitus.
  1732. Exploring transformative learning when developing medical students' non-technical skills.
  1733. Selinexor for the treatment of multiple myeloma.
  1734. MicroRNA-574-5p in gastric cancer cells promotes angiogenesis by targeting protein tyrosine phosphatase non-receptor type 3 (PTPN3).
  1735. Amidase, a novel detoxifying enzyme, is involved in cyflumetofen resistance in Tetranychus cinnabarinus (Boisduval).
  1736. The Prevalence of Vitamin B12 Defi ciency in Patients with Hypothyroidism.
  1737. Protein homodimer sequestration with small molecules: focus on PD-L1.
  1738. An atypical case of early-onset trichotillomania - Management implications.
  1739. Activity of human serum antibodies in an influenza virus hemagglutinin stalk-based ADCC reporter assay correlates with activity in a CD107a degranulation assay.
  1740. Developmental changes in transporter and receptor protein expression levels at the rat blood-brain barrier based on quantitative targeted absolute proteomics.
  1741. Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions.
  1742. Metabonomic-Transcriptome Integration Analysis on Osteoarthritis and Rheumatoid Arthritis.
  1743. Psychological and behavioral determinants of weight loss: A need for research to determine causation.
  1744. Does Ranolazine Reduce Pain Perception With Cerebral Effect?
  1745. Teaching Children With Autism Spectrum Disorder to Report Past Behavior With the Use of a Speech-Generating Device.
  1746. Intensification of polyphenols extraction from orange peels using infrared as a novel and energy saving pretreatment.
  1747. Are Serum Ion Levels Elevated in Pediatric Patients with Growing Spine Implants vs. Controls?
  1748. Neisseria meningitidis induces pathology-associated cellular and molecular changes in trigeminal Schwann cells.
  1749. Binding of myeloperoxidase to the extracellular matrix of smooth muscle cells and subsequent matrix modification.
  1750. Metabolomics analysis of Camellia sinensis with respect to harvesting time.
  1751. 1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages.
  1752. Involvement of GPR4 in increased growth hormone and prolactin expressions by extracellular acidification in MtT/S cells.
  1. Int J Mol Sci. 2020 Jan 17. pii: E619. [Epub ahead of print]21(2):
    Metformin Mitigates Nickel-Elicited Angiopoietin-Like Protein 4 Expression via HIF-1α for Lung Tumorigenesis.
    Kang YT, Hsu WC, Ou CC, Tai HC, Hsu HT, Yeh KT, Ko JL.
      Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.
    Keywords:  Nickel; angiopoietin-like protein 4; chemoprevention; hypoxia-inducible factor 1 alpha; metformin
    DOI:  https://doi.org/10.3390/ijms21020619
  2. Transl Res. 2019 Dec 27. pii: S1931-5244(19)30259-2. [Epub ahead of print]
    Preclinical safety and antitumor activity of the arginine-degrading therapeutic enzyme pegzilarginase, a PEGylated, cobalt-substituted recombinant human arginase 1.
    Agnello G, Alters SE, Rowlinson SW.
      Metabolic remodeling contributes to the development and progression of some cancers and exposes them to vulnerabilities, including specific nutrient dependencies that can be targeted therapeutically. Arginine is a semiessential amino acid, and several cancers are unable to endogenously synthesize sufficient levels of arginine for survival and proliferation, most commonly due to reduced expression of argininosuccinate synthase (ASS1). Such cancers are dependent on arginine and they can be targeted via enzyme-mediated depletion of systemic arginine. We report the preclinical safety, antitumor efficacy, and immune-potentiating effects of pegzilarginase, a highly potent human arginine-degrading enzyme. Toxicology studies showed that pegzilarginase-mediated arginine depletion is well tolerated at therapeutic levels that elicit an antitumor growth effect. To determine which tumor types are best suited for clinical development, we profiled clinical tumor samples for ASS1 expression, which correlated with pegzilarginase sensitivity in vivo in patient-derived xenograft (PDx) models. Among the histologies tested, malignant melanoma, small cell lung cancer and Merkel cell carcinoma had the highest prevalence of low ASS1 expression, the highest proportion of PDx models responding to pegzilarginase, and the strongest correlation between low or no ASS1 expression and sensitivity to pegzilarginase. In an immune-competent syngeneic mouse model, pegzilarginase slowed tumor growth and promoted the recruitment of CD8+ tumor infiltrating lymphocytes. This is consistent with the known autophagy-inducing effects of arginine depletion, and the link between autophagy and major histocompatibility complex antigen presentation to T cells. Our work supports the ongoing clinical investigations of pegzilarginase in solid tumors and clinical combination of pegzilarginase with immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1016/j.trsl.2019.12.005
  3. Cancer Lett. 2020 Jan 16. pii: S0304-3835(20)30018-5. [Epub ahead of print]
    Flumethasone enhances the efficacy of chemotherapeutic drugs in lung cancer by inhibiting Nrf2 signaling pathway.
    Zhou Y, Zhou Y, Wang K, Li T, Yang M, Wang R, Chen Y, Cao M, Hu R.
      Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, participates in protecting cells from electrophilic or oxidative stresses through regulating expression of cytoprotective and antioxidant genes. It has become one of the emerging targets for cancer chemosensitization, and small molecule inhibitors of Nrf2 can enhance the efficacy of chemotherapeutic drugs. Here, we found that flumethasone, a glucocorticoid, inhibited Nrf2 signaling in A549 and H460 cells by promoting Nrf2 protein degradation. Moreover, flumethasone significantly increased the sensitivity of A549 and H460 cells to chemotherapeutic drugs including cisplatin, doxorubicin and 5-FU. In mice bearing A549-shControl cells-derived xenografts, the size and weight of xenografts in the flumethasone and cisplatin combination group had a significant reduction compared with those in the cisplatin group, while in mice bearing A549-shNrf2 cells-derived xenografts, the size and weight of the xenografts in the combination group had no significant difference compared with those in the cisplatin group, demonstrating that chemosensitization effect of flumethasone is Nrf2-dependent. This work suggests that flumethasone can potentially be used as an adjuvant sensitizer to enhance the efficacy of chemotherapeutic drugs in lung cancer.
    Keywords:  Flumethasone; Nrf2; chemosensitization; lung cancer
    DOI:  https://doi.org/10.1016/j.canlet.2020.01.010
  4. Proc Natl Acad Sci U S A. 2020 Jan 22. pii: 201921404. [Epub ahead of print]
    Requirement for epithelial p38α in KRAS-driven lung tumor progression.
    Vitos-Faleato J, Real SM, Gutierrez-Prat N, Villanueva A, Llonch E, Drosten M, Barbacid M, Nebreda AR.
      Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.
    Keywords:  KRAS; TIMP-1; lung adenocarcinoma; nononcogene addiction; p38α
    DOI:  https://doi.org/10.1073/pnas.1921404117
  5. Cancers (Basel). 2020 Jan 17. pii: E237. [Epub ahead of print]12(1):
    Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo.
    Conroy LR, Dougherty S, Kruer T, Metcalf S, Lorkiewicz P, He L, Yin X, Zhang X, Arumugam S, Young LEA, Sun RC, Clem BF.
      Dysregulated metabolism is a hallmark of cancer cells and is driven in part by specific genetic alterations in various oncogenes or tumor suppressors. The retinoblastoma protein (pRb) is a tumor suppressor that canonically regulates cell cycle progression; however, recent studies have highlighted a functional role for pRb in controlling cellular metabolism. Here, we report that loss of the gene encoding pRb (Rb1) in a transgenic mutant Kras-driven model of lung cancer results in metabolic reprogramming. Our tracer studies using bolus dosing of [U-13C]-glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of Rb1 did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact Rb1. Additional tracer studies using [U-13C,15N]-glutamine and [U-13C]-lactate demonstrated that loss of Rb1 did not alter glutaminolysis or utilization of circulating lactate within the tricarboxylic acid cycle (TCA) in vivo. Taken together, these data suggest that the loss of Rb1 promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in Kras-driven lung tumors.
    Keywords:  Rb1; TCA anaplerosis; glycolysis; lung cancer; metabolomics
    DOI:  https://doi.org/10.3390/cancers12010237
  6. Thorac Cancer. 2020 Jan 21.
    Actin-like protein 8 promotes cell proliferation, colony-formation, proangiogenesis, migration and invasion in lung adenocarcinoma cells.
    Ma S, Wang X, Zhang Z, Liu D.
      BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality worldwide of which lung adenocarcinoma (LUAD) is the most common. The identification of oncogenes and effective drug targets is the key to individualized LUAD treatment. Actin-like protein 8 (ACTL8), a member of the cancer/testis antigen family, is associated with tumor growth and patient prognosis in various types of cancer. However, whether ACTL8 is involved in the development of LUAD remains unknown. The aim of the present study was to demonstrate the role of ACTL8 in human LUAD cells.METHODS: The expression of ACTL8 in LUAD tissues and cell lines was assessed using immunohistochemistry and western blotting. Additionally, plasmids expressing ACTL8-specific short hairpin RNAs were used to generate lentiviruses which were subsequently used to infect A549 and NCI-H1975 human LUAD cells. Cell proliferation, migration, invasion and apoptosis, as well as cell cycle progression and the expression of protein markers of epithelial to mesenchymal transition were investigated. A549 cell tumor growth in nude mice was also examined.
    RESULTS: The results showed that ACTL8 was highly expressed in A549 and NCI-H1975 LUAD cell lines. Additionally, ACTL8-knockdown inhibited proliferation, colony formation, cell cycle progression, migration and invasion, and increased apoptosis in both cell lines. Furthermore, in vivo experiments in nude mice revealed that ACTL8-knockdown inhibited A549 cell tumor growth.
    CONCLUSION: These results suggest that ACTL8 serves an oncogenic role in human LUAD cells, and that ACTL8 may represent a potential therapeutic target for LUAD.
    KEY POINTS: Our results suggest that ACTL8 serves an oncogenic role in human LUAD cells, and that ACTL8 may represent a potential therapeutic target for LUAD.
    Keywords:  ACTL8; angiogenesis; cell proliferation; lung adenocarcinoma; migration
    DOI:  https://doi.org/10.1111/1759-7714.13247
  7. FASEB J. 2020 Jan 20.
    FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1α-PINK1-Parkin pathway.
    Li C, Zhou J, Liu Z, Zhou J, Yao W, Tao J, Shen M, Liu H.
      In developing follicles, the granulosa cells (GCs) live in a hypoxic environment due to the devoid of blood supply. Upon hypoxic conditions, several types of mammalian cells have been reported to undergo apoptosis. Follicle-stimulating hormone (FSH) is known as the primary survival factor for antral follicles by preventing GCs apoptosis. Mitophagy is a type of organelle-specific autophagy that removes damaged or stressed mitochondria to maintain cellular health. This study provides the first evidence suggesting that FSH-mediated mitophagy protected porcine GCs from hypoxia-induced apoptosis. Our data showed that the GCs apoptosis caused by mitochondrial pathway upon hypoxia stress was markedly attenuated after FSH treatment, which was correlated with enhanced activation of mitophagy. Interestingly, FSH also stimulated mitochondrial biogenesis as suggested by increased expression of mitochondrial transcription factor A and nuclear respiratory factor 1 during hypoxia exposure. Notably, the protein level of hypoxia inducible factor-1α (HIF-1α) was significantly increased in hypoxic GCs following FSH treatment, accompanied by elevated mitophagic activity and dampened apoptotic signaling. Blocking HIF-1α inhibited mitophagy and restored hypoxia-induced apoptosis despite FSH treatment. Importantly, FSH promoted the expression of serine/threonine kinase PTEN induced putative kinase 1 (PINK1) and the E3 ligase Parkin during hypoxia stress through a HIF-1α dependent manner. This induced the mitophagic clearance of damaged mitochondria, hence inhibiting apoptosis by reducing cytochrome c releasing. The inhibition of HIF-1α and/or PINK1 using inhibitor or RNAi further confirmed the role of the FSH-HIF-1α-PINK1-Parkin-mitophagy axis in suppressing GC apoptosis under hypoxic conditions. These findings highlight a novel function of FSH in preserving GCs viability against hypoxic damage by activating HIF-1α-PINK1-Parkin-mediated mitophagy.
    Keywords:  FSH; HIF-1α; PINK1; Parkin; apoptosis; hypoxia; mitophagy; porcine granulosa cells
    DOI:  https://doi.org/10.1096/fj.201901808RRR
  8. Int J Clin Oncol. 2020 Jan 18.
    Psoas muscle mass in patients undergoing lung cancer surgery: a prognostic difference between squamous cell carcinoma and adenocarcinoma.
    Ozeki N, Kawaguchi K, Fukui T, Nakamura S, Hakiri S, Mori S, Goto M, Iwano S, Yokoi K, Chen-Yoshikawa TF.
      BACKGROUND: Psoas muscle mass is a surrogate marker for sarcopenia: a depletion of skeletal muscle mass. This study was conducted to elucidate the prognostic significance of the psoas muscle index (PMI: cross-sectional area of the bilateral psoas muscle at the umbilical level on computed tomography/height2 [cm2/m2]) in patients undergoing surgery for lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC).METHODS: One hundred and sixty-five patients with SCC and 556 patients with ADC who underwent R0 resection between 2007 and 2014 were reviewed for analysis. In SCC patients, the mean value (standard deviation) of the PMI was 6.15 (1.49) in men and 4.65 (1.36) in women. Among ADC patients, the PMI was 7.12 (1.60) in men and 5.29 (1.22) in women. Clinicopathological characteristics as well as the survival were evaluated.
    RESULTS: The PMI was associated with the age, body mass index (BMI), and serum albumin. In the multivariable Cox regression analysis, after adjusting for age, BMI, serum albumin, sex, pathological stage, and diffusing capacity for carbon monoxide, the PMI showed a significant association with the overall survival (OS) and disease-free survival (DFS) in SCC patients (hazard ratios 0.50 and 0.56, 95% confidence intervals 0.39-0.65 and 0.45-0.71, respectively). On the other hand, in ADC patients, the PMI had no impact on the OS or DFS.
    CONCLUSIONS: The PMI was significantly associated with the survival of lung SCC patients, but not of lung ADC patients, suggesting the presence of a previously unidentified relationship between skeletal muscle and lung SCC progression.
    Keywords:  Lung cancer; Psoas muscle; Sarcopenia; Survival
    DOI:  https://doi.org/10.1007/s10147-020-01624-x
  9. Int J Mol Sci. 2020 Jan 17. pii: E596. [Epub ahead of print]21(2):
    SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner.
    Ramos H, Calheiros J, Almeida J, Barcherini V, Santos S, Carvalho ATP, Santos MMM, Saraiva L.
      The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination.
    Keywords:  OXPHOS; anti-angiogenic; anti-migratory; anticancer drug; glycolysis; p53
    DOI:  https://doi.org/10.3390/ijms21020596
  10. Life Sci. 2020 Jan 15. pii: S0024-3205(20)30072-2. [Epub ahead of print] 117325
    Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in non-small cell lung cancer.
    Zeng Z, Wang ZY, Li YK, Ye DM, Zeng J, Hu JL, Chen PF, Xiao J, Zou J, Li ZH.
      Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor that can regulate downstream target gene expression. Kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2 activation and translocation to target its 26S proteasomal degradation. It has been widely reported that the Keap1/Nrf2 pathway is associated with tumorigenesis, chemotherapy resistance and progression and development of non-small cell lung cancer (NSCLC). High expression of Nrf2 and low abundance of Keap1 contribute to the abnormalities and unrealistic treatment prognosis of NSCLC. Therefore, elucidating the role and potential mechanism of Nrf2 in NSCLC is essential for understanding tumorigenesis and for the development of strategies for effective clinical management. Here, we summarize current knowledge about the molecular structure and biological function of Nrf2, and we discuss the roles of Nrf2 in tumorigenesis, which will further provide a possible therapeutic strategy for NSCLC.
    Keywords:  Chemoresistance; NSCLC; Nrf2; Oxidant stress
    DOI:  https://doi.org/10.1016/j.lfs.2020.117325
  11. Ann Oncol. 2020 Feb;pii: S0923-7534(19)35401-8. [Epub ahead of print]31(2): 274-282
    Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.
    Pros E, Saigi M, Alameda D, Gomez-Mariano G, Martinez-Delgado B, Alburquerque-Bejar JJ, Carretero J, Tonda R, Esteve-Codina A, Catala I, Palmero R, Jove M, Lazaro C, Patiño-Garcia A, Gil-Bazo I, Verdura S, Teulé A, Torres-Lanzas J, Sidransky D, Reguart N, Pio R, Juan-Vidal O, Nadal E, Felip E, Montuenga LM, Sanchez-Cespedes M.
      BACKGROUND: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs).PATIENTS AND METHODS: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs.
    RESULTS: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors.
    CONCLUSIONS: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.
    Keywords:  EGFR; RB1; lung adenocarcinoma; nonsmokers; tyrosine kinase inhibitors; whole-exome sequencing
    DOI:  https://doi.org/10.1016/j.annonc.2019.09.001
  12. Cell Death Dis. 2020 Jan 20. 11(1): 38
    NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter.
    Lee DE, Yoo JE, Kim J, Kim S, Kim S, Lee H, Cheong H.
      In mammals, autophagosome formation is initiated by ULK1 via the posttranslational modification of this protein. However, the precise role of ULK1 ubiquitination in modulating autophagy is unknown. Here, we show that NEDD4L, an E3 ubiquitin ligase, binds ULK1 in pancreatic cancer cells. ULK1 expression was stabilized in NEDD4L knockdown cells compared to that in control cells, suggesting that NEDD4L is involved in ULK1 ubiquitination and its subsequent degradation. Autophagy activity was enhanced in NEDD4L knockdown cells compared to control cells. NEDD4L-depleted cells exhibited an increase in the cellular oxygen consumption rate (OCR) and mitochondrial membrane potential, and maintained mitochondrial fusion status in response to metabolic stress. Enhanced OCR and mitochondrial fusion morphology in NEDD4L knockdown cells were repressed by siRNA targeting ULK1. In addition to ULK1, ASCT2, a glutamine transporter, was accumulated in NEDD4L-depleted cells; this is important for maintaining autophagy activation and mitochondrial metabolic function. Finally, the cellular growth and survival rate increased in NEDD4L knockdown cells compared to control cells. However, the genetic or pharmacological blockade of either ULK1 or ASCT2 in NEDD4L-depleted cells sensitized pancreatic cancer cells, particularly in response to nutrient deprivation. In a mouse xenograft model of pancreatic cancer, the use of autophagy inhibitors suppressed tumor growth more in NEDD4L-depleted cells than in tumors from control cells. NEDD4L and ULK1 levels were inversely correlated in two different pancreatic cancer mouse models-xenograft mouse and KPC mouse models. These results suggest that NEDD4L suppressed autophagy and mitochondrial metabolism by reducing cellular ULK1 or ASCT2 levels, and thus could repress the growth and survival of pancreatic cancer cells. Therefore, ubiquitin ligase-mediated autophagy plays a critical role in regulating mitochondrial metabolism, thereby contributing to the growth and survival of certain cancers with low NEDD4L levels.
    DOI:  https://doi.org/10.1038/s41419-020-2242-5
  13. Support Care Cancer. 2020 Jan 25.
    The association of physical function and quality of life on physical activity for non-small cell lung cancer survivors.
    Yoo JS, Yang HC, Lee JM, Kim MS, Park EC, Chung SH.
      PURPOSE: Our study aimed to assess the association between physical function and quality of life (QOL) with physical activity among non-small cell lung cancer (NSCLC) survivors.METHODS: Participants were 92 NSCLC survivors. Physical activity was assessed by a self-report with physiatrist's interview and the Korean version of the short form of the International Physical Activity Questionnaire (IPAQ-SF). All participants were required to perform three standardized fitness tests. The Korean version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to assess QOL. Factors associated with physical functioning and QOL were determined using multiple linear regression.
    RESULTS: A significant correlation between metabolic equivalent task minutes per week (MET-min/wk) and aerobic fitness was found (r = 0.277, p = 0.008). Factors associated with aerobic fitness include gender, age, and MET-min/wk. The meeting physical activity guideline group was also a factor associated with aerobic fitness. In the QOL aspect, a significant correlation between MET-min/wk and some QOL score was found. The meeting physical activity guideline group was a factor associated with QOL (global health status, physical function, and role function), not total MET-min/wk.
    CONCLUSIONS: Increased physical activity was associated with higher aerobic fitness and QOL. Engagement in physical activity that met physical activity guidelines was a factor related to aerobic fitness and better QOL in some domains. To improve aspects of aerobic fitness and QOL, we may consider the pattern of physical activity, including regular participation and intensity, rather than total physical activity including basal activity.
    Keywords:  Cancer survivors; Non-small cell lung cancer; Physical activity; Physical function; Quality of life
    DOI:  https://doi.org/10.1007/s00520-020-05302-6
  14. Eur J Nucl Med Mol Imaging. 2020 Jan 23.
    Influx rate constant of 18F-FDG increases in metastatic lymph nodes of non-small cell lung cancer patients.
    Yang M, Lin Z, Xu Z, Li D, Lv W, Yang S, Liu Y, Cao Y, Cao Q, Jin H.
      PURPOSE: Primary tumor (PT) and metastatic lymph node (MLN) status have a great influence on diagnosis and treatment of lung cancer. Our main purpose was to investigate the imaging characteristics of PT or MLN by applying the 18F-FDG PET dynamic modeling approach for non-small cell lung cancer (NSCLC).METHODS: Dynamic 18F-FDG PET scans were performed for 76 lung cancer patients, and 62 NSCLC cases were finally included in this study: 37 with newly diagnosed early and locally advanced lung cancer without distant metastases (group M0) and 25 metastatic lung cancer (group M1). Patlak graphic analysis (Ki calculation) based on the dynamic modeling and SUV analysis from conventional static data were performed.
    RESULTS: For PT, both KiPT (0.050 ± 0.005 vs 0.026 ± 0.004 min-1, p < 0.001) and SUVPT (8.41 ± 0.64 vs 5.23 ± 0.73, p < 0.01) showed significant higher values in group M1 than M0. For MLN, KiMLN showed significant higher values in M1 than M0 (0.033 ± 0.005 vs 0.016 ± 0.003 min-1, p < 0.01), while no significant differences were found for SUVMLN between M0 and M1 (4.22 ± 0.49 vs 5.57 ± 0.59, p > 0.05). Both SUV PT and KiPT showed significant high values in squamous cell carcinoma than adenocarcinoma, but neither SUVPT nor KiPT showed significant differences between EGFR mutants versus wild types. The overall Spearman analysis for SUV and Ki from different groups showed variable correlation (r = 0.46-0.94).
    CONCLUSION: The dynamic modeling for MLN (KiMLN) showed more sensitive than the static analysis (SUV) to detect metastatic lymph nodes in NSCLC, although both methods were sensitive for PT. This methodology of non-invasive imaging may become an important tool to evaluate MLN and PT status for patients who cannot undergo histological examination.
    CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT03679936 (http://www.clinicaltrials.gov/).
    Keywords:  18F-FDG; Dynamic PET/CT; Metastatic lymph nodes; Non-small cell lung cancer; Patlak
    DOI:  https://doi.org/10.1007/s00259-020-04682-5
  15. Expert Opin Pharmacother. 2020 Jan 20. 1-16
    Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer.
    Spagnuolo A, Palazzolo G, Sementa C, Gridelli C.
      Introduction: Angiogenesis is the process by which the tumor develops its potential for growth and distant metastasis. The main proangiogenic switch is vascular endothelial growth factor (VEGF), which, along with its receptor VEGFR, is a target for biological drugs such as multi-targeted tyrosine kinase inhibitors used for many neoplasms, including non-small cell lung cancer (NSCLC).Areas covered: The fact that angiokinase inhibitors act on several signaling molecules simultaneously means that the use of alternative transmission pathways, which nullifies the effect of drugs directed against a single target, is avoided. Nevertheless, most of these drugs have failed to improve any outcome in NSCLC patients. The authors discuss these points and provide their expert perspectives.Expert opinion: Multikinase inhibitors are the fruit of research which regards cancer as a complex system of interacting processes. However, the lack of predictive biomarkers of response has limited the development of this class of drugs in NSCLC. Combination trials with chemotherapy, immunotherapy or other targeted drugs are ongoing, and while some have already confirmed the role of antiangiogenic small molecules in integrated regimes, others are still evaluating the efficacy of these drugs and raising questions about their cost and tolerability.
    Keywords:  Angiogenesis; NSCLC; TKIs; VEGF; VEGFR tyrosine kinase inhibitors; anlotinib; antiangiogenic therapy; molecular targeted drugs; nintedanib; second-line treatment
    DOI:  https://doi.org/10.1080/14656566.2020.1713092
  16. Molecules. 2020 Jan 23. pii: E495. [Epub ahead of print]25(3):
    Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity.
    Okada J, Yamada E, Saito T, Yokoo H, Osaki A, Shimoda Y, Ozawa A, Nakajima Y, Pessin JE, Okada S, Yamada M.
      Dapagliflozin, empagliflozin, tofogliflozin, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2), is used clinically to reduce circulation glucose levels in patients with type 2 diabetes mellitus by blocking the reabsorption of glucose by the kidneys. Dapagliflozin is metabolized and inactivated by UGT1A9. Empagliflozin is metabolized and inactivated by UGT1A9 and by other related isoforms UGT2B7, UGT1A3, and UGT1A8. Tofogliflozin is metabolized and inactivated by five different enzymes CYP2C18, CYP3A4, CYP3A5, CYP4A11, and CYP4F3. Dapagliflozin treatment of HCT116 cells, which express SGLT2 but not UGT1A9, results in the loss of cell adhesion, whereas HepG2 cells, which express both SGLT2 and UGT1A9, are resistant to the adhesion-related effects of dapagliflozin. PANC-1 and H1792 cells, which do not express either SGLT2 or UGT1A9, are also resistant to adhesion related effects of dapagliflozin. On the other hand, either empagliflozin or tofogliflozin treatment of HCT116, HepG2, PANC-1, and H1792 cells are resistant to the adhesion-related effects as observed in dapagliflozin treated HCT116 cells. Knockdown of UGT1A9 by shRNA in HepG2 cells increased dapagliflozin sensitivity, whereas the overexpression of UGT1A9 in HCT116 cells protected against dapagliflozin-dependent loos of cell adhesion. Dapagliflozin treatment had no effect on cellular interactions with fibronectin, vitronectin, or laminin, but it induced a loss of interaction with collagen I and IV. In parallel, dapagliflozin treatment reduced protein levels of the full-length discoidin domain receptor I (DDR1), concomitant with appearance of DDR1 cleavage products and ectodomain shedding of DDR1. In line with these observations, unmetabolized dapagliflozin increased ADAM10 activity. Dapagliflozin treatment also significantly reduced Y792 tyrosine phosphorylation of DDR1 leading to decrement of DDR1 function and detachment of cancer cells. Concomitant with these lines of results, we experienced that CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus treated by dapagliflozin in addition to chemotherapy was decreased (case 1). CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus was treated by dapagliflozin alone after radiation therapy was decreased but started to rise after cessation of dapagliflozin (case 2). CA19-9 in two of patients with pancreatic cancer and type 2 diabetes mellitus was resistant to the combination therapy of dapagliflozin and chemotherapy (case 3 and 4 respectively). PIVKAII in patients with liver cancer and type 2 diabetes mellitus, and CYFRA in patients with squamous lung cancer and type 2 diabetes mellitus was also resistant the combination therapy of dapagliflozin and chemotherapy (case 5 and 6 respectively). Taken together, these data suggest a potential role for dapagliflozin anticancer therapy against colon cancer cells that express SGLT2, but not UGT1A9.
    Keywords:  ADAM10; colon cancer; diabetes mellitus; discoidin domain receptor; sodium-glucose cotransporter 2 inhibitor
    DOI:  https://doi.org/10.3390/molecules25030495
  17. Cancers (Basel). 2020 Jan 22. pii: E266. [Epub ahead of print]12(2):
    Pre-Disease and Pre-Surgery BMI, Weight Loss and Sarcopenia Impact Survival of Resected Lung Cancer Independently of Tumor Stage.
    Icard P, Schussler O, Loi M, Bobbio A, Lupo AM, Wislez M, Iannelli A, Fournel L, Damotte D, Alifano M.
      Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung resection for NSCLC.METHODS: A retrospective analysis of a prospectively collected database was made on 304 consecutive patients.
    RESULTS: Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 5% and 44.4% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m2 (p < 0.000001). Overall survival was positively affected by pre-disease (p = 0.036) and pre-surgery (p = 0.017) BMI > 25 kg/m2, and, even more, in case of BMI > 25 kg/m2 and increasing weight (p = 0.012). Long-term outcome was negatively influenced by low muscle mass (p = 0.042) and weight loss (p = 0.0052) as well as age (p = 0.017), ASA categories (p = 0.025), extent of resection (p = 0.0001), pleural invasion (p = 0.0012) and higher pathologic stage (p < 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.66[0.49-0.89], p = 0.006) and pre-surgery BMI (RR 0.72[0.54-0.98], p = 0.034), and the absence of low muscle mass (RR 0.56[0.37-0.87], p = 0.0091).
    CONCLUSIONS: Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered.
    Keywords:  body mass index; lung cancer; morphomics; outcome; sarcopenia; surgery; weight loss
    DOI:  https://doi.org/10.3390/cancers12020266
  18. Am J Nucl Med Mol Imaging. 2019 ;9(6): 282-295
    Preliminary data on circulating tumor cells in metastatic NSCLC patients candidate to immunotherapy.
    Monterisi S, Castello A, Toschi L, Federico D, Rossi S, Veronesi G, Lopci E.
      In the current paper, we aimed to investigate circulating tumor cells (CTCs) in non-small cell lung carcinoma (NSCLC) candidates to immunotherapy and correlate findings with clinical and metabolic parameters. Seventeen metastatic NSCLC patients (12 males, 5 females), were prospectively enrolled. All patients underwent 18F-Fluorodeoxyglucose (FDG) PET/CT and CTCs detection before treatment. CTCs isolation by size was carried out with the ISET method. CTCs were characterized based on cytopathological features and were compared with smoking status, histological subtype, pre-immunotherapy treatment, PDL-1 expression, performance status, and semi-quantitative parameters on PET, including SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). We found CTCs in 10 out of 17 patients (59%). Mean number of CTCs was 3 (range 1-7). Only one cell with 3 malignant features was detected in the blood of a healthy control out of 7 (16%). A significantly lower number of CTCs was found in patients previously treated with chemotherapy (P=0.041). No correlation between CTCs and other clinical pathologic characteristics was observed. Patients with an extensive tumor burden, i.e. MTV and TLG, were associated with a higher number of CTCs (P=0.004 and P=0.028, respectively). Likewise, patients with a higher metabolism determined with SUVmean resulted having a higher CTCs count (P=0.048). The presence of CTCs was associated with tumor uptake and metabolic burden on PET/CT, while results were influenced by previous chemotherapy. Whether confirmed in larger series, the combination of the presence of CTCs and FDG PET metabolic parameters might improve prognostic stratification and allow more personalized treatment paradigm.
    Keywords:  FDG; Non-small-cell lung cancer; PET/CT; chemotherapy; circulating tumor cells; immunotherapy
  19. Lung Cancer. 2020 Jan 07. pii: S0169-5002(20)30017-9. [Epub ahead of print]141 78-81
    COPD and lung cancer incidence in the Women's Health Initiative Observational Study: A brief report.
    Nagasaka M, Lehman A, Chlebowski R, Haynes BM, Ho G, Patel M, Sakoda LC, Schwartz AG, Simon MS, Cote ML.
      OBJECTIVES: Lung cancer is the leading cause of cancer mortality in both men and women in the United States. COPD is associated with lung cancer independently of cigarette smoking, but remains understudied in women. Utilizing data from the Women's Health Initiative Observational Study (WHI-OS), this report investigates the association between COPD and development of lung cancer, with a focus on ethnicity and cancer subtype.MATERIALS AND METHODS: The WHI-OS, part of the larger Women's Health Initiative (WHI), is comprised of postmenopausal women between ages 50 and 79 years old at enrollment. Self-administered questionnaires were utilized to gather baseline demographic, socioeconomic, and behavioral information from participants. For this analysis, COPD status was determined at study entry (baseline) and on annual survey (incident). Information on the primary outcome of interest, diagnosis of lung cancer, was also collected annually.
    RESULTS AND CONCLUSION: Of the 92,789 women examined, 1,536 developed lung cancer. Overall, women with COPD were 1.64 times more likely to develop lung cancer than those without COPD, after adjusting for smoking status and intensity, ethnicity, education, body mass index, and income (HR = 1.64, 95 % CI: 1.43, 1.89). The relationship between COPD and lung cancer was not found to be significantly different between ethnic groups (p-value = 0.697). The associations between COPD and lung cancer was similar across subtypes (HR range 1.31-2.16), after adjusting for smoking status and intensity. COPD increases risk of lung cancer in women, thus they may benefit from more intensive surveillance compared to similar women without COPD.
    Keywords:  COPD; Emphysema; Ethnic difference; Lung cancer; Smoking
    DOI:  https://doi.org/10.1016/j.lungcan.2020.01.006
  20. Mol Cancer Res. 2020 Jan 23. pii: molcanres.0732.2019. [Epub ahead of print]
    O-GlcNAc Transferase Regulates Cancer Stem-like Potential of Breast Cancer Cells.
    Akella NM, Le Minh G, Ciraku L, Mukherjee A, Bacigalupa ZA, Mukhopadhyay D, Sodi VL, Reginato MJ.
      Breast tumors are heterogeneous and composed of different sub-population of cells, each with dynamic roles that can change with stage, site and microenvironment. Cellular heterogeneity is in part due to cancer stem-like cells (CSC) that share properties with stem cells and associated with treatment-resistance. CSCs rewire metabolism to meet energy demands of increased growth and biosynthesis. O-GlcNAc transferase enzyme (OGT) uses UDP-GlcNAc as a substrate for adding O-GlcNAc moieties to nuclear and cytoplasmic proteins. OGT/O-GlcNAc levels are elevated in multiple cancers and reducing OGT in cancer cells blocks tumor growth. Here, we report that breast CSCs enriched in mammosphere cultures contain elevated OGT/O-GlcNAcylation. Inhibition of OGT genetically or pharmacologically reduced mammosphere forming efficiency, the CD44H/CD24L, NANOG+ and ALDH+ CSC population in breast cancer cells. Conversely, breast cancer cells over-expressing OGT increased mammosphere formation, CSC populations in-vitro and also increased tumor initiation and CSC frequency in-vivo. Furthermore, OGT regulates expression of a number of epithelial to mesenchymal transition (EMT) and cancer stem-like cell markers including CD44, NANOG, and c-Myc. In addition, we identify KLF8 as a novel regulator of breast cancer mammosphere formation and a critical target of OGT in regulating cancer stem-like cells. Implications: These findings demonstrate that OGT plays a key role in the regulation of breast CSCs in-vitro and tumor initiation in-vivo, in part, via regulation of KLF8 and thus inhibition of OGT may serve as a therapeutic strategy to regulate tumor-initiating activity.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-19-0732
  21. Cancer Res. 2020 Jan 22. pii: canres.1027.2019. [Epub ahead of print]
    The MEK5-ERK5 kinase axis controls lipid metabolism in small cell lung cancer.
    Cristea S, Coles GL, Hornburg D, Gershkovitz M, Arand J, Cao S, Sen T, Williamson SC, Kim JW, Drainas AP, He A, Le Cam L, Byers LA, Snyder MP, Contrepois K, Sage J.
      Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here we investigated the contribution of the MAP kinase module MEK5/ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacological inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-1027
  22. Molecules. 2020 Jan 16. pii: E366. [Epub ahead of print]25(2):
    New Paradigms to Assess Consequences of Long-Term, Low-Dose Curcumin Exposure in Lung Cancer Cells.
    Smagurauskaite G, Mahale J, Brown K, Thomas AL, Howells LM.
      Curcumin has been investigated extensively for cancer prevention, but it has been proposed that long-term treatments may promote clonal evolution and gain of cellular resistance, potentially rendering cancer cells less sensitive to future therapeutic interventions. Here, we used long-term, low-dose treatments to determine the potential for adverse effects in non-small cell lung cancer (NSCLC) cells. IC50s for curcumin, cisplatin, and pemetrexed in A549, PC9, and PC9ER NSCLC cells were evaluated using growth curves. IC50s were subsequently re-assessed following long-term, low-dose curcumin treatment and a three-month treatment withdrawal period, with a concurrent assessment of oncology-related protein expression. Doublet cisplatin/pemetrexed-resistant cell lines were created and the IC50 for curcumin was determined. Organotypic NSCLC-fibroblast co-culture models were used to assess the effects of curcumin on invasive capacity. Following long-term treatment/treatment withdrawal, there was no significant change in IC50s for the chemotherapy drugs, with chemotherapy-resistant cell lines exhibiting similar sensitivity to curcumin as their non-resistant counterparts. Curcumin (0.25-0.5 µM) was able to inhibit the invasion of both native and chemo-resistant NSCLC cells in the organotypic co-culture model. In summary, long-term curcumin treatment in models of NSCLC neither resulted in the acquisition of pro-carcinogenic phenotypes nor caused resistance to chemotherapy agents.
    Keywords:  chemotherapy; curcumin; lung cancer; resistance
    DOI:  https://doi.org/10.3390/molecules25020366
  23. J Biol Chem. 2020 Jan 24. pii: jbc.RA119.011081. [Epub ahead of print]
    Improved workflow for mass spectrometry-based metabolomics analysis of the heart.
    Andres DA, Young LEA, Veeranki S, Hawkinson TR, Levitan BM, He D, Wang C, Satin J, Sun RC.
      MS-based metabolomics methods are powerful techniques to map the complex and interconnected metabolic pathways of the heart; however, normalization of metabolite abundance to sample input in heart tissues remains a technical challenge. Herein, we describe an improved GCMS-based metabolomics workflow that uses insoluble protein-derived glutamate for the normalization of metabolites within each sample and includes normalization to protein-derived amino acids to reduce biological variation and detect small metabolic changes. Moreover, glycogen is measured within the metabolomics workflow. We applied this workflow to study heart metabolism by first comparing two different methods of heart removal: the Langendorff heart method (reverse aortic perfusion), and in situ freezing of mouse heart with a modified tissue freeze-clamp approach. We then used the in situ freezing method to study the effects of acute β-adrenergic receptor stimulation (through isoproterenol treatment (ISO)) on heart metabolism. Using our workflow and within minutes, ISO reduced the levels of metabolites involved in glycogen metabolism, glycolysis, and the Krebs cycle, but the levels of pentose phosphate pathway metabolites and of many free amino acids remained unchanged. This observation was coupled to a 6-fold increase in phosphorylated adenosine nucleotide abundance. These results support the notion that ISO acutely accelerates oxidative metabolism of glucose to meet the ATP demand required to support increased heart rate and cardiac output. In summary, our MS-based metabolomics workflow enables improved quantification of cardiac metabolites and may also be compatible with other methods such as liquid chromatography or capillary electrophoresis.
    Keywords:  Cardiac metabolism; GCMS; Glycogen; Metabolomics; adrenergic receptor; cardiac metabolism; gas chromatography-mass spectrometry (GC-MS); glycogen; metabolomics
    DOI:  https://doi.org/10.1074/jbc.RA119.011081
  24. Acta Biomater. 2020 Jan 17. pii: S1742-7061(20)30033-7. [Epub ahead of print]
    Co-delivery of 2-Deoxyglucose and a Glutamine Metabolism Inhibitor V9302 via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer.
    Luo Z, Xu J, Sun J, Huang H, Zhang Z, Ma W, Wan Z, Liu Y, Pardeshi A, Li S.
      The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells' compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2-DG prodrug-based micellar carrier poly-(oligo ethylene glycol)-co-poly(4-((4-oxo-4-((4-vinylbenzyl)oxy)butyl)disulfaneyl)butanoic acid)-(2-deoxyglucose) (POEG-p-2DG) was developed. POEG-p-2DG well retained the pharmacological activity of 2-DG in vitro and in vivo, More importantly, POEG-p-2DG could self-assemble to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (∼10nm), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo. Interestingly, 2-DG treatment further decreased the glutamine uptake when combined with V9302, likely due to inhibition of ASCT2 glycosylation. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers.
    Keywords:  2-Deoxyglucose; Cancer metabolism; Co-delivery; Prodrug micelles; V9302
    DOI:  https://doi.org/10.1016/j.actbio.2020.01.019
  25. J Pharmacopuncture. 2019 Dec;22(4): 269-278
    Naesohwangryeon-tang Induced Apoptosis and Autophagy in A549 Human Lung Cancer Cells.
    Kim HJ, Jeong JW, Park C, Choi YH, Hong SH.
      Objectives: Naesohwangryeon-tang (NHT) is a type of traditional herbal formula, however, little is known about its antitumor activity. In this study, the antitumor properties of NHT was evaluated in human lung adenocarcinoma cells.Methods: To check the inhibitory effect of NHT, MTT assay was performed. Cell cycle analysis and detection of ROS production were conducted by flow cytometry. To evaluate the signaling pathway, Western blotting was conducted.
    Results: Our results showed that the decrease of cell proliferation by NHT stimulation occurred more significantly in A549 cells than in NCI-H460 cells. In addition, NHT-induced apoptosis was associated with the activation of caspases and production of reactive oxygen species (ROS). NHT-induced apoptosis was attenuated after pretreatments with z-VAD-fmk or N-acetylcysteine, suggesting that NHT-induced apoptosis was caspase- and ROS-dependent. Interestingly, NHT treatment led to the development of autophagic vesicular organelles and upregulation of several autophagy-related genes. The pretreatment of bafilomycin A1 decreased apoptosis slightly but increased cell viability in the presence of NHT.
    Conclusion: These findings indicated that NHT induces both apoptosis and cell-protective autophagy in human lung cancer cells. This data suggests that NHT might be a novel herbal drug for lung cancer.
    Keywords:  A549 Lung Cancer Cells; Apoptosis; Autophagy; Caspases; Naesohwangryeon-tang; Reactive Oxygen Species
    DOI:  https://doi.org/10.3831/KPI.2019.22.036
  26. Neurosci Lett. 2020 Jan 16. pii: S0304-3940(20)30032-X. [Epub ahead of print]720 134762
    Activation of AMPK pathway compromises Rab11 downregulation-mediated inhibition of Schwann cell proliferation in a Glut1 and Glut3-dependent manner.
    Li F, Du W, Wang H, Zhao S, Zhu L, Hao J.
      Rab11, a small GTPase, is an important protein in the regulation of intracellular plasma membrane trafficking. Schwann cells are the main cells of peripheral nerves and knockdown of Rab11 in these cells inhibits the formation of functional tunneling nanotubes (TNTs). However, the role of Rab11 in the functioning of Schwann cells remains elusive. Herein, using cell viability analysis, live/dead cell staining, BrdU assay, and western blot analysis with an AMPK antibody, we observed that the knockdown of Rab11 significantly inhibited the proliferation of RSC96 cells. Further investigations showed that the AMPK pathway was activated by the knockdown of Rab11, as indicated by the enhanced levels of phosphorylated AMPK. Moreover, suppression of AMPK pathway with Compound C aggravated Rab11 knockdown-induced inhibition of cell proliferation. In contrast, activation of the AMPK pathway with AICAR ameliorated the Rab11 knockdown-mediated inhibition of cell proliferation. Furthermore, the levels of Glut1 and Glut3 were decreased in the RSC96 cells upon Rab11 knockdown. Additionally, the knockdown of Glut1 and Glut3 led to the activation of the AMPK pathway in RSC96 cells. We conclude that the knockdown of Rab11 suppresses the proliferation of RSC96 cells, and as a compensatory mechanism, the activation of AMPK pathway, in a Glut1 and Glut3-dependent manner, improves RSC96 cell proliferation.
    Keywords:  AMPK; Glut1; Glut3; Proliferation; Rab11; Schwann cells
    DOI:  https://doi.org/10.1016/j.neulet.2020.134762
  27. Am J Physiol Cell Physiol. 2020 Jan 22.
    Carotid body Type I cells engage flavoprotein and Pin1 for oxygen sensing.
    Bernardini A, Wolf A, Brockmeier U, Riffkin H, Metzen E, Acker-Palmer A, Fandrey J, Acker H.
      Carotid body (CB) Type I cells sense the blood pO2 and generate a nervous signal for stimulating ventilation and circulation when blood oxygen levels decline. Three oxygen sensing enzyme complexes may be used for this purpose: 1) mitochondrial electron transport chain metabolism, 2) heme oxygenase 2 (HO-2) generating CO and/or 3) an NAD(P)H oxidase (NOX). We hypothesize that intracellular redox changes are the link between the sensor and nervous signals. To test this hypothesis Type I cell autofluorescence of flavoproteins (Fp) and NAD(P)H within the mouse CB ex vivo was recorded as Fp/(Fp+NAD(P)H) redox ratio. CB Type I cell redox ratio transiently declined with the onset of hypoxia. Upon reoxygenation, CB Type I cells showed a significantly increased redox ratio. As a control organ, the non-oxygen sensing sympathetic superior cervical ganglion (SCG) showed a continuously reduced redox ratio upon hypoxia. CN-, DPI or ROS influenced chemoreceptor discharge (CND) with subsequent loss of O2 sensitivity and inhibited hypoxic Fp reduction only in the CB but not in SCG Fp, indicating a specific role of Fp in the oxygen sensing process. Hypoxia induced changes in CB Type I cell redox ratio affected peptidyl prolyl isomerase Pin1, which is believed to co-localize with the NADPH oxidase subunit p47phox in the cell membrane to trigger the opening of potassium channels. We postulate that hypoxia-induced changes in the Fp mediated redox ratio of the CB regulate the Pin1/p47phox tandem to alter Type I cell potassium channels and therewith CND.
    Keywords:  Hypoxia; NAD(P)H/FAD autofluorescence; pH-sensitivity; redox ratio
    DOI:  https://doi.org/10.1152/ajpcell.00320.2019
  28. Oncol Lett. 2020 Feb;19(2): 1368-1374
    Centromere protein F and Forkhead box M1 correlation with prognosis of non-small cell lung cancer.
    Li R, Wang X, Zhao X, Zhang X, Chen H, Ma Y, Liu Y.
      Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Altered expression of centromere protein F (CENPF), a transient kinetochore protein, has been found in a variety of human cancers. However, its clinical significance in NSCLC remains unknown. In the present study the results of quantitative PCR and western blot analyses demonstrated that CENPF and Forkhead box M1 (FOXM1) were significantly higher in NSCLC tissues than in the non-cancerous controls at both transcriptional and translational levels. Immunohistochemical staining results showed 58.7% (44/75) and 64.0% (48/75) of NSCLC tissues displayed high expression of CENPF and FOXM1, respectively. CENPF protein expression showed a positive correlation with tumor size (P=0.0179), vital status (P=0.0008) and FOXM1 expression (P=0.0013) in NSCLC. Poor overall survival was correlated with high levels of CENPF and FOXM1 in NSCLC patients as evaluated by Kaplan-Meier and log rank test. Multivariate analyses showed that CENPF expression was an independent prognostic factor for NSCLC. In conclusion, our study provides evidence of the prognostic function of CENPF in NSCLC.
    Keywords:  CENPF; FOXM1; NSCLC; prognosis
    DOI:  https://doi.org/10.3892/ol.2019.11232
  29. Cancer Chemother Pharmacol. 2020 Jan 23.
    Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma.
    Ahmad Z, Jacobson BA, McDonald MW, Vattendahl Vidal N, Vattendahl Vidal G, Chen S, Dillenburg M, Okon AM, Patel MR, Wagner CR, Kratzke RA.
      Activated cap-dependent translation promotes cancer by stimulating translation of mRNAs encoding malignancy-promoting proteins. The nucleoside monophosphate Protide, 4Ei-10, undergoes intracellular uptake and conversion by Hint1 to form 7-Cl-Ph-Ethyl-GMP. 7-Cl-Ph-Ethyl-GMP is an analog of cap and inhibits protein translation by binding and sequestering eIF4E thus blocking eIF4E from binding to the mRNA cap. The effects of inhibiting translation initiation by disruption of the eIF4F complex with 4Ei-10 were examined in malignant mesothelioma (MM). In a cell-free assay system, formation of the eIF4F complex was disabled in response to exposure to 4Ei-10. Treatment of MM with 4Ei-10 resulted in decreased cell proliferation, increased sensitivity to pemetrexed and altered expression of malignancy-related proteins. In light of these findings, suppression of translation initiation by small molecule inhibitors like 4Ei-10 alone or in combination with pemetrexed represents an encouraging strategy meriting further evaluation in the treatment of MM.
    Keywords:  4Ei-10; 7-Cl-Ph-Ethyl-GMP; Cap-dependent translation; Mesothelioma; ProTide; eIF4E; eIF4G
    DOI:  https://doi.org/10.1007/s00280-020-04029-9
  30. Neurologia. 2020 Jan 18. pii: S0213-4853(19)30141-0. [Epub ahead of print]
    Neoplastic meningitis in solid tumours: Updated review of diagnosis, prognosis, therapeutic management, and future directions.
    García Molina E, Penas-Prado M.
      Neoplastic meningitis (NM) is a relatively frequent metastatic complication of cancer associated with high levels of neurological morbidity and generally poor prognosis. It appears in 5%-15% of patients with solid tumours, the most frequent being breast and lung cancer and melanoma. Symptoms are caused by involvement of the cerebral hemispheres, cranial nerves, spinal cord, and nerve roots, and are often multifocal or present with signs and symptoms of intracranial hypertension. The main diagnostic tools are the neurological examination, brain and spinal cord contrast-enhanced magnetic resonance imaging, and cerebrospinal fluid analysis including cytology, although studies have recently been conducted into the detection of tumour cells and DNA in the cerebrospinal fluid, which increases diagnostic sensitivity. With the currently available therapies, treatment aims not to cure the disease, but to delay and ameliorate the symptoms and to preserve quality of life. Treatment of NM involves a multimodal approach that may include radiotherapy, intrathecal and/or systemic chemotherapy, and surgery. Treatment should be individualised, and is based mainly on clinical practice guidelines and expert opinion. Promising clinical trials are currently being conducted to evaluate drugs with molecular and immunotherapeutic targets. This article is an updated review of NM epidemiology, clinical presentation, diagnosis, prognosis, management, and treatment; it is aimed at general neurologists and particularly at neurologists practicing in hospital settings with oncological patients.
    Keywords:  Citarabina; Cytarabine; Diseminación leptomeníngea; Intrathecal chemotherapy; Intrathecal therapy; Leptomeningeal disease; Meningitis neoplásica; Methotrexate; Metotrexato; Neoplastic meningitis; Quimioterapia intratecal; Terapia intratecal
    DOI:  https://doi.org/10.1016/j.nrl.2019.10.010
  31. Thorac Cancer. 2020 Jan 22.
    Overexpression of molecule GRP94 favors tumor progression in lung adenocarcinoma by interaction with regulatory T cells.
    Duan XF, Xin YW.
      BACKGROUND: Endoplasmic reticulum stress exists within a tumor. Glucose-regulated protein 94 (GRP94) is a stress-induced chaperone protein involved in tumor development and progression. Its role in myeloma, colon cancer, and other tumors has been confirmed, but its role in lung cancer is unclear. This study aimed to determine the role of GRP94 in lung cancer progression and prognostic prediction.METHODS: Immunohistochemical staining of GRP94 in human lung adenocarcinoma (AD) and corresponding normal tissue was performed, and its relationship with FOXP3+ regulatory T-cell (Treg) infiltration analyzed. We investigated the role of GRP94 in the behavior of lung AD cells by inhibiting GRP94 expression in A549 cells. Western blotting was used to detect the TGF-β/SMAD2 signaling molecules and explore the possible molecular mechanism of GRP94.
    RESULTS: GRP94 mRNA (encoded by HSP90B1) and protein levels were upregulated and elevated, respectively, in lung AD compared to normal lung tissues. High GRP94 expression was associated with an advanced disease stage and poor survival. There was a positive correlation between GRP94 expression and FOXP3+ Treg infiltration into lung AD tissues. Our results confirm that GRP94 knockdown inhibits cell proliferation and promotes cell apoptosis by increasing caspase-7 and CHOP levels in lung AD cells. TGF-β and SMAD2 protein levels were decreased after GRP94 depletion.
    CONCLUSIONS: Our study revealed that that GRP94 expression in lung AD favors tumor progression and predicts poor prognosis. The oncogenic role of GRP94 may involve inducing Treg infiltration by promoting the TGF-β signaling pathway.
    KEY POINTS: GRP94 protein levels were elevated in lung AD tissues compared to normal lung tissues. The high expression of GRP94 in lung AD favors tumor progression and predicts poor prognosis. The oncogenic role of the molecule GRP94 may involve the stimulation of Treg infiltration via promotion of the TGF-β signaling pathway.
    Keywords:  Bioinformatics; Tregs; glucose-regulated protein 94; lung adenocarcinoma; prognosis
    DOI:  https://doi.org/10.1111/1759-7714.13321
  32. Nat Commun. 2020 Jan 23. 11(1): 454
    TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.
    Corbet C, Bastien E, Santiago de Jesus JP, Dierge E, Martherus R, Vander Linden C, Doix B, Degavre C, Guilbaud C, Petit L, Michiels C, Dessy C, Larondelle Y, Feron O.
      Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.
    DOI:  https://doi.org/10.1038/s41467-019-14262-3
  33. J Pak Med Assoc. 2020 Jan;70(1): 29-34
    Is it possible to achieve more accurate mediastinal nodal radiotherapy planning for NSCLC with PET/CT?
    Simsek FS, Koroglu R, Elmali F, Ulutas H, Balci TA, Asik M, Akatli A, Kekilli E, Oner AO.
      Objective: To assess whether more accurate mediastinal lymph nodes radiotherapy can be performed with fluorode oxyglu cosepositron emission tomogaphy/computed tomography.METHODS: The retrospective study was conducted at Inonu University Medical Faculty, Malatya, Turkey, and Afyon Kocatepe University Medical Faculty, Afyon, Turkey, and comprised record of patients histopathologically diagnosed with non-small cell lung carcinoma and who underwent fluorodeoxyglucose positron emission tomography / computed tomography between January 2013 and December 2016. Surgery and pathology reports of the patients were reviewed. Histopathologically proven malignant and benign lymph nodes were re-identified with fluorodeoxyglucose positron emission tomography / computed tomography imaging. Anatomical and metabolic parameters of lymph nodes were re-assessed by specialists and compared with histopathology reports. Maximum standardised uptake values were used to assess sensitivity, specificity, positive predictive value, and negative predictive values. SPSS 22 was used for data analysis.
    RESULTS: The study included 144 mediastinal lymph nodes related to 42 patients who had a mean age of 62.4±9.8 years (range: 41-79 years). In terms of subtypes of the primary squamous cell carcinoma was found in 24(57.2%) patients, adenocarcinoma in 12(27.5%), and other subtypes in 6(15.3%) patients. Of the 144 lymph nodes, 48(33.3%) were metastatic. Sensitivity, specificity, positive predictive value, and negative predictive value were 92.8%, 64.3%, 56.9%, and 94.7%, respectively when maximum standardised uptake value >2.5 was used as the malignancy criterion. When lymph node maximum standardised uptake value / liver standardised uptake value-mean>1.69 was used as the criterion, the sensitivity, specificity, positive predictive value, and negative predictive value were 95.83%, 91.67%, 85.2%, and 97.8%, respectively. When the same values with lymph node >8mm was used as the criterion, the four resultant values were 89.6%, 93.8%, 87.8%, and 94.7%, respectively. When lymph node was replaced with mean attenuation >35 as the criterion, the consequent values were 79.2%, 93.8%, 86.4%, and 90.0%, respectively.
    CONCLUSIONS: Lymph node maximum standardised uptake value / liver standardised uptake valuemean> 1.69 was associated with higher negative predictive value and more useful positive predictive value compared to maximum standardised uptake value >2.5. When this parameter was used along with short axis or mean attenuation value, there were no significant increase in positive predictive value, but there was a decrease in negative predictive value.
    Keywords:   Carcinoma, Non-small-cell lung, Radiation therapy, PET scan
    DOI:  https://doi.org/10.5455/JPMA.296815
  34. J Cancer. 2020 ;11(5): 1125-1140
    Nicotinic-nAChR signaling mediates drug resistance in lung cancer.
    Cheng WL, Chen KY, Lee KY, Feng PH, Wu SM.
      Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the most common risk factor for lung carcinoma; other risks include genetic factors and exposure to radon gas, asbestos, secondhand smoke, and air pollution. Nicotine, the primary addictive constituent of cigarettes, contributes to cancer progression through activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated ion channels. Activation of nicotine/nAChR signaling is associated with lung cancer risk and drug resistance. We focused on nAChR pathways activated by nicotine and its downstream signaling involved in regulating apoptotic factors of mitochondria and drug resistance in lung cancer. Increasing evidence suggests that several sirtuins play a critical role in multiple aspects of cancer drug resistance. Thus, understanding the consequences of crosstalk between nicotine/nAChRs and sirtuin signaling pathways in the regulation of drug resistance could be a critical implication for cancer therapy.
    Keywords:  drug resistance; lung cancer; mitochondria; nicotinic acetylcholine receptor; sirtuin
    DOI:  https://doi.org/10.7150/jca.36359
  35. Biochem Biophys Res Commun. 2020 Jan 17. pii: S0006-291X(20)30097-8. [Epub ahead of print]
    HIF1α-dependent upregulation of ATAD2 promotes proliferation and migration of stomach cancer cells in response to hypoxia.
    Nayak A, Roy AD, Rout N, Singh SP, Bhattacharyya A, Roychowdhury A.
      Stomach cancer is a difficult-to-treat disease. Lack of detection markers and limited understanding of the disease mechanisms contribute to the aggressive nature of stomach cancer cells (SCCs). Recently, an ATPase, ATAD2 has been found to be highly expressed in stomach cancer contributing to increased malignancy. However, nothing is known about the mechanism of ATAD2 upregulation and its involvement in stomach carcinogenesis. Since hypoxic microenvironment plays a crucial role in the progression of solid tumors like stomach cancer; we have examined the regulation and function of ATAD2 expression in hypoxic SCCs. ATAD2 is induced in hypoxia-treated SCCs. Stomach adenocarcinoma and metastatic tissues with high HIF1α level also show enhanced ATAD2 expression. In the absence of hypoxia-inducible factor HIF1α, ATAD2 protein level is found to be less indicating towards a potential correlation between them. We identify the presence of HIF1α-binding site (HBS) and HIF1α ancillary site (HAS) in the ATAD2 promoter. Using both in vitro and in vivo binding studies, we confirm that HIF1α binds with the ATAD2 promoter in hypoxic condition. ATAD2 upregulation promotes proliferation and migration of SCCs exposed to hypoxia. Thus, we identify ATAD2 as a hypoxia-responsive and HIF1α-regulated gene and elucidate that upregulated expression of ATAD2 enhances tumor-promoting functions in hypoxic SCCs. Therefore, we propose ATAD2 as a promising therapeutic target for stomach cancer.
    Keywords:  AAA+ ATPase; ATAD2; HIF1α; Hypoxia; Stomach or gastric cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.130
  36. Int J Mol Sci. 2020 Jan 17. pii: E597. [Epub ahead of print]21(2):
    Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges.
    Kunimasa K, Goto T.
      The immune system plays a dual role in tumor evolution-it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.
    Keywords:  immune checkpoint inhibitors; immunoedition; immunotherapy; non-small cell lung cancer
    DOI:  https://doi.org/10.3390/ijms21020597
  37. Mol Med Rep. 2020 Feb;21(2): 597-606
    Polyphyllin VII induces apoptotic cell death via inhibition of the PI3K/Akt and NF‑κB pathways in A549 human lung cancer cells.
    He H, Xu C, Zheng L, Wang K, Jin M, Sun Y, Yue Z.
      Polyphyllin VII is an active compound isolated from Paris polyphylla, which is termed Chonglou in China. The present study was designed to investigate the underlying mechanisms of the antitumor effect of Polyphyllin VII in lung cancer cells. The cytotoxic effect of Polyphyllin VII in human lung cancer A549 cells was analyzed; the results revealed an IC50 value of 0.41±0.10 µM at 24 h. The associated mechanisms were investigated by phase‑contrast microscopy, fluorescence microscopy, flow cytometry and western blot analysis. Exposure of A549 cells to Polyphyllin VII resulted in apoptosis. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF‑κB, and wortmannin, an inhibitor of PI3K, both decreased the proportion of viable A549 cells in the presence of Polyphyllin VII. The ratio of apoptotic cells increased in the presence of wortmannin and PDTC. Western blot analysis revealed that PI3K, phosphorylated (p)‑PI3K, Akt, p‑Akt, NF‑κB and p‑NF‑κB were downregulated following treatment with Polyphyllin VII. Increased caspase‑3 activity, increased poly‑(ADP‑ribose) polymerase cleavage and a downregulation of inhibitor of caspase‑activated DNase were observed following treatment with Polyphyllin VII, and these effects were enhanced by either wortmannin or PDTC. The present results revealed that Polyphyllin VII was able to induce apoptotic cell death in A549 human lung cancer cells via inhibition of the PI3K/Akt and NF‑κB pathways.
    DOI:  https://doi.org/10.3892/mmr.2019.10879
  38. Exp Mol Med. 2020 Jan 24.
    Amino acids in cancer.
    Lieu EL, Nguyen T, Rhyne S, Kim J.
      Over 90 years ago, Otto Warburg's seminal discovery of aerobic glycolysis established metabolic reprogramming as one of the first distinguishing characteristics of cancer1. The field of cancer metabolism subsequently revealed additional metabolic alterations in cancer by focusing on central carbon metabolism, including the citric acid cycle and pentose phosphate pathway. Recent reports have, however, uncovered substantial non-carbon metabolism contributions to cancer cell viability and growth. Amino acids, nutrients vital to the survival of all cell types, experience reprogrammed metabolism in cancer. This review outlines the diverse roles of amino acids within the tumor and in the tumor microenvironment. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, amino acid derivatives contribute to epigenetic regulation and immune responses linked to tumorigenesis and metastasis. Furthermore, in discussing the transporters and transaminases that mediate amino acid uptake and synthesis, we identify potential metabolic liabilities as targets for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s12276-020-0375-3
  39. Clin Endocrinol (Oxf). 2020 Jan 18.
    Correlation between glucose metabolism and serum steroid hormones in patients with polycystic ovary syndrome.
    Li X, Zhang T, Li S, Deng Y, Wang L, Tao T, Wang S, Gu Y, Gu W, Hong J, Liu W, Wang W, Zhang Y.
      OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with an increased prevalence of dysglycaemia, which includes impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Patients with PCOS demonstrate abnormal patterns of steroid hormones. Here, we analyse the correlation between glucose metabolism and serum steroid hormones in PCOS.DESIGN: Observational double-centre study.
    PATIENTS: 914 patients with PCOS.
    MEASUREMENTS: We assessed the glucose metabolism status of all patients according to the 1999 WHO criteria. Serum steroid hormones were measured by liquid chromatography-tandem mass spectrometry.
    RESULTS: The median age of the patients was 26 years (interquartile range: 21-30), and 40.6% (371/914) had abnormal glucose metabolism: 29.3% (268/914) had prediabetes, and 11.3% (103/914) had T2DM. Correlation analysis not adjusting for confounding factors revealed that serum aldosterone, androstenedione, estrone, pregnenolone and the free androgen index were positively correlated, while progesterone was negatively correlated with the risk of abnormal glucose metabolism. After adjusting for age, body mass index and fasting insulin levels in the logistic regression model, only aldosterone (P=0.013), androstenedione (P=0.046) and estrone (P=0.014) (in quartiles) were correlated with the risk of abnormal glucose metabolism.
    CONCLUSIONS: This study indicates a high prevalence of prediabetes and T2DM in patients with PCOS. Furthermore, there were positive correlations of serum aldosterone, androstenedione and estrone with the risk of abnormal glucose metabolism after adjusting for confounding factors.
    Keywords:  aldosterone; androstenedione; estrone; liquid chromatography-tandem mass spectrometry; polycystic ovary syndrome; steroid hormones; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1111/cen.14154
  40. J Cancer. 2020 ;11(5): 1240-1249
    TRIM67 Promotes the Proliferation, Migration, and Invasion of Non-Small-Cell Lung Cancer by Positively Regulating the Notch Pathway.
    Jiang J, Ren H, Xu Y, Wudu M, Wang Q, Liu Z, Su H, Jiang X, Zhang Y, Zhang B, Qiu X.
      Tripartite motif-containing 67 (TRIM67), an E3 ubiquitin ligase, belongs to the TRIM protein family. The relationship between TRIM67 and tumorigenesis is not fully clear. Here, we elucidated TRIM67 function in non-small cell lung cancer (NSCLC). TRIM67 immunostaining results were correlated with clinicopathological features. Moreover, the function of TRIM67 in cultured NSCLC cells was evaluated by MTT, colony formation, and Transwell assays. TRIM67 expression was associated with tumor size, lymph node metastasis, p-TNM stage, cancer cell differentiation, and poor prognosis. We altered TRIM67 expression in A549 and H1299 cell lines, and the results showed that TRIM67 promoted cell proliferation, migration, invasion and EMT by positively regulating the Notch pathway. Collectively, the results showed that TRIM67 promotes NSCLC progression through the Notch pathway and that TRIM67 expression is associated with clinicopathological features, indicating that TRIM67 may play an important role in promoting the development of NSCLC and could be applied as not only an important prognostic biomarker but also a therapeutic target in NSCLC.
    Keywords:  Notch pathway; TRIM67; cell invasion; cell migration; cell proliferation; non-small-cell lung cancer
    DOI:  https://doi.org/10.7150/jca.38286
  41. Oncol Lett. 2020 Feb;19(2): 1400-1408
    TRIM59 as a novel molecular biomarker to predict the prognosis of patients with NSCLC.
    Lou M, Gao Z, Zhu T, Mao X, Wang Y, Yuan K, Tong J.
      As a member of the tripartite motif family, tripartite motif-containing protein 59 (TRIM59) serves as an E3 ubiquitin ligase in various cellular processes, including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy and carcinogenesis. The present study aimed to investigate the expression and prognostic value of TRIM59 in patients with non-small cell lung cancer (NSCLC). Expression of TRIM59 in patients with NSCLC was measured by immunohistochemistry in tissue microarrays. Datasets from The Cancer Genome Atlas (TCGA) were used to further verify the expression level of TRIM59 in NSCLC, lung adenocarcinoma and lung squamous cell carcinoma (LUSC). The prognostic value of TRIM59 in NSCLC was also analyzed. Immunohistochemistry revealed that TRIM59 was primarily located in the cytoplasm of tumor cells. Analysis of TCGA datasets revealed that TRIM59 was more highly expressed in tumor tissues than in normal tissues (P<0.0001). Furthermore, the TRIM59 expression level was associated with tumor differentiation (P=0.012), while no association was observed between TRIM59 expression and any other clinicopathological parameters. However, the average overall survival rate of patients with NSCLC in the high TRIM59 expression group was significantly lower than that in the low expression group (P=0.014), especially in patients with LUSC (P=0.016) and patients with poor differentiation (P=0.033). The multivariate analysis indicated that high TRIM59 expression is an independent prognostic factor in patients with NSCLC (P=0.018) and was associated with poor prognosis in patients with NSCLC. Therefore, TRIM59 may serve as a novel molecular biomarker to predict the prognosis of patients with NSCLC.
    Keywords:  expression; non-small cell lung cancer; prognosis; tripartite motif-containing protein 59
    DOI:  https://doi.org/10.3892/ol.2019.11199
  42. J Immunother Cancer. 2020 Jan;pii: e000376. [Epub ahead of print]8(1):
    Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy in EGFR / ALK wild-type advanced non-small cell lung cancer.
    Peng XX, Yu RY, Wu X, Wu SY, Pi C, Chen ZH, Zhang XC, Gao CY, Shao YW, Liu L, Wu YL, Zhou Q.
      BACKGROUND: Immunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advanced EGFR / ALK negative NSCLC to immunotherapy.METHODS: From June 2017 to February 2019, 30 patients with advanced EGFR / ALK wild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis.
    RESULTS: In order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients.
    CONCLUSION: Patients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.
    Keywords:  immunology; tumours
    DOI:  https://doi.org/10.1136/jitc-2019-000376
  43. Cancer Sci. 2020 Jan 22.
    p62 promotes bladder cancer cell growth by activating KEAP1/NRF2-dependent antioxidative response.
    Li T, Jiang D, Wu K.
      p62 is associated with two major cellular defense mechanisms against metabolic and oxidative stress, autophagy and the Kelch-like ECH-associated protein 1(KEAP1)-NF-E2-related factor 2 (NRF2) system. Recent studies indicate that the p62-KEAP1-NRF2 pathway promotes tumorigenesis and tumor growth mediated by NRF2-dependent antioxidative response. However, whether p62 is involved in bladder cancer (BCa) development remains unknown. Here we found that p62 is overexpressed in the BCa tissue and several BCa cell lines. The knockdown of p62 inhibits BCa cell growth both in vitro and in vivo, with increased intracellular reactive oxygen species (ROS) level. Mechanically, p62 activates NRF2 signaling by sequestrating KEAP1, which leads to the upregulation of antioxidant genes (Gclc, Gstm5, Gpx2), thus protecting BCa cells from oxidative stress. Our findings indicate that p62 might be involved in the development of BCa and serve as a potential therapeutic target.
    Keywords:  Bladder cancer; KEAP1; NRF2; Oxidative stress; p62
    DOI:  https://doi.org/10.1111/cas.14321
  44. J Exp Med. 2020 Mar 02. pii: e20191226. [Epub ahead of print]217(3):
    Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth.
    Liu M, Wang Y, Yang C, Ruan Y, Bai C, Chu Q, Cui Y, Chen C, Ying G, Li B.
      Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.
    DOI:  https://doi.org/10.1084/jem.20191226
  45. Ann Oncol. 2020 Feb;pii: S0923-7534(19)53227-6. [Epub ahead of print]31(2): 169-170
    Inactivation of RB1 and histological transformation in EGFR-mutant lung adenocarcinoma.
    Zhai H, Moore D, Jamal-Hanjani M.
      
    DOI:  https://doi.org/10.1016/j.annonc.2019.12.004
  46. Technol Cancer Res Treat. 2020 Jan-Dec;19:19 1533033819901115
    MicroRNA-425-5p Inhibits Lung Cancer Cell Growth in Vitro and in Vivo by Downregulating TFIIB-Related Factor 2.
    Yu X, Zheng H, Sun R, Qian X, Jiang P, Yang B, Liu J, Li X.
      Lung cancer is the most common cancer type with increasingly high incidence. MicroRNAs provide the potential biomarkers for lung cancer treatment. Thus, we aimed to investigate the function of microRNA-425-5p in lung cancer development and the underlying mechanisms. MicroRNA-425-5p overexpression inhibited A549 lung cancer cell proliferation in vitro and in vivo. On the other hand, microRNA-425-5p inhibition increased A549 proliferation. Mechanistically, the underlying mechanism by which microRNA-425-5p inhibits lung cancer cell growth was mediated through its ability in targeting and downregulating the TFIIB-related factor 2. Our results for the first time identified microRNA-425-5p as a tumor suppressor in lung cancer. Thus, microRNA-425-5p may serve as a potential therapeutic target for lung cancer.
    Keywords:  TFIIB-related factor 2; biomarker; cell growth; lung cancer; microRNA-425-5p
    DOI:  https://doi.org/10.1177/1533033819901115
  47. Cancer Genet. 2019 Dec 18. pii: S2210-7762(19)30566-6. [Epub ahead of print]241 12-19
    hsa_circ_0062389 promotes the progression of non-small cell lung cancer by sponging miR-103a-3p to mediate CCNE1 expression.
    She Y, Han Y, Zhou G, Jia F, Yang T, Shen Z.
      Recently, increasing evidence showed that circular RNAs (circRNAs) play critical roles in tumor progression. However, the roles of hsa_circ_0062389 in non-small cell lung cancer (NSCLC) development remain unclear. In the present study, hsa_circ_0062389 expression was significantly increased in NSCLC tissues and cell lines. High hsa_circ_0062389 expression was associated with advanced TNM stage and lymph-node metastasis. Function assays showed that hsa_circ_0062389 suppression reduced NSCLC cells proliferation and arrested cell cycle in G0/G1 phase. In mechanism, hsa_circ_0062389 directly interacted with miR-103a-3p in NSCLC, and CCNE1 acted as a target of miR-103a-3p. Furthermore, rescue assays showed that miR-103a-3p suppression or CCNE1 overexpression abolished the effects of hsa_circ_0062389 suppression on lung cancer cells progression. Therefore, our results showed that the hsa_circ_0062389/miR-103a-3p/CCNE1 axis might contribute to the tumorigenesis of NSCLC, which provided a new strategy for cancer treatment.
    Keywords:  CCNE1; Non-small cell lung cancer; hsa_circ_0062389; miR-103a-3p
    DOI:  https://doi.org/10.1016/j.cancergen.2019.12.004
  48. Aging (Albany NY). 2020 Jan 23. 12
    PAS kinase deficiency reduces aging effects in mice.
    Dongil P, Pérez-García A, Hurtado-Carneiro V, Herrero-de-Dios C, Álvarez E, Sanz C.
      Several signaling pathways may be affected during aging. All are regulated by nutrient levels leading to a decline in mitochondrial function and autophagy and to an increase in oxidative stress. PAS Domain Kinase (PASK) is a nutrient and bioenergetic sensor. We have previously found that PASK plays a role in the control of hepatic metabolic balance and mitochondrial homeostasis. To investigate PASK's role in hepatic oxidative stress during aging, we analyzed the mitochondrial function, glucose tolerance, insulin resistance, and lipid-related parameters in aged PASK-deficient mice. Hepatic Pask mRNA decreased in step with aging, being undetectable in aged wild-type (WT) mice. Aged PASK-deficient mice recorded lower levels of ROS/RNS compared to aged WT. The regulators of mitochondrial biogenesis, PGC1a, SIRT1 and NRF2, decreased in aged WT, while aged PASK-deficient mice recorded a higher expression of NRF2, GCLm and HO1 proteins and CS activity under fasted conditions. Additionally, aged PASK-deficient mice recorded an overexpression of the longevity gene FoxO3a, and maintained elevated PCNA protein, suggesting that hepatic cell repair mechanisms might be functional. PASK-deficient mice have better insulin sensitivity and no glucose intolerance, as confirmed by a normal HOMA-IR index. PASK may be a good target for reducing damage during aging.
    Keywords:  antioxidant enzymes; hepatic ROS; liver regeneration; mitochondrial function; oxidative stress
    DOI:  https://doi.org/10.18632/aging.102745
  49. Life Sci. 2020 Jan 16. pii: S0024-3205(20)30044-8. [Epub ahead of print]244 117297
    Exosomal miR-106b serves as a novel marker for lung cancer and promotes cancer metastasis via targeting PTEN.
    Sun S, Chen H, Xu C, Zhang Y, Zhang Q, Chen L, Ding Q, Deng Z.
      As novel non-invasive tumor diagnostic biomarkers, exosomal bioactive miRNAs have received increasing attention. Herein, the aim of this study is to explore the clinical values and roles of exosomal miR106b in lung cancer. The exosomal miR-106b level was much higher in the serum of patients with lung cancer than that in healthy volunteers. Also, the exosomal miR-106b level in the lung cancer patient serum was associated with TNM stages and lymph node metastasis. Furthermore, exosomal miR-106b enhanced the migrated and invasive ability of lung cancer cells and increased the MMP-2 and MMP-9 expression. Mechanistically, exosomal miR-106b could target PTEN, and promote lung cancer cell migration and invasion. More importantly, PTEN overexpression reversed the effect of exosomal miR-106b on lung cancer cell migration and invasion. Taken together, these findings indicate that exosomal miR-106b may be a promising diagnostic biomarker and drug target for patients with lung cancer.
    Keywords:  Exosome; Invasion; Lung cancer; Migration; PTEN; miR-106b
    DOI:  https://doi.org/10.1016/j.lfs.2020.117297
  50. Hum Pathol. 2020 Jan 21. pii: S0046-8177(20)30014-9. [Epub ahead of print]
    Successful lung Cancer EGFR sequencing from DNA extracted from TTF-1 immunohistochemistry slides: a new means to extend insufficient tissue.
    Deftereos G, Sandoval A, Furtado LV, Bronner M, Matynia AP.
      Lung cancer biopsy material is limited and is used for morphologic diagnosis, immunohistochemical and molecular testing. This can lead to tissue exhaustion, resulting in repeat biopsies (when clinically possible), delayed testing, and increased risks. Consequently, there is a need to optimize pre-analytical specimen use for molecular testing. While hematoxylin/eosin (H&E) can be used for as a DNA source for molecular testing, little is known regarding the potential use of immunohistochemistry (IHC) slides, as these are subject to harsh conditions that can lead to DNA degradation. Our aim was to evaluate whether DNA extracted from TTF-1 IHC slides, a common stain for lung adenocarcinoma, can be tested for EGFR mutations. Twenty-two lung adenocarcinoma samples (11 EGFR wild-type and 11 mutated) were selected. Slides were stained for TTF-1 IHC. Following TTF-1 staining, tissue underwent DNA extraction. Pyrosequencing for mutations in exons 18, 19, 20 and 21 of EGFR was performed and results were compared to clinical EGFR testing data. All 22 TTF-1 samples produced successful results and 21 were concordant. Of the 11 originally EGFR-mutated cases, 10 TTF-1 samples showed identical mutations, in all exons of interest. One case with an L858R mutation on original testing was negative on sequencing of the TTF-1 sample, possibly due to lower tumor burden on the TTF-1 stained slide. All 11 originally EGFR wild-type cases showed identical results on the TTF-1 samples. TTF-1 IHC slides can be a viable DNA source for molecular testing, especially important in lung biopsies with insufficient material following diagnostic evaluation.
    Keywords:  EGFR; Immunohistochemistry; Lung Cancer; Molecular Testing; Sequencing; TTF-1
    DOI:  https://doi.org/10.1016/j.humpath.2019.12.009
  51. Toxicol Lett. 2020 Jan 18. pii: S0378-4274(20)30006-0. [Epub ahead of print]
    N-acetyl cysteine protects against chlorine-induced tissue damage in an ex vivo model.
    Ågren L, Elfsmark L, Akfur C, Hägglund L, Ekstrand-Hammarström B, Jonasson S.
      High-level concentrations of chlorine (Cl2) can cause life-threatening lung injuries and the objective in this study was to understand the pathogenesis of short-term sequelae of Cl2-induced lung injury and to evaluate whether pre-treatment with the antioxidant N-acetyl cysteine (NAC) could counteract these injuries using Cl2-exposed precision-cut lung slices (PCLS). The lungs of Sprague-Dawley rats were filled with agarose solution and cut into 250 µm-thick slices that were exposed to Cl2 (20-600 ppm) and incubated for 30 min. The tissue slices were pre-treated with NAC (5-25 mM) before exposure to Cl2. Toxicological responses were analyzed after 5 h by measurement of LDH, WST-1 and inflammatory mediators (IL-1β, IL-6 and CINC-1) in medium or lung tissue homogenate. Exposure to Cl2 induced a concentration-dependent cytotoxicity (LDH/WST-1) and IL-1β release in medium. Similar cytokine response was detected in tissue homogenate. Contraction of larger airways was measured using electric-field-stimulation method, 200 ppm and control slices had similar contraction level (39 ± 5%) but in the 400 ppm Cl2 group, the evoked contraction was smaller (7 ± 3%) possibly due to tissue damage. NAC-treatment improved cell viability and reduced tissue damage and the contraction was similar to control levels (50 ± 11%) in the NAC treated Cl2-exposed slices. In conclusion, Cl2 induced a concentration-dependent lung tissue damage that was effectively prevented with pre-treatment with NAC. There is a great need to improve the medical treatment of acute lung injury and this PCLS method offers a way to identify and to test new concepts of treatment of Cl2-induced lung injuries.
    Keywords:  N-acetyl cysteine; chlorine; lung-injury; precision-cut lung slices (PCLS); rat; treatment
    DOI:  https://doi.org/10.1016/j.toxlet.2020.01.006
  52. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30137-6. [Epub ahead of print]
    Endothelial cell sprouting driven by RhoJ directly activated by a membrane-anchored Intersectin 1 (ITSN1) RhoGEF module.
    Color-Aparicio VM, Cervantes-Villagrana RD, García-Jiménez I, Beltrán-Navarro YM, Castillo-Kauil A, Escobar-Islas E, Reyes-Cruz G, Vázquez-Prado J.
      Endothelial cell sprouting is a critical event in tumor-induced angiogenesis. In melanoma and lung cancer murine models, targeting RhoJ prevents endothelial sprouting, tumor growth and metastasis and enhances the effects of conventional anti-neoplastic therapy. Aiming to understand how RhoJ is activated, we used a gain of function approach to identify constitutively active Rho guanine nucleotide exchange factors (RhoGEFs) able to promote RhoJ-dependent actin-driven membrane protrusions. We demonstrate that a membrane-anchored Intersectin 1 (ITSN1) DH-PH construct promotes endothelial cell sprouting via RhoJ. Mechanistically, this is controlled by direct interaction between the catalytic ITSN1 DH-PH module and RhoJ, it is sensitive to phosphorylation by focal adhesion kinase (FAK) and to endosomal trapping of the ITSN1 construct by dominant negative RhoJ. This ITSN1/RhoJ signaling axis is independent of Cdc42, a previously characterized ITSN1 target and a RhoJ close homologue. In conclusion, our results elucidate an ITSN1/RhoJ molecular link able to promote endothelial cell sprouting and set the basis to explore this signaling pathway in the context of tumor-induced angiogenesis.
    Keywords:  DH-PH catalytic module; Endothelial cell sprouting; Intersectin; Rho GTPase; RhoGEF; RhoJ
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.068
  53. Sci Rep. 2020 Jan 21. 10(1): 843
    MTAP-deficiency could predict better treatment response in advanced lung adenocarcinoma patients initially treated with pemetrexed-platinum chemotherapy and bevacizumab.
    Jing W, Zhu H, Liu W, Zhai X, Tian H, Yu J.
      To investigate the predictive value of methylthioadenosine phosphorylase (MTAP) on treatment response and survival in advanced lung adenocarcinoma. MTAP expression was detected by immunohistochemistry. Treatment response and survival were compared according to MTAP expression level. The results indicated MTAP-low expression was observed in 61.2% (101/165) of all patients. The objective response rate and disease control rate improved in the MTAP-low group (64.4% vs 46.9%, p = 0.035; 92.1% vs. 79.7%, p = 0.03; respectively). The median progression-free survival and survival time in the MTAP-low group were significantly lower than that in the MTAP-high group (8.1 vs. 13.1 months, p = 0.002; 22 vs. 32 months, p = 0.044). Multivariate analysis demonstrated that brain metastasis (HR 1.55, p = 0.046), thoracic radiation (HR 0.52, p = 0.026), and MTAP-low expression (HR 1.36, p = 0.038) were independent factors on survival. It is concluded that MTAP-low expression could predict improved treatment response but worsened survival in advanced lung adenocarcinoma.
    DOI:  https://doi.org/10.1038/s41598-020-57812-2
  54. Cell Mol Life Sci. 2020 Jan 22.
    Melatonin inhibits Warburg-dependent cancer by redirecting glucose oxidation to the mitochondria: a mechanistic hypothesis.
    Reiter RJ, Sharma R, Ma Q, Rorsales-Corral S, de Almeida Chuffa LG.
      Melatonin has the ability to intervene in the initiation, progression and metastasis of some experimental cancers. A large variety of potential mechanisms have been advanced to describe the metabolic and molecular events associated with melatonin's interactions with cancer cells. There is one metabolic perturbation that is common to a large number of solid tumors and accounts for the ability of cancer cells to actively proliferate, avoid apoptosis, and readily metastasize, i.e., they use cytosolic aerobic glycolysis (the Warburg effect) to rapidly generate the necessary ATP required for the high metabolic demands of the cancer cells. There are several drugs, referred to as glycolytic agents, that cause cancer cells to abandon aerobic glycolysis and shift to the more conventional mitochondrial oxidative phosphorylation for ATP synthesis as in normal cells. In doing so, glycolytic agents also inhibit cancer growth. Herein, we hypothesize that melatonin also functions as an inhibitor of cytosolic glycolysis in cancer cells using mechanisms, i.e., downregulation of the enzyme (pyruvate dehydrogenase kinase) that interferes with the conversion of pyruvate to acetyl CoA in the mitochondria, as do other glycolytic drugs. In doing so, melatonin halts the proliferative activity of cancer cells, reduces their metastatic potential and causes them to more readily undergo apoptosis. This hypothesis is discussed in relation to the previously published reports. Whereas melatonin is synthesized in the mitochondria of normal cells, we hypothesize that this synthetic capability is not present in cancer cell mitochondria because of the depressed acetyl CoA; acetyl CoA is necessary for the rate limiting enzyme in melatonin synthesis, arylalkylamine-N-acetyltransferase. Finally, the ability of melatonin to switch glucose oxidation from the cytosol to the mitochondria also explains how tumors that become resistant to conventional chemotherapies are re-sensitized to the same treatment when melatonin is applied.
    Keywords:  Acetyl CoA; Chemosensitivity; Citric acid cycle; Dichloroacetate; Glycolysis; Glycolytics; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.1007/s00018-019-03438-1
  55. Cancer Discov. 2020 Jan 24.
    Multikinase Inhibitor Crizotinib Is Active in MET Exon 14-Altered Lung Cancer.
      Crizotinib showed efficacy in non-small cell lung cancer (NSCLC) with alterations in MET exon 14.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-015
  56. Radiol Case Rep. 2020 Mar;15(3): 254-258
    Stanford type IV venous collateral blood flow following complete chronic occlusion of the superior vena cava in a patient with lung cancer.
    Ameku K, Higa M, Ganaha F.
      In superior vena cava occlusion, multiple collateral pathways develop to maintain venous drainage. Major patterns and pathways of venous collateral blood flow are well described, but rarely in complete chronic superior vena cava occlusion secondary to malignancy. A 59-year-old man with facial and upper extremity edema had a severely compressed superior vena cava at the initial diagnosis of stage IV mediastinal lung adenocarcinoma. The occlusion of superior vena cava progressed. After 10 months of treatment, the complete occlusion led to mild symptoms of hoarseness, muscle weakness, cough, and slight upper extremity edema. Venography clearly illustrated well-developed venous collateral blood flow through lateral thoracic, azygos-hemiazygos, and vertebral collateral venous pathways classified as Stanford type IV. The patient survived for a total of 20 months. He maintained Eastern Cooperative Oncology Group performance status of 1-2 until 2 months before death without severe symptoms of superior vena cava occlusion. This case described a rarely occurring venographic demonstration of well-developed Stanford type IV collateral pathway. Moreover, even with complete superior vena cava occlusion, well-developed Stanford type IV lateral thoracic collateral pathway can compensate for the venous flow without deterioration of performance status for a long period in certain cases.
    Keywords:  Collateral; Complete occlusion; Lateral thoracic pathway; Lung cancer; Stanford type IV; Superior vena cava syndrome
    DOI:  https://doi.org/10.1016/j.radcr.2019.12.010
  57. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31728-0. [Epub ahead of print]30(3): 771-782.e6
    Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma.
    Liu Y, Yin N, Wang X, Khoor A, Sambandam V, Ghosh AB, Fields ZA, Murray NR, Justilien V, Fields AP.
      Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2. Overexpression of PRKCI, SOX2, and ECT2 in the context of Trp53 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, PRKCI and SOX2 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas PRKCI and ECT2 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the PRKCI, SOX2, and ECT2 oncogenes represent a multigenic driver of LSCC.
    Keywords:  3q26 copy number gain; CNG; ECT2; LSCC; PRKCI; SOX2; lung basal stem cells; lung squamous cell carcinoma; oncogenic transformation
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.071
  58. Metabolomics. 2020 Jan 24. 16(2): 21
    Extracellular volatilomic alterations induced by hypoxia in breast cancer cells.
    Taware R, Taunk K, Kumar TVS, Pereira JAM, Câmara JS, Nagarajaram HA, Kundu GC, Rapole S.
      INTRODUCTION: The metabolic shift induced by hypoxia in cancer cells has not been explored at volatilomic level so far. The volatile organic metabolites (VOMs) constitute an important part of the metabolome and their investigation could provide us crucial aspects of hypoxia driven metabolic reconfiguration in cancer cells.OBJECTIVE: To identify the altered volatilomic response induced by hypoxia in metastatic/aggressive breast cancer (BC) cells.
    METHODS: BC cells were cultured under normoxic and hypoxic conditions and VOMs were extracted using HS-SPME approach and profiled by standard GC-MS system. Univariate and multivariate statistical approaches (p < 0.05, Log2 FC ≥ 0.58/≤ - 0.58, PC1 > 0.13/< - 0.13) were applied to select the VOMs differentially altered after hypoxic treatment. Metabolic pathway analysis was also carried out in order to identify altered metabolic pathways induced by the hypoxia in the selected BC cells.
    RESULTS: Overall, 20 VOMs were found to be significantly altered (p < 0.05, PC1 > 0.13/< - 0.13) upon hypoxic exposure to BC cells. Further, cell line specific volatilomic alterations were extracted by comparative metabolic analysis of aggressive (MDA-MB-231) vs. non-aggressive (MCF-7) cells incubated under hypoxia and normoxia. In this case, 15 and 12 VOMs each were found to be significantly altered in aggressive cells when exposed to hypoxic and normoxic condition respectively. Out of these, 9 VOMs were found to be uniquely associated with hypoxia, 6 were specific to normoxia and 6 were found common to both the conditions. Formic acid was identified as the most prominent molecule with higher abundance levels in aggressive as compared to non-aggressive cells in both conditions. Furthermore, metabolic pathway analyses revealed that fatty acid biosynthesis and nicotinate and nicotinamide metabolism were significantly altered in aggressive as compared to non-aggressive cells in normoxia and hypoxia respectively.
    CONCLUSIONS: Higher formate overflow was observed in aggressive cells compared to non-aggressive cells incubated under both the conditions, reinforcing its correlation with aggressive and invasive cancer type. Moreover, under hypoxia, aggressive cells preferred to be bioenergetically more efficient whereas, under normoxia, fatty acid biosynthesis was favoured when compared to non-aggressive cells.
    Keywords:  Breast cancer; GC–MS; Hypoxia; Volatile organic metabolites (VOMs); Volatilomics
    DOI:  https://doi.org/10.1007/s11306-020-1635-x
  59. Anal Biochem. 2020 Jan 19. pii: S0003-2697(19)31083-8. [Epub ahead of print] 113591
    Development of a lateral flow aptamer assay strip for facile identification of theranostic exosomes isolated from human lung carcinoma cells.
    Yu Q, Zhao Q, Wang S, Zhao S, Zhang S, Yin Y, Dong Y.
      Exosomes are Extracellular Vesicles (EV) that own unique structural features and functions and have gradually become the hot research spot in recent years. The tumor-derived exosomes contain various types of useful biological information, and medical identification of exosomes relied on the specific characterization of membrane surface proteins. In this study, in order to rapidly identify non-small cell lung cancer (NSCLC)-derived exosomes, based on an aptamer against CD63 protein on exosome membrane, a low cost lateral flow aptamer assay (LFAA) test strip using nanogold particles as visualization probes was successfully developed for facile identification of A549 exosomes isolated from human lung carcinoma cells diluted from 6.4 × 109 particles/mL herein.
    Keywords:  Aptamer; Exosomes; Lateral flow aptamer assay (LFAA); Non-small cell lung cancer (NSCLC)
    DOI:  https://doi.org/10.1016/j.ab.2020.113591
  60. PLoS Med. 2020 Jan;17(1): e1003012
    Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.
    Mahajan UV, Varma VR, Griswold ME, Blackshear CT, An Y, Oommen AM, Varma S, Troncoso JC, Pletnikova O, O'Brien R, Hohman TJ, Legido-Quigley C, Thambisetty M.
      BACKGROUND: There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.METHODS AND FINDINGS: We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.
    CONCLUSIONS: In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.
    DOI:  https://doi.org/10.1371/journal.pmed.1003012
  61. Oncol Lett. 2020 Feb;19(2): 1516-1522
    Inhibition mechanism of lung cancer cell metastasis through targeted regulation of Smad3 by miR-15a.
    Guo S, Li M, Li J, Lv Y.
      Effect of targeted regulation of mothers against decapentaplegic homolog 3 (Smad3) by microRNA-15a (miR-15a) on the proliferation, invasion and metastasis of non-small cell lung cancer (NSCLC) cells and its related mechanisms were investigated. Fifty pairs of NSCLC and para-cancerous tissues were collected to identify the expression level of miR-15a in NSCLC, para-cancerous tissue, and cell lines A549, H1299, H1975 and BEAS-2B by real-time fluorescence quantitative PCR (RT-PCR); A549 cells were transfected with miR-15a mimic; the MTT assay was performed to detect the role of miR-15a transfection in proliferation of A549 cells, the wound healing assay was carried out to identify the role of miR-15a in migration of A549 cells; Transwell invasion assay was conducted to analyze the role of miR-15a in invasion of A549 cells; western blotting was carried out to find the effect of miR-15a on Smad3 expression, and Spearman's rank correlation was used to analyze the correlation between miR-15a and Smad3 expression. NSCLC tissues and cells showed significantly lower miR-15a expression, compared with para-cancerous tissues and normal cell lines (P=0.023). miR-15a was significantly more expressed in A549 cells transfected with miR-15a mimic (P=0.043). Overexpression of miR-15a can significantly inhibit A549 cell proliferation (P=0.038), migration (P=0.033) and invasion (P=0.025), and significantly reduced the expression level of Smad3 (P=0.031) in A549 cells. Spearman's rank correlation showed negative correlation of miR-15a expression with Smad3, which may indicate negative regulation (r=-0.34, P<0.0001). Inhibition of proliferation, migration and invasion of NSCLC cells can be achieved with targeted regulation of Smad3 by miR-15a.
    Keywords:  Smad3; TGF-β; miR-15a; migration; non-small cell lung cancer
    DOI:  https://doi.org/10.3892/ol.2019.11194
  62. Sci Rep. 2020 Jan 20. 10(1): 727
    Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities.
    Song Z, Pearce MC, Jiang Y, Yang L, Goodall C, Miranda CL, Milovancev M, Bracha S, Kolluri SK, Maier CS.
      Osteosarcoma (OS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. The proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMPOS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|zHMPOS - zPOS|), and "sensitivity" score (|zHypoxia - zNormoxia) to quantitatively evaluate the proteome shifts exhibited by OS cells in response to hypoxia. Evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.
    DOI:  https://doi.org/10.1038/s41598-019-56878-x
  63. Clin Cancer Res. 2020 Jan 22. pii: clincanres.3280.2018. [Epub ahead of print]
    A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis.
    Van Meir EG, Lee SH, Rehman FK, Tyler KC, Yu B, Zhang Z, Zerrouqi A, Kaluzova M, Hadjipanayis CG, Cummings RD, Olson JJ, Devi NS, Osuka S.
      PURPOSE: Exploitation of altered glycosylation in cancer is a major goal for the design of new cancer therapy. Here designed a novel chimeric signal peptide-Galectin-3 conjugate (sGal-3) and investigated its ability to induce cancer-specific cell death by targeting aberrantly N-glycosylated cell surface receptors in cancer cells.EXPERIMENTAL DESIGN: sGal-3 was genetically engineered from Gal-3 by extending its N-terminus with a non-cleavable signal peptide from tissue plasminogen activator (tPA). sGal-3 killing ability was tested on normal and tumor cells in vitro and its anti-tumor activity evaluated in subcutaneous lung cancer and orthotopic malignant glioma models. The mechanism of killing was investigated through assays detecting sGal-3 interaction with specific glycans at the surface of tumor cells and the elicited downstream pro-apoptotic signaling.
    RESULTS: We found sGal-3 preferentially binds to b1 integrin on the surface of tumor cells due to aberrant N-glycosylation resulting from cancer-associated upregulation of several glycosyltransferases. This interaction inducespotent cancer-specific death by triggering an oncoglycan-b1/calpain/caspase-9 pro-apoptotic signaling cascade. sGal-3 could reduce the growth of subcutaneous lung cancers and malignant gliomas in brain, leading to increased animal survival.
    CONCLUSIONS: We demonstrate that sGal-3 kills aberrantly glycosylated tumor cells and antagonizes tumor growth through a novel integrin b1-dependent cell-extrinsic apoptotic pathway. These findings provide proof of concept that aberrant N-oncoglycans represent valid cancer targets and support further translation of the chimeric sGal-3 peptide conjugate for cancer therapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-18-3280
  64. Fitoterapia. 2020 Jan 15. pii: S0367-326X(20)30066-6. [Epub ahead of print] 104484
    A new abietane diterpenoid from Ajuga ovalifolia var. calantha induces human lung epithelial A549 cell apoptosis by inhibiting SHP2.
    Liu DM, Cao ZX, Yan HL, Li W, Yang F, Zhao WJ, Diao QC, Tan YZ.
      The Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, has been reported oncogenic tyrosine phosphatase associated with various tumors and played critical roles in many cell signaling events. Targeting SHP2 by small molecules may be a promising way for cancer therapy. Herein, a new abietane diterpenoid, named 3-acetoxylteuvincenone G (3-AG), was isolated from the whole plants of Ajuga ovalifolia var. calantha. The structure of the new compound was elucidated by means of extensive spectroscopic analyses. Using recombinant enzyme activity assay and cellular thermal shift assay, we found that 3-AG was a selective inhibitor of SHP2. Molecular docking suggested 3-AG displayed an orientation favorable to nucleophilic attack in the catalytic domain of SHP2. 3-AG suppressed A549 cell proliferation (IC50 = 10.79 ± 0.14 μM), invasion and induced cell apoptosis through SHP2/ERK1/2 and SHP2/AKT pathways. In summary, 3-AG, a potent, selective, and efficacious SHP2 inhibitor, may be a promising small molecule to treat human lung epithelial cancer.
    Keywords:  3-AG; Abietane diterpene; Ajuga ovalifolia var. calantha; Apoptosis; SHP2
    DOI:  https://doi.org/10.1016/j.fitote.2020.104484
  65. Oncol Lett. 2020 Feb;19(2): 1559-1566
    Radiomics predicts survival of patients with advanced non-small cell lung cancer undergoing PD-1 blockade using Nivolumab.
    Nardone V, Tini P, Pastina P, Botta C, Reginelli A, Carbone SF, Giannicola R, Calabrese G, Tebala C, Guida C, Giudice A, Barbieri V, Tassone P, Tagliaferri P, Cappabianca S, Capasso R, Luce A, Caraglia M, Mazzei MA, Pirtoli L, Correale P.
      Immune checkpoint blockade is an emerging anticancer strategy, and Nivolumab is a human mAb to PD-1 that is used in the treatment of a number of different malignancies, including non-small cell lung cancer (NSCLC), kidney cancer, urothelial carcinoma and melanoma. Although the use of Nivolumab prolongs survival in a number of patients, this treatment is hampered by high cost. Therefore, the identification of predictive markers of response to treatment in patients is required. In this context, PD-1/PDL1 blockade antitumor effects occur through the reactivation of a pre-existing immune response, and the efficacy of these effects is strictly associated with the presence of necrosis, hypoxia and inflammation at the tumour sites. It has been indicated that these events can be evaluated by specific assessments using a computed tomography (CT) texture analysis (TA) or radiomics. Therefore, a retrospective study was performed, which aimed to evaluate the potential use of this analysis in the identification of patients with NSCLC who may benefit from Nivolumab treatment. A retrospective analysis was performed of 59 patients with metastatic NSCLC who received Nivolumab treatment between January 2015 and July 2017 at Siena University Hospital (35 patients, training dataset), Catanzaro University Hospital and Reggio Calabria Grand Metropolitan Hospital, Italy (24 patients, validation dataset). Pre- and post-contrast CT sequences were used to contour the gross tumour volume (GTV) of the target lesions prior to Nivolumab treatment. The impact of variations on contouring was analysed using two delineations, which were performed on each patient, and the TA parameters were tested for reliability using the Intraclass Coefficient Correlation method (ICC). All analyses for the current study were performed using LifeX Software©. Imaging, clinical and pathological parameters were correlated with progression free survival and overall survival (OS) using Kaplan Meier analysis. An external validation testing was performed for the TA Score using the validation dataset. A total of 59 patients were included in the analysis of the present study. The reliability ICC analysis of 14 TA parameters indicated a highly reproducibility (ICC >0.70, single measure) in 12 (85%) pre- contrast and 13 (93%) post-contrast exams. A specific cut-off was detected for each of the following parameters: volume (score 1 >36 ml), histogram entropy (score 1 > 1.30), compacity (score 1 <3), gray level co-occurrence matrix (GLCM)-entropy (score 1 >1.80), GLCM-Dissimilarity (score 1 >5) and GLCM-Correlation (score 1<0.54). The global texture score allowed the classification of two subgroups of Low (Score 0-1; 36 patients; 61%) and High Risk patients (Score >1; 23 patients; 39%) that respectively, showed a median OS of 26 (mean +/- SD: 18 +/- 1.98 months; 95% CI 14-21 months) and 5 months (mean +/- SD: 6 +/- 0.99 months; 95% CI: 4-8 months; P=0.002). The current study indicated that TA parameters can identify patients that will benefit from PD-1 blockage by defining the radiological settings that are potentially suggestive of an active immune response. These results require further confirmation in prospective trials.
    Keywords:  immunology; nivolumab; non-small cell lung cancer; programmed cell death protein 1; radiomics; survival; texture analysis
    DOI:  https://doi.org/10.3892/ol.2019.11220
  66. Thorax. 2020 Jan 21. pii: thoraxjnl-2019-214014. [Epub ahead of print]
    Great debate: surgery versus stereotactic radiotherapy for early-stage non-small cell lung cancer.
    Hiley C, Salem A, Batchelor T, McDonald F, Evison M.
      
    Keywords:  Lung Cancer
    DOI:  https://doi.org/10.1136/thoraxjnl-2019-214014
  67. Cell Calcium. 2020 Jan 13. pii: S0143-4160(20)30002-6. [Epub ahead of print]86 102160
    NCX and EAAT transporters in ischemia: At the crossroad between glutamate metabolism and cell survival.
    Piccirillo S, Magi S, Castaldo P, Preziuso A, Lariccia V, Amoroso S.
      Energy metabolism impairment is a central event in the pathophysiology of ischemia. The limited availability of glucose and oxygen strongly affects mitochondrial activity, thus leading to ATP depletion. In this setting, the switch to alternative energy sources could ameliorate cells survival by enhancing ATP production, thus representing an attractive strategy for ischemic treatment. In this regard, some studies have recently re-evaluated the metabolic role of glutamate and its potential to promote cell survival under pathological conditions. In the present review, we discuss the ability of glutamate to exert an "energizing role" in cardiac and neuronal models of hypoxia/reoxygenation (H/R) injury, focusing on the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino acid transporters (EAATs) as key players in this metabolic pathway.
    Keywords:  Brain; Glutamate; Heart; Ischemia; Na(+)-dependent excitatory amino acid transporters; Na(+)/Ca(2+)exchanger
    DOI:  https://doi.org/10.1016/j.ceca.2020.102160
  68. Conserv Physiol. 2020 ;8(1): coz105
    The endemic and endangered Maugean Skate (Zearaja maugeana) exhibits short-term severe hypoxia tolerance.
    Morash AJ, Lyle JM, Currie S, Bell JD, Stehfest KM, Semmens JM.
      The endangered and range-restricted Maugean skate (Zearaja maugeana) is subjected to large environmental variability coupled with anthropogenic stressors in its endemic habitat, Macquarie Harbour, Tasmania. However, little is known about the basic biology/physiology of this skate, or how it may respond to future environmental challenges predicted from climate change and/or increases in human activities such as aquaculture. These skate live at a preferred depth of 5-15 m where the dissolved oxygen (DO) levels are moderate (~55% air saturation), but can be found in areas of the Harbour where DO can range from 100% saturation to anoxia. Given that the water at their preferred depth is already hypoxic, we sought to investigate their response to further decreases in DO that may arise from potential increases in anthropogenic stress. We measured oxygen consumption, haematological parameters, tissue-enzyme capacity and heat shock protein (HSP) levels in skate exposed to 55% dissolved O2 saturation (control) and 20% dissolved O2 saturation (hypoxic) for 48 h. We conclude that the Maugean skate appears to be an oxyconformer, with a decrease in the rate of O2 consumption with increasing hypoxia. Increases in blood glucose and lactate at 20% O2 suggest that skate are relying more on anaerobic metabolism to tolerate periods of very low oxygen. Despite these metabolic shifts, there was no difference in HSP70 levels between groups, suggesting this short-term exposure did not elicit a cellular stress response. The metabolic state of the skate suggests that low oxygen stress for longer periods of time (i.e. >48 h) may not be tolerable and could potentially result in loss of habitat or shifts in their preferred habitat. Given its endemic distribution and limited life-history information, it will be critical to understand its tolerance to environmental challenges to create robust conservation strategies.
    Keywords:  anaerobic metabolism; endangered species; environmental stress; hypoxia; metabolism
    DOI:  https://doi.org/10.1093/conphys/coz105
  69. Prz Menopauzalny. 2019 Dec;18(3): 161-165
    Population morbidity in elderly lung cancer patients from Poland with specific trends in elderly women.
    Śliwczyński A, Kalinka E, Sierocka A, Iltchev P, Kowalski D, Marczak M.
      Introduction: Lung cancer remains a leading cause of morbidity and mortality in Poland and globally. The objective of the study was to assess lung cancer incidence among elderly patients in Poland, including data for urban and rural populations, with trend analysis between 2008 and 2012.Material and methods: Differences between lung cancer prevalence in the Polish population aged 65 years or older were assessed with respect to province, gender, and rural vs. urban areas during the 2008-2012 period. Data were extracted from the Polish National Health Authority and Statistical Bureau databases.
    Results: Lung cancer morbidity among the elderly increased by 14.05% in urban areas but only by 4.01% in rural areas. A 22.41% overall increase was noted in the elderly female population, compared to a 7.29% increase among men aged 65 years and over. Regional differences in morbidity were observed.
    Conclusions: The rationale behind the differences is likely to be multi-factorial. A change in risk factor exposure in the past is probably now being reflected in lung cancer morbidity. The difference between sexes can potentially be regarded as an unfortunate side-effect of increasing female empowerment. Urban vs. rural, as well as regional, variances are probably due to a multitude of factors, including differences in socio-economic status.
    Keywords:  elderly patients; incidence; lung cancer; urban/rural
    DOI:  https://doi.org/10.5114/pm.2019.90811
  70. J Cancer. 2020 ;11(5): 1195-1202
    Down-regulation of tissue factor inhibits invasion and metastasis of non-small cell lung cancer.
    Xia Q, Zhang X, Chen Q, Chen X, Teng J, Wang C, Li M, Fan L.
      Objective: Tissue factor (TF) is clinically identified as a marker for the detection of various types of cancer as well as the prediction of prognosis for cancer patients. This present study aims to explore the possibility and feasibility to use plasma TF as a biomarker for the prediction of prognosis of patients with non-small cell lung cancer (NSCLC). Methods: A total of 100 patients with NSCLC at stage I to IV was included in the study, in whom the expression of plasma TF was detected. The Cox proportional-hazards regression model was then used to analyze the collected information, attempting to identify how patients' overall survival (OS) was associated with the expression of plasma TF. To verify the function of TF in invasion and metastasis, the expression of plasma TF was downregulated by SiRNA both in vivo and in vitro. Results: The expression of plasma TF in NSCLC patients was related to the diagnosis age of the patient. It was noted that patients with high TF expression levels tended to have worse OS performance, which implied that TF could be used as a marker for patients with stage I-IV NSCLC (HR = 2.030, 95% CI = 1.21-3.398, P = 0.007). TF down-regulation inhibited the growth of tumor in vitro as well as the metastasis and invasion of NSCLC cells in vivo. Conclusion: Both in vivo and in vitro, the invasion and migration of NSCLC cells are suppressed by TF knockdown. TF has the potential to become an effective biomarker for the prediction of prognosis of patients with stage I-IV NSCLC.
    Keywords:  biomarker; non-small cell lung cancer (NSCLC); prognosis; tissue factor
    DOI:  https://doi.org/10.7150/jca.37321
  71. J Bone Oncol. 2020 Apr;21 100275
    Bone decalcification to assess programmed cell death ligand 1 expression in bone metastases of non-small cell lung cancers.
    Pontarollo G, Confavreux CB, Pialat JB, Isaac S, Forest F, Yvorel V, Maury JM, Girard N, Brevet M.
      As for molecular alterations of lung adenocarcinoma, it is critical that pathologists are able to give PD-L1 expression status before first-line of treatment. The present study compared PD-L1 expression (clone 22-C3) in decalcified using EDTA or formic acid and non-decalcified lung cancer metastases bone samples. Amongst the 84 bone samples analysed for PD-L1 expression, and independently of decalcification, TPS ≥ 1% was 25.0% and ≥ 50% was 11.4%. There was no significant difference between decalcified samples (n = 45) and non-decalcified samples (n = 39) for both TPS ≥ 1% (p = 0.32) and TPS ≥ 50% (p = 1). To conclude, we confirm decalcified bone metastasis specimens may be used for PD-L1 IHC in routine practice. These results also highlight potentially interesting specificities of the bone microenvironment that should be further studied.
    Keywords:  Bone metastases; Decalcification; Immunotherapy; Lung carcinoma; PD-L1
    DOI:  https://doi.org/10.1016/j.jbo.2020.100275
  72. FASEB J. 2020 Jan 19.
    Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis.
    Shaul ME, Eyal O, Guglietta S, Aloni P, Zlotnik A, Forkosh E, Levy L, Weber LM, Levin Y, Pomerantz A, Nechushtan H, Eruslanov E, Singhal S, Robinson MD, Krieg C, Fridlender ZG.
      The accumulation of circulating low-density neutrophils (LDN) has been described in cancer patients and associated with tumor-supportive properties, as opposed to the high-density neutrophils (HDN). Here we aimed to evaluate the clinical significance of circulating LDN in lung cancer patients, and further assessed its diagnostic vs prognostic value. Using mass cytometry (CyTOF), we identified major subpopulations within the circulating LDN/HDN subsets and determined phenotypic modulations of these subsets along tumor progression. LDN were highly enriched in the low-density (LD) fraction of advanced lung cancer patients (median 7.0%; range 0.2%-80%, n = 64), but not in early stage patients (0.7%; 0.05%-6%; n = 35), healthy individuals (0.8%; 0%-3.5%; n = 15), or stable chronic obstructive pulmonary disease (COPD) patients (1.2%; 0.3%-7.4%, n = 13). Elevated LDN (>10%) remarkably related with poorer prognosis in late stage patients. We identified three main neutrophil subsets which proportions are markedly modified in cancer patients, with CD66b+ /CD10low /CXCR4+ /PDL1inter subset almost exclusively found in advanced lung cancer patients. We found substantial variability in subsets between patients, and demonstrated that HDN and LDN retain a degree of inherent spontaneous plasticity. Deep phenotypic characterization of cancer-related circulating neutrophils and their modulation along tumor progression is an important advancement in understanding the role of myeloid cells in lung cancer.
    Keywords:  lung cancer; mass cytometry; neutrophils; phenotypic modulation
    DOI:  https://doi.org/10.1096/fj.201902467R
  73. J Proteome Res. 2020 Jan 23.
    MDMA hepatotoxicity under heat stress condition: novel insights from in vitro metabolomic studies.
    Araujo AM, Enea M, Fernandes E, Carvalho F, Bastos ML, Carvalho M, Guedes de Pinho P.
      Hyperthermia has been extensively reported as a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. In this work, we used a sensitive untargeted metabolomic approach based on gas chromatography-mass spectrometry to evaluate the impact of hyperthermia on the hepatic metabolic changes caused by MDMA. For this purpose, primary mouse hepatocytes were exposed to subtoxic (LC01 and LC10) and toxic (LC30) concentrations of MDMA for 24 h, at 37.0 °C or 40.5 °C (simulating body temperature increase after MDMA consumption), and alterations on both intracellular metabolome and extracellular volatilome were evaluated. Multivariate analysis showed that metabolic patterns clearly discriminate MDMA treated cells from control cells, both in normothermic and hyperthermic conditions. Metabolic signature was found to be largely common to MDMA subtoxic and toxic concentrations, although with evident differences in the magnitude of response, with metabolic changes significantly more pronounced at 40.5 °C. Discriminant metabolites associated with MDMA-induced hepatotoxicity are mostly involved in amino acids metabolism, aminoacyl tRNA byosynthesis, glutathione metabolism, tricarboxylic acid cycle and pyruvate metabolism. Moreover, our metabolomic findings were corroborated by classical toxicity parameters, demonstrating the high sensitivity of this omic approach to assess molecular-level effects. Overall, this study indicates that MDMA triggers significant metabolic alterations on hepatic cells, even at low concentrations, that are clearly exacerbated at high temperatures. These findings provide new metabolic pieces to solve the puzzle of MDMA's hepatotoxicity mechanism and emphasize the increased risks of MDMA abuse due to the thermogenic action of the drug.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00741
  74. Biomed Eng Online. 2020 Jan 21. 19(1): 5
    Elaboration of a multimodal MRI-based radiomics signature for the preoperative prediction of the histological subtype in patients with non-small-cell lung cancer.
    Tang X, Xu X, Han Z, Bai G, Wang H, Liu Y, Du P, Liang Z, Zhang J, Lu H, Yin H.
      BACKGROUND: Non-invasive discrimination between lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes of non-small-cell lung cancer (NSCLC) could be very beneficial to the patients unfit for the invasive diagnostic procedures. The aim of this study was to investigate the feasibility of utilizing the multimodal magnetic resonance imaging (MRI) radiomics and clinical features in classifying NSCLC. This retrospective study involved 148 eligible patients with postoperative pathologically confirmed NSCLC. The study was conducted in three steps: (1) feature extraction was performed using the online freely available package with the multimodal MRI data; (2) feature selection was performed using the Student's t test and support vector machine (SVM)-based recursive feature elimination method with the training cohort (n = 100), and the performance of these selected features was evaluated using both the training and the validation cohorts (n = 48) with a non-linear SVM classifier; (3) a Radscore model was then generated using logistic regression algorithm; (4) Integrating the Radscore with the semantic clinical features, a radiomics-clinical nomogram was developed, and its overall performance was evaluated with both cohorts.RESULTS: Thirteen optimal features achieved favorable discrimination performance with both cohorts, with area under the curve (AUC) of 0.819 and 0.824, respectively. The radiomics-clinical nomogram integrating the Radscore with the independent clinical predictors exhibited more favorable discriminative power, with AUC improved to 0.901 and 0.872 in both cohorts, respectively. The Hosmer-Lemeshow test and decision curve analysis results furtherly showed good predictive precision and clinical usefulness of the nomogram.
    CONCLUSION: Non-invasive histological subtype stratification of NSCLC can be done favorably using multimodal MRI radiomics features. Integrating the radiomics features with the clinical features could further improve the performance of the histological subtype stratification in patients with NSCLC.
    Keywords:  Clinical features; Lung adenocarcinoma; Lung squamous cell carcinoma; Multimodal MRI radiomics features; Nomogram; Non-small-cell lung cancer
    DOI:  https://doi.org/10.1186/s12938-019-0744-0
  75. Mol Cell Proteomics. 2020 Jan 24. pii: mcp.RA119.001821. [Epub ahead of print]
    Integrative metabolic pathway analysis reveals novel therapeutic targets in osteoarthritis.
    Rocha B, Cillero-Pastor B, Eijkel G, Fernandez-Puente P, Paine MRL, Ruiz-Romero C, Heeren RMA, Calamia V, Blanco FJ.
      In osteoarthritis (OA), impairment of cartilage regeneration can be related to a defective chondrogenic differentiation of mesenchymal stromal cells (MSCs). Therefore, understanding the proteomic- and metabolomic-associated molecular events during the chondrogenesis of MSCs could provide alternative targets for therapeutic intervention. Here, a SILAC-based proteomic analysis identified 43 proteins related with metabolic pathways whose abundance was significantly altered during the chondrogenesis of OA human bone marrow MSCs (hBMSCs). Then, the level and distribution of metabolites was analyzed in these cells and healthy controls by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), leading to the recognition of characteristic metabolomic profiles at the early stages of differentiation. Finally, integrative pathway analysis showed that UDP-glucuronic acid synthesis and amino sugar metabolism were downregulated in OA hBMSCs during chondrogenesis compared to healthy cells. Alterations in these metabolic pathways may disturb the production of hyaluronic acid (HA) and other relevant cartilage extracellular matrix (ECM) components. This work provides a novel integrative insight into the molecular alterations of osteoarthritic MSCs and potential therapeutic targets for OA drug development through the enhancement of chondrogenesis.
    Keywords:  CHONDROCYTES; Cell biology*; Cell differentiation*; Imaging; Immunohistochemistry; Metabolites; OSTEOARTHRITIS; chondrogenesis
    DOI:  https://doi.org/10.1074/mcp.RA119.001821
  76. Exp Gerontol. 2020 Jan 16. pii: S0531-5565(19)30765-X. [Epub ahead of print] 110841
    Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan.
    Castro-Portuguez R, Sutphin GL.
      Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that plays a critical role in mitochondrial energy production as well as many enzymatic redox reactions. Age-associated decline in NAD+ is implicated as a driving factor in several categories of age-associated disease, including metabolic and neurodegenerative disease, as well as deficiency in the mechanisms of cellular defense against oxidative stress. The kynurenine metabolic pathway is the sole de novo NAD+ biosynthetic pathway, generating NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases. Kynurenine pathway interventions can extend lifespan in both fruit flies and nematodes, and altered NAD+ metabolism represents one potential mediating mechanism. Recent studies demonstrate that supplementation with NAD+ or NAD+-precursors increase longevity and promote healthy aging in fruit flies, nematodes, and mice. NAD+ levels and the intrinsic relationship to mitochondrial function have been widely studied in the context of aging. Mitochondrial function and dynamics have both been are implicated in longevity determination in a range of organisms from yeast to humans, at least in part due to their intimate link to regulating an organism's cellular energy economy and capacity to resist oxidative stress. Recent findings support the idea that complex communication between the mitochondria and the nucleus orchestrates a series of events and stress responses involving mitophagy, mitochondrial number, mitochondrial unfolded protein response (UPRmt), and mitochondria fission and fusion events. In this review, we discuss how mitochondrial morphological changes and dynamics operate during aging, and how altered metabolism of tryptophan to NAD+ through the kynurenine pathway interacts with these processes.
    Keywords:  Kynurenine pathway; Mitochondria; NAD; Oxidative stress; Tryptophan
    DOI:  https://doi.org/10.1016/j.exger.2020.110841
  77. Oncol Lett. 2020 Feb;19(2): 1635
    Erratum: Long non-coding RNA transcribed from pseudogene PPIAP43 is associated with radiation sensitivity of small cell lung cancer cells.
    Wang S, Yu J.
      [This corrects the article DOI: 10.3892/ol.2019.10806.].
    DOI:  https://doi.org/10.3892/ol.2019.11202
  78. Biochem Pharmacol. 2020 Jan 20. pii: S0006-2952(20)30030-7. [Epub ahead of print] 113820
    Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification.
    Shin JW, Chun KS, Kim DH, Kim SJ, Hoon Kim S, Cho NC, Na HK, Surh YJ.
      The present study was aimed to investigate the effects of curcumin, a representative chemopreventive phytochemical with pronounced antioxidant and anti-inflammatory properties, on activation of Nrf2 and its target protein heme oxygenase-1 (HO-1) in mouse skin in vivo and in cultured murine epidermal cells. Treatment of mouse epidermal JB-6 cells with curcumin resulted in the induction of HO-1 expression, and this was abrogated in cells transiently transfected with Nrf2 siRNA. While curcumin treatment increased protein expression of Nrf2, it failed to did not alter the steady-state level of the Nrf2 mRNA transcript. Treatment of cells with curcumin stabilized Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of this transcription factor. Tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the α,β-unsaturated carbonyl group, failed to induce HO-1 expression as well as Nrf2 nuclear translocation of Nrf2 and its binding to the antioxidant/electrophile response elements. Cells transfected with a mutant Keap1 protein in which cysteine 151 is replaced by serine exhibited marked reduction in curcumin-induced Nrf2 transactivation. Mass spectrometric analysis revealed that curcumin binds to Keap1 Cys151, supporting that this amino acid is a critical target for curcumin modification of Keap1, which facilitates the liberation of Nrf2. Thus, it is likely that the α,β-unsaturated carbonyl moiety of curcumin is critical essential for its binding to Keap1 and stabilization of Nrf2 by hampering ubiquitination and proteasomal degradation.
    Keywords:  Chemoprevention; Curcumin; Heme oxygenase; Keap1; Nrf2
    DOI:  https://doi.org/10.1016/j.bcp.2020.113820
  79. J Cancer. 2020 ;11(5): 1270-1276
    Nicotine Upregulates the Level of Mcl-1 through STAT3 in H1299 Cells.
    Zhou M, Zhao J, Zhang Q, Jin X, Liao M, Zhang L, Wang J, Yang M.
      Background: Nicotine contributes to development of human lung cancer and chemoresistance through activation of myeloid cell leukemia-1 (Mcl-1). Signal transducer and activator of transcription 3 (STAT3) generally participates in development and progression of human cancers. Therefore, we examined the STAT3 cascade in nicotine regulation of Mcl-1 transcription in human lung cancer cells. Methods: The effects of nicotine on the expression of STAT3 and Mcl-1 were determined using western blot. The sub-cellular localization was tested using immunofluorescence. The activity of STAT3 promoter was checked using dual luciferase reporter assay. Results: STAT3 was constitutively activated (i.e., tyrosine-phosphorylated, serine-phosphorylated and nuclear translocation), meanwhile the expression and transcriptional activity of Mcl-1 were up-regulated in lung cancer cells following treatment with nicotine. Transfection with siRNA targeting STAT3 or treatment with STAT3 inhibitor JSI-124 diminished Mcl-1 protein levels. Deleted mutagenesis of a putative STAT3 consensus binding sequence decreased Mcl-1 promoter activity and eliminated the increase of Mcl-1 promoter activity induced by nicotine. Abnormally, JAK (Jannus kinase) inhibitor AG490 can't induce the downregulation of Mcl-1 or inhibit the tyrosine-phosphorylation of STAT3. In addition, deactivated mutagenesis of STAT3 the tyrosine 705 site had no effect on the aggregation of STAT3 into nucleus induced by nicotine. Conclusions: We have demonstrated that nicotine induces up-regulation of Mcl-1 through STAT3, which process may be independent on JAKs and not only dependent on the phosphorylation of Y705. Downregulation of Mcl-1 transcription by inhibiting STAT3 cascade may be a potential strategy for the treatment of this cancer.
    Keywords:  Mcl-1; STAT3; lung cancer; nicotine
    DOI:  https://doi.org/10.7150/jca.35453
  80. In Vitro Cell Dev Biol Anim. 2020 Jan 22.
    Delineating cell behavior and metabolism of non-melanoma skin cancer in vitro.
    Mendez T, Saffari S, Cowan JM, Laver NMV, Baleja JD, Alt-Holland A.
      Non-melanoma skin cancers - basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) - are the most frequent forms of malignant neoplasm in humans worldwide. The etiology of these carcinomas is multifactorial. In addition to the harmful effect of UV light, altered cross-talk between neoplastic epithelial cells and the supporting dermal fibroblasts contributes to the regulation of tumor cell behavior, growth and survival. Metabolic cooperation between these cell types allows them to adapt and react to changes in their surrounding microenvironment by modifying their cellular bioenergetics and biosynthesis. We characterized the growth, behavior, and metabolic activity of human BCC cells, E-cadherin-competent SCC cells and E-cadherin-suppressed SCC cells in the presence or absence of dermal fibroblasts. In mono-cultures and co-cultures, BCC and SCC cells demonstrated distinct morphology, growth and organizational patterns. These tumor cells also exhibited unique patterns of consumption and secretion profiles of glucose, lactate, acetate, glutamine, glutamate, and pyruvate. In comparison to mono-cultures, growth of fibroblasts with either BCC cells or SCC cells enriched the cell growth environment, allowed for metabolic cooperation between these two cell types, and resulted in alterations in the metabolic profiles of the co-cultures. These alterations were affected by the cancer cell type, culture confluence and the composition of the growth medium. Characterizing the bioenergetics of BCC and SCC cells in the context of tumor-stromal interactions is not only important for further understanding of tumor pathogenesis, but also can illuminate potential new targets for novel, metabolic-based therapies for non-melanoma skin cancers.
    Keywords:  Basal cell carcinoma; Fibroblasts; Human; Metabolomics; Squamous cell carcinoma
    DOI:  https://doi.org/10.1007/s11626-019-00416-6
  81. Surg Today. 2020 Jan 21.
    Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy.
    Sugimoto S, Soh J, Suzawa K, Miyoshi K, Otani S, Yamamoto H, Okazaki M, Yamane M, Oto T, Kanazawa S, Kiura K, Toyooka S.
      PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment.METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018.
    RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59).
    CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.
    Keywords:  Aspergillosis; Chemotherapy; Lung cancer; Radiation; Surgery
    DOI:  https://doi.org/10.1007/s00595-020-01960-5
  82. Sci Rep. 2020 Jan 22. 10(1): 959
    Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines.
    Otahal A, Aydemir D, Tomasich E, Minichsdorfer C.
      Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to overcome tyrosine kinase inhibitor (TKI) resistance in epithelial growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) cells in vivo and in vitro. However, little is known about the putative induction of non-apoptotic cell death pathways by statins. We investigated the effects of pitavastatin and fluvastatin alone or in combination with erlotinib in three NSCLC cell lines and examined the activation of different cell death pathways. We assessed apoptosis via fluorometric caspase assay and poly (ADP-ribose) polymerase 1 (PARP) cleavage. Furthermore, annexinV/propidium iodide (PI) flow cytometry was performed. Small molecule inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD), necrostatin 1 (Nec1), ferrostatin 1 (Fer1), Ac-Lys-Lys-Norleucinal (Calp1) were used to characterise cell death pathway(s) putatively (co-)activated by pitavastatin/erlotinib co-treatment. Synergism was calculated by additivity and isobolographic analyses. Pitavastatin and fluvastatin induced cell death in EGFR TKI resistant NSCLC cells lines A549, Calu6 and H1993 as shown by caspase 3 activation and PARP cleavage. Co-treatment of cells with pitavastatin and the EGFR TKI erlotinib resulted in synergistically enhanced cytotoxicity compared to pitavastatin monotherapy. Flow cytometry indicated the induction of alternative regulated cell death pathways. However, only co-treatment with mevalonic acid (Mev) or the pan-caspase inhibitor zVAD could restore cell viability. The results show that cytotoxicity mediated by statin/erlotinib co-treatment is synergistic and can overcome erlotinib resistance in K-ras mutated NSCLC and relies only on apoptosis.
    DOI:  https://doi.org/10.1038/s41598-020-57707-2
  83. Pathol Int. 2020 Jan 23.
    Negative reactions of BRAF mutation-specific immunohistochemistry to non-V600E mutations of BRAF.
    Seto K, Haneda M, Masago K, Fujita S, Kato S, Sasaki E, Hosoda W, Murakami Y, Kuroda H, Horio Y, Hida T, Okubo K, Yatabe Y.
      BRAF mutations are rare driver mutations in non-small cell lung cancer (NSCLC), accounting for 1%-2% of the driver mutations, and the mutation spectrum has a wide range in contrast to other tumors. While V600E is a dominant mutation in melanoma, more than half of the mutations in NSCLCs are non-V600E. However, treatment with dabrafenib plus trametinib targets the BRAF V600E mutation exclusively. Therefore, distinguishing between V600E and non-V600E mutations is crucial for biomarker testing in NSCLC in order to determine treatment of choice. Immunohistochemistry (IHC) using the BRAF V600E mutation-specific antibody is clinically used in melanoma patients, but little is known about its application in NSCLC, particularly with regard to the assay performance for non-V600E mutations. In the present study, we examined 117 tumors with BRAF mutations, including 30 with non-V600E mutations, using BRAF mutation-specific IHC. None of the tumors with non-V600E mutations, including two compound mutations, showed a positive reaction. Furthermore, all V600E mutations were positive except for one case with combined BRAF V600E and K601_W604 deletion. Our findings confirmed that the BRAF V600E mutation-specific IHC is specific without any cross-reactions to non-V600E mutations, suggesting that this assay can be a useful screening tool in clinical practice.
    Keywords:  BRAF; biomarker testing; immunohistochemistry; lung cancer
    DOI:  https://doi.org/10.1111/pin.12903
  84. Haematologica. 2020 Jan 23. pii: haematol.2019.238865. [Epub ahead of print]
    AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes.
    Rab MAE, van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, van Straaten S, van Solinge WW, van Beers EJ, Kung C, van Wijk R.
      Pyruvate kinase (PK) deficiency is a rare hereditary disorder affecting red cell (RBC) glycolysis, causing changes in metabolism including a deficiency in ATP. This affects red cell homeostasis, promoting premature removal of RBCs from the circulation. In this study we characterized and evaluated the effect of AG-348, an allosteric activator of PK that is currently in clinical trials for treatment of PK deficiency, on RBCs and erythroid precursors from PK-deficient patients. In 15 patients ex vivo treatment with AG-348 resulted in increased enzymatic activity in all patient cells after 24 hours (mean increase 1.8-fold, range 1.2-3.4). ATP levels increased (mean increase 1.5-fold, range 1.0-2.2) similar to control cells (mean increase 1.6-fold, range, 1.4-1.8). Generally, PK thermostability was strongly reduced in PK-deficient RBCs. Ex vivo treatment with AG-348 increased residual activity 1.4 to >10-fold than residual activity of vehicle-treated samples. Protein analyses suggests that a sufficient level of PK protein is required for cells to respond to AG-348 treatment ex-vivo, as treatment effects were minimal in patient cells with very low or undetectable levels of PK-R. In half of the patients, ex vivo treatment with AG-348 was associated with an increase in RBC deformability. These data support the hypothesis that drug intervention with AG-348 effectively upregulates PK enzymatic activity and increases stability in PK-deficient RBCs over a broad range of PKLR genotypes. The concomitant increase in ATP levels suggests that glycolytic pathway activity may be restored. AG-348 treatment may represent an attractive way to correct the underlying pathologies of PK deficiency. (AG-348 is currently in clinical trials for the treatment of PK deficiency. ClinicalTrials.gov: NCT02476916, NCT03853798, NCT03548220, NCT03559699).
    Keywords:  Hemolytic anemia; Pyruvate kinase deficiency; Red Cell Enzyme Abnormalities; Red Cells; Treatment of pyruvate kinase deficiency
    DOI:  https://doi.org/10.3324/haematol.2019.238865
  85. Chin J Integr Med. 2020 Jan 23.
    Modified Liujunzi Decoction () Alleviates Chemotherapy-Induced Anorexia in Advanced Non-Small Cell Lung Cancer: A Propensity Score Matched Case-Control Study.
    Sun LL, Lai HZ, Chen ZZ, Zhu XS, Lin LZ.
      OBJECTIVE: To evaluate the effect of Chinese herbal medicine formula, modified Liujunzi Decoction (, MLJZT), for anorexia, utilized as adjunct therapy during chemotherapy treatment for patients with advanced non-small cell lung cancer (NSCLC).METHODS: The study adopted a propensity score-matched design based on a prospective database. From February 2016 to September 2017, patients with advanced NSCLC that received both cisplatin-based chemotherapy and MLJZT (IM group) were 1:1 propensity score-matched to patients that received the cisplatin-based chemotherapy alone (control group). Changes in anorexia and weight, as well as side effects were evaluated per week within 4-cycle chemotherapy.
    RESULTS: Overall, 156 patients with advanced NSCLC that had received chemotherapy from our database were identified and 53 pairs were matched successfully. In total, 48.6% (50/53) of patients in the IM group had anorexia-improvement compared to 28.3% (15/53) of patients in the control group, and a total of 39.6% (21/53) of patients in the control group had a worsening of anorexia compared to only 7.8% (8/53) of patients in the IM group (P<0.01). The weight reduced significantly over time in the control group (-2.36 ± 2.53 kg) as compared to the IM group (-0.62 ± 3.89 kg, P<0.01). CHM didn't reduce the efficacy of chemotherapy in shrinking tumor size, and didn't increase the incidence of side effects such as hematological and hepatorenal toxicity.
    CONCLUSION: MLJZT is effective and safe for alleviating anorexia in patients with NSCLC. These findings warrant the conduct of a randomized controlled trial.
    Keywords:  Chinese medicine; anorexia; chemotherapy; food intake; lung cancer
    DOI:  https://doi.org/10.1007/s11655-020-3185-5
  86. ESMO Open. 2020 Jan;pii: e000567. [Epub ahead of print]5(1):
    Exploratory analysis of front-line therapies in REVEL: a randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy.
    Garon EB, Scagliotti GV, Gautschi O, Reck M, Thomas M, Iglesias Docampo L, Kalofonos H, Kim JH, Gans S, Brustugun OT, Orlov SV, Cuyun Carter G, Zimmermann AH, Oton AB, Alexandris E, Lee P, Wolff K, Stefaniak VJ, Socinski MA, Pérol M.
      INTRODUCTION: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease. Front-line therapy may affect responses to subsequent treatment regimens, thus influencing second-line therapy decision making. In the randomised phase 3 REVEL study, second-line ramucirumab plus docetaxel (ram+doc) versus docetaxel (doc) improved survival of patients with metastatic NSCLC. We explore efficacy, safety and quality-of-life (QoL) in REVEL based on front-line therapy.METHODS: Patients were grouped by specific front-line therapy received. Overall survival (OS), progression-free survival (PFS), objective response rate, safety and QoL were assessed descriptively. Kaplan-Meier estimation and Cox proportional hazards modelling were used; frequencies reported in percentages.
    RESULTS: Baseline characteristics of 1253 patients were generally well balanced between treatment arms within each front-line therapy subgroup. For patients with non-squamous disease (n=912), induction therapies included platinum-based chemotherapy plus a taxane (n=227; 25%) or pemetrexed (n=449; 49%), with (n=172; 19%) or without bevacizumab. For patients with squamous disease (n=328), induction therapies included platinum-based chemotherapy plus gemcitabine (n=176; 54%) or a taxane (n=69; 21%). A highly selected subgroup (n=127; 14%) received pemetrexed continuation maintenance therapy. Ram+doc improved median OS and PFS versus doc across front-line therapy subgroups, as reflected by HRs ranging from 0.78 to 0.91 and 0.66 to 0.92, respectively, similar to results in the overall intention-to-treat cohort (HRs: 0.86 and 0.76, respectively). High-grade treatment-emergent adverse events of special interest (including neutropenia, febrile neutropenia, leucopenia and hypertension) were generally higher in ram+doc-treated patients relative to doc-treated patients regardless of front-line therapy. No clear differences in safety or QoL were seen across front-line therapy subgroups; outcomes were consistent with those reported in the overall intention-to-treat cohort.
    CONCLUSIONS: Results of this exploratory analysis suggest that second-line ram+doc may be effective regardless of prior treatment with platinum-based chemotherapy plus a taxane, pemetrexed, gemcitabine or bevacizumab. Overall, ram+doc is clinically beneficial across a wide range of patients with metastatic NSCLC who have progressed after various front-line therapies.
    TRIAL REGISTRATION NUMBER: NCT01168973.
    Keywords:  chemotherapy; metastatic; non-squamous; squamous; vascular endothelial growth factor receptor
    DOI:  https://doi.org/10.1136/esmoopen-2019-000567
  87. Clin Lung Cancer. 2019 Dec 28. pii: S1525-7304(19)30373-0. [Epub ahead of print]
    Patient-reported Outcomes After the Treatment of Early Stage Non-small-cell Lung Cancer With Stereotactic Body Radiotherapy Compared With Surgery.
    Alberts L, Wolff HB, Kastelijn EA, Schramel FMNH, Coupe VMH.
      
    DOI:  https://doi.org/10.1016/j.cllc.2019.12.005
  88. Sci Rep. 2020 Jan 20. 10(1): 700
    Systematic impacts of chronic unpredictable mild stress on metabolomics in rats.
    Geng C, Guo Y, Wang C, Liao D, Han W, Zhang J, Jiang P.
      Depression is the most common disabling psychiatric disease, with a high prevalence and mortality. Chronic unpredictable mild stress (CUMS) is a well-accepted method used to mimic clinical depression. Recent evidence has consistently suggested that the cumulative effects of CUMS could lead to allostatic overload in the body, thereby inducing systemic disorders; however, there are no previous systematic metabonomics studies on the main stress-targeted tissues associated with depression. A non-targeted gas chromatography-mass spectrometry (GC-MS) approach was used to identify metabolic biomarkers in the main stress-targeted tissues (serum, heart, liver, brain, and kidney) in a CUMS model of depression. Male Sprague-Dawley rats were randomly allocated to the CUMS group (n = 8) or a control group (n = 8). Multivariate analysis was performed to identify the metabolites that were differentially expressed between the two groups. There were 10, 10, 9, 4, and 7 differentially expressed metabolites in the serum, heart, liver, brain and kidney tissues, respectively, between the control and CUMS groups. These were linked to nine different pathways related to the metabolism of amino acids, lipids, and energy. In summary, we provided a comprehensive understanding of metabolic alterations in the main stress-targeted tissues, helping to understand the potential mechanisms underlying depression.
    DOI:  https://doi.org/10.1038/s41598-020-57566-x
  89. J Bras Pneumol. 2020 ;pii: S1806-37132020000100207. [Epub ahead of print]46(1): e20180251
    Tumor-node-metastasis staging and treatment patterns of 73,167 patients with lung cancer in Brazil.
    Costa GJ, Mello MJG, Bergmann A, Ferreira CG, Thuler LCS.
      OBJECTIVE: To characterize the clinical and histological profile, as well as treatment patterns, of patients with early-stage, locally advanced (LA), or advanced/metastatic (AM) lung cancer, diagnosed between 2000 and 2014, in Brazil.METHODS: This was an analytical cross-sectional epidemiological study employing data obtained for the 2000-2014 period from the hospital cancer registries of two institutions in Brazil: the José Alencar Gomes da Silva National Cancer Institute, in the city of Rio de Janeiro; and the São Paulo Cancer Center Foundation, in the city of São Paulo.
    RESULTS: We reviewed the data related to 73,167 patients with lung cancer. The proportions of patients with early-stage, LA, and AM lung cancer were 13.3%, 33.2%, and 53.4%, respectively. The patients with early-stage lung cancer were older and were most likely to receive a histological diagnosis of adenocarcinoma; the proportion of patients with early-stage lung cancer remained stable throughout the study period. In those with LA lung cancer, squamous cell carcinoma predominated, and the proportion of patients with LA lung cancer decreased significantly over the period analyzed. Those with AM lung cancer were younger and were most likely to have adenocarcinoma; the proportion of patients with AM lung cancer increased significantly during the study period. Small cell carcinoma accounted for 9.2% of all cases. In our patient sample, the main treatment modality was chemotherapy.
    CONCLUSIONS: It is noteworthy that the frequency of AM lung cancer increased significantly during the study period, whereas that of LA lung cancer decreased significantly and that of early-stage lung cancer remained stable. Cancer treatment patterns, by stage, were in accordance with international guidelines.
    DOI:  https://doi.org/10.1590/1806-3713/e20180251
  90. Cell Death Differ. 2020 Jan 22.
    Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer.
    Yang L, Li N, Xue Z, Liu LR, Li J, Huang X, Xie X, Zou Y, Tang H, Xie X.
      Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.
    DOI:  https://doi.org/10.1038/s41418-019-0485-4
  91. Genes (Basel). 2020 Jan 16. pii: E104. [Epub ahead of print]11(1):
    Transmission of Functional, Wild-Type Mitochondria and the Fittest mtDNA to the Next Generation: Bottleneck Phenomenon, Balbiani Body, and Mitophagy.
    Tworzydlo W, Sekula M, Bilinski SM.
      The most important role of mitochondria is to supply cells with metabolic energy in the form of adenosine triphosphate (ATP). As synthesis of ATP molecules is accompanied by the generation of reactive oxygen species (ROS), mitochondrial DNA (mtDNA) is highly vulnerable to impairment and, consequently, accumulation of deleterious mutations. In most animals, mitochondria are transmitted to the next generation maternally, i.e., exclusively from female germline cells (oocytes and eggs). It has been suggested, in this context, that a specialized mechanism must operate in the developing oocytes enabling escape from the impairment and subsequent transmission of accurate (devoid of mutations) mtDNA from one generation to the next. Literature survey suggest that two distinct and irreplaceable pathways of mitochondria transmission may be operational in various animal lineages. In some taxa, the mitochondria are apparently selected: functional mitochondria with high inner membrane potential are transferred to the cells of the embryo, whereas those with low membrane potential (overloaded with mutations in mtDNA) are eliminated by mitophagy. In other species, the respiratory activity of germline mitochondria is suppressed and ROS production alleviated leading to the same final effect, i.e., transmission of undamaged mitochondria to offspring, via an entirely different route.
    Keywords:  Balbiani body; mitochondria selection; mitophagy; oocyte; oogenesis
    DOI:  https://doi.org/10.3390/genes11010104
  92. Cancers (Basel). 2020 Jan 20. pii: E250. [Epub ahead of print]12(1):
    Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells.
    Elaskalani O, Domenchini A, Abdol Razak NB, E Dye D, Falasca M, Metharom P.
      Background: Extensive research has reported that extracellular ADP in the tumour microenvironment can stimulate platelets through interaction with the platelet receptor P2Y12. In turn, activated platelets release biological factors supporting cancer progression. Experimental data suggest that the tumour microenvironment components, of which platelets are integral, can promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Thus, overcoming chemoresistance requires combining multiple inhibitors that simultaneously target intrinsic pathways in cancer cells and extrinsic factors related to the tumour microenvironment. We aimed to determine whether ticagrelor, an inhibitor of the ADP-P2Y12 axis and a well-known antiplatelet drug, could be a therapeutic option for PDAC. Methods: We investigated a functional P2Y12 receptor and its downstream signalling in a panel of PDAC cell lines and non-cancer pancreatic cells termed hTERT-HPNE. We tested the synergistic effect of ticagrelor, a P2Y12 inhibitor, in combination with chemotherapeutic drugs (gemcitabine, paclitaxel and cisplatin), in vitro and in vivo. Results: Knockdown studies revealed that P2Y12 contributed to epidermal growth factor receptor (EGFR) activation and the expression of SLUG and ZEB1, which are transcriptional factors implicated in metastasis and chemoresistance. Studies using genetic and pharmacological inhibitors showed that the P2Y12-EGFR crosstalk enhanced cancer cell proliferation. Inhibition of P2Y12 signalling significantly reduced EGF-dependent AKT activation and promoted the anticancer activity of anti-EGFR treatment. Importantly, ticagrelor significantly decreased the proliferative capacity of cancer but not normal pancreatic cells. In vitro, synergism was observed when ticagrelor was combined with several chemodrugs. In vivo, a combination of ticagrelor with gemcitabine significantly reduced tumour growth, whereas gemcitabine or ticagrelor alone had a minimal effect. Conclusions: These findings uncover a novel effect and mechanism of action of the antiplatelet drug ticagrelor in PDAC cells and suggest a multi-functional role for ADP-P2Y12 signalling in the tumour microenvironment.
    Keywords:  ADP; P2Y12; antiplatelet drug; chemoresistance; pancreatic cancer
    DOI:  https://doi.org/10.3390/cancers12010250
  93. Clin Transl Oncol. 2020 Jan 18.
    Sequential blinded treatment decisions in ALK-positive non-small cell lung cancers in the era of precision medicine.
    Remon J, Tabbò F, Jimenez B, Collazo A, de Castro J, Novello S.
      Next-generation ALK TKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, sequential strategies at progression are relevant, as may have an impact on patients' outcome. In this commentary we discuss whether genomic-tailored strategies at progression would be more suitable for improving outcome of ALK-positive NSCLC patients.
    Keywords:  ALK; Liquid biopsy; Next-generation; Non-small cell lung cancer; Sequential treatment
    DOI:  https://doi.org/10.1007/s12094-020-02290-1
  94. Cancer Biother Radiopharm. 2020 Jan 20.
    Target Alpha Therapy with Thorium-227.
    Frantellizzi V, Cosma L, Brunotti G, Pani A, Spanu A, Nuvoli S, De Cristofaro F, Civitelli L, De Vincentis G.
      Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity to normal surrounding cell. Radium-223 (223Ra), the first-in-class a-emitter approved for bone metastatic castration-resistant prostate cancer has shown the ability to prolong patient survival. Targeted Thorium-227 (227Th) conjugates represent a new class of therapeutic radiopharmaceuticals for TAT. They are comprised of the α-emitter 227Th complexed to a chelator conjugated to a tumor-targeting monoclonal antibody. In this review, the authors will focus out interest on this therapeutic agent. In recent studies 227Th-labeled radioimmunoconjugates showed a relevant stability both in serum and vivo conditions with a significant antigen-dependent inhibition of cell growth. Unlike 223Ra, the parent radionuclide 227Th can form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. The authors discuss the future potential role of 227Th TAT in the treatment of several solid as well as hematologic malignancies.
    Keywords:  cancer; radionuclide therapy; review; targeted therapy; thorium-227; α-emitter
    DOI:  https://doi.org/10.1089/cbr.2019.3105
  95. Ann Oncol. 2020 Feb;pii: S0923-7534(19)36079-X. [Epub ahead of print]31(2): 289-294
    Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.
    Mazieres J, Cropet C, Montané L, Barlesi F, Souquet PJ, Quantin X, Dubos-Arvis C, Otto J, Favier L, Avrillon V, Cadranel J, Moro-Sibilot D, Monnet I, Westeel V, Le Treut J, Brain E, Trédaniel J, Jaffro M, Collot S, Ferretti GR, Tiffon C, Mahier-Ait Oukhatar C, Blay JY.
      BACKGROUND: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort.PATIENTS AND METHODS: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS).
    RESULTS: Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications.
    CONCLUSION: Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations.
    TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02304809.
    Keywords:  BRAF; basket trial; biomarker; lung cancer; personalised therapy; vemurafenib
    DOI:  https://doi.org/10.1016/j.annonc.2019.10.022
  96. Nat Commun. 2020 Jan 23. 11(1): 449
    Chromosome arm aneuploidies shape tumour evolution and drug response.
    Shukla A, Nguyen THM, Moka SB, Ellis JJ, Grady JP, Oey H, Cristino AS, Khanna KK, Kroese DP, Krause L, Dray E, Fink JL, Duijf PHG.
      Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform  mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology.
    DOI:  https://doi.org/10.1038/s41467-020-14286-0
  97. Aging (Albany NY). 2020 Jan 20. 12
    DNAH10 mutation correlates with cisplatin sensitivity and tumor mutation burden in small-cell lung cancer.
    Li M, Lin A, Luo P, Shen W, Xiao D, Gou L, Zhang J, Guo L.
      Chemotherapies based on platinum have been the standard first-line treatment for patients with small-cell lung cancer(SCLC) in the past years. However, the progression of patients occurs mostly due to rapid development of resistance to chemotherapy. In addition, the mechanisms involved in development of cisplatin-resistance in SCLC remain undetermined. Here, we analyzed whole-exome sequencing(WES) datasets from Genomics of Drug Sensitivity in Cancer(GDSC, N=55) and WES data and overall survival(OS) from a published cohort(N=101) to search for cisplatin-resistant target genes and genes associated with poor prognosis. We use our cohort(NCT03162705) as the validation set. We applied single sample gene set enrichment analysis(ssGSEA) to explore the potential molecular mechanisms of cisplatin-resistance. DNAH10 mutations in SCLC was significantly associated with cisplatin-resistance(P=0.0350), poor OS(HR:3.445;P=0.00035) and worse progression-free survival (PFS)(P=0.0142). ssGSEA showed that the negative regulation of FGFR, the SPRY regulation of FGF, and the positive regulation of noncanonical WNT and PI3K/AKT/IKK signaling pathways are differentially up- or downregulated in DNAH10-mutated cell lines. A higher TMB was observed in DNAH10-mutated cell lines. Taken together, DNAH10 mutations may have a potential value in prediction of cisplatin resistance and poor survival in SCLC. Moreover, DNAH10 mutations may have a positive correlation with high TMB in SCLC.
    Keywords:  DNAH10; cisplatin; resistance; small cell lung cancer; tumor mutation burden
    DOI:  https://doi.org/10.18632/aging.102683
  98. PLoS One. 2020 ;15(1): e0227634
    Restoration of Mal overcomes the defects of apoptosis in lung cancer cells.
    Yang LT, Ma F, Zeng HT, Zhao M, Zeng XH, Liu ZQ, Yang PC.
      BACKGROUND AND AIMS: Cancer is one of the life-threatening diseases of human beings; the pathogenesis of cancer remains to be further investigated. Toll like receptor (TLR) activities are involved in the apoptosis regulation. This study aims to elucidate the role of Mal (MyD88-adapter-like) molecule in the apoptosis regulation of lung cancer (LC) cells.METHODS: The LC tissues were collected from LC patients. LC cells and normal control (NC) cells were isolated from the tissues and analyzed by pertinent biochemical and immunological approaches.
    RESULTS: We found that fewer apoptotic LC cells were induced by cisplatin in the culture as compared to NC cells. The expression of Fas ligand (FasL) was lower in LC cells than that in NC cells. FasL mRNA levels declined spontaneously in LC cells. A complex of FasL/TDP-43 was detected in LC cells. LC cells expressed less Mal than NC cells. Activation of Mal by lipopolysaccharide (LPS) increased TDP-43 expression in LC cells. TDP-43 formed a complex with FasL mRNA to prevent FasL mRNA from decay. Reconstitution of Mal or TDP-43 restored the sensitiveness of LC cells to apoptotic inducers.
    CONCLUSIONS: LC cells express low Mal levels that contributes to FasL mRNA decay through impairing TDP-43 expression. Reconstitution of Mal restores sensitiveness of LC cells to apoptosis inducers that may be a novel therapeutic approach for LC treatment.
    DOI:  https://doi.org/10.1371/journal.pone.0227634
  99. Blood. 2020 Jan 23. pii: blood.2019003543. [Epub ahead of print]
    Thrombin-mediated activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease.
    Sparkenbaugh EM, Chen C, Brzoska T, Nguyen J, Wang S, Vercellotti GM, Key NS, Sundd P, Belcher JD, Pawlinski R.
      Vaso-occlusive crisis (VOC) is the primary cause of morbidity and hospitalization in sickle cell disease (SCD). However, only three therapies (hydroxyurea, L-glutamine, and crizanlizumab) are currently approved in SCD. These agents limit the duration, severity, and frequency of crises. Activation of coagulation is a hallmark of SCD. Studies in animal models of SCD have shown that coagulation contributes to the chronic inflammation and end-organ damage associated with the disease. However, it is unknown if coagulation directly contributes to the microvascular stasis that causes VOC. Herein, we demonstrate that inhibition of tissue factor (TF) and the downstream coagulation proteases, factor Xa and thrombin, significantly attenuates heme-induced microvascular stasis in mouse models of VOC. Pharmacologic inhibition of the principal thrombin receptor, protease activated receptor-1 (PAR-1) as well as deficiency of PAR-1 in all non-hematopoietic cells, also reduces stasis in sickle mice. PAR-1 deficiency was associated with reduced endothelial von Willebrand factor (vWF) expression, which has been shown to mediate microvascular stasis. In addition, TF inhibition reduces lung vaso-occlusion in sickle mice mediated by arteriolar neutrophil-platelet microemboli. In sum, these results suggest that prophylactic anticoagulation might attenuate the incidence of VOC.
    DOI:  https://doi.org/10.1182/blood.2019003543
  100. South Asian J Cancer. 2020 Jan-Mar;9(1):9(1): 22
    A rare case of hyperprogression of nonsmall cell lung cancer in a patient on atezolizumab therapy.
    Kollimuttathuillam SV, Kaur S, Shaaban H, Guron G.
      
    DOI:  https://doi.org/10.4103/sajc.sajc_166_19
  101. Gene. 2020 Jan 20. pii: S0378-1119(20)30002-0. [Epub ahead of print] 144333
    Association between COMT gene Val108/158Met and antidepressive treatment response: a meta-analysis.
    Tang Z, Zhang S, Guo D, Wang H.
      Multiple antidepressive treatment methods are widely used in the clinic, but different patients showed considerable differences in response to the same treatment. The catechol-O-methyltransferase (COMT) rs4680 polymorphism is involved in the antidepressive treatment reaction; however, the results in different studies are inconsistent. Thus, we performed a meta-analysis to explore the association of the COMT rs4680 polymorphism with the treatment response in major depressive disorder (MDD) patients. An online search was performed through PubMed, EMBASE and the Cochrane library up to December 2018. The odds ratios (ORs), 95% confidence intervals (95% CI) and heterogeneity were calculated in four genetic models. Subgroup analysis and Galbraith plot were carried out to detect the potential source of heterogeneity. Sensitivity and publication bias analyses were performed to identify the reliability of the results. A total of 11 studies involving 2845 individuals were included in this meta-analysis. The results of the subgroup analysis indicated that patients who carried the G allele had remission or a better response to electroconvulsive therapy (ECT) in four genetic models. Excluding the studies that might lead to heterogeneity, overall ORs were recalculated, and no obvious association between rs4680 polymorphism and therapeutic reaction was detected in the allelic, recessive and additive models. In the dominant model, COMT rs4680 variants showed significant associations with antidepressive treatment, but the result was highly dependent on the individual study. In addition, the patients with the GG or AG+GG genotype in comparison to AA were associated with a better response to ECT treatment. However, due to the small number of studies using ECT treatment, we suggest that more research should be performed to verify this result.
    Keywords:  COMT rs4680; antidepressive treatment; major depressive disorder; meta-analysis; polymorphism
    DOI:  https://doi.org/10.1016/j.gene.2020.144333
  102. Front Pharmacol. 2019 ;10 1512
    Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway.
    Wu Y, Lin L, Wang X, Li Y, Liu Z, Ye W, Huang W, Lin G, Liu H, Zhang J, Li T, Zhao B, Lv L, Li J, Wang N, Liu X.
      Krüppel-like factor 4 (KLF4) is a transcription factor and plays a vital role in cancer initiation and development. However, the role of Krüppel-like factor 4 in the metastasis of non-small cell lung cancer (NSCLC) is not clear. Here, we demonstrated that the expression of Krüppel-like factor 4 was significantly decreased in human non-small cell lung cancer tissues compared with that in normal tissues using Western blot. We performed immunohistochemical staining and observed the decreased expression of Krüppel-like factor 4 in human lung cancer tissues, and metastatic tumor tissues located in the trachea and main bronchus. We also found that the E-cadherin expression was decreased, while vimentin expression was increased in human NSCLC tissues and metastatic tumor tissues located in the trachea and main bronchus. Additionally, enforced expression of Krüppel-like factor 4 in mouse lungs significantly inhibited the metastasis of circulating Lewis lung carcinoma cells to the lungs by attenuating mesenchymal-epithelial transition (MET). Furthermore, cell scratch assays and Matrigel invasion assays revealed that overexpression of Krüppel-like factor 4 inhibited the migration and invasion of non-small cell lung cancer cell lines A549, H1299, H226, and H1650 cells. Moreover, overexpression of Krüppel-like factor 4 attenuated TGF-β1-induced epithelial-mesenchymal transition (EMT) in A549, and inhibited the phosphorylation of c-Jun-NH2-terminal kinase (JNK), an important pathway in metastasis in non-small cell lung cancer. Our in vivo and in vitro findings illustrate that Krüppel-like factor 4 inhibited metastasis and migration of non-small cell lung cancer, and indicate that Krüppel-like factor 4 could be a potential therapeutic target for the treatment of non-small cell lung cancer.
    Keywords:  Krüppel-like factor 4; invasion; metastasis; migration; non-small cell lung cancer
    DOI:  https://doi.org/10.3389/fphar.2019.01512
  103. Biochem Pharmacol. 2020 Jan 20. pii: S0006-2952(20)30027-7. [Epub ahead of print] 113817
    The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.
    Gore A, Gauthier AG, Lin M, Patel V, Thomas DD, Ashb CR, Mantell LL.
      Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize Pseudomonas aeruginosa (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O2) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O2) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM - 800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.
    Keywords:  bacterial killing; hyperoxia; macrophages; migration; nitric oxide; phagocytosis
    DOI:  https://doi.org/10.1016/j.bcp.2020.113817
  104. Cancers (Basel). 2020 Jan 20. pii: E252. [Epub ahead of print]12(1):
    Role of Interleukin-34 in Cancer.
    Franzè E, Stolfi C, Troncone E, Scarozza P, Monteleone G.
      Cross-talk between cancer cells and the immune cells occurring in the tumor microenvironment is crucial in promoting signals that foster tumor growth and metastasis. Both cancer cells and immune cells secrete various interleukins (IL), which, either directly or indirectly, stimulate cancer-cell proliferation, survival, and diffusion, as well as contribute to sculpt the immune microenvironment, thereby amplifying tumorigenic stimuli. IL-34, a cytokine produced by a wide range of cells, has been initially involved in the control of differentiation, proliferation, and survival of myeloid cells. More recent studies documented the overexpression of IL-34 in several cancers, such as hepatocarcinoma, osteosarcoma, multiple myeloma, colon cancer, and lung cancer, and showed that tumor cells can produce and functionally respond to this cytokine. In this review, we summarize the multiple roles of IL-34 in various cancers, with the aim to better understand the relationship between the expression of this cytokine and cancer behavior and to provide new insights for exploring a new potential therapeutic target.
    Keywords:  M-CSF1-R; interleukins; tumor associated macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers12010252
  105. Cancer Immunol Immunother. 2020 Jan 21.
    Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma.
    Li X, Zhang Y, Ma W, Fu Q, Liu J, Yin G, Chen P, Dai D, Chen W, Qi L, Yu X, Xu W.
      From a metabolic perspective, cancer may be considered as a metabolic disease characterized by reprogrammed glycolytic metabolism. The aim of the present study was to investigate CD147-mediated glucose metabolic regulation in hepatocellular carcinoma (HCC) and its contribution to altered immune responses in the tumor microenvironment. Several HCC cell lines and corresponding nude mice xenografts models differing in CD147 expressions were established to directly investigate the role of CD147 in the reprogramming of glucose metabolism, and to determine the underlying molecular mechanisms. Immunohistochemistry (IHC) analyses and flow cytometry were used to identify the relationship between reprogrammed glycolysis and immunosuppression in HCC. Upregulated CD147 expressions were found to be associated with enhanced expressions of GLUT1, MCT1 in HCC tumorous tissues. CD147 promoted the glycolytic metabolism in HCC cell lines in vitro via the PI3K/Akt/mTOR signaling pathway. A positive correlation existed between a profile of immunosuppressive lymphocytes infiltration and CD147 expression in HCC tissues. Accumulation of FOXP3-expressing regulatory T cells was induced under a stimulation with lactate in vitro. In conclusion, CD147 promoted glycolytic metabolism in HCC via the PI3K/Akt/mTOR signaling pathway, and was related to immunosuppression in HCC.
    Keywords:  CD147; Glucose metabolism; Hepatocellular carcinoma; Immunosuppression
    DOI:  https://doi.org/10.1007/s00262-019-02457-y
  106. Sci Rep. 2020 Jan 23. 10(1): 1036
    The optimal sequence of bronchial brushing and washing for diagnosing peripheral lung cancer using non-guided flexible bronchoscopy.
    Lim JH, Kim MJ, Jeon SH, Park MH, Kim WY, Lee M, Kim JH, Kim JS, Kim YS, Kim L, Lee KH, Kwak SM, Shin H, Nam HS.
      The optimum sequence of bronchial brushing and washing for diagnosing peripheral lung cancer, defined as an invisible endobronchial tumour, is not clear and requires further study. We prospectively obtained washing samples after brushing in patients with peripheral lung tumours during non-guided flexible bronchoscopy (FB) to investigate the diagnostic yield of these samples and conducted a retrospective review of the prospectively collected data. The study included 166 patients who met the inclusion criteria. The overall diagnostic yield of bronchial brushing and washing for peripheral lung cancer was 52.4%. The diagnostic yields of brushing and washing were 37.3% and 46.4%, respectively, and that of washing was superior according to McNemar's test (p = 0.017, κ = 0.570). Furthermore, washing was diagnostic, whereas brushing was not, in 15.1% of all cases. Comparison of positive washing cytology (brushing) with the respective pathological diagnosis yielded a concordance rate of 88.3% (90.3%), with κ = 0.769 (0.801) (p < 0.001). Performing washing after brushing during non-guided FB is a very safe, cost-effective procedure that may help improve the diagnostic yield in patients with suspected peripheral lung cancer. Our information will also benefit clinicians performing diagnostic bronchoscopy in patients with suspected peripheral lung cancer when fluoroscopic guidance or advanced bronchoscopy techniques are not available.
    DOI:  https://doi.org/10.1038/s41598-020-58010-w
  107. Molecules. 2020 Jan 17. pii: E392. [Epub ahead of print]25(2):
    PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice.
    Arruda AC, Perilhão MS, Santos WA, Gregnani MF, Budu A, Neto JCR, Estrela GR, Araujo RC.
      Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.
    Keywords:  MATE-1; OCT-2; PPARα; kidney; metformin; transcription
    DOI:  https://doi.org/10.3390/molecules25020392
  108. Adv Respir Med. 2019 ;87(6): 265-267
    Not everything is what it seems: malignant pleural mesothelioma mimicking lung cancer.
    Prisciandaro E, Girelli L, Rampinelli C, Ghioni M, Spaggiari L.
      Malignant pleural mesothelioma usually arises from the pleural surface and progressively encases the lungs. Pulmonary involvement generally occurs at an advanced stage, while intraparenchymal nodules, in the absence of pleural lesions, constitute a less frequent presentation. We describe the case of a patient with multiple bilateral pulmonary nodules, mediastinal lymphadenopathies and left pleural effusion in the absence of pleural lesions, simulating advanced stage lung cancer. Thoracoscopic inspection did not detect any lesions. Pathological examination on one pulmonary nodule revealed malignant pleural mesothelioma. Despite its rarity, intraparenchymal malignant pleural mesothelioma should always be taken into account, when lung nodules are present, to prevent misdiagnosis and avoid delayed treatment.
    Keywords:  differential diagnosis; intraparenchymal mesothelioma; lung cancer; lung nodule; malignant pleural mesothelioma
    DOI:  https://doi.org/10.5603/ARM.2019.0065
  109. Clin Nucl Med. 2020 Jan 17.
    18F-FDG PET/CT Evaluation of Crizotinib and Lorlatinib Therapy in Metastatic ROS-1-Positive Non-Small Cell Lung Cancer.
    Dejust S, Moubtakir A, Prevost A, El Farsaoui K, Morland D.
      ROS-1-positive non-small cell lung cancers (NSCLCs) are rare (approximately 1% of all NSCLCs) and require a first-line treatment by crizotinib. Crizotinib resistance is frequent within the first 12 months of treatment. Lorlatinib is a novel tyrosine kinase inhibitor of ROS-1 recently indicated for metastatic or locally advanced crizotinib-resistant NSCLC. We report the use of lorlatinib as second-line with a complete tumoral response after only 3 months of treatment. This case shows the major role of F-FDG PET/CT in treatment evaluation and monitoring targeted therapy in metastatic NSCLC.
    DOI:  https://doi.org/10.1097/RLU.0000000000002912
  110. Cancer Med. 2020 Jan 22.
    Relevance and prognostic ability of Twist, Slug and tumor spread through air spaces in lung adenocarcinoma.
    Liu A, Sun X, Xu J, Xuan Y, Zhao Y, Qiu T, Hou F, Qin Y, Wang Y, Lu T, Wo Y, Li Y, Xing X, Jiao W.
      BACKGROUND: Tumor spread through air spaces (STAS) is a novel pathologic characteristic in lung adenocarcinomas that indicates invasive tumor behavior. We aimed to explore the relationship between Twist, Slug and STAS in lung adenocarcinoma and to investigate the potential relationship between epithelial-mesenchymal transition (EMT) and STAS.MATERIALS AND METHODS: Our study retrospectively analyzed 115 patients with resected lung adenocarcinomas to evaluate the relationship between Twist, Slug and STAS. STAS was diagnosed using hematoxylin-eosin (H&E) staining. Immunohistochemistry was used to evaluate the expression levels of Slug and Twist.
    RESULTS: In this study, 56 (48.7%) patients had STAS, 40 (34.8%) patients had Slug overexpression, and 28 (24.3%) patients had Twist overexpression. Patients with either STAS or Slug and Twist overexpression experienced poor recurrence-free survival (RFS) and overall survival (OS). There were significant associations between Twist overexpression, Slug overexpression and the presence of STAS. The logistic model further revealed that pathological stage, Twist overexpression and Slug overexpression were independent risk factors for STAS. A multivariate analysis that contained Twist, Slug, pathologic stage and STAS, showed that pathologic stage and STAS were independent prognostic factors for poor RFS and OS. Another multivariate model that contained Twist, Slug and pathologic stage, showed that pathologic stage, Twist overexpression and Slug overexpression were independent risk factors for poor RFS and OS. In the cohort with STAS, the multivariate analysis showed that pathologic stage and Twist overexpression were independent risk factors for poor survival. The subgroup analysis showed that patients with both Slug overexpression and Twist overexpression with STAS received a poor prognosis.
    CONCLUSIONS: STAS, Slug and Twist were correlated with poor RFS and OS in resected lung adenocarcinomas. Additionally, STAS was correlated with the overexpression of Twist and Slug, which could potentially provide information on the mechanism of STAS.
    Keywords:  Slug; Twist; lung adenocarcinoma; tumor spread through air spaces
    DOI:  https://doi.org/10.1002/cam4.2858
  111. Clin Lung Cancer. 2019 Dec 30. pii: S1525-7304(19)30324-9. [Epub ahead of print]
    Stereotactic Body Radiation Therapy for Extracranial Oligometastatic Non-small-cell Lung Cancer: A Systematic Review.
    Tsao MN, Ven LI', Cheung P, Poon I, Ung Y, Louie AV.
      Stereotactic body radiation therapy (SBRT) has emerged as a treatment modality for selected patients with oligometastatic non-small-cell lung cancer (NSCLC). The objectives of this systematic review were to explore the benefits and risks of SBRT for extracranial oligometastatic NSCLC. The MEDLINE, Embase, PubMed, and CENTRAL databases were searched for relevant articles from January 1, 2000 to July 23, 2019. Fully published phase III or phase II trials of any sample size were included. Retrospective series published in manuscript form with at least 50 patients were also included. Four prospective phase II randomized trials (total, 188 participants), 4 prospective non-randomized studies (total, 140 participants), and eleven retrospective studies (total, 1288 participants) were included in this systematic review. A variety of dose fractionation schemes were used. The median overall survival (OS) ranged from 13.5 to 55 months. Progression-free survival (PFS) ranged from 4.4 to 14.7 months. Quality of life outcomes were reported in 2 studies. None of the studies reported symptom control outcomes. There are no fully completed phase III randomized trials that clarify the risks and benefits of SBRT for oligometastatic NSCLC. Higher PFS and OS with SBRT were reported in 4 phase II randomized studies. The results from mature phase III randomized data regarding whether SBRT for oligometastatic NSCLC benefits patients in terms of OS, PFS, quality of life, and symptom control are needed.
    Keywords:  Chest; Malignancy; Metastatic; SBRT; Summary
    DOI:  https://doi.org/10.1016/j.cllc.2019.11.007
  112. J Cancer. 2020 ;11(5): 1075-1081
    Systematic analyses of genetic variants in chromatin interaction regions identified four novel lung cancer susceptibility loci.
    Ji P, Ding D, Qin N, Wang C, Zhu M, Li Y, Dai J, Jin G, Hu Z, Shen H, Chen L, Ma H.
      Genome-wide association studies (GWAS) have reported 45 single-nucleotide polymorphisms (SNPs) that may contribute to the susceptibility of lung cancer, with the majority in non-coding regions. However, no study has ever systematically evaluated the association between SNPs in physical chromatin interaction regions and lung cancer risk. In this study, we integrated the chromatin interaction information (Hi-C data) of lung cancer cell line and conducted a meta-analysis with two Asian GWASs (7,127 cases and 6,818 controls) to evaluate the association of potentially functional SNPs in chromatin interaction regions with lung cancer risk. We identified four novel lung cancer susceptibility loci located at 1q21.1 (rs17160062, P=4.00×10-6), 2p23.3 (rs670343, P=4.87×10-7), 2p15 (rs9309336, P=3.24×10-6) and 17q21.2 (rs9252, P=1.51×10-5) that were significantly associated with lung cancer risk after correction for multiple tests. Functional annotation result indicated that these SNPs may contribute to the development of lung cancer by affecting the availability of transcription factor binding sites. The HaploReg analysis suggested that rs9309336 may affect binding motif of transcription factor Foxp1. Expression quantitative trait loci analysis revealed that rs9309336 and rs17160062 could regulate the expressions of cancer-related genes (PUS10 and CHD1L). Our results revealed that variants in chromatin interaction regions could contribute to the development of lung cancer by regulating the expression of target genes, which providing novel implications for the understanding of functional variants in the development of lung cancer.
    Keywords:  Genome-wide association studies (GWAS); chromatin interactions; expression quantitative trait loci.; lung cancer; single-nucleotide polymorphisms (SNPs)
    DOI:  https://doi.org/10.7150/jca.35127
  113. Nutrients. 2020 Jan 17. pii: E242. [Epub ahead of print]12(1):
    Association Between Diet, Physical Activity and Body Mass Index, Fat Mass Index and Bone Mineral Density of Soldiers of the Polish Air Cavalry Units.
    Anyżewska A, Łakomy R, Lepionka T, Szarska E, Maculewicz E, Tomczak A, Bertrandt J.
      Research from recent years indicates a problem of excessive body weight among soldiers, who, due to the kind of work carried out, should possess good health and fitness levels. The aim of the study was to determine the association between diet and physical activity and the nutritional status of soldiers of the Polish Air Cavalry Units. One hundred and twenty male soldiers (aged 28 ± 5 years) completed a questionnaire (food frequency questionnaire, long-form International Physical Activity Questionnaire). Body composition was determined by bioelectrical impedance analysis, and bone calcification of the forearm was assessed by the DXA (Dual Energy X-ray Absorptiometry) densitometric method. This study confirmed the association between both the diet and physical activity and body mass index (BMI), fat mass index (FMI), and bone mineral density (BMD) expressed as T-score. Significant negative correlations were found between BMI and the frequency of consumption of cereal products, meat products and fish, and nonalcoholic beverages, between FMI and cereal products, and between BMD T-score and meat products and fish, fat, nuts, and grains, sweets and snacks, and nonalcoholic beverages. Physical activity expressed as metabolic equivalent (MET-minutes/week) negatively correlated with FMI (but not BMI) and positively correlated with the BMD T-score. This study confirmed numerous irregularities in eating behavior and in nutritional status indices; therefore, there is a need for nutritional education and further monitoring of both dietary behaviors and nutritional status of soldiers.
    Keywords:  body mass index; bone calcification; fat mass index; nutrition; nutritional status; physical activity; soldiers
    DOI:  https://doi.org/10.3390/nu12010242
  114. Methods Mol Biol. 2020 ;2117 293-303
    Characterization of Arsenic-Induced Cancer Stem-Like Cells.
    Chang Q, Bi Z, Fu Y, Rice MKA, Zhang Q, Wadgaonkar P, Almutairy B, Zhang W, Lu Y, Xu L, Thukar C, Chen F.
      Arsenic is a well-known human carcinogen. However, the mechanisms underlying arsenic-induced carcinogenesis remain elusive. Here we show that chronic and low level of arsenic stress induces transformation of the human bronchial epithelial cells, BEAS-2B, and that some of the transformed cells show characteristics of cancer stem-like cells (CSCs). Meanwhile, we demonstrate that arsenic stress dedifferentiates CD61+ BEAS-2B cells into CSC-like CD61- cells featured with noncanonical epithelial-mesenchymal transition (EMT), enhanced chemoresistance, and metastasis. Finally, we show that oncogene c-Myc expression is associated with arsenic-induced tumor initiation and progression. Altogether, our findings highlight a unique mechanism of arsenic-induced transformation of human bronchial epithelial cells and provide a novel therapeutic target for arsenic-initiated lung cancer.
    Keywords:  Arsenic; Cancer; Cancer stem cells; Environment; Transformation
    DOI:  https://doi.org/10.1007/978-1-0716-0301-7_19
  115. J Bioenerg Biomembr. 2020 Jan 21.
    Acanthamoeba castellanii phosphate transporter (AcPHS) is important to maintain inorganic phosphate influx and is related to trophozoite metabolic processes.
    Carvalho-Kelly LF, Pralon CF, Rocco-Machado N, Nascimento MT, Carvalho-de-Araújo AD, Meyer-Fernandes JR.
      Acanthamoeba castellanii is a free-living amoeba and the etiological agent of granulomatous amoebic encephalitis and amoebic keratitis. A. castellanii can be present as trophozoites or cysts. The trophozoite is the vegetative form of the cell and has great infective capacity compared to the cysts, which are the dormant form that protect the cell from environmental changes. Phosphate transporters are a group of proteins that are able to internalize inorganic phosphate from the extracellular to intracellular medium. Plasma membrane phosphate transporters are responsible for maintaining phosphate homeostasis, and in some organisms, regulating cellular growth. The aim of this work was to biochemically characterize the plasma membrane phosphate transporter in A. castellanii and its role in cellular growth and metabolism. To measure inorganic phosphate (Pi) uptake, trophozoites were grown in liquid PYG medium at 28 °C for 2 days. The phosphate uptake was measured by the rapid filtration of intact cells incubated with 0.5 μCi of 32Pi for 1 h. The Pi transport was linear as a function of time and exhibited Michaelis-Menten kinetics with a Km = 88.78 ± 6.86 μM Pi and Vmax = 547.5 ± 16.9 Pi × h-1 × 10-6 cells. A. castellanii presented linear phosphate uptake up to 1 h with a cell density ranging from 1 × 105 to 2 × 106 amoeba × ml-1. The Pi uptake was higher in the acidic pH range than in the alkaline range. The oxygen consumption of living trophozoites increased according to Pi addition to the extracellular medium. When the cells were treated with FCCP, no effect from Pi on the oxygen flow was observed. The addition of increasing Pi concentrations not only increased oxygen consumption but also increased the intracellular ATP pool. These phenomena were abolished when the cells were treated with FCCP or exposed to hypoxia. Together, these results reinforce the hypothesis that Pi is a key nutrient for Acanthamoeba castellanii metabolism.
    Keywords:  Achantamoeba castellanii; Energetic metabolism; PHO84 inorganic phosphate transporter
    DOI:  https://doi.org/10.1007/s10863-020-09822-y
  116. J Cachexia Sarcopenia Muscle. 2019 Nov 13.
    Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.
    Kunzke T, Buck A, Prade VM, Feuchtinger A, Prokopchuk O, Martignoni ME, Heisz S, Hauner H, Janssen KP, Walch A, Aichler M.
      BACKGROUND: Cachexia is the direct cause of at least 20% of cancer-associated deaths. Muscle wasting in skeletal muscle results in weakness, immobility, and death secondary to impaired respiratory muscle function. Muscle proteins are massively degraded in cachexia; nevertheless, the molecular mechanisms related to this process are poorly understood. Previous studies have reported conflicting results regarding the amino acid abundances in cachectic skeletal muscle tissues. There is a clear need to identify the molecular processes of muscle metabolism in the context of cachexia, especially how different types of molecules are involved in the muscle wasting process.METHODS: New in situ -omics techniques were used to produce a more comprehensive picture of amino acid metabolism in cachectic muscles by determining the quantities of amino acids, proteins, and cellular metabolites. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging, we determined the in situ concentrations of amino acids and proteins, as well as energy and other cellular metabolites, in skeletal muscle tissues from genetic mouse cancer models (n = 21) and from patients with cancer (n = 6). Combined results from three individual MALDI mass spectrometry imaging methods were obtained and interpreted. Immunohistochemistry staining for mitochondrial proteins and myosin heavy chain expression, digital image analysis, and transmission electron microscopy complemented the MALDI mass spectrometry imaging results.
    RESULTS: Metabolic derangements in cachectic mouse muscle tissues were detected, with significantly increased quantities of lysine, arginine, proline, and tyrosine (P = 0.0037, P = 0.0048, P = 0.0430, and P = 0.0357, respectively) and significantly reduced quantities of glutamate and aspartate (P = 0.0008 and P = 0.0124). Human skeletal muscle tissues revealed similar tendencies. A majority of altered amino acids were released by the breakdown of proteins involved in oxidative phosphorylation. Decreased energy charge was observed in cachectic muscle tissues (P = 0.0101), which was related to the breakdown of specific proteins. Additionally, expression of the cationic amino acid transporter CAT1 was significantly decreased in the mitochondria of cachectic mouse muscles (P = 0.0133); this decrease may play an important role in the alterations of cationic amino acid metabolism and decreased quantity of glutamate observed in cachexia.
    CONCLUSIONS: Our results suggest that mitochondrial dysfunction has a substantial influence on amino acid metabolism in cachectic skeletal muscles, which appears to be triggered by diminished CAT1 expression, as well as the degradation of mitochondrial proteins. These findings provide new insights into the pathobiochemistry of muscle wasting.
    Keywords:  Amino acids; Cancer cachexia; MALDI; Mass spectrometry imaging; Mitochondrial dysfunctions
    DOI:  https://doi.org/10.1002/jcsm.12498
  117. J Physiol. 2020 Jan 24.
    The role of vascular function on exercise capacity in health and disease.
    Poole DC, Behnke BJ, Musch TI.
      KEY POINTS: For the majority of athletic events or activities of more than ∼2 min duration exercise tolerance is determined principally by three aerobic parameters: the speed of the oxygen uptake (V̇O2) kinetics following exercise onset, Critical Power (CP) or Speed (CS) and the maximal V̇O2 (V̇O2max). These three parameters have different O2 delivery (Q̇O2) dependencies. The preponderance of evidence demonstrates that, in healthy individuals initiating cycling or running, for example, the kinetics of muscle Q̇O2 is faster than that of V̇O2 supporting a mitochondrial site of control. In contrast, CP/CS and V̇O2max have high Q̇O2-dependency in health and major diseases that impact the O2 transport pathway. Notwithstanding the above, recent evidence has demonstrated that there exists substantial spatial and temporal heterogeneity of Q̇O2-to-V̇O2 matching within exercising skeletal muscles and also that the kinetics of microvascular O2 distribution may be slower than that of bulk Q̇O2. Vascular adaptations to, at least short-term (several weeks), exercise training may exceed the speeding of V̇O2 kinetics such that the Q̇O2-to-V̇O2 ratio is increased and microvascular O2 pressures are elevated which may constitute an important mechanism for improved metabolic control and enhanced endurance after training. This training-induced vascular and metabolic plasticity is retained with aging and in diseases such as heart failure where all three parameters may be improved contributing to enhanced life quality, exercise tolerance and disease prognosis. Targeting the nitric oxide pathway with nitrate/nitrite supplementation, phosphodiesterase inhibition and potentially via soluble guanylate cyclase activators/stimulators offers the potential to improve V̇O2 kinetics, CP/CS and V̇O2max in select patient populations: Either as adjuncts to improve exercise rehabilitation efficacy or in patients unwilling or unable to exercise.ABSTRACT: Three sentinel parameters of aerobic performance are: The maximal oxygen uptake (V̇O2 max), Critical Power (CP) and the speed of the V̇O2 kinetics following exercise onset. Of these, the latter is, perhaps, the cardinal test of integrated function along the O2 transport pathway from lungs to skeletal muscle mitochondria. Fast V̇O2 kinetics demand that the cardiovascular system distribute exercise-induced blood flow elevations among and within those vascular beds subserving the contracting muscle(s). Ideally, this process must occur at least as rapidly as mitochondrial metabolism elevates V̇O2 . Chronic disease and aging create an O2 delivery (i.e., blood flow x arterial [O2 ], Q̇O2 )-dependency that slows V̇O2 kinetics, decreasing CP and V̇O2 max, increasing the O2 deficit and sowing the seeds of exercise intolerance. Exercise training, in contrast, does the opposite. Within the context of these three parameters (see graphical abstract), this brief review examines the training-induced plasticity of key elements in the O2 transport pathway. It asks how structural and functional vascular adaptations accelerate and redistribute muscle Q̇O2 and thus defend microvascular O2 partial pressures and capillary blood-myocyte O2 diffusion across a ∼100-fold range of muscle V̇O2 s. Recent discoveries, especially within the muscle microcirculation and Q̇O2 -to-V̇O2 heterogeneity, are integrated within the O2 transport pathway to appreciate how local and systemic vascular control helps defend V̇O2 kinetics and determine CP and V̇O2 max in health and how vascular dysfunction in disease predicates exercise intolerance. Finally, the latest evidence that nitrate supplementation improves vascular and therefore aerobic function in health and disease is presented. Three sentinel parameters of aerobic performance are the O2 uptake, (V̇O2 ) kinetics following the onset of exercise, Critical Power (CP) or Speed (CS) (asymptote of the Power/Speed - Time relation for high intensity exercise), and the maximal O2 uptake, V̇O2 max. The dependence of each parameter on O2 delivery is highly subject, exercise mode and context dependent. That said, for upright rhythmic cycling or running exercise the boxes apportion the relative importance of cardiac, vascular and mitochondrial O2 delivery/utilization to each in the untrained state (Pre-) and the participation of each in the training adaptation (Post-) for each parameter. This brief review explores that dependency in health and disease utilizing exercise training and other conditions such as nitrate supplementation to unveil how vascular function and dysfunction predicate exercise tolerance and intolerance within the scope of these three parameters of aerobic function. This article is protected by copyright. All rights reserved.
    Keywords:  critical power; exercise intolerance; exercise training; heart failure; maximal oxygen uptake; oxygen transport; oxygen uptake kinetics; parameters of aerobic function
    DOI:  https://doi.org/10.1113/JP278931
  118. Cell Mol Life Sci. 2020 Jan 20.
    Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation.
    Schäbler S, Amatobi KM, Horn M, Rieger D, Helfrich-Förster C, Mueller MJ, Wegener C, Fekete A.
      The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period01 (per01) clock mutants and Canton-S wildtype (WTCS) flies in an isogenic and non-isogenic background using LC-MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, and fatty acid esters. Notably, detectable diacylglycerols (DAG) and acylcarnitines (AC), involved in lipid metabolism, showed lower levels in per01 mutants. Most of these differences disappeared in the isogenic background, yet the level differences for AC as well as DAG were consistent for fly bodies. AC levels were dependent on the time of day in WTCS in phase with food consumption under LD conditions, while DAGs showed weak daily oscillations. Two short-chain ACs continued to cycle even in constant darkness. per01 mutants in LD showed no or very weak diel AC oscillations out of phase with feeding activity. The low levels of DAGs and ACs in per01 did not correlate with lower total food consumption, body mass or weight. Clock mutant flies showed higher sensitivity to starvation independent of their background-dependent activity level. Our results suggest that neither feeding, energy storage nor mobilisation is significantly affected in per01 mutants, but point towards impaired mitochondrial activity, supported by upregulation of the mitochondrial stress marker 4EBP in the clock mutants.
    Keywords:  Acylcarnitine; Circadian rhythms; Feeding; Metabolomics; Mitochondrial activity; Tryptophan
    DOI:  https://doi.org/10.1007/s00018-019-03441-6
  119. Respir Med Case Rep. 2020 ;29 100992
    Choroidal metastasis as the initial presentation of lung adenocarcinoma: A case report.
    Migaou A, Ben Saad A, Joobeur S, Ben Abdeljelil N, Zina S, Cheikh Mhammed S, Rouatbi N, Fahem N.
      Clinical reports of symptomatic choroidal metastasis as the initial presentation of lung cancer are rare. Here, we report such a presentation in a female patient of non small cell lung cancer. She presented with loss of vision in her left eye. On further analyses, the patient was diagnosed with a lung adenocarcinoma.
    DOI:  https://doi.org/10.1016/j.rmcr.2019.100992
  120. Strahlenther Onkol. 2020 Jan 24.
    Effect of lung volume on helical radiotherapy in esophageal cancer: are there predictive factors to achieve acceptable lung doses?
    Kirli Bolukbas M, Karaca S.
      PURPOSE: The dose received by the lungs in radiotherapy (RT) is affected by the patient's current lung volume. The presence of predictive factors and cut-off points were investigated to achieve acceptable lung doses in esophageal cancer (EC) treatment.METHODS: Virtual RT volumes of supracarinal EC were delineated. RT plans were designed with standard criteria in the TomoTherapy planning system (TomoTherapy Inc., Madison, WI, USA). The total dose was 50.4 Gy (1.8 Gy/fraction). ROC (Receiver operating characteristic) analysis and Mann-Whitney U tests were performed.
    RESULTS: There was a total of 65 patient plans included. ROC analysis showed that lung/PTV (Planning target volume) volume ratio (AUC [Area under curve]: 0.91, 95% CI: 0.83-0.99, p = 0.000) and bilateral lung volume (AUC: 0.81, 95% CI: 0.70-0.92, p = 0.000) have diagnostic power to predict the suitability of RT plans according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) for lung dose constraints. The cut-off points of 7 and 3500 cc were selected for lung/PTV ratio and bilateral lung volume, respectively. The effect of the cut-off points on the dose data was assessed with the Mann-Whitney U test. The mean lung and heart doses, lung V5, V15, and V20, as well as heart V5, V20, V30, and V45 values were found to be lower in both groups separated by cut-off points (p < 0.05).
    CONCLUSION: The lung/PTV ratio ≥7 and bilateral lung volume ≥3500 cc cut-off points are predictive of whether TomoTherapy plans may meet QUANTEC lung dose limits in patients with supracarinal esophageal cancer. The patients with lung/PTV ratio and lung volume above these cut-off points may be candidates for treatment with TomoTherapy.
    Keywords:  Dose-volume parameters; Dosimetric effects; Esophageal cancer neoplasms; Helical TomoTherapy; Normal tissue sparing
    DOI:  https://doi.org/10.1007/s00066-020-01581-4
  121. J Clin Rheumatol. 2020 Jan 21.
    Nivolumab-Induced Psoriatic Arthritis in a Patient With Advanced Small Cell Lung Cancer.
    Jatwani K, Kaur H, Chugh K, Jatwani S.
      
    DOI:  https://doi.org/10.1097/RHU.0000000000001301
  122. J Nanobiotechnology. 2020 Jan 23. 18(1): 20
    Gold nanoparticle based double-labeling of melanoma extracellular vesicles to determine the specificity of uptake by cells and preferential accumulation in small metastatic lung tumors.
    Lara P, Palma-Florez S, Salas-Huenuleo E, Polakovicova I, Guerrero S, Lobos-Gonzalez L, Campos A, Muñoz L, Jorquera-Cordero C, Varas-Godoy M, Cancino J, Arias E, Villegas J, Cruz LJ, Albericio F, Araya E, Corvalan AH, Quest AFG, Kogan MJ.
      BACKGROUND: Extracellular vesicles (EVs) have shown great potential for targeted therapy, as they have a natural ability to pass through biological barriers and, depending on their origin, can preferentially accumulate at defined sites, including tumors. Analyzing the potential of EVs to target specific cells remains challenging, considering the unspecific binding of lipophilic tracers to other proteins, the limitations of fluorescence for deep tissue imaging and the effect of external labeling strategies on their natural tropism. In this work, we determined the cell-type specific tropism of B16F10-EVs towards cancer cell and metastatic tumors by using fluorescence analysis and quantitative gold labeling measurements. Surface functionalization of plasmonic gold nanoparticles was used to promote indirect labeling of EVs without affecting size distribution, polydispersity, surface charge, protein markers, cell uptake or in vivo biodistribution. Double-labeled EVs with gold and fluorescent dyes were injected into animals developing metastatic lung nodules and analyzed by fluorescence/computer tomography imaging, quantitative neutron activation analysis and gold-enhanced optical microscopy.RESULTS: We determined that B16F10 cells preferentially take up their own EVs, when compared with colon adenocarcinoma, macrophage and kidney cell-derived EVs. In addition, we were able to detect the preferential accumulation of B16F10 EVs in small metastatic tumors located in lungs when compared with the rest of the organs, as well as their precise distribution between tumor vessels, alveolus and tumor nodules by histological analysis. Finally, we observed that tumor EVs can be used as effective vectors to increase gold nanoparticle delivery towards metastatic nodules.
    CONCLUSIONS: Our findings provide a valuable tool to study the distribution and interaction of EVs in mice and a novel strategy to improve the targeting of gold nanoparticles to cancer cells and metastatic nodules by using the natural properties of malignant EVs.
    Keywords:  Drug delivery; Exosomes; Extracellular vesicles; Gold nanoparticles; Metastasis; Targeting; Tracking
    DOI:  https://doi.org/10.1186/s12951-020-0573-0
  123. Phys Med Biol. 2020 Jan 21.
    A prognostic analysis method for non-small cell lung cancer based on the computed tomography radiomics.
    Wang X, Duan H, Li X, Ye X, Huang G, Nie SD.
      OBJECTIVE: In order to assist doctors in arranging the postoperative treatments and re-examinations for non-small cell lung cancer (NSCLC) patients, this study was initiated to explore a prognostic analysis method for non-small cell lung cancer based on computed tomography (CT) radiomics.METHODS: The data of 173 NSCLC patients were collected retrospectively and the clinically meaningful 3-year survival was used as the predictive limit to predict the patient's prognosis survival time range. Firstly, lung tumors were segmented and the radiomics features were extracted. Secondly, the feature weighting algorithm was used to screen and optimize the extracted original feature data. Then, the selected feature data combining with the prognosis survival of patients were used to train machine learning classification models. Finally, a prognostic survival analysis model and radiomics prognostic factors were obtained to predict the prognosis survival time range of NSCLC patients.
    RESULTS: The classification accuracy rate under cross-validation was up to 88.7% in the prognosis survival analysis model. When verifying on an independent data set, the model also yielded a high prediction accuracy which is up to 79.6%. Inverse different moment, lobulation sign and angular second moment were NSCLC prognostic factors based on radiomics.
    CONCLUSIONS: This study proved that CT radiomics features could effectively assist doctors to make more accurate prognosis survival prediction for NSCLC patients, so as to help doctors to optimize treatment and re-examination for NSCLC patients to extend their survival time.
    Keywords:  CT radiomics features; Non-small cell lung cancer; Prognostic factors; Prognostic survival prediction model
    DOI:  https://doi.org/10.1088/1361-6560/ab6e51
  124. Biosci Biotechnol Biochem. 2020 Jan 21. 1-12
    Neuroprotective effect of Annona muricata-derived polysaccharides in neuronal HT22 cell damage induced by hydrogen peroxide.
    Kim WS, Kim YE, Cho EJ, Byun EB, Park WY, Song HY, Kim K, Park SH, Byun EH.
      Crude extracts and phytochemical compounds derived from Annona muricata leaves have been demonstrated to exert neuroprotective effects. However, the neuroprotective effects of Annona muricata leaves-derived polysaccharide extracts (ALPs) have not been investigated. ALP treatment was shown to induce concentration-dependent antioxidant activity in HT22 cells, and to increase cell viability in H2O2-treated HT22 cells. These effects were correlated with a decrease in major components of oxidation, including: Ca2+, ROS, and malondialdehyde (MDA). Mediators of the intracellular response to oxidation, including Bax, cytochrome c, and cleaved caspases-3, -8, -9, MAPKs, and NF-κB, were positively influenced by ALP treatment under conditions of H2O2-mediated oxidative stress. In addition, ALP restored the expression of superoxide dismutase (SOD) and associated signaling pathways (PARP, PI3K/AKT and Nrf2-mediated HO-1/NQO-1) following H2O2 treatment. These results provide new pharmacological evidence that ALP facilitates neuroprotection via prevention of neuronal oxidative stress and promotion of cell survival signaling pathways.Abbreviations: ABTS: 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonicacid); AD: Alzheimer's disease; ALP: polysaccharide extracts isolated from Annona muricata leaves; ARE: antioxidant response element; DPPH: 1,1-diphenyl-picrylhydrazyl; DCFH-DA: 2',7'-dichlorofluorescin diacetate; ECL: electrochemiluminescence; ERK: extracellular regulated kinase; FBS: Fetal bovine serum; FITC: fluorescein isothiocyanate; FRAP: ferric reducing antioxidant power; HO-1: Heme oxygenase-1; JNK: c-jun N-terminal kinase; MAPKs: mitogen-activated protein kinases; MDA: malondialdehyde; MMP: mitochondrial membrane potential; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; NQO1: NAD(P)H:quinine oxidoreductase 1, Nrf2: nuclear factor-E2-related factor 2; PD: parkinson's disease; PI3K: phosphatidylinositol-3kinase; PVDF: polyvinylidene difluoride; ROS: reactive oxygen species; SOD: Superoxidedismutase; TPTZ: tripydyltriazine.
    Keywords:  Annona muricata leaves; neuroprotection; neurotoxicity; oxidative stress; polysaccharide
    DOI:  https://doi.org/10.1080/09168451.2020.1715201
  125. J Proteome Res. 2020 Jan 22.
    Lipid profiling of serum and lipoprotein fractions in response to pitavastatin using an animal model of familial hypercholesterolemia.
    Takeda H, Izumi Y, Tamura S, Koike T, Yu Y, Shiomi M, Bamba T.
      Statins are widely used for the treatment of atherosclerotic cardiovascular diseases. They inhibit cholesterol biosynthesis in the liver and cause pleiotropic effects including anti-inflammatory and antioxidant effects. To develop novel therapeutic drugs, the effect of blood-borne lipid molecules on the pleiotropic effects of statins must be elucidated. Myocardial-infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for hypercholesterolemia, are suitable for the determination of lipid molecules in blood in response to statins because their lipoprotein metabolism is similar to that of humans. Herein, lipid molecules were investigated by lipidome analysis in response to pitavastatin using WHHLMI rabbits. Various lipid molecules in the blood were measured using a supercritical fluid chromatography triple quadrupole mass spectrometry. Cholesterol and cholesterol ester blood levels decreased by reducing the secretion of very low density lipoproteins from the liver. Independent of the inhibition effects of cholesterol biosynthesis, the concentrations of some lipids with anti-inflammation and antioxidant effects (phospholipid molecules with n-6 fatty acid side chains, lysophosphatidylcholines, phosphatidylethanolamine plasmalogens, and ceramide molecules) were significantly altered. These findings may lead to further investigation of the mechanism of statin action.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00602
  126. J Cell Mol Med. 2020 Jan 19.
    Hyperbaric oxygen activates visfatin expression and angiogenesis via angiotensin II and JNK pathway in hypoxic human coronary artery endothelial cells.
    Chiu CZ, Wang BW, Yu YJ, Shyu KG.
      Visfatin is an adipocytokine with important roles in endothelial angiogenesis. Hyperbaric oxygen (HBO) has been widely used to treat various medical illness with enhanced angiogenesis. The molecular effects of HBO on visfatin under hypoxia are poorly understood. This study aimed to investigate the effect of HBO on visfatin in hypoxic human coronary arterial endothelial cells (HCAECs). HCAECs under chemical hypoxia (antimycin A, 0.01 mmol/L) were exposed to HBO (2.5 atmosphere absolute; ATA) for 2-4 hours. Western blot, real-time polymerase chain reaction, electrophoretic mobility shift assay, luciferase promoter activity, migration and tube formation assay, and in vitro glucose uptake were measured. Visfatin protein expression increased in hypoxic HCAECs with earlier angiotensin II (AngII) secretion and c-Jun N-terminal kinase (JNK) phosphorylation, which could be effectively suppressed by the JNK inhibitor (SP600125), AngII antibody or AngII receptor blocker (losartan). In hypoxic HCAECs, HBO further induced earlier expression of visfatin and AngII. Hypoxia significantly increased DNA-protein binding activity of hypoxia-inducible factor-1α (HIF-1α) and visfatin. Hypoxia, hypoxia with HBO and exogenous addition of AngII also increased promoter transcription to visfatin; SP600125 and losartan blocked this activity. In HCAECs, glucose uptake, migration and tube formation were increased in the presence of hypoxia with HBO, but were inhibited by visfatin small interfering RNA, SP600125 and losartan. In conclusion, HBO activates visfatin expression and angiogenesis in hypoxic HCAECs, an effect mediated by AngII, mainly through the JNK pathway.
    Keywords:  adipocytokine; angiogenesis; hyperbaric oxygen; hypoxia
    DOI:  https://doi.org/10.1111/jcmm.14926
  127. Nat Biotechnol. 2020 Jan 20.
    Identifying drug targets in tissues and whole blood with thermal-shift profiling.
    Perrin J, Werner T, Kurzawa N, Rutkowska A, Childs DD, Kalxdorf M, Poeckel D, Stonehouse E, Strohmer K, Heller B, Thomson DW, Krause J, Becher I, Eberl HC, Vappiani J, Sevin DC, Rau CE, Franken H, Huber W, Faelth-Savitski M, Savitski MM, Bantscheff M, Bergamini G.
      Monitoring drug-target interactions with methods such as the cellular thermal-shift assay (CETSA) is well established for simple cell systems but remains challenging in vivo. Here we introduce tissue thermal proteome profiling (tissue-TPP), which measures binding of small-molecule drugs to proteins in tissue samples from drug-treated animals by detecting changes in protein thermal stability using quantitative mass spectrometry. We report organ-specific, proteome-wide thermal stability maps and derive target profiles of the non-covalent histone deacetylase inhibitor panobinostat in rat liver, lung, kidney and spleen and of the B-Raf inhibitor vemurafenib in mouse testis. In addition, we devised blood-CETSA and blood-TPP and applied it to measure target and off-target engagement of panobinostat and the BET family inhibitor JQ1 directly in whole blood. Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.
    DOI:  https://doi.org/10.1038/s41587-019-0388-4
  128. Drug Metab Pharmacokinet. 2019 Nov 01. pii: S1347-4367(19)30097-7. [Epub ahead of print]
    rs622342A>C in SLC22A1 is associated with metformin pharmacokinetics and glycemic response.
    Naja K, El Shamieh S, Fakhoury R.
      Polymorphisms in SLC22A1 lead to variability in metformin clinical efficacy. Sixty-three Lebanese patients with type 2 diabetes who administered metformin, were followed up for six months and genotyped for rs622342A>C. The area under the plasma concentration-time curve and the maximum concentration of metformin was highest in CC patients (P ≤ 0.03). There was a significant difference between groups in the percentage decrease in fasting blood sugar (FBS) and glycated hemoglobin (HbA1c). Going into the same direction, rs622342C was associated with decrease in FBS levels after three and six months of treatment (P ≤ 0.02), whereas with HbA1c, the decrease was noticed after six months (β = -2.78; P = 0.03). In contrast, the serum levels of lactate and creatinine did not vary significantly according to rs622342A>C genotypes. The rs622342A>C in SLC22A1 may be associated with metformin pharmacokinetics and variability in therapeutic efficacy.
    Keywords:  Metformin pharmacokinetics; SLC22A1; Type 2 diabetes mellitus; rs622342A>C
    DOI:  https://doi.org/10.1016/j.dmpk.2019.10.007
  129. Life Sci. 2020 Jan 21. pii: S0024-3205(20)30093-X. [Epub ahead of print] 117346
    Berberine induces dose-dependent quiescence and apoptosis in A549 cancer cells by modulating cell cyclins and inflammation independent of mTOR pathway.
    Kumar R, Awasthi M, Sharma A, Padwad Y, Sharma R.
      AIM: Emerging studies have shown that application of low concentration of bioactive phytomolecules can confer anti-proliferative effects on tumour cells by inducing senescence pathways. The alkaloid berberine is recognized for its anti-cancer attributes but its potential to induce senescence in tumour cells is least understood.MATERIALS AND METHODS: The present work assessed the mechanisms pertaining to dose-dependent anti-proliferative effects of berberine in the perspective of senescence and inflammation using human non-small cell lung cancer cell line (A549).
    KEY FINDINGS: Amongst the different tested bioactive phytomolecules, berberine treatment suppressed the proliferation of A549 cells regardless of the concentration applied. Application of low doses of berberine induced a weak SA-β-gal activity and p21WAF1 expression but did not show evidence of SASP activation due to absence of NF-κB activation and expression of proinflammatory genes. However, treatment with higher dose of berberine showed no evidence of SA-β-gal activity or p21WAF1 expression, but instead induced apoptosis and suppressed the expression of cell cyclins. The proliferative capacity of berberine treated cells was at par with control cells and no SA-β-gal activity could be observed in first generation of berberine treated cells. mTOR pathway showed no distinct activation on account of berberine treatment thereby further emphasizing that low dose of berberine induced quiescence and not senescence in A549 cells.
    SIGNIFICANCE: Taken together, our observations indicate that despite its strong anti-proliferative effects, low dose berberine treatment may only induce transient changes akin to quiescence that needs to be considered before implying pro-senescence attributes of berberine in cancer therapeutics.
    Keywords:  Apoptosis; Berberine; Proliferation; Quiescence; Senescence
    DOI:  https://doi.org/10.1016/j.lfs.2020.117346
  130. Nat Commun. 2020 Jan 23. 11(1): 460
    Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis.
    Fu R, Lv WC, Xu Y, Gong MY, Chen XJ, Jiang N, Xu Y, Yao QQ, Di L, Lu T, Wang LM, Mo R, Wu ZQ.
      Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation.
    DOI:  https://doi.org/10.1038/s41467-019-14076-3
  131. J Cell Physiol. 2020 Jan 21.
    Autophagy decreases alveolar epithelial cell injury by regulating the release of inflammatory mediators.
    Fan T, Yang S, Huang Z, Wang W, Guo X, Pan S, Zhang B, Xu Y, Fang Y, Mao Z, Hu H, Geng Q.
      To research the impact of autophagy on alveolar epithelial cell inflammation and its possible mechanism in the early stages of hypoxia, we established a cell hypoxia-reoxygenation model and orthotopic left lung ischemia-reperfusion model. Rat alveolar epithelial cells stably expressing GFP-LC3 were treated with an autophagy inhibitor (3-MA) or an autophagy promoter (rapamycin), followed by hypoxia-reoxygenation treatment for 2, 4, and 6 hr in vitro. In vivo, 20 male Sprague Dawley rats were randomly divided into four groups (model group: No blocking of the hilum in the left lung; control group: Blocking of the hilum in the left lung for 1 hr with dimethyl sulfoxide lavage; 3-MA group: Blocking of the hilum in the left lung for 1 hr with 100 ml/kg of 3-MA (5 μmol/L) solution lavage; and rapamycin group: Blocking of the hilum in the left lung for 1 hr with 100 ml/kg of rapamycin (250 nmol/L) solution lavage) to establish an orthotopic left lung ischemia model. This study demonstrated that rapamycin significantly suppressed the nuclear factor kappa B signaling pathway and limited the expression of proinflammatory factors. A contrary result was found after the 3-MA pretreatment. These findings indicate that autophagy reduces ischemia-reperfusion injury by repressing inflammatory signaling pathways in the early stages of hypoxia in vitro and in vivo. Autophagy could be a new protective method for application in lung ischemia-reperfusion injury.
    Keywords:  alveolar epithelial cell; autophagy; hypoxia-reoxygenation (H/R); inflammation; ischemia-reperfusion (I/R)
    DOI:  https://doi.org/10.1002/jcp.29453
  132. Eur Respir J. 2020 Jan 24. pii: 1901519. [Epub ahead of print]
    Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent.
    Invernizzi R, Barnett J, Rawal B, Nair A, Ghai P, Kingston S, Chua F, Wu Z, Wells AU, Renzoni ER, Nicholson AG, Rice A, Lloyd CM, Byrne AJ, Maher TM, Devaraj A, Molyneaux PL.
      Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.Increased bacterial burden significantly associated with disease progression (hazard ratio 2.1; 95% confidence interval 1.287-3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.
    DOI:  https://doi.org/10.1183/13993003.01519-2019
  133. Case Rep Pulmonol. 2020 ;2020 2475725
    Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review.
    Ogawa T, Miyata J, Fukunaga K, Kawana A, Inoue T.
      Hypercalcemia of malignancy frequently manifests as paraneoplastic syndrome in patients with solid tumors. A 71-year-old man was diagnosed with stage IIIB lung squamous cell carcinoma. Laboratory examination revealed high serum calcium concentration with elevated serum parathyroid hormone-related protein (PTHrP) and 1,25-dihydroxyvitamin D3 levels. As the patient did not respond to the initial treatment with calcitonin, extracellular fluid infusion, and chemotherapy, systemic prednisolone was administered additionally. Thus, the levels of serum calcium normalized and PTHrP and 1,25-dihydroxyvitamin D3 decreased simultaneously. To our knowledge, this is the first case report on the successful treatment of hypercalcemia of malignancy caused by PTHrP and 1,25-dihydroxyvitamin D3 cosecretion in a patient with lung cancer.
    DOI:  https://doi.org/10.1155/2020/2475725
  134. Br J Dermatol. 2020 Jan 18.
    Genetic variants in the folate metabolic pathway genes predict melanoma-specific survival.
    Dai W, Liu H, Liu Y, Xu X, Qian D, Luo S, Cho E, Zhu D, Amos CI, Fang S, Lee JE, Li X, Nan H, Li C, Wei Q.
      BACKGROUND: Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWAS) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway.OBJECTIVE: To examine associations between SNPs in folate metabolic pathway genes and CMSS.
    METHODS: We comprehensively evaluated 2,645 (422 genotyped and 2,223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas M.D. Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11.1%) and 48/409 (11.5%) patients died of cutaneous melanoma, respectively.
    RESULTS: We identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1.75 (95% confidence interval=1.32-2.32, P=9.96×10-5 ) and 2.05 (1.39-3.01, P=2.84×10-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for biologic plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS.
    CONCLUSION: Two possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated.
    Keywords:  cutaneous melanoma-specific survival; folate metabolism; genome-wide association study; single-nucleotide polymorphism
    DOI:  https://doi.org/10.1111/bjd.18878
  135. ACS Appl Mater Interfaces. 2020 Jan 22.
    Tumor Microenvironment-Responsive Theranostic Nanoplatform for in situ Self-Boosting Combined Phototherapy through Intracellular Reassembly.
    Liu Y, Jing J, Jia F, Su S, Tian Y, Gao N, Yang C, Zhang RB, Wang W, Zhang X.
      Through rational design, in vivo supramolecular construction of nanodrugs could precisely proceed in the lesion areas, which may apparently improve the theranostic performance of nanomaterials. Herein, a tumor microenvironment-responsive theranostic nanoplatform (Ce6-GA@MnO2-HA-PEG) has been constructed to achieve in vivo supramolecular construction and enhance therapeutic efficacy of combined phototherapy through intracellular reassembly. Under the tumor microenvironment, such nanoplatform could undergo the process of decomposition-reassembly and form in situ photothermal assemblies. The generation of assemblies would endow this nanoplatform with the capacity of photothermal therapy. Meanwhile, this nanoplatform could effectively alleviate hypoxia and improve the therapeutic efficacy of photodynamic therapy. The results of in vitro and in vivo experiments reveal that tumors can be ablated efficiently by the designed nanoplatform under laser irradiation. In addition, fluorescence imaging and magnetic resonance imaging can be activated by the decomposition of MnO2 to realize tumor imaging in vivo. Therefore, this multifunctional nanoplatform exhibits the capacity for boosting dual-modal imaging-guided combined phototherapy through intracellular reassembly, which may propose a new thought in cancer theranostics.
    DOI:  https://doi.org/10.1021/acsami.9b22097
  136. IUBMB Life. 2020 Jan 20.
    Upregulation of 6-phosphofructo-2-kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex.
    Wang Y, Tang S, Wu Y, Wan X, Zhou M, Li H, Zha X.
      Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss-of-function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression in Tsc1-/- and Tsc2-/- mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma-derived Tsc2-null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia-inducible factor 1α (HIF-1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1- or Tsc2-deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1- or Tsc2-null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1/HIF-1α signaling pathway and co-administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1-related tumors.
    Keywords:  PFK15; PFKFB3; TSC; mTORC1; rapamycin
    DOI:  https://doi.org/10.1002/iub.2232
  137. J Cancer Res Clin Oncol. 2020 Jan 25.
    Treatment patterns and survival after 18F-fluorodeoxyglucose positron emission tomography/computed tomography-guided local consolidation therapy for oligometastatic non-small cell lung cancer: a two-center propensity score-matched analysis.
    Song YQ, Wang N, Qiao Y, He L, Li X, Zhang XF, Yang QK, Wang RZ, He R, Wang CY, Ren YW, Li G, Wang TL.
      PURPOSE: In this retrospective study, we evaluated the treatment patterns and survival after positron emission tomography-computed tomography (PET/CT)-guided local consolidation therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC).METHODS: We reviewed the medical records of Chinese patients with oligometastatic stage IV non-small cell lung cancer (≤ 5 metastases) who had undergone PET/CT and were eligible for systemic therapy at two centers between May 2005 and August 2019. Propensity score matching (1:1) was used to reduce selection bias and imbalanced distribution of confounding factors.
    RESULTS: We identified 84 eligible patients and used propensity scores to create well-matched groups of 35 patients who did or did not undergo LCT. Among all patients, the 1-year overall survival (OS) rate was 47.6% and the 2-year OS rate was 22.6%. Relative to the group that did not receive LCT, the LCT group had a significantly higher OS rate (13 months vs. 7 months, p = 0.002). The two groups had similar incidences and classifications of LCT-related side effects. In multivariable analysis, LCT was found to be strongly associated with a favorable OS (hazard ratio: 0.508, 95% confidence interval: 0.311-0.828, p = 0.001).
    CONCLUSION: We concluded that LCT was significantly associated with improved clinical outcomes among the Chinese patients with oligometastatic NSCLC who were eligible for systemic treatment and could undergo PET/CT evaluation.
    Keywords:  Local consolidation therapy; Non-small cell lung cancer; Oligometastasis; Prognosis
    DOI:  https://doi.org/10.1007/s00432-020-03134-9
  138. Hum Mol Genet. 2020 Jan 21. pii: ddaa007. [Epub ahead of print]
    The signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type Ia.
    Gautam S, Zhang L, Arnaoutova I, Lee C, Mansfield BC, Chou JY.
      Glucose-6-phosphatase-α (G6Pase-α or G6PC) deficiency in glycogen storage disease type-Ia (GSD-Ia) leads to impaired hepatic autophagy, a recycling process important for cellular metabolism and homeostasis. Autophagy can be regulated by several energy sensing pathways, including sirtuin 1 (SIRT1), forkhead box O (FoxO), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and mammalian target of rapamycin (mTOR). Using 10-day old global G6pc-deficient (G6pc-/-) mice, hepatic autophagy impairment was attributed to activation of mTOR and inhibition of AMPK signaling. In other studies, using adult liver-specific G6pc-deficient mice at both pre-tumor and tumor stages, hepatic autophagy impairment was attributed to downregulation of SIRT1 signaling and mTOR was not implicated. In this study, we provide a detailed analysis of the major autophagy pathways in young G6pc-/- mice over the first 4 weeks of life. We show that impaired SIRT1, FoxO3a, AMPK, and PPAR-α signaling are responsible for autophagy impairment but mTOR is involved minimally. Hepatic SIRT1 overexpression corrects defective autophagy, restores the expression of FoxO3a and liver kinase B1 but fails to normalize impaired PPAR-α expression or metabolic abnormalities associated with GSD-Ia. Importantly, restoration of hepatic G6Pase-α expression in G6pc-/- mice corrects defective autophagy, restores SIRT1/FoxO3a/AMPK/PPAR-α signaling and rectifies metabolic abnormalities. Taken together, these data show that hepatic autophagy impairment in GSD-Ia is mediated by downregulation of SIRT1/FoxO3a/AMPK/PPAR-α signaling.
    DOI:  https://doi.org/10.1093/hmg/ddaa007
  139. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19916. [Epub ahead of print]24(1): 238-248
    LncRNA NNT-AS1 regulates the progression of lung cancer through the NNT-AS1/miR-3666/E2F2 axis.
    Huang JW, Luo XY, Li ZH, Lang BP.
      OBJECTIVE: Lung cancer is the main burden on human health, with high mortality and poor prognosis. The involvement of long non-coding RNAs (lncRNAs) in the development of cancer has attracted wide attention. This study aimed to investigate the role and novel mechanisms of lncRNA nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) in the progression of lung cancer.MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to detect the expression of NNT-AS1, microRNA-3666 (miR-3666), and E2F transcription factor 2 (E2F2). 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to analyze cell proliferation. Flow cytometry was carried out to investigate cell apoptosis. Transwell assay was conducted to observe cell invasion. The interaction between miR-3666 and NNT-AS1 or E2F2 was predicted by bioinformatics tool starBase v2.0 and verified by Dual-Luciferase reporter assay. The protein level of E2F2 was quantified by Western blot.
    RESULTS: NNT-AS1 and E2F2 were upregulated, but miR-3666 was downregulated in lung cancer tissues and cells. NNT-AS1 knockdown attenuated proliferation and invasion but enhanced apoptosis of lung cancer cells, while miR-3666 inhibition reversed these effects. It was confirmed that miR-3666 was a target of NNT-AS1 and it directly interacted with E2F2. The inhibitory proliferation and invasion, and acceleratory apoptosis of lung cancer cells, caused by miR-3666 enrichment, were overturned by E2F2 overexpression. Furthermore, E2F2 was regulated by NNT-AS1 through miR-3666.
    CONCLUSIONS: NNT-AS1 participated in the progression of lung cancer through NNT-AS1/miR-3666/E2F2 regulatory axis at least in part. Our study supplied a promising strategy for the treatment of lung cancer.
    DOI:  https://doi.org/10.26355/eurrev_202001_19916
  140. Cancers (Basel). 2020 Jan 23. pii: E280. [Epub ahead of print]12(2):
    Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma and Paraganglioma.
    Liu Y, Pang Y, Caisova V, Ding J, Yu D, Zhou Y, Huynh TT, Ghayee H, Pacak K, Yang C.
      Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are characterized by alterations in the electron transport chain, metabolic reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased oxidative stress burden, which leads to elevated demands for glutathione metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown (SDHBKD) cells. NRF2 blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHBKD metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.
    Keywords:  NRF2; SDHB mutation; glutathione metabolism; paraganglioma; pheochromocytoma
    DOI:  https://doi.org/10.3390/cancers12020280
  141. Ann Thorac Surg. 2020 Jan 18. pii: S0003-4975(20)30033-3. [Epub ahead of print]
    Lung cancer surgery for patients on hemodialysis: A decade of experience at multicenter institutions.
    Yamamoto Y, Kanzaki R, Ose N, Funakoshi Y, Ikeda N, Takami K, Iwasaki T, Iwazawa T, Yokouchi H, Shiono H, Kodama K, Shintani Y, .
      BACKGROUND: The clinical outcome of patients receiving hemodialysis (HD) has not yet been clarified in lung cancer surgery. The aims of this study were to assess the clinical features, outcomes and main cause of death following lung cancer surgery in HD patients and to evaluate the risk factors of postoperative complications.METHODS: We identified 39 patients receiving HD who underwent lung cancer surgery in 9 institutions under the Thoracic Surgery Study Group of Osaka University between 2007 and 2016. We retrospectively analyzed the surgical outcomes of these patients.
    RESULTS: Most patients were male and had a smoking habit. Diabetes mellitus was the most common cause of primary renal disease. Lobectomy with systemic lymph node dissection was performed in 16 patients, and an extended operation was performed in 6 patients. The most patients diagnosed with pStage IA (69.2%). The overall complication and mortality rates were 30.8% and 7.7%, respectively. Pneumonia was the most frequently observed complication. Extended operation was significantly associated with complications (p=0.04). The five-year overall survival rate was 57.9%, and the most common cause of death was a disease other than primary lung cancer that was related to HD.
    CONCLUSIONS: Lung cancer surgery for HD patients provides favorable long-term outcomes despite higher postoperative mortality and morbidity rates. As an extended operation is significantly associated with postoperative complications, thoracic surgeons should carefully select the type of resection based on a balance between the therapeutic benefit and invasiveness in these patients.
    Keywords:  hemodialysis; lung cancer; surgery
    DOI:  https://doi.org/10.1016/j.athoracsur.2019.11.044
  142. Br J Radiol. 2020 Jan 24. 20190584
    Assessment of robustness against setup uncertainties using probabilistic scenarios in lung cancer: a comparison of proton with photon therapy.
    Teoh S, George B, Fiorini F, Vallis KA, Van den Heuvel F.
      OBJECTIVES: We compared the sensitivity of intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT) plans to setup uncertainties in locally advanced non-small cell lung cancer (NSCLC) using probabilistic scenarios.METHODS: Minimax robust-(MM) and planning target volume-(PTV) optimised IMPT and VMAT nominal plans were created with physical dose of 70 Gy in 35 fractions in 10 representative patients. Using population data of setup errors, a fractionated treatment course was simulated, summed (Dsum) and compared to the nominal plan. Three treatment-course simulations were done for each plan. Target robustness criteria were: dose deviation of ≤5% to clinical target volume (CTV)D98% and CTV V95% ≥ 99.9%. Voxel-wise simulation repeatability was analysed using Bland-Altman plots. Acceptable limits-of-agreement (LoA) were 2% of the prescription dose.
    RESULTS: All Dsum met target robustness criteria. While fraction VMAT and MM-IMPT doses were excellent, simulated fraction doses in PTV-IMPT were suboptimal. Almost all (>99%) of VMAT and MM-IMPT fraction doses met both target robustness criteria. For PTV-IMPT, only 96.9 and 80.3% of fractions met CTVD98% and V95% criteria respectively. Simulation repeatability was excellent (LoA range: 0.41-1.1 Gy) with strong positive correlations.
    CONCLUSION: When considering the whole treatment course, setup errors do not influence robustness irrespective of planning techniques used. However, on a fraction level, VMAT and MM-IMPT plans are superior compared to PTV-IMPT plans.
    ADVANCES IN KNOWLEDGE: Probabilistic analysis provides a fast and practical method for evaluating VMAT and IMPT plan sensitivity against setup uncertainty. VMAT and robust-optimised IMPT plans have comparable sensitivity to setup uncertainties in conventionally-fractionated treatment for NSCLC.
    DOI:  https://doi.org/10.1259/bjr.20190584
  143. Eur J Ophthalmol. 2020 Jan 21. 1120672120902022
    Rhegmatogenous retinal detachment secondary to isolated retinal metastasis from small cell lung carcinoma: An uncommon complication.
    Ucgul AY, Ozdek S, Hasanreisoğlu M, Aydın K, Atalay HT.
      PURPOSE: To report a case of rhegmatogenous retinal detachment associated with isolated retinal metastasis from lung carcinoma.METHODS: Multimodal imaging, including wide-field retinal imaging, ultrasonic imaging, and magnetic resonance imaging.
    RESULTS: Systemic chemotherapy and cranial prophylactic radiotherapy resulted in shrinkage of these lesions and retinal breaks making them much smaller and preventing progression of retinal detachment transiently.
    CONCLUSION: This is the first reported case of rhegmatogenous retinal detachment secondary to retinal metastasis from a lung cancer.
    Keywords:  Lung cancer; retinal metastasis; rhegmatogenous retinal detachment
    DOI:  https://doi.org/10.1177/1120672120902022
  144. Lung Cancer. 2020 Jan 07. pii: S0169-5002(19)30761-5. [Epub ahead of print]141 56-63
    Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer.
    Haentschel M, Boeckeler M, Ehab A, Wagner R, Spengler W, Steger V, Boesmueller H, Horger M, Lewis RA, Fend F, Kanz L, Bonzheim I, Hetzel J.
      OBJECTIVES: Detection of activating epidermal growth factor receptor (EGFR) mutation is crucial for individualized treatment of advanced non-small-cell lung cancer (NSCLC). However little is known about how biopsy technique affects the detection rate of EGFR mutations. This retrospective, single center study evaluated the detection rate of EGFR mutations in tissue obtained by bronchoscopic cryobiopsy and compared this to other standard tissue sampling techniques.MATERIALS AND METHODS: We retrospectively analyzed 414 patients with histologically confirmed NSCLC and known EGFR mutation status between 3/2008-7/2014. Tumor specimens obtained by tissue preserving bronchoscopic cryobiopsy were compared to those obtained by other techniques.
    RESULTS AND CONCLUSION: Analysis of bronchoscopic cryobiopsy tissue detected 29 activating EGFR mutations in 27 (21.6 %) out of 125 patients, while analysis of tissue obtained by non-cryobiopsy techniques (bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracical and surgical procedures) detected 42 EGFR mutations in 40 (13.8 %) out of 298 patients (p < 0.05). Cryobiopsy increased detection rate of EGFR mutations in central tumors compared with forceps biopsy (19.6 % versus 6.5 %, p < 0.05), while an insignificant trend was detected also for peripheral tumors (33.3 % versus 26.9 %). Bronchosopic cryobiopsy increases the detection rate of activating EGFR mutations in NSCLC in comparison to other tissue sampling techniques. This will help to optimize individualized treatment of patients with advanced tumors. Because of the retrospective nature of this analysis, a prospective trial is mandatory for final assessment.
    Keywords:  Cryobiopsy; Epidermal growth factor receptor mutation; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.lungcan.2019.12.008
  145. Plants (Basel). 2020 Jan 20. pii: E128. [Epub ahead of print]9(1):
    Investigation of the EIL/EIN3 Transcription Factor Gene Family Members and Their Expression Levels in the Early Stage of Cotton Fiber Development.
    Salih H, He S, Li H, Peng Z, Du X.
      The ethylene-insensitive3-like/ethylene-insensitive3 (EIL/EIN3) protein family can serve as a crucial factor for plant growth and development under diverse environmental conditions. EIL/EIN3 protein is a form of a localized nuclear protein with DNA-binding activity that potentially contributes to the intricate network of primary and secondary metabolic pathways of plants. In light of recent research advances, next-generation sequencing (NGS) and novel bioinformatics tools have provided significant breakthroughs in the study of the EIL/EIN3 protein family in cotton. In turn, this paved the way to identifying and characterizing the EIL/EIN3 protein family. Hence, the high-throughput, rapid, and cost-effective meta sequence analyses have led to a remarkable understanding of protein families in addition to the discovery of novel genes, enzymes, metabolites, and other biomolecules of the higher plants. Therefore, this work highlights the recent advance in the genomic-sequencing analysis of higher plants, which has provided a plethora of function profiles of the EIL/EIN3 protein family. The regulatory role and crosstalk of different metabolic pathways, which are apparently affected by these transcription factor proteins in one way or another, are also discussed. The ethylene hormone plays an important role in the regulation of reactive oxygen species in plants under various environmental stress circumstances. EIL/EIN3 proteins are the key ethylene-signaling regulators and play important roles in promoting cotton fiber developmental stages. However, the function of EIL/EIN3 during initiation and early elongation stages of cotton fiber development has not yet been fully understood. The results provided valuable information on cotton EIL/EIN3 proteins, as well as a new vision into the evolutionary relationships of this gene family in cotton species.
    Keywords:  Cis-element; EIL/EIN3; developmental stages; gene structure; identification; phylogeny
    DOI:  https://doi.org/10.3390/plants9010128
  146. Respirology. 2020 Jan 20.
    Letter from Jordan.
    Altous M.
      
    Keywords:  lung cancer; smoking; tuberculosis
    DOI:  https://doi.org/10.1111/resp.13767
  147. J Exp Bot. 2020 Jan 24. pii: eraa025. [Epub ahead of print]
    The Glycosyltransferase Gene OsUGT90A1 Helps Protect Plasma Membranes During Chilling Stress in Rice.
    Shi Y, Phan H, Liu Y, Cao S, Zhang Z, Chu C, Schläppi MR.
      Due to its subtropical origin, rice (Oryza sativa L.) is sensitive to low-temperature stress. We report the identification of LOC_Os04g24110, annotated to encode the UDP-glycosyltransferase enzyme UGT90A1, as a gene associated with the low-temperature seedling survivability (LTSS) quantitative trait locus qLTSS4-1. Haplotype differences in the control region of OsUGT90A1 affecting differential expression in chilling tolerant and chilling sensitive rice accessions rather than differences in protein sequences correlate with chilling tolerance phenotypes. OsUGT90A1 expression is cold regulated, and its overexpression helps to maintain membrane integrity during cold stress and promotes leaf growth during stress recovery, correlating with reduced levels of reactive oxygen species due to increased antioxidant enzyme activities. Overexpression of OsUGT90A1 in Arabidopsis moreover improves freezing survival and salt stress tolerance, correlating with enhanced antioxidant enzyme activities. In rice, overexpression of OsUGT90A1 decreases while gene knockout increases root lengths of three-week-old seedlings, indicating that differential expression of this gene may affect phytohormone activities. Thus, higher OsUGT90A1 expression in chilling tolerant than chilling sensitive accessions helps maintain cell membrane integrity as an abiotic stress tolerance response mechanism to prepare plants to resume growth and development during stress recovery.
    Keywords:  Abiotic stress; Antioxidant enzyme activity; Cold tolerance; Gene knockout; Low temperature seedlings survivability; Reactive oxygen species; Salt tolerance; Transgenic rice
    DOI:  https://doi.org/10.1093/jxb/eraa025
  148. Epidemiology. 2020 Jan 20.
    Lung cancer mortality among smokers and never-smokers in the United States.
    Hosgood HD, Cosgrove C, Klugman M, Rohan T, Altekruse S.
      
    DOI:  https://doi.org/10.1097/EDE.0000000000001159
  149. Obstet Gynecol Sci. 2020 Jan;63(1): 55-63
    Potential predictors for chemotherapeutic response and prognosis in epithelial ovarian, fallopian tube and primary peritoneal cancer patients treated with platinum-based chemotherapy.
    Jeerakornpassawat D, Suprasert P.
      Objective: This study aimed to investigate the potential predictive factors for platinum resistance and poor prognosis in epithelial ovarian, fallopian tube, and primary peritoneal cancer treated with platinum-based chemotherapy.Methods: Medical records of 306 patients with the above mentioned cancers treated with platinum-based chemotherapy between 2007 and 2017 were retrospective reviewed. Clinical data, preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), platinum-free interval, and survival time were recorded. NLR, PLR, and cancer antigen 125 (CA125) levels were calculated for an optimal cutoff point using receiver operating characteristic curves. The clinicopathological variables were compared using univariate and multivariate analyses to identify independent predictive factors for platinum resistance and poor survival outcomes.
    Results: The optimal cutoff points for NLR, PLR, and CA125 were 3.38, 210, and 365 IU/L, respectively. Univariate analysis indicated that NLR >3.38, PLR >210, CA125 >365, advanced stage, suboptimal disease, serous type, and ascites were significant predictive factors for platinum resistance. However, only NLR >3.38 and advanced stage were independent predictive factors with an adjusted odds ratio of 1.880 and 3.333, respectively. Regarding factors associated with poor survival outcomes, only PLR >210 and advanced stage were independent factors, with a hazard ratio of 1.578 and 3.994, respectively.
    Conclusion: High NLR and advanced stage were potential independent predictive factors for platinum resistance, whereas high PLR and advanced stage were potential independent predictive factors for poor survival outcomes.
    Keywords:  Lymphocyte; Neutrophil; Ovarian cancer; Platelet; Platinum
    DOI:  https://doi.org/10.5468/ogs.2020.63.1.55
  150. BMC Pulm Med. 2020 Jan 21. 20(1): 20
    Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle.
    Leermakers PA, Remels AHV, Langen RCJ, Schols AMWJ, Gosker HR.
      BACKGROUND: Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation.METHODS: We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle.
    RESULTS: Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found.
    CONCLUSIONS: These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.
    Keywords:  Inflammation; Mitochondrial biogenesis; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12890-020-1047-8
  151. Expert Rev Respir Med. 2020 Jan 23.
    Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer.
    Pinto JA, Raez LE, Domingo G.
      Introduction: ALK rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the EML4-ALK fusion is the most frequent. Rearrangement of ALK with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefit from ALK inhibitors and currently, there are three generations of drugs as standard of care. The first generation ALK inhibitor crizotinib is approved in the front line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation ALK inhibitors, ceritinib, alectinib and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor.Areas covered: In this review, an unstructured search in Pubmed and SCOPUS was conducted. We summarized the mechanisms of resistance to ALK inhibitors and its consequences in the treatment-decision making in advanced or metastatic NSCLC after failure to a first-line ALK inhibitor.Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencing of agents is crucial to deal with the tumor evolution.
    Keywords:  ALK; Non-small cell lung cancer; Tyrosine-kinase inhibitors; drug resistance; genomic profiling
    DOI:  https://doi.org/10.1080/17476348.2020.1721285
  152. Respir Med Case Rep. 2020 ;29 100998
    Endoscopic ultrasound-guided ascites aspiration in the hands of the chest physician using the EBUS endoscope in the oesophagus.
    Nessar R, Toennesen LL, Bodtger U, Christiansen IS, Clementsen PF.
      Background: The use of the endobronchial ultrasound (EBUS) scope in the oesophagus, the so-called EUS-B procedure, for the diagnosis and staging of lung cancer is quickly gaining ground.Case presentation: We here present a case demonstrating that EUS-B guided aspiration of intraperitoneal fluid (ascites) is possible. This has never been described before.The procedure was performed with the use of a 22 G needle in a 71 years old woman suspected of lung cancer. No complications were seen.
    Conclusion: We hereby demonstrate that EUS-B fine needle aspiration from ascites fluid is feasible and appears to be safe.
    Keywords:  Ascites; EUS-B-FNA; Endoscopic ultrasound-guided fine needle aspiration; Interventional pulmonoloy; Lung cancer
    DOI:  https://doi.org/10.1016/j.rmcr.2020.100998
  153. Clin Psychopharmacol Neurosci. 2020 Feb 29. 18(1): 67-74
    Metformin Attenuates Liver Fat Content: Finding from Schizophrenia Patients with Olanzapine-induced Weight Gain.
    Wang L, Chen Y, Sui YC, Tan XQ, Zhou Z, Li N, Xu LP.
      Objective: This study was performed to evaluate the efficacy of metformin on liver fat content (LFC) in first episode schizophrenia patients with olanzapine-induced weight gain, and the relationship between the change of LFC and the other metabolic indices.Methods: In a double-blind study, the clinically stable inpatients with first-episode schizophrenia under olanzapine monotherapy who gained more than 7% of their baseline weight were randomly assigned to two groups; one with olanzapine plus metformin (1,000 mg/day) (metformin group) and the other with olanzapine plus placebo (placebo group) for 16 weeks. All patients continued to maintain the original olanzapine dosage. LFC was measured by magnetic resonance imaging at baseline and at the end of 16 weeks, respectively. At the same time, glucose and lipid metabolism, homeostasis model assessment of insulin resistance index (HOMA-IR) were measured respectively, analyzing the correlation between the change value of LFC and other indicators.
    Results: Over the 16-week study period, LFC value in metformin group decreased compared with baseline. LFC change across the 16-week treatment period was -2.91% for the metformin group and 0.59% for the placebo group, with a between-group difference of -3.5% (95% confidence interval, -6.08 to -0.93; p = 0.009). Compared to baseline, in the metformin group, triglyceride and HOMA-IR reduced significantly, while high density lipoprotein cholesterol increased significantly at weeks 16. There was positive correlation between LFC changes and triglycerides, HOMA-IR changes significantly.
    Conclusion: Metformin can significantly attenuate LFC in schizophrenia patients with olanzapine-induced weight gain. It may be related to the improvement of the part of the glucolipid metabolic indices.
    Keywords:  Insulin resistance; Liver fat.; Metabolic syndrome; Metformin; Olanzapine; Schizophrenia
    DOI:  https://doi.org/10.9758/cpn.2020.18.1.67
  154. J Cell Biol. 2020 Feb 03. pii: e201807127. [Epub ahead of print]219(2):
    The stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival.
    Schulz A, Sekine Y, Oyeyemi MJ, Abrams AJ, Basavaraju M, Han SM, Groth M, Morrison H, Strittmatter SM, Hammarlund M.
      Maladaptive responses to stress might play a role in the sensitivity of neurons to stress. To identify novel cellular responses to stress, we performed transcriptional analysis in acutely stressed mouse neurons, followed by functional characterization in Caenorhabditis elegans. In both contexts, we found that the gene GDPGP1/mcp-1 is down-regulated by a variety of stresses. Functionally, the enzyme GDPGP1/mcp-1 protects against stress. Knockdown of GDPGP1 in mouse neurons leads to widespread neuronal cell death. Loss of mcp-1, the single homologue of GDPGP1 in C. elegans, leads to increased degeneration of GABA neurons as well as reduced survival of animals following environmental stress. Overexpression of mcp-1 in neurons enhances survival under hypoxia and protects against neurodegeneration in a tauopathy model. GDPGP1/mcp-1 regulates neuronal glycogen levels, indicating a key role for this metabolite in neuronal stress resistance. Together, our data indicate that down-regulation of GDPGP1/mcp-1 and consequent loss of neuronal glycogen is a maladaptive response that limits neuronal stress resistance and reduces survival.
    DOI:  https://doi.org/10.1083/jcb.201807127
  155. J Pak Med Assoc. 2020 Jan;70(1): 3-6
    Correlation between serum leptin level and Body mass index (BMI) in patients with type 2 diabetes Mellitus.
    , Khan A, Ghaffar T, Kainat A, Arabdin M, Rehman Orakzai SU.
      OBJECTIVE: To correlate serum leptin levels in obese and non-obese type 2 diabetic patients and compare them with healthy individuals.METHODS: The case-control study was conducted at the Lady Reading Hospital, Peshawar, and the Rehman Medical College, Peshawar, Pakistan, from June to November 2017, and comprised type 2 diabetic patients and and an equal number of healthy controls. Fasting blood glucose, glycated haemoglobin, serum leptin, and body mass index were assessed in obese and non-obese subjects. Relation between body mass index and serum leptin level was explored. Data was analysed using SPSS 20.
    RESULTS: Of the 96 subjects, 48(50%) were in each of the two groups. Among the cases, there were 23(48%) men and 25(52%) women with an overall mean age of 51.27±11.7 years. The control group had 28(58%) men and 20(42%) women with an overall mean age of 49.3±12.1 years. Serum leptin levels were significantly higher in obese 9.42±1.87ng/ml and non-obese 7.21±3.78 ng/ml patients than the controls 5.38±2.20 ng/ml (p<0.05). Serum leptin concentration was significantly correlated with body mass index, fasting blood glucose and BMI, FBG and glycated haemoglobin (p<0.001 each).
    CONCLUSIONS: Increased levels of serum leptin could be used as a risk factor in the development of type 2 diabetes mellitus.
    Keywords:   Serum leptin, BMI, Diabetes mellitus
    DOI:  https://doi.org/10.5455/JPMA.301135
  156. J Phys Chem A. 2020 Jan 21.
    Correlation Between Equilibrium Constant and Stabilization Energy: A Combined Approach Based on Chemical Thermodynamics, Statistical Thermodynamics and Density Functional Reactivity Theory.
    Hamid A, Roy RK.
      In the present article an attempt is made to establish the correlation between equilibrium constant and stabilization energy 〖[∆E〗_(SE(AB))] generated from density functional reactivity theory (DFRT). The reactions chosen here are of type A + B AB (i.e., adduct formation type) between electron acceptor, A and electron donor, B. The representative acceptors are methyltrioxorhenium (MTO) and substituted benzaldehydes whereas donors are 26 mono- and bidentate ligands (having N-donors) and semicarbazide. The trends of experimentally generated equilibrium constant (K) values match with those of 〖∆E〗_(SE(AB)) in most of the cases, both in gas phase as well as in solvent. Justification of this reliable correlation is provided analytically using the expressions of standard Gibbs free energy of reaction (i.e., ∆_r G^ѳ) and the stabilization energy expression generated by DFRT. A further analytical explanation (albeit not very rigorous) is provided through statistical thermodynamics showing how equilibrium constant (K) is related to 〖∆E〗_(SE(AB)) for reactions of the type A + B AB, where either A or B is a common species.
    DOI:  https://doi.org/10.1021/acs.jpca.9b07920
  157. Medicine (Baltimore). 2020 Jan;99(4): e18779
    D-dimer and diffusion-weighted imaging pattern as two diagnostic indicators for cancer-related stroke: A case-control study based on the STROBE guidelines.
    Shen Y, Li Y, Chen C, Wang W, Li T.
      The aim of this study was to evaluate the risk factors and elucidate the clinical characteristics of cancer-associated ischemic stroke to differentiate it from conventional ischemic stroke in China and East Asia. Between June 2012 and June 2016, a retrospective analysis was performed on 609 stroke patients with cancer. They were divided into 3 groups: cancer-stroke group (CSG, 203 cases), stroke group (SG, 203 cases), and cancer group (CG, 203 cases). The D-dimer levels and diffusion-weighted imaging lesion (DWI) pattern were compared to an age- and sex-matched control group. The most common cancer types were colorectal cancer (20.2%) and lung cancer (18.72%). The average D-dimer level in stroke patients and cancer patients were 0.34 and 1.50 mg/L, respectively. The descending levels of D-dimer from cancer types were lung cancer (2.06 mg/L), pancreas (1.74 mg/L), gastric (1.61 mg/L), among others. Univariate analysis of the CSG and the others shows there were significant differences in the prevalence of the levels of D-dimer and DWI pattern, hypertension, diabetes mellitus, and thrombus. CSG has a unique pathological characteristic including high plasma D-dimer levels and multiple vascular lesions. The results show that D-dimer and DWI can be used as diagnostic index in clinical practice.
    DOI:  https://doi.org/10.1097/MD.0000000000018779
  158. Mol Med Rep. 2020 Feb;21(2): 540-548
    Metabolic disparities of different oxidative stress‑inducing conditions in HTR8/SVneo cells.
    Chen J, Han TL, Zhou X, Baker P, Shao Y, Zhang H.
      Placental oxidative stress is present throughout the duration of pregnancy, but it is when oxidative stress exceeds the normal physiological level that complications can occur. Trophoblast cell lines are commonly utilized for oxidative stress research due to their distinct uniform cell population and easy‑to‑apply interventions. However, conflicting results are often reported when different oxidative stress cell models are used. In this study, the aim was to characterize the intracellular and extracellular metabolite profiles of different oxidative stress cell models commonly used in the research of pregnancy complications. HTR8/SVneo human trophoblast cell lines were treated with five different oxidative stress‑inducing conditions: Hypoxia (1% oxygen); hypoxia and reoxygenation; cobalt chloride (CoCl2; 300 µmol/l); sodium nitroprusside (SNP; 2.5 mmol/l); and the serum of women with preeclampsia (10% v/v). Intracellular metabolites were extracted from cells and extracellular metabolites were collected from spent media for metabolomic analysis via gas chromatography‑mass spectrometry. The results demonstrated that there were distinct differences in the intracellular and extracellular metabolome between the different cell models. Meanwhile, treatments with exogenous drugs, such as CoCl2 and SNP, resulted in more similar metabolite profiles. These disparities between the different oxidative stress cell models will have implications for the applications of these results, and highlight the need for the standardization of oxidative stress cell models in obstetric research.
    DOI:  https://doi.org/10.3892/mmr.2019.10861
  159. Sci Transl Med. 2020 Jan 22. pii: eaax3772. [Epub ahead of print]12(527):
    PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.
    Tan X, Banerjee P, Pham EA, Rutaganira FUN, Basu K, Bota-Rabassedas N, Guo HF, Grzeskowiak CL, Liu X, Yu J, Shi L, Peng DH, Rodriguez BL, Zhang J, Zheng V, Duose DY, Solis LM, Mino B, Raso MG, Behrens C, Wistuba II, Scott KL, Smith M, Nguyen K, Lam G, Choong I, Mazumdar A, Hill JL, Gibbons DL, Brown PH, Russell WK, Shokat K, Creighton CJ, Glenn JS, Kurie JM.
      Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.
    DOI:  https://doi.org/10.1126/scitranslmed.aax3772
  160. Cancers (Basel). 2020 Jan 16. pii: E219. [Epub ahead of print]12(1):
    Cell Electropermeabilisation Enhancement by Non-Thermal-Plasma-Treated PBS.
    Chung TH, Stancampiano A, Sklias K, Gazeli K, André FM, Dozias S, Douat C, Pouvesle JM, Santos Sousa J, Robert É, Mir LM.
      The effectiveness of electrochemotherapy (ECT) in local eradication of tumours in human and veterinary medicine has been proven. ECT consists of increasing the uptake of cytotoxic drugs by means of pulsed electric fields (PEFs) that transiently permeabilise the cell membrane. Still, this tumour treatment includes some drawbacks that are linked to the characteristics of the intense electric pulses (EPs) used. Meanwhile, the emerging field of cancer therapies that are based on the application of non-thermal plasmas (NTP) has recently garnered interest because of their potentialities as rich sources of reactive species. In this work, we investigated the potential capabilities of the combined application of indirect NTP treatment and microsecond PEFs (µsPEFs) to outperform in vitro cell electropermeabilisation, the basis of ECT. Thus, phosphate-buffered saline (PBS) was plasma-treated (pPBS) and used afterwards to explore the effects of its combination with µsPEFs. Analysis of two different cell lines (DC-3F Chinese hamster lung fibroblasts and malignant B16-F10 murine melanoma cells), by flow cytometry, revealed that this combination resulted in significant increases of the level of cell membrane electropermeabilisation, even at very low electric field amplitude. The B16-F10 cells were more sensitive to the combined treatment than DC-3F cells. Importantly, the percentage of permeabilised cells reached values similar to those of cells exposed to classical electroporation field amplitude (1100 V/cm) when the cells were treated with pPBS before and after being exposed only to very low PEF amplitude (600 V/cm). Although the level of permeabilisation of the cells that are treated by the pPBS and the PEFs at 600 V/cm is lower than the level reached after the exposure to µsPEFs alone at 1100 V/cm, the combined treatment opens the possibility to reduce the amplitude of the EPs used in ECT, potentially allowing for a novel ECT with reduced side-effects.
    Keywords:  cancer; electric pulses; electroporation; indirect treatment; long-lived reactive species; melanoma; non-thermal atmospheric pressure plasma (NTP); plasma medicine; plasma-treated phosphate-buffered saline; pulsed electric field amplitude
    DOI:  https://doi.org/10.3390/cancers12010219
  161. Ecotoxicol Environ Saf. 2020 Jan 18. pii: S0147-6513(19)31490-3. [Epub ahead of print]191 110159
    Spinal cord neurodegeneration after inorganic mercury long-term exposure in adult rats: Ultrastructural, proteomic and biochemical damages associated with reduced neuronal density.
    Corrêa MG, Bittencourt LO, Nascimento PC, Ferreira RO, Aragão WAB, Silva MCF, Gomes-Leal W, Fernandes MS, Dionizio A, Buzalaf MR, Crespo-Lopez ME, Lima RR.
      Mercury chloride (HgCl2) is a chemical pollutant widely found in the environment. This form of mercury is able to promote several damages to the Central Nervous System (CNS), however the effects of HgCl2 on the spinal cord, an important pathway for the communication between the CNS and the periphery, are still poorly understood. The aim of this work was to investigate the effects of HgCl2 exposure on spinal cord of adult rats. For this, animals were exposed to a dose of 0.375 mg/kg/day, for 45 days. Then, they were euthanized, the spinal cord collected and we investigated the mercury concentrations in medullary parenchyma and the effects on oxidative biochemistry, proteomic profile and tissue structures. Our results showed that exposure to this metal promoted increased levels of Hg in the spinal cord, impaired oxidative biochemistry by triggering oxidative stress, mudulated antioxidant system proteins, energy metabolism and myelin structure; as well as caused disruption in the myelin sheath and reduction in neuronal density. Despite the low dose, we conclude that prolonged exposure to HgCl2 triggers biochemical changes and modulates the expression of several proteins, resulting in damage to the myelin sheath and reduced neuronal density in the spinal cord.
    Keywords:  CNS.; Mercury; Mercury chloride; Neurotoxicology; Proteomics; Spinal cord
    DOI:  https://doi.org/10.1016/j.ecoenv.2019.110159
  162. J Endocrinol. 2020 Jan 01. pii: JOE-19-0451.R1. [Epub ahead of print]
    Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes.
    Tanday N, Flatt PR, Irwin N, Moffett RC.
      Transdifferentiation of beta- to alpha-cells has been implicated in the pathogenesis of diabetes. To investigate the impact of contrasting aetiologies of beta-cell stress, as well as clinically approved incretin therapies on this process, lineage tracing of beta-cells in transgenic Ins1Cre/+/Rosa26-eYFP mice was investigated. Diabetes-like syndromes were induced by streptozotocin (STZ), high fat feeding (HFF) or hydrocortisone (HC), and effects of treatment with liraglutide or sitagliptin investigated. Mice developed the characteristic metabolic features associated with beta-cell destruction or development of insulin resistance. Liraglutide was effective in preventing weight gain in HFF mice, with both treatments decreasing energy intake in STZ and HC mice. Treatment intervention also significantly reduced blood glucose levels in STZ and HC mice, as well as increasing either plasma or pancreatic insulin while decreasing circulating or pancreatic glucagon in all models. The recognised changes in pancreatic morphology induced by STZ, HFF or HC were partially, or fully, reversed by liraglutide and sitagliptin, and related to advantageous effects on alpha- and beta-cell growth and survival. More interestingly, induction of diabetes-like phenotype, regardless of pathogenesis, led to increased numbers of beta-cells losing their identity, as well as decreased expression of Pdx1 within beta-cells. Both treatment interventions, and especially liraglutide, countered detrimental islet cell transitioning effects in STZ and HFF mice. Only liraglutide imparted benefits on beta- to alpha-cell transdifferentiation in HC mice. These data demonstrate that beta- to alpha-cell transdifferentiation is a common consequence of beta-cell destruction or insulin resistance, and that clinically approved incretin-based drugs effectively limit this.
    DOI:  https://doi.org/10.1530/JOE-19-0451
  163. Interact Cardiovasc Thorac Surg. 2020 Jan 21. pii: ivz315. [Epub ahead of print]
    Is surgical resection of primary tumour superior to exploratory thoracotomy without resection in treating lung cancer patients with unexpected pleural metastasis detected during operation?
    Deng HY, Zheng X, Zhu DX, Zhou Q.
      A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In lung cancer patients with unexpected pleural metastasis detected during operation, is surgical resection of primary tumour superior to exploratory thoracotomy without resection in improving long-term survival?'. Altogether, 1443 papers were found using the reported search, of which 1 meta-analysis and 10 retrospective observational cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. One meta-analysis and 9 cohort studies found that surgical resection of the primary tumour, on the discovery of pleural metastases, yielded a better overall survival than exploratory thoracotomy alone, while 1 cohort study showed no difference. Six studies found that main tumour resection was an independent favourable prognostic factor for overall survival in lung cancer patients with unexpected pleural metastasis detected during operation, while 3 cohort studies also showed improved progression-free survival over exploratory thoracotomy. Therefore, we conclude that surgical resection of the primary tumour is superior to exploratory thoracotomy in treating lung cancer patients with unexpected pleural metastasis detected during operation.
    Keywords:  Intraoperatively detected; Lung cancer; Pleural metastasis; Surgical resection
    DOI:  https://doi.org/10.1093/icvts/ivz315
  164. Mol Cell Biol. 2020 Jan 21. pii: MCB.00518-19. [Epub ahead of print]
    Therapeutic IDOL reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice.
    Gao J, Littman R, Diamante G, Xiao X, Ahn IS, Yang X, Cole TA, Tontonoz P.
      Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and β-amyloid (Aβ) and are potential therapeutic targets for Alzheimer's Disease (AD). Previously, we identified E3 ubiquitin ligase IDOL as a negative regulator of brain lipoprotein receptors. Genetic ablation of Idol increases low-density lipoprotein receptor (LDLR) protein levels, which facilitates Aβ uptake and clearance by microglia. In this study, we utilized an antisense oligonucleotide (ASO) to reduce IDOL expression therapeutically in the brains of APP/PS1 male mice. ASO treatment led to decreased Aβ pathology, and improved spatial learning and memory. Single-cell transcriptomic analysis of hippocampus revealed that IDOL inhibition upregulated lysosomal/phagocytic genes in microglia. Furthermore, clustering of microglia revealed that IDOL-ASO treatment shifted the composition of the microglia population by increasing the prevalence of disease-associated microglia (DAM). Our results suggest that reducing IDOL expression in the adult brain promotes the phagocytic clearance of Aβ and ameliorates Aβ-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD.Significance Statement Enhancing the expression of LDLR, a primary metabolic receptor for ApoE-containing lipoproteins, has been shown to improve AD pathology. However, this basic science observation has not yet been translated to therapy because overexpression of LDLR in the brain is not a feasible approach. In the current paper, we demonstrate that it is possible to raise brain LDLR levels using an antisense oligonucleotide targeting the E3 ubiquitin ligase IDOL. Remarkably, therapeutic targeting of IDOL improves AD pathology and cognitive function without obvious deleterious side effects. Our study also reveals that IDOL reduction alters the microglial phagocytosis in response to Aβ, providing new insight into the plasticity of microglial functionality and its link to ApoE metabolism.
    DOI:  https://doi.org/10.1128/MCB.00518-19
  165. Oncol Lett. 2020 Feb;19(2): 1427-1433
    MicroRNA-519 inhibits hypoxia-induced tumorigenesis of pancreatic cancer by regulating immune checkpoint PD-L1.
    Nong K, Zhang D, Chen C, Yang Y, Yang Y, Liu S, Cai H.
      Pancreatic cancer is highly prevalent and exhibits a high incidence and mortality rate. Hypoxia contributes to tumorigenesis and the progression of pancreatic cancer. To the best of our knowledge, the role of microRNA (miR)-519 has not been investigated in hypoxia-induced pancreatic cancer progression. The purpose of the present study was to elucidate the mechanism underlying miR-519-mediated regulation of pancreatic cancer progression. Reverse transcription-quantitative PCR and western blotting were performed to investigate miR-519 and programmed death ligand 1 (PD-L1) mRNA and protein levels, respectively. Additionally, a Transwell assay was performed to examine the invasiveness of PANC-1 and SW1990 cells. Cells were subsequently stained with Annexin V to determine the apoptotic rate of cells. Furthermore, bioinformatics analysis and a dual-luciferase reporter assay were performed to confirm the direct association between miR-519 and PD-L1, and a xenograft experiment was conducted to test the role of miR-519 in vivo. The results revealed that the expression levels of miR-519 in pancreatic cancer cells were reduced following hypoxia treatment. Furthermore, transfection with miR-519 mimics inhibited PANC-1 and SW1990 cell invasiveness, and induced apoptosis under hypoxic conditions. PD-L1 was also identified as a downstream target of miR-519, and rescued the miR-519 mimic-attenuated tumorigenesis of pancreatic cancer cells under hypoxic conditions. Additionally, treatment with miR-519 mimics significantly suppressed the tumor growth of PANC-1 cells. The results of the present study indicated a novel mechanism of miR-519-mediated tumorigenesis in pancreatic cancer cells under hypoxic conditions. The conclusions may be crucial for the improvement of future pancreatic cancer treatment.
    Keywords:  hypoxia; microRNA-519; pancreatic cancer; programmed death ligand 1; tumorigenesis
    DOI:  https://doi.org/10.3892/ol.2019.11234
  166. Semin Roentgenol. 2020 Jan;pii: S0037-198X(19)30077-X. [Epub ahead of print]55(1): 23-40
    Epidemiology of Lung Cancer.
    Kastner J, Hossain R, White CS.
      
    DOI:  https://doi.org/10.1053/j.ro.2019.10.003
  167. J Proteome Res. 2020 Jan 24.
    BLOOD PLASMA METABOLOMICS PREDICTS PREGNANCY IN HOLSTEIN CATTLE TRANSFERRED WITH FRESH AND VITRIFIED/WARMED EMBRYOS PRODUCED IN VITRO.
    Gómez E, Salvetti P, Gatien J, Carrocera S, Martin-Gonzalez D, Muñoz M.
      Metabolomics may identify biomarkers in blood that differentiate pregnant from open embryo recipients. Fresh and vitrified/warmed, in-vitro produced embryos, were transferred to Holstein recipients (discovery group). Recipient blood plasma collected on Day-0 (estrus) and Day-7 (before embryo transfer) was analysed by nuclear magnetic resonance, (N=36 metabolites quantified). Metabolites whose concentrations differed between open and pregnant recipients were analysed [(P<0.05); FDR (P<0.05)]. Biomarkers were identified in Day-7 plasma (ROC-AUC>0.650; T-Test P<0.05; Random Forests, mean decrease accuracy) and cross-validated in independent Holstein, beef and crossbred recipients (overall classification accuracy -OCA-; P<0.05). Recipients with fresh embryos showed N=6 biomarkers consistently on Day-40, Day-62 and at birth. Recipients with vitrified embryos showed N=5 biomarkers on Day-40 and Day-62 but only one biomarker at birth. The most predictive biomarkers identified at birth within fresh embryos were Oxoglutaric acid (ROC-AUC=0.709; OCA=0.812) and Ornithine (ROC-AUC=0.731; OCA=0.727), while L-Glycine was identified in vitrified embryos (ROC-AUC=0.796; OCA=0.667) together with other predictive biomarkers not identified at birth (Day-62: L-Glutamine ROC-AUC= 0.757; OCA=0.767) and L-Lysine (Day-62: ROC-AUC=0.680; OCA=0.767). Pathway enrichment analysis distinguished between pregnant recipients for fresh (enriched energy oxidative metabolism from fat) and vitrified embryos (lower lipid metabolism). Metabolomics can select individuals which will become pregnant in a defined cycle.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00688
  168. J Clin Pathol. 2020 Jan 22. pii: jclinpath-2019-206252. [Epub ahead of print]
    Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) for PD-L1 testing in triple-negative breast cancer: a translational assay compared with conventional IHC.
    Yeong J, Tan T, Chow ZL, Cheng Q, Lee B, Seet A, Lim JX, Lim JCT, Ong CCH, Thike AA, Saraf S, Tan BYC, Poh YC, Yee S, Liu J, Lim E, Iqbal J, Dent R, Tan PH.
      BACKGROUND: Programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has recently gained approval for treating metastatic triple-negative breast cancer (TNBC) -, in particular in the PD-L1+ patient subgroup of the recent IMpassion130 trial. The SP142 PD-L1 antibody clone was used as a predictive assay in this trial, but this clone was found to be an outlier in previous harmonisation studies in lung cancer.AIMS: To address the comparability of PD-L1 clones in TNBC, we evaluated the concordance between conventional immunohistochemistry (IHC) and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) that allowed simultaneous quantification of three different PD-L1 antibodies (22C3, SP142 and SP263).
    METHODS: Our cohort comprised 25 TNBC cases, 12 non-small-cell lung carcinomas and 8 other cancers. EpCAM labelling was used to distinguish tumour cells from immune cells.
    RESULTS: Moderate-to-strong correlations in PD-L1 positivity were found between results obtained through mIHC/IF and IHC. Individual concordance rates in the study ranged from 67% to 100%, with Spearman's rank correlation coefficient values up to 0.88.
    CONCLUSIONS: mIHC/IF represents a promising tool in the era of cancer immunotherapy, as it can simultaneously detect and quantify PD-L1 labelling with multiple antibody clones, and allow accurate evaluation of tumour and immune cells. Clinicians and pathologists require this information to predict patient response to anti-PD-1/PD-L1 therapy. The adoption of this assay may represent a significant advance in the management of therapeutically challenging cancers. Further analysis and assay harmonisation are essential for translation to a routine diagnostic setting.
    Keywords:  breast pathology; immunohistochemistry; immunopathology
    DOI:  https://doi.org/10.1136/jclinpath-2019-206252
  169. Ann Surg Oncol. 2020 Jan 22.
    Impact of Sarcopenia on Surgical Outcomes in Non-small Cell Lung Cancer.
    Shinohara S, Otsuki R, Kobayashi K, Sugaya M, Matsuo M, Nakagawa M.
      BACKGROUND: Sarcopenia influences overall survival (OS) and tumor progression in non-small cell lung cancer (NSCLC) patients. However, the impact of postoperative complications and the outcome of limited surgery have not been highlighted. Therefore, the aim of this study is to elucidate the prognostic impact of sarcopenia on surgical outcomes.PATIENTS AND METHODS: This study included NSCLC patients who had undergone lung cancer resection between 2007 and 2017. Sarcopenia was confirmed based on computed tomography of the cross-sectional area of the psoas muscle at the third lumbar vertebra level. We used propensity score-matched analysis to elucidate the impact of sarcopenia on postoperative complications and limited surgery.
    RESULTS: A total of 391 patients were enrolled, including 198 sarcopenic patients. Multivariate analysis showed that sarcopenia was an independent unfavorable prognostic factor associated with OS and recurrence-free survival [hazard ratio (HR), 3.33, P < 0.001; HR, 2.76, P < 0.001, respectively]. Regarding the incidence of postoperative complications, there was no difference between sarcopenic and nonsarcopenic patients (69/198 versus 55/193, P = 0.19). After propensity score matching, among patients without sarcopenia, the 5-year OS was lower in those with limited surgery than in those with standard surgery (70.7% vs. 96.4%, P = 0.011). In contrast, among sarcopenic patients, there was no difference in the 5-year OS between patients with limited surgery and those with standard surgery (53.2% vs. 60.7%, P = 0.66).
    CONCLUSIONS: Sarcopenia is a prognostic predictor for poor OS and may contribute to the selection of limited surgery for sarcopenic patients. Preoperative assessment of sarcopenia may provide clinically important information.
    DOI:  https://doi.org/10.1245/s10434-020-08224-z
  170. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31662-6. [Epub ahead of print]30(3): 714-724.e5
    Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy.
    He B, Johansson-Percival A, Backhouse J, Li J, Lee GYF, Hamzah J, Ganss R.
      Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the pre-metastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intra-metastatic blood vessels and increases GrzB+ effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to anti-PD-1 checkpoint inhibitors. These findings demonstrate an important application for LIGHT-VTP therapy in preventing metastatic development as well as exerting anti-tumor effects in established metastases.
    Keywords:  angiogenesis; high endothelial venules; immunotherapy; metastasis; peptide tumor targeting; pre-metastatic niche; tertiary lymph node structures; vessel normalization
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.013
  171. Acta Clin Croat. 2019 Sep;58(3): 540-545
    Nocardial brain abscess mimicking lung cancer metastasis in immunocompetent patient with pulmonary nocardiasis: a case report.
    Karan M, Vučković N, Vuleković P, Rotim A, Lasica N, Rasulić L.
      Nocardia is a ubiquitous microorganism which can be the cause of local and disseminated infection in humans. Immunocompetent and immunocompromised patients both can be affected and Nocardia cyriacigeorgica was reported as a pathogen isolated in patients worldwide. In most cases, nocardiosis is present as pulmonary infection because inhalation is the primary way of bacterial exposure. Nocardial brain abscess occurs usually secondary to a septic focus elsewhere in the body. Considering the facts that the elderly population is growing, such as the number of immunocompromised patients together with high mortality rate in patients with nocardial infection of the central nervous system, we have to raise awareness of the possibility for this rare but potentially fatal condition. We present a case where nocardial abscesses of lung and brain were initially suspected as lung cancer with brain metastases. The patient was treated with a combination of surgical resection and antimicrobial therapy with good outcome.
    Keywords:  Brain abscess; Case reports; Lung neoplasms; Nocardia, infections
    DOI:  https://doi.org/10.20471/acc.2019.58.03.20
  172. DNA Cell Biol. 2020 Jan 21.
    Glycolysis-Based Genes Associated with the Clinical Outcome of Pancreatic Ductal Adenocarcinoma Identified by The Cancer Genome Atlas Data Analysis.
    Tian G, Li G, Liu P, Wang Z, Li N.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadly tumors in digestive tract tumors. Although there has been advancement in PDAC treatment, its prognosis still remains unsatisfactory, mainly because of dismal diagnosis. This article aims to develop new prognostic factors related to energy metabolism in PDAC and to use these genes for novel risk stratification. Hundred fifty messenger RNA (mRNA) expression profiles and clinicopathological data of PDAC were downloaded from The Cancer Genome Atlas dataset. The glycolysis pathway was the significant pathway based on the gene set enrichment analysis. We chose the glycolysis pathway-related 176 genes for further analysis. Multivariate Cox regression analysis and forward stepwise Cox regression model established a novel three-gene glycolytic signature (including MET, B3GNT3, and SPAG4) for PDAC patients' prognosis prediction. All 150 patients were classified into two groups by the median risk score. High-risk group had a worse outcome compared to the low-risk group. The risk score was also significantly correlated with age and radiotherapy. A nomogram, including the glycolytic gene signature, has shown some clinical net benefit for overall survival prediction. We also validated the validity and reliability in the Puleo dataset. This novel gene expression signature may be involved in the pathophysiology and used for risk stratification and prognosis prediction in PDAC.
    Keywords:  gene signature; glycolysis; pancreatic ductal adenocarcinoma; prognosis
    DOI:  https://doi.org/10.1089/dna.2019.5089
  173. Am J Physiol Lung Cell Mol Physiol. 2020 Jan 22.
    The emergence of preclinical studies on the role of the microbiome in lung development and experimental animal models of bronchopulmonary dysplasia.
    Casado F, Morty RE.
      
    Keywords:  BPD; bronchopulmonary dysplasia; dysbiosis; hyperoxia; microbiome
    DOI:  https://doi.org/10.1152/ajplung.00509.2019
  174. Food Funct. 2020 Jan 20.
    High fat diet incorporated with meat proteins changes biomarkers of lipid metabolism, antioxidant activities, and the serum metabolomic profile in Glrx1-/- mice.
    Ahmad MI, Umair Ijaz M, Hussain M, Ali Khan I, Mehmood N, Siddiqi SM, Liu C, Zhao D, Xu X, Zhou G, Li C.
      Red and processed meat consumption has been associated with oxidative stress, diabetes and non-alcoholic fatty liver disease (NAFLD). This study was aimed at exploring the effects of high-fat meat protein diets on potential metabolite biomarkers in Glrx1-/- mice, a well-documented mouse model to study NAFLD. Male Glrx1-/- mice were fed a control diet with 12% energy (kcal) from fat, a high-fat diet supplemented with casein (HFC) with 60% energy (kcal) from fat, and a high-fat diet supplemented with fish (HFF) or mutton proteins (HFM) for 12 weeks. The results of biochemical and histological analyses indicated that the intake of HFM increased hepatic total cholesterol, triglycerides, serum alanine transaminase and aspartate transaminase, and macro- and micro-vesicular lipid droplet accumulation, which were accompanied by altered gene expression associated with the lipid and cholesterol metabolism. HFF diet fed Glrx1-/- mice significantly ameliorated diet-induced NAFLD biomarkers compared to HFC and HFM diets. In addition, serum metabolome profiling identified metabolites specifically associated with lipid metabolism bile acid metabolism, sphingolipid and amino acid metabolism pathways. A HFM diet increased the abundance of LysoPC(15:0), LysoPC(16:0), LysoPC(20:1), LysoPE(18:2), LysoPE(22:0), LysoPE(20:6), O-arachidonoylglycidol, 12-ketodeoxycholic acid and sphinganine that are associated with NAFLD. The KEGG metabolic pathway of identified metabolites of high fat diets showed that the differential metabolites were associated with lipid metabolism, linoleic acid metabolism, amino acid metabolism, bile acid metabolism, sphingolipid metabolism, and glutathione metabolism pathways whereas HFF diet ameliorated NAFLD by modifying these pathways. These results provide potential metabolite biomarkers for NAFLD induced by HFM diet.
    DOI:  https://doi.org/10.1039/c9fo02207d
  175. Mol Cancer. 2020 Jan 22. 19(1): 12
    Autophagy and autophagy-related proteins in cancer.
    Li X, He S, Ma B.
      Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.
    Keywords:  Autophagy; Autophagy-related proteins; Cancer promotor; Cancer suppressor; Cancer therapy
    DOI:  https://doi.org/10.1186/s12943-020-1138-4
  176. Nat Commun. 2020 Jan 24. 11(1): 520
    Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements.
    Henderson R, Lu M, Zhou Y, Mu Z, Parks R, Han Q, Hsu AL, Carter E, Blanchard SC, Edwards RJ, Wiehe K, Saunders KO, Borgnia MJ, Bartesaghi A, Mothes W, Haynes BF, Acharya P, Munir Alam S.
      The trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusion via a network of conformational transitions, with allosteric elements in each protomer orchestrating host receptor-induced exposure of the co-receptor binding site and fusion elements. To understand the molecular details of this allostery, here, we introduce Env mutations aimed to prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis and single-molecule Förster Resonance Energy Transfer confirm that these mutations prevent CD4-induced transitions of the HIV-1 Env. Structural analysis by single-particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins shows rearrangements in the gp120 topological layer contacts with gp41. Displacement of a conserved tryptophan (W571) from its typical pocket in these Env mutants renders the Env insensitive to CD4 binding. These results reveal the critical function of W571 as a conformational switch in Env allostery and receptor-mediated viral entry and provide insights on Env conformation that are relevant for vaccine design.
    DOI:  https://doi.org/10.1038/s41467-019-14196-w
  177. Crit Rev Toxicol. 2019 Aug;49(7): 597-613
    Critical review of the evidence for a causal association between exposure to asbestos and esophageal cancer.
    Peterson MK, Mohar I, Lam T, Cook TJ, Engel AM, Lynch H.
      Esophageal cancers comprise about 1% of all cancers diagnosed in the US but are more prevalent in other regions of the world. Several regulatory agencies have classified asbestos as a known human carcinogen, and it is linked to multiple diseases and malignancies, including lung cancer and mesothelioma. In a 2006 review of the epidemiological literature, the Institute of Medicine (IOM) did not find sufficient evidence to demonstrate a causal relationship between asbestos exposure and esophageal cancer. To reevaluate this conclusion, we performed a critical review of the animal toxicological, epidemiological, and mechanism of action literature on esophageal cancer and asbestos, incorporating studies published since 2006. Although there is some evidence in the epidemiological literature for an increased risk of esophageal cancer in asbestos-exposed occupational cohorts, these studies generally did not control for critical esophageal cancer risk factors (e.g. smoking, alcohol consumption). Furthermore, data from animal toxicological studies do not indicate that asbestos exposure increases esophageal cancer risk. Based on our evaluation of the literature, and reaffirming the IOM's findings, we conclude that there is insufficient evidence to demonstrate a causal link between asbestos exposure and esophageal cancer.
    Keywords:  Asbestos; causal analysis; epidemiology; esophageal cancer; mechanism of action; toxicology
    DOI:  https://doi.org/10.1080/10408444.2019.1692190
  178. Oncol Lett. 2020 Feb;19(2): 1203-1214
    Effects of hub genes on the clinicopathological and prognostic features of lung adenocarcinoma.
    Yu DH, Huang JY, Liu XP, Ruan XL, Chen C, Hu WD, Li S.
      Lung adenocarcinoma (LUAD) is a common malignancy; however, the majority of its underlying molecular mechanisms remain unknown. In the present study, weighted gene co-expression network analysis was applied to construct gene co-expression networks for the GSE19804 dataset, in order to screen hub genes associated with the pathogenesis of LUAD. In addition, with the aid of the Database for Annotation, Visualization and Integrated Discovery, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes, pathway enrichment analyses were performed on the genes in the selected module. Using the GSE40791 dataset and The Cancer Genome Atlas database, the hub genes were identified. It was discovered that the turquoise module was the most significant module associated with the tumor stage of LUAD. After performing functional enrichment analyses, it was indicated that the turquoise module was mainly enriched in signal transduction. Additionally, at the transcriptional and translational level, nine hub genes were identified and validated: Carbonic anhydrase 4 (CA4), platelet and endothelial cell adhesion molecule 1 (PECAM1), DnaJ member B4 (DNAJB4), advanced glycosylation end-product specific receptor (AGER), GTPase, IMAP family member 6 (GIMAP6), chromosome 10 open reading frame 54 (C10orf54), dedicator of cytokinesis 4 (DOCK4), Golgi membrane protein 1 (GOLM1) and platelet activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3). CA4, PECAM1, DNAJB4, AGER, GIMAP6, C10orf54 and DOCK4 were expressed at lower levels in the tumor samples, whereas GOLM1 and PAFAH1B3 were highly expressed in tumor samples. In addition, all hub genes were associated with prognosis. In conclusion, one module and nine genes were recognized to be associated with the tumor stage of LUAD. These findings may enhance the understanding of the progression and prognosis of LUAD.
    Keywords:  Gene Expression Omnibus; The Cancer Genome Atlas; clinical prognosis; hub genes; lung adenocarcinoma; weighted gene co-expression network analysis
    DOI:  https://doi.org/10.3892/ol.2019.11193
  179. South Asian J Cancer. 2020 Jan-Mar;9(1):9(1): 6
    An exceptional response to olaparib in relapsed and refractory BRCA2 mutated non-small cell lung cancer in hereditary breast-ovarian cancer syndrome.
    Talreja VT, Noronha V, Joshi A, Patil V, Prabhash K.
      
    DOI:  https://doi.org/10.4103/sajc.sajc_157_19
  180. Drug Metab Dispos. 2020 Jan 24. pii: dmd.119.089391. [Epub ahead of print]
    Metabolism and Disposition of Ataluren following Oral Administration to Mice, Rats, Dogs, and Humans.
    Kong R, Ma J, Hwang S, Goodwin E, Northcutt V, Babiak J, Almstead N, McIntosh J.
      Ataluren is a unique small molecule developed for the treatment of diseases due to presence of nonsense mutations, which result in premature termination of ribosomal translation and lack of full-length protein production. This study investigated the in vivo metabolism and disposition of ataluren in mice, rats, dogs and humans. Following single oral administration of [14C] ataluren, the overall recovery of radioactivity was ≥ 93.7%, with approximately 39%, 17% to 21%, 12%, and 55% in the urine, and 54%, 70%, 80%, and 47% in the feces from intact mice, rats, dogs, and humans, respectively. In bile-duct cannulated (BDC) rats, approximately 10%, 7%, and 82% of the dose were recovered in the urine, feces, and bile, respectively, suggesting that biliary secretion was a major route for the elimination of ataluren in the rats. Ataluren was extensively metabolized following oral administration and the metabolic profiles of ataluren were quantitatively similar across all species. Unchanged ataluren was the dominant radioactive component in plasma. Ataluren acyl glucuronide was the most prominent metabolite in plasma of all species and the dominant metabolite in BDC rat bile and human urine, while the oxadiazole cleavage products were the major or prominent metabolites in the feces of all species. Overall, the results indicate that, unlike most small molecules, phase I metabolism is negligible, and the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species. SIGNIFICANCE STATEMENT: Ataluren is a novel carboxylic acid containing small molecule drug for treating nonsense mutation Duchenne muscular dystrophy (nmDMD). In vivo metabolism and disposition after a single dose of the drug were investigated in mice, rats, dogs and humans. Unlike most small molecules, phase I metabolism of ataluren was negligible, and the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species.
    Keywords:  animal/nonclinical/preclinical; drug absorption; drug development/discovery; glucuronidation/UDP-glucuronyltransferases/UGT; human/clinical; metabolite disposition; metabolite identification
    DOI:  https://doi.org/10.1124/dmd.119.089391
  181. Int J Mol Sci. 2020 Jan 17. pii: E599. [Epub ahead of print]21(2):
    Cadmium-Related Effects on Cellular Immunity Comprises Altered Metabolism in Earthworm Coelomocytes.
    Höckner M, Piechnik CA, Fiechtner B, Weinberger B, Tomanek L.
      The heavy metal cadmium (Cd) is known to modulate the immune system, challenging soil-dwelling organisms where environmental Cd pollution is high. Since earthworms lack adaptive immunity, we determined Cd-related effects on coelomocytes, the cellular part of innate immunity, which is also the site of detoxification processes. A proteomics approach revealed a set of immunity-related proteins as well as gene products involved in energy metabolism changing in earthworms in response to Cd exposure. Based on these results, we conducted extracellular flux measurements of oxygen and acidification to reveal the effect of Cd on coelomocyte metabolism. We observed a significantly changing oxygen consumption rate, extracellular acidification, as well as metabolic potential, which can be defined as the response to an induced energy demand. Acute changes in intracellular calcium levels were also observed, indicating impaired coelomocyte activation. Lysosomes, the cell protein recycling center, and mitochondrial parameters did not change. Taken together, we were able to characterize coelomocyte metabolism to reveal a potential link to an impaired immune system upon Cd exposure.
    Keywords:  coelomocytes; earthworm; metabolism
    DOI:  https://doi.org/10.3390/ijms21020599
  182. Nat Commun. 2020 Jan 22. 11(1): 431
    Environmental arginine controls multinuclear giant cell metabolism and formation.
    Brunner JS, Vulliard L, Hofmann M, Kieler M, Lercher A, Vogel A, Russier M, Brüggenthies JB, Kerndl M, Saferding V, Niederreiter B, Junza A, Frauenstein A, Scholtysek C, Mikami Y, Klavins K, Krönke G, Bergthaler A, O'Shea JJ, Weichhart T, Meissner F, Smolen JS, Cheng P, Yanes O, Menche J, Murray PJ, Sharif O, Blüml S, Schabbauer G.
      Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.
    DOI:  https://doi.org/10.1038/s41467-020-14285-1
  183. Mol Cancer. 2020 Jan 21. 19(1): 11
    Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response.
    Huan L, Guo T, Wu Y, Xu L, Huang S, Xu Y, Liang L, He X.
      BACKGROUND: Hypoxic tumors are refractory to DNA damage drugs. However, the underlying mechanism has yet to be elucidated. We aimed to identify lncRNAs that upregulated under hypoxia and their effects on colorectal cancer (CRC).METHODS: CRC cells were treated with 1% O2 to identify lncRNAs that upregulated under hypoxia. We integrated these lncRNAs with RNA-seq of 4 paired CRC tissues and TCGA data to get candidate lncRNAs. Multiple in vitro and in vivo assays were used to explore the role of LUCAT1 in CRC.
    RESULTS: We identified a hypoxia-induced lncRNA LUCAT1 that facilitated the growth of CRC cells and contributed to drug resistance of CRC cells both in vitro and in vivo. Mechanically, LUCAT1 interacts with polypyrimidine tract binding protein 1 (PTBP1) in CRC cells, facilitates the association of a set of DNA damage related genes with PTBP1, thus resulting in altered alternative splicing of these genes. Moreover, ectopic expression of PTBP1 in CRC cells with knockdown of LUCAT1 abrogated the effects induced by LUCAT1 knockdown. Chemotherapeutics drug combined with LUCAT1 knockdown via antisense oligonucleotides (ASO) would get a better outcome in vivo, compared with group treated with chemotherapeutic drug only. Notably, LUCAT1 is upregulated in CRC tissues, compared to adjacent normal tissues; and CRC patients with higher LUCAT1 have a worse prognosis and poorly responded to chemotherapy in the clinic.
    CONCLUSIONS: Our data suggested CRC cells utilizes LUCAT1 to develop resistance to DNA damage drugs, and disrupting the LUCAT1/PTBP1 axis might be a promising therapeutic strategy for refractory hypoxic tumors.
    Keywords:  Alternative splicing; Chemoresistance; Hypoxia; LUCAT1; PTBP1; lncRNA
    DOI:  https://doi.org/10.1186/s12943-019-1122-z
  184. J Cell Mol Med. 2020 Jan 23.
    Metformin upregulates mitophagy in patients with T2DM: A randomized placebo-controlled study.
    Bhansali S, Bhansali A, Dutta P, Walia R, Dhawan V.
      Impaired mitochondrial autophagy (mitophagy) and NLRP3 inflammasome activation have been incriminated in the pathogenesis of T2DM. Metformin besides being an insulin sensitizer also induces autophagy; however, its effect on mitophagy and NLRP3 activation in patients with T2DM still remains elusive. Forty-five drug-naïve T2DM patients with HbA1C 7%-9% (53-75 mmol/mol) were randomly assigned to receive either metformin, voglibose, or placebo for 3 months, and were also recommended for lifestyle intervention programme (n = 15 each). Mitochondrial oxidative stress (MOS) parameters, qPCR and immunoblotting of mitophagy-related markers (PINK1, PARKIN, MFN2, NIX, LC3-II, LAMP2), p-AMPKα (T172), and NLRP3 proteins, as well as transmission electron microscopy (TEM) for assessing mitochondrial morphology were performed in the mononuclear cells of study patients. Both metformin and voglibose showed a similar efficacy towards the reduction in HbA1c and MOS indices. However, multivariate ANCOVA divulged that mRNA and protein expression of mitophagy markers, NLRP3 and p-AMPKα (T172), were significantly increased only with metformin therapy. Moreover, PINK1 expression displayed a significant positive association with HOMA-β indices, and TEM studies further confirmed reduced distortions in mitochondrial morphology in the metformin group only. Our observations underscore that metformin upregulates mitophagy and subsequently ameliorates the altered mitochondrial morphology and function, independent of its glucose-lowering effect. Further, restoration of normal mitochondrial phenotype may improve cellular function, including β-cells, which may prevent further worsening of hyperglycaemia in patients with T2DM.
    Keywords:  metformin; mitophagy; nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3); randomized controlled trial; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1111/jcmm.14834
  185. J Food Sci. 2020 Jan 24.
    Untargeted metabolic fingerprinting reveals impact of growth stage and location on composition of sea buckthorn (Hippophaë rhamnoides) leaves.
    Pariyani R, Kortesniemi M, Liimatainen J, Sinkkonen J, Yang B.
      Sea buckthorn (Hippophaë rhamnoides) is increasingly cultivated to produce raw materials for food and nutraceuticals. There is little knowledge on composition of sea buckthorn leaves (SBLs) and the key factors influencing the composition. This research aims to unravel the metabolic profile of SBLs and the effects of cultivar, location and stage of growth, and climatic conditions on the metabolic profile of SBLs. Leaves of two sea buckthorn cultivars grown in the south and north of Finland during two consecutive growth seasons were studied using untargeted nuclear magnetic resonance (NMR) metabolomics. The highest variance in the metabolic profile was linked to the growth stage, wherein leaves from the first 7 weeks of harvest were characterized with higher abundance of polyphenols, while relatively higher abundance of carbohydrates and sugars was observed in the later weeks. The growth location attributed for the second highest variation, wherein the north-south comparison identified fatty acids and sugars as discriminatory metabolites, and the potential association of metabolome to natural abiotic stressors was revealed. An inverse correlation between carbohydrate/sugar content as well as fatty acids of higher carbon chain length with the temperature variables was evident. The supervised chemometric models with high sensitivity and specificity classified and predicted the samples based on growth stage and location, and cultivar. Nontargeted NMR-metabolomics revealed the metabolic profile of SBLs and their variation associated with various biotic and abiotic factors. Cultivar and growth stage are key factors to consider when harvesting SBLs for use in food and nutraceuticals. PRACTICAL APPLICATION: Globally, sea buckthorn cultivation has been rapidly increasing due to the known health-promoting benefits of the berries and leaves of the plant. The current research obtained new comprehensive information on the compositional profile of sea buckthorn leaves as well as the impact of major contributory factors, such as cultivars, the advancement of growth stage, geographical location, and weather parameters. The findings of this research provide new knowledge and guidance for plant breeding, cultivation and commercial utilization of sea buckthorn leaves as raw materials for food, feed, and nutraceuticals.
    Keywords:  Hippohaë rhamnoides; NMR metabolomics; growth stage; sea buckthorn leaves; weather conditions
    DOI:  https://doi.org/10.1111/1750-3841.15025
  186. BMC Cancer. 2020 Jan 20. 20(1): 46
    IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα- BCa and AR- PCa cells and promotes cell survival.
    Nawas AF, Kanchwala M, Thomas-Jardin SE, Dahl H, Daescu K, Bautista M, Anunobi V, Wong A, Meade R, Mistry R, Ghatwai N, Bayerl F, Xing C, Delk NA.
      BACKGROUND: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Thus, BCa and PCa patients are given therapies that reduce hormone levels or directly block HR activity; but most patients eventually develop treatment resistance. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERα and AR mRNA in HR-positive (HR+) BCa and PCa cell lines, yet the cells can remain viable. Additionally, we identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells to promote HR-independent survival and tumorigenicity.METHODS: We performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in the BCa and PCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) and used the gene ontology web-based tool, GOrilla, to identify signaling pathways encoded by our RNA-seq data set.
    RESULTS: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in HR-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired hormone receptor independence and treatment resistance. We also assessed HR- cell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HR- cell lines.
    CONCLUSIONS: Our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic HR-independent BCa and PCa.
    Keywords:  Androgen receptor; Breast cancer; Estrogen receptor; Interleukin-1; Prostate cancer; p62/SQSTM1
    DOI:  https://doi.org/10.1186/s12885-020-6529-9
  187. Sci Rep. 2020 Jan 24. 10(1): 1109
    Insights into the regulation of molecular mechanisms involved in energy shortage in detached citrus fruit.
    Romero P, Alférez F, Establés-Ortiz B, Lafuente MT.
      Harvested fruit undergo carbon and energy deprivation. However, the events underlying this energy-related stress in detached fruit and their involvement in cell damage have not yet been elucidated. We showed that supplementing detached sweet oranges with additional carbon or energy sources reduced peel damage, while inhibitors of energy metabolism increased it. We investigated the effect of an exogenous source of carbon (glycerol), energy (ATP), and an inhibitor of energy metabolism 2-deoxy-D-glucose (DeOGlc) + sodium iodoacetate (IAc), on the transcriptome of harvested fruit flavedo (outer peel part). ATP and Gly induced common, but also specific, alternative modes of energy metabolism by reducing the stress caused by energy shortage. They also induced shifts in energy metabolism that led to the production of the intermediates required for plant defense secondary metabolites to form. ATP and Gly triggered changes in the expression of the genes involved in cell lesion containment through a defined pathway involving hormones and redox-mediated signaling. DeOGlc + IAc had a contrasting effect on some of these mechanisms. These chemicals altered the biological processes related to membrane integrity and molecular mechanisms involving reactive oxygen species (ROS) production, and lipid and protein degradation.
    DOI:  https://doi.org/10.1038/s41598-019-57012-7
  188. Nat Commun. 2020 Jan 24. 11(1): 498
    Targeting glutamine metabolism slows soft tissue sarcoma growth.
    Lee P, Malik D, Perkons N, Huangyang P, Khare S, Rhoades S, Gong YY, Burrows M, Finan JM, Nissim I, Gade TPF, Weljie AM, Simon MC.
      Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.
    DOI:  https://doi.org/10.1038/s41467-020-14374-1
  189. Sci Rep. 2020 Jan 24. 10(1): 1127
    Hypoxic environment may enhance migration/penetration of endocrine resistant MCF7- derived breast cancer cells through monolayers of other non-invasive cancer cells in vitro.
    Barrak NH, Khajah MA, Luqmani YA.
      The response of cancer cells to hypoxic conditions found within the interior of a tumor mass is mediated through the hypoxia inducible factor (HIF) cascade and is thought to promote metastasis. However, given their distant proximity from blood vessels as compared to normoxic cells at the vascularised tumor periphery, it is uncertain if these cells can migrate through the tumor mass to gain access. Hypoxia was simulated by exposure to cobalt chloride or deferoxamine in normal (MCF10A) and cancerous [estrogen receptor (ER)-ve (pII), and ER +ve (YS1.2/ EII)] cells. In this report, HIF1α expression and localization was measured using western blotting, ELISA, and immunofluorescence, cell proliferation by MTT assay, motility and invasion by wound healing, live cell imaging, matrigel and co-culture in chambered slides. We found that the expression and nuclear translocation of HIF1α was significantly elevated by hypoxia, which inhibited cell proliferation, but significantly increased motility of pII cells and their penetration into and through a dense layer of adjacent EII cells, as well as their selective emergence out of a co-culture. These data suggest that endocrine resistant pII cancer cells, having undergone epithelial to mesenchymal transition are able to penetrate through other cell layers, with possible enhancement in response to hypoxia.
    DOI:  https://doi.org/10.1038/s41598-020-58055-x
  190. Nanoscale. 2020 Jan 22.
    MnO2@Ce6-loaded mesenchymal stem cells as an "oxygen-laden guided-missile" for the enhanced photodynamic therapy on lung cancer.
    Cao W, Liu B, Xia F, Duan M, Hong Y, Niu J, Wang L, Liu Y, Li C, Cui D.
      The critical issue in nanoscale medicine delivery systems is the targeted efficiency to guarantee the maximum accumulation of nanodrugs in tumors to exert better therapeutic action. In this study, we adopted an active and potent strategy based on mesenchymal stem cells (MSCs) certified with excellent tumor-tropism ability to load and ship MnO2@Ce6 nanoparticles into a tumor site. Notably, under the premise of the negligible cellular toxicity of MnO2@Ce6 on MSCs, its considerable uptake by MSCs enabled this nanoplatform (MnO2@Ce6-MSCs) to distribute increasingly inside the tumor. Briefly, a Ce6 photosensitizer was bound to MnO2 nanospheres by physical adsorption, improving its own stability in blood circulation. Furthermore, the delivered MnO2@Ce6 could modulate the tumor microenvironment (TME) by high sensitivity to excess hydrogen protons (H+) and H2O2. Thus, O2 generated by these reactions served as an abundant source for 1O2 conversion under a 633 nm laser exposure, which overcame the crucial bottleneck of the unfavorable hypoxia condition in TME for photodynamic therapy (PDT). In addition, MnO2 decomposed into Mn2+, which was represented by high T1 relaxivity in magnetic resonance imaging (MRI). The Mn2+ was finally removed rapidly from the body by liver metabolism and kidney filtration. These results endowed the original nanoplatform with striking potential for MSC-guided, Ce6-converted, MRI-monitored PDT for further innovation of a clinical cancer diagnosis-treatment agent.
    DOI:  https://doi.org/10.1039/c9nr07947e
  191. Sociol Health Illn. 2020 Jan 24.
    Uncertainty and certain death: the role of clinical trials in terminal cancer care.
    Cortez D, Halpin M.
      We consider uncertainty in relation to clinical trials for terminal non-small cell lung cancer, which is an aggressive and difficult to treat form of cancer. Using grounded theory to analyse 85 clinical interactions between doctors, patients and family members, we argue that uncertainty is a major source of tension for terminally ill patients, with individuals confronting a choice between transitioning to palliative care or volunteering for an experimental/trial medication that might postpone death. Regardless of their efficacy, patients must also consider how such experimental treatments might impact their quality-of-life. We argue that clinical trials produce uncertainty through (i) discussions about the efficacy of clinical trials; (ii) the physiological consequences of clinical trial medications; and (iii) the impact clinical trials have on patient's prognostic understanding of their terminal cancer. Accordingly, while study participants encounter high prognostic certainty (i.e. they have a fatal cancer), they nonetheless experience considerable uncertainty in relation to their participation in clinical trials.
    Keywords:  clinical trials; end-of-life care; health and illness; lung cancer; prognosis; uncertainty and risk
    DOI:  https://doi.org/10.1111/1467-9566.13059
  192. Interact Cardiovasc Thorac Surg. 2020 Feb 01. 30(2): 328
    A novel technique for robotic-assisted lobectomy for lung cancer: the anterior approach.
    Yamazaki K, Toyokawa G, Shoji F, Takeo S.
      
    Keywords:  Lung cancer; Robotic-assisted thoracic surgery (RATS); Thoracic surgery
    DOI:  https://doi.org/10.1093/icvts/ivz264
  193. Brain Behav Immun. 2020 Jan 21. pii: S0889-1591(19)31480-1. [Epub ahead of print]
    Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells.
    Mela V, Mota BC, Milner M, McGinley A, Mills KHG, Kelly ÁM, Lynch MA.
      Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, β-galactosidase and p16INK4A, were increased in microglia from sedentary aged mice, and expression of these markers was significantly decreased by exercise. The data demonstrate that the exercise-related improved cognition is orchestrated by a normalization of the metabolic profile and functionality of microglia.
    Keywords:  Glycolysis; IL-1β; exercise; microglia; neuroinflammation; oxidative metabolism; phagocytosis
    DOI:  https://doi.org/10.1016/j.bbi.2020.01.012
  194. Neurosci Lett. 2020 Jan 21. pii: S0304-3940(20)30047-1. [Epub ahead of print] 134777
    Alterations in α-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons.
    Furlong RM, O'Keeffe GW, O'Neill C, Sullivan AM.
      Accumulation of α-synuclein is a pathological hallmark of Parkinson's disease (PD) and has been linked to reductions in neurite length and axonal degeneration of midbrain dopaminergic neurons. Mutations in SNCA, which encodes α-synuclein, and loss of function mutations in PTEN-induced putative kinase-1 (PINK1) cause familial PD. There is a need to identify the mechanisms by which α-synuclein overexpression and the loss of PINK1 induce neurodegeneration in PD. To do this, we employed rat ventral midbrain cultures to investigate the effects of overexpression of wildtype or mutant (A53 T) α-synuclein, and of siRNA knockdown of PINK1, on neurite length and on mitochondrial and Golgi integrity. We found reduced neurite length and increased levels of both Golgi fragmentation and mitochondrial fission in response to overexpression of wildtype or mutant α-synuclein, and to PINK1 knockdown. Reductions in neurite length induced by these two PD risk genes were significantly correlated with increases in Golgi fragmentation and mitochondrial fission. Combined α-synuclein overexpression and PINK1 knockdown induced a greater reduction in neurite length and increase in Golgi fragmentation, than either alone. This study provides novel evidence that α-synuclein overexpression and PINK1 deletion converge to induce significant increases in Golgi fragmentation and mitochondrial fission in midbrain neurons, that are correlated with decreases in neurite length. This highlights the need for further studies on these converging mechanisms in dopaminergic neurodegeneration in PD.
    Keywords:  Golgi fragmentation; PINK1; midbrain dopaminergic neurons; mitochondrial fission; neurite growth; α-synuclein
    DOI:  https://doi.org/10.1016/j.neulet.2020.134777
  195. J Thorac Cardiovasc Surg. 2019 Dec 12. pii: S0022-5223(19)37081-3. [Epub ahead of print]
    Commentary: The role of low-dose computed tomography for lung cancer screening among the nonsmoking Asian population.
    Lee IH, Chen CY.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.11.101
  196. Biochem Cell Biol. 2020 Jan 22.
    Exogenous Ubiquitin Attenuates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via the Involvement of CXCR4 and Modulation of Mitochondrial Homeostasis.
    Dalal S, Daniels CR, Li Y, Wright GL, Singh M, Singh K.
      Exogenous ubiquitin (UB) plays a protective role in β-AR-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). Activation of Akt was higher, while activation of GSK-3β was lower in UB-treated cells post-H/R. Oxidative stress was lower, while the number of ARVMs with polarized mitochondria was significantly greater in UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3β or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mDivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, key player of mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via the modulation of mitochondrial homeostasis and mitochondrial death pathway of apoptosis.
    DOI:  https://doi.org/10.1139/bcb-2019-0339
  197. Clin Transl Sci. 2020 Jan 21.
    Short-term Efficacy of Different First-Line Chemotherapy Regimens for Advanced Non-Small Cell Lung Cancer: A Network Meta-Analysis.
    Zhang BB, Zhu W, Tao J, Li Y, Du CC, Chen YX, Liu YD.
      The study intends to compare short-term efficacy of 12 chemotherapy regimens in treatment of advanced NSCLC by a network meta-analysis (NMA). PubMed, Cochrane Library and Embase were searched from the inception of each database to June, 2018. Randomized controlled trials (RCTs) of the 12 chemotherapy regimens for advanced NSCLC were included. Direct and indirect evidence were combined by NMA to evaluate the odds ratio (OR) and the surface under the cumulative ranking curves (SUCRA) of the 12 chemotherapy regimens. Totally 19 RCTs met our inclusion criteria were collected in this study. For partial response (PR), gemcitabine exhibited relatively poor efficacy compared with cisplatin + gemcitabine, carboplatin + gemcitabine, carboplatin + paclitaxel, paclitaxel + gemcitabine and cisplatin + gemcitabine + vinorelbine. For overall response rate (ORR), gemcitabine had poorer efficacy than cisplatin + gemcitabine and paclitaxel + gemcitabine. For disease control rate (DCR), compared with carboplatin + gemcitabine and gemcitabine, paclitaxel + gemcitabine had a better efficacy. Gemcitabine had the lowest SUCRA values in terms of complete response, PR, ORR, stable disease and DCR; while paclitaxel + gemcitabine ranked the highest in ORR, progressive disease and DCR. The cluster analysis revealed that cisplatin + gemcitabine, paclitaxel + gemcitabine and cisplatin + gemcitabine + vinorelbine had better short-term efficacy for advanced NSCLC. Collectively, short-term efficacy of multi-drug combination chemotherapy regimens was superior to that of single-drug chemotherapy regimens for advanced NSCLC. Cisplatin + gemcitabine, paclitaxel + gemcitabine and cisplatin + gemcitabine + vinorelbine may have particularly prominent short-term efficacy for advanced NSCLC.
    Keywords:  Bayesian network model; Chemotherapy; Efficacy; Non-small cell lung cancer; Randomized controlled trials
    DOI:  https://doi.org/10.1111/cts.12744
  198. Int J Mol Sci. 2020 Jan 17. pii: E612. [Epub ahead of print]21(2):
    Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells.
    Cai L, Kirchleitner SV, Zhao D, Li M, Tonn JC, Glass R, Kälin RE.
      Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment.
    Keywords:  Iba1; LAT1; PBR; SLC7A5; TSPO; glioblastoma
    DOI:  https://doi.org/10.3390/ijms21020612
  199. Nanoscale. 2020 Jan 22.
    Advanced nanotechnology for hypoxia-associated antitumor therapy.
    Zhao L, Fu C, Tan L, Li T, Zhong H, Meng X.
      Hypoxia is a hallmark of the tumor microenvironment, which promotes the proliferation, metastasis and invasion of tumors and stimulates the resistance of cancer treatments, leading to the serious consequence of tumor recurrence. Many nanotechnology-based studies have been conducted to improve the efficacy of cancer treatments using a hypoxia strategy. This is usually achieved by (i) activating bioreductive prodrugs in the tumor hypoxic/exacerbated hypoxic microenvironment, or (ii) delivering therapeutic agents to hypoxic tumor tissue using targeting molecules. Normally, a good therapeutic effect can be expected upon modulating the hypoxic microenvironment for tumor treatments. To achieve this, various nanotechnology strategies based on overcoming hypoxia have been exploited to alleviate tumor hypoxia and enhance the therapeutic efficacy of tumor therapy, including (i) reducing oxygen consumption by inhibiting cell respiration, (ii) normalizing tumor vessels to promote blood flow in the tumor, (iii) carrying exogenous oxygen into the tumor, and (iv) generating oxygen in situ. The strategy of in situ oxygen production is refined, and the scope of this strategy is further expanded. Finally, the inspiration of using advanced nanotechnology in hypoxia-associated antitumor therapy guides the study of tumor hypoxia for clinical use.
    DOI:  https://doi.org/10.1039/c9nr09071a
  200. Acta Clin Croat. 2019 Sep;58(3): 439-445
    LIFESTYLE RISK FACTORS AND BONE MASS IN RECURRENT STONE-FORMING PATIENTS: A CROSS-SECTIONAL STUDY IN 144 SUBJECTS.
    Marić I, Kizivat T, Smolić M, Smolić R, Opačak-Bernardi T, Šolić K, Roguljić H, Milas Ahić J, Tucak A, Mihaljević I.
      Patients with urolithiasis, particularly hypercalciuria, may have reduced bone mineral density (BMD). There are numerous risk factors contributing to reduction of BMD such as advanced age, sedentary lifestyle, smoking, low calcium intake, etc. The aim of our study was to investigate the association of lifestyle risk factors and daily intake of milk and dairy products with determinants of BMD in a group of recurrent calcium stone formers (RSF) compared with healthy subjects (HS). The study was carried out at the Department of Mineral Research, Faculty of Medicine in Osijek, Croatia. The study included 144 subjects, i.e. 56 RSF and 78 HS. BMD was assessed by dual-energy x-ray absorptiometry. A standard self-reported questionnaire was used to collect data on lifestyle risk factors. Current dietary intake was assessed by personal interview that included questions about milk and dairy product intake. Low BMD was observed in 44.64% of RSF and 35.90% of HS. RSF consumed significantly less milk and dairy products than HS. Calcium restriction in dietary recommendations might be unnecessary due to the impact on bone mineral loss in RSF and dual-energy x-ray absorptiometry should be included in the routine evaluation of RSF.
    Keywords:  body mass index; body weight; bone mineral density; calcium intake; physical activity; smoking; urolithiasis
    DOI:  https://doi.org/10.20471/acc.2019.58.03.06
  201. Bull Math Biol. 2020 Jan 22. 82(2): 20
    Close Encounters of the Cell Kind: The Impact of Contact Inhibition on Tumour Growth and Cancer Models.
    Grimes DR, Fletcher AG.
      Cancer is a complex phenomenon, and the sheer variation in behaviour across different types renders it difficult to ascertain underlying biological mechanisms. Experimental approaches frequently yield conflicting results for myriad reasons, and mathematical modelling of cancer is a vital tool to explore what we cannot readily measure, and ultimately improve treatment and prognosis. Like experiments, models are underpinned by certain biological assumptions, variation of which can lead to divergent predictions. An outstanding and important question concerns contact inhibition of proliferation (CIP), the observation that proliferation ceases when cells are spatially confined by their neighbours. CIP is a characteristic of many healthy adult tissues, but it remains unclear to which extent it holds in solid tumours, which exhibit regions of hyper-proliferation, and apparent breakdown of CIP. What precisely occurs in tumour tissue remains an open question, which mathematical modelling can help shed light on. In this perspective piece, we explore the implications of different hypotheses and available experimental evidence to elucidate the implications of these scenarios. We also outline how erroneous conclusions about the nature of tumour growth may be arrived at by looking selectively at biological data in isolation, and how this might be circumvented.
    Keywords:  Cancer; Growth laws; Mathematical oncology; Tumour growth
    DOI:  https://doi.org/10.1007/s11538-019-00677-y
  202. Mol Cell. 2020 Jan 09. pii: S1097-2765(19)30927-X. [Epub ahead of print]
    p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis.
    Olivero CE, Martínez-Terroba E, Zimmer J, Liao C, Tesfaye E, Hooshdaran N, Schofield JA, Bendor J, Fang D, Simon MD, Zamudio JR, Dimitrova N.
      The tumor suppressor p53 transcriptionally activates target genes to suppress cellular proliferation during stress. p53 has also been implicated in the repression of the proto-oncogene Myc, but the mechanism has remained unclear. Here, we identify Pvt1b, a p53-dependent isoform of the long noncoding RNA (lncRNA) Pvt1, expressed 50 kb downstream of Myc, which becomes induced by DNA damage or oncogenic signaling and accumulates near its site of transcription. We show that production of the Pvt1b RNA is necessary and sufficient to suppress Myc transcription in cis without altering the chromatin organization of the locus. Inhibition of Pvt1b increases Myc levels and transcriptional activity and promotes cellular proliferation. Furthermore, Pvt1b loss accelerates tumor growth, but not tumor progression, in an autochthonous mouse model of lung cancer. These findings demonstrate that Pvt1b acts at the intersection of the p53 and Myc transcriptional networks to reinforce the anti-proliferative activities of p53.
    Keywords:  MYC; Pvt1; long noncoding RNA; lung cancer; mouse model of cancer; p53; tumor suppressor
    DOI:  https://doi.org/10.1016/j.molcel.2019.12.014
  203. Semin Roentgenol. 2020 Jan;pii: S0037-198X(19)30078-1. [Epub ahead of print]55(1): 14-22
    Lung Cancer Screening: How We do It and Why.
    Verma N, Wu M, Altmayer S.
      
    DOI:  https://doi.org/10.1053/j.ro.2019.10.004
  204. Lung. 2020 Jan 20.
    Resveratrol Attenuates Intermittent Hypoxia-Induced Lung Injury by Activating the Nrf2/ARE Pathway.
    Lian N, Zhang S, Huang J, Lin T, Lin Q.
      PURPOSE: Obstructive sleep apnea (OSA) is associated with lung injury. As a novel pathophysiological hallmark of OSA, chronic intermittent hypoxia (CIH) enhances apoptosis. The present study aims to evaluate the effect of resveratrol (Res) on CIH-induced lung apoptosis and inflammation in a rat model of CIH.METHODS: Rats were randomly allocated to normoxia (control), CIH, and CIH + Res groups (n = 10 in each group). The CIH exposure duration was 12 weeks. Rats in the CIH + Res group were additionally administered Res (50 mg kg-1 d-1). Inflammatory cytokine levels were detected by enzyme-linked immunosorbent assays (ELISAs). A terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was conducted to evaluate the apoptosis rate. Bax, cleaved caspase-3, Nrf2 and HO-1 protein levels were detected by western blotting.
    RESULTS: The IL-6 and TNF-α levels in the serum and alveolar lavage fluid in the CIH group were markedly higher than those in the control group. The percentage of apoptotic cells in the CIH group was higher than that in the control group. Bax and cleaved caspase-3 protein levels were increased in the CIH group compared with those in the control group. Nrf2 and HO-1 protein levels were decreased in the CIH group compared with those in the control group (p < 0.05). Compared with the CIH group, rats in the CIH + Res group had lower percentages of apoptotic cells, lower IL-6, TNF-α, Bax and cleaved caspase-3 protein levels, and higher Nrf2 and HO-1 protein levels (p < 0.05).
    CONCLUSION: Res attenuates CIH-related inflammatory reactions and apoptosis in lung tissue by activating the Nrf2/ARE pathway.
    Keywords:  Apoptosis; Intermittent hypoxia; Lung injury; Nrf2; Resveratrol
    DOI:  https://doi.org/10.1007/s00408-020-00321-w
  205. Hum Mol Genet. 2020 Jan 24. pii: ddaa015. [Epub ahead of print]
    DMD carrier model with mosaic dystrophin expression in the heart reveals complex vulnerability to myocardial injury.
    Meyers TA, Heitzman JA, Townsend D.
      Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease that causes progressive muscle wasting and cardiomyopathy. This X-linked disease results from the mutations of the DMD allele on the X-chromosome resulting in the loss of expression of the protein dystrophin. Dystrophin loss causes cellular dysfunction that drives the loss of healthy skeletal muscle and cardiomyocytes. As gene therapy strategies strive toward dystrophin restoration through micro-dystrophin delivery or exon skipping, preclinical models have shown that incomplete restoration in the heart results in heterogeneous dystrophin expression throughout the myocardium. This outcome prompts the question of how much dystrophin restoration is sufficient to rescue the heart from DMD-related pathology. Female DMD carrier hearts can shed light on this question, due to their mosaic cardiac dystrophin expression resulting from random X-inactivation. In this work, a dystrophinopathy carrier mouse model was derived by breeding male or female dystrophin-null mdx mice with a wild type mate. We report that these carrier hearts are significantly susceptible to injury induced by one or multiple high doses of isoproterenol, despite expressing ~ 57% dystrophin. Importantly, only carrier mice with dystrophic mothers showed mortality after isoproterenol. These findings indicate that dystrophin restoration in approximately half of the heart still allows for marked vulnerability to injury. Additionally, the discovery of divergent stress-induced mortality based on parental origin in mice with equivalent dystrophin expression underscores the need for better understanding of the epigenetic, developmental, and even environmental factors that may modulate vulnerability in the dystrophic heart.
    DOI:  https://doi.org/10.1093/hmg/ddaa015
  206. J Nutr Biochem. 2020 Jan 07. pii: S0955-2863(19)30574-1. [Epub ahead of print]78 108335
    Lycopene attenuates body weight gain through induction of browning via regulation of peroxisome proliferator-activated receptor γ in high-fat diet-induced obese mice.
    Zhu R, Wei J, Liu H, Liu C, Wang L, Chen B, Li L, Jia Q, Tian Y, Li R, Zhao D, Mo F, Li Y, Gao S, Wang XD, Zhang D.
      Lycopene (LYC), one of the major carotenoids in tomatoes, has been preclinically and clinically used to obesity and type 2 diabetes management. However, whether its ability of countering body weight gain is related to induction of brown-like adipocyte phenotype in white adipose tissues (WAT) remains largely unknown. Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves the brown-like phenotype conversion and energy expenditure. Here, we show that LYC treatment promotes glucose consumption and improves insulin sensitivity, as well as fosters white adipocytes browning through up-regulating mRNA and protein expression levels of PPARγ, uncoupling protein 1, PPARγ coactivator-1α and PR domain-containing 16 in the differentiated 3T3-L1 adipocytes and primary adipocytes, as well as in the WAT of HFD-exposed obese mice. In addition, LYC treatment attenuates body weight gain and improves serum lipid profiles as well as promotes brown adipose tissue activation in obese mice. Moreover, PPARγ is induced with LYC intervention in mitochondria respiration and browning in white adipocytes and tissues. Taken together, these results suggest that LYC counteracts obesity and improves glucose and lipid metabolism through induction of the browning via up-regulation of PPARγ, which offers a new perspective of this compound to combat obesity and obesity-related disorders.
    Keywords:  Brown adipose tissue; Lycopene; Obese mice; Peroxisome proliferator-activated receptor γ; White adipose tissue browning
    DOI:  https://doi.org/10.1016/j.jnutbio.2019.108335
  207. Acta Neuropathol Commun. 2020 Jan 21. 8(1): 3
    A robust TDP-43 knock-in mouse model of ALS.
    Huang SL, Wu LS, Lee M, Chang CW, Cheng WC, Fang YS, Chen YR, Cheng PL, Shen CJ.
      Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS- TDP.
    Keywords:  ALS-TDP pathogenesis; Amyotrophic lateral sclerosis (ALS); Autonomous spinal cord motor neuron degeneration; Homologous knock-in mouse models with ALS-associated TDP-43 mutations; Mis-splicing of Bcl-2 pre-mRNA; TAR DNA-binding protein 43 (TDP-43)
    DOI:  https://doi.org/10.1186/s40478-020-0881-5
  208. Nat Commun. 2020 Jan 23. 11(1): 463
    Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance.
    Yabut JM, Desjardins EM, Chan EJ, Day EA, Leroux JM, Wang B, Crane ED, Wong W, Morrison KM, Crane JD, Khan WI, Steinberg GR.
      Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. Increasing thermogenic brown and beige adipose tissue futile cycling may be an important strategy to increase energy expenditure in obesity, however, brown adipose tissue metabolic activity is lower with obesity. Herein, we report that the exposure of mice to thermoneutrality promotes the infiltration of white adipose tissue with mast cells that are highly enriched with tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme regulating peripheral serotonin synthesis. Engraftment of mast cell-deficient mice with Tph1-/- mast cells or selective mast cell deletion of Tph1 enhances uncoupling protein 1 (Ucp1) expression in white adipose tissue and protects mice from developing obesity and insulin resistance. These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-019-14080-7
  209. Kyobu Geka. 2020 Jan;73(1): 63-67
    [Pericardial Fenestration and Multidisciplinary Treatment to Improve the Prognosis of the Malignant Pericarditis Due to Lung Cancer].
    Oshima Y, Tabata T, Nonomura R, Sasaki T, Mitomo H, Ishibashi N, Sugawara T, Sagawa M, Kondo T.
      We experienced 3 cases in whom multidisciplinary treatment with pericardial fenestration was effective for malignant pericardial effusion associated with lung cancer. Case 1:Right upper lobectomy for lung adenocarcinoma, EGFR (-) and ALK (-) had been performed. After 34 months, malignant pericarditis occurred and left pericardial fenestration was performed. After fenestration, anticancer drugs and immune checkpoint inhibitor( ICI) were administered. He died of lung cancer in 53 months after fenestration. Case 2:Thirty-three months after left upper lobectomy for lung adenocarcinoma [EGFR (+) and ALK (-)], malignant pleuritis and pericarditis occurred and right pericardial fenestration was performed. After fenestration, anticancer drugs, EGFR-TKI and ICI were administered. He died of lung cancer in 35 months after fenestration. Case 3:Pericardial fenestration was performed for malignant pericarditis due to lung adenocarcinoma with EGFR (-), ALK (-) and PD-L1 [tumor propotion score (TPS) 0%]. After fenestration, anticancer drugs and ICI were administered. The patient died of lung cancer in 15 months after fenestration. Pericardial fenestration for malignant pericarditis is possibly useful for the management of patients, which in turns is also useful in continuing the medical treatment to prolong the prognosis.
  210. Benef Microbes. 2019 Dec 09. 10(8): 823-839
    Bifidobacterium longum-fermented rice bran and rice bran supplementation affects the gut microbiome and metabolome.
    Nealon NJ, Parker KD, Lahaie P, Ibrahim H, Maurya AK, Raina K, Ryan EP.
      This study investigated gut microbiota composition along with food, host, and microbial derived metabolites in the colon and systemic circulation of healthy mice following dietary rice bran and fermented rice bran intake. Adult male BALB/c mice were fed a control diet or one of two experimental diets containing 10% w/w rice bran fermented by Bifidobacterium longum or 10% w/w non-fermented rice bran for 15 weeks. Metabolomics was performed on the study diets (food), the murine colon and whole blood. These were analysed in concert with 16S rRNA amplicon sequencing of faeces, caecum, and colon microbiomes. Principal components analysis of murine microbiota composition displayed marked separation between control and experimental diets, and between faecal and tissue (caecum and colon) microbiomes. Colon and caecal microbiomes in both experimental diet groups showed enrichment of Roseburia, Lachnospiraceae, and Clostridiales related amplicon sequence variants compared to control. Bacterial composition was largely similar between experimental diets. Metabolite profiling revealed 530 small molecules comprising of 39% amino acids and 21% lipids that had differential abundances across food, colon, and blood matrices, and statistically significant between the control, rice bran, and fermented rice bran groups. The amino acid metabolite, N-delta-acetylornithine, was notably increased by B. longum rice bran fermentation when compared to non-fermented rice bran in food, colon, and blood. These findings support that dietary intake of rice bran fermented with B. longum modulates multiple metabolic pathways important to the gut and overall health.
    Keywords:  colon; fermentation; metabolites; microbiome; rice bran
    DOI:  https://doi.org/10.3920/BM2019.0017
  211. Cell Death Dis. 2020 Jan 23. 11(1): 51
    Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue.
    Turchi R, Tortolici F, Guidobaldi G, Iacovelli F, Falconi M, Rufini S, Faraonio R, Casagrande V, Federici M, De Angelis L, Carotti S, Francesconi M, Zingariello M, Morini S, Bernardini R, Mattei M, Rosa P, Piemonte F, Lettieri-Barbato D, Aquilano K.
      Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
    DOI:  https://doi.org/10.1038/s41419-020-2253-2
  212. Immunobiology. 2019 Sep 14. pii: S0171-2985(19)30219-0. [Epub ahead of print] 151848
    A panel of autoantibodies against tumor-associated antigens in the early immunodiagnosis of lung cancer.
    Jiang D, Wang Y, Liu M, Si Q, Wang T, Pei L, Wang P, Ye H, Shi J, Wang X, Song C, Wang K, Dai L, Zhang J.
      OBJECTIVE: Lung cancer (LC) is one of the most common malignant tumors worldwide with low five-year survival rate due to lack of effective diagnosis. This study aims to find an optimal combination of autoantibodies for detecting of early-stage LC.METHODS: Nine relatively novel autoantibodies against tumor-associated (TAAs) (PSIP1, TOP2A, ACTR3, RPS6KA5, HMGB3, MMP12, GREM1, ZWINT and NUSAP1) were detected by using ELISA. Diagnostic models were developed by using the training set (n = 644) and further validated in another independent set (n = 248). We also evaluated the diagnostic accuracy of the model to detect benign lung diseases (BLD) from the early-stage lung cancer.
    RESULTS: The areas under the receiver operating characteristic curve (AUC) for the model with three TAAs panel (GREM1, HMGB3 and PSIP1) was 0.711(95% CI 0.674-0.746) in the training set and 0.858 (95% CI 0.808-0.899) in the validation set, which demonstrated a higher diagnostic capability. The AUC of this three TAAs model was 0.833 (95%CI 0.780-0.878) in discriminating LC from BLD. This model could identify early-stage LC patients from normal control (NC) individuals, with AUC of 0.687(95% CI 0.634-0.736) in training set and AUC of 0.920(95% CI 0.860-0.960) in validation set, and the overall AUC for early-stage LC was 0.779(95% CI 0.739-0.816) when the training set and validation set were combined.
    CONCLUSIONS: The model with three TAAs panel would detect LC with higher effectiveness, and might be potential screening method for the early LC.
    Keywords:  Autoantibody; Lung cancer (LC); Model; Tumor-associated antigens (TAAs)
    DOI:  https://doi.org/10.1016/j.imbio.2019.09.007
  213. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31739-5. [Epub ahead of print]30(3): 783-792.e5
    A Mouse Homolog of a Human TP53 Germline Mutation Reveals a Lipolytic Activity of p53.
    Kang JG, Lago CU, Lee JE, Park JH, Donnelly MP, Starost MF, Liu C, Kwon J, Noguchi AC, Ge K, Wang PY, Hwang PM.
      The physiological effects of the many germline mutations of TP53, encoding the tumor suppressor protein p53, are poorly understood. Here we report generating a p53 R178C knockin mouse modeling the human TP53 R181C mutation, which is notable for its prevalence and prior molecular characterization. Consistent with its weak cancer penetrance in humans, homozygous p53178C/C mice show a modest increase in tumorigenesis but, surprisingly, are lean with decreased body fat content. They display evidence of increased lipolysis and upregulation of fatty acid metabolism in their inguinal white adipose tissue (iWAT). Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses show that the mutant p53 bound and transactivated Beta-3-Adrenergic Receptor (ADRB3), a gene that is known to promote lipolysis and is associated with obesity. This study reveals that a germline mutation of p53 can affect fat metabolism, which has been implicated in cancer development.
    Keywords:  ADRB3; Li-Fraumeni syndrome; TP53 mutation; cancer; fat; lipolysis; mouse model
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.074
  214. Eur Cytokine Netw. 2019 Sep 01. 30(3): 88-97
    Dexmedetomidine alleviates hepatic injury via the inhibition of oxidative stress and activation of the Nrf2/HO-1 signaling pathway.
    Zhao Y, Kong GY, Pei WM, Zhou B, Zhang QQ, Pan BB.
      Dexmedetomidine (Dex), frequently used as an effective sedative, was reported to play a critical role in the protection of multiple organs. However, its underlying mechanism of a putative protective effect on ischemia/reperfusion (I/R)-induced liver injury is still unclear. A hepatocyte injury model was established by treating WRL-68 cells with oxygen and glucose deprivation/reoxygenation (OGD/R). Enzyme Linked Immunosorbent Assay (ELISA) kits were used to determine the level of inflammatory factors (IL-6, IL-1β, and TNF-α), and oxidative stress indicators (ROS, MDA, GSH-Px, and SOD). MTT assay and flow cytometry analysis were used to determine the influence of Dex on cell viability and cell apoptosis. Expression of nuclear factor erythroid-derived 2- like 2 (Nrf2), HO-1, and apoptosis-related proteins (Bax, Bcl-2, caspase3, and caspase9) were detected by qRT-PCR and western blotting. Dex promoted cell viability and suppressed cell apoptosis in OGD/R-treated WRL-68 cells. Dex reduced TNF-α, IL-6, IL-1β, ROS, and MDA production, whereas it increased that of SOD and GSH-Px in OGD/R-treated WRL-68 cells. Moreover, Nrf2, HO-1, and Bcl-2 expression was upregulated, whereas, in contrast, transcripts for Bax, caspase3, and caspase9 were downregulated following Dex treatment under OGD/R. Knockdown of Nrf2 reversed the Dex effects on cell proliferation, apoptosis, and expression of TNF-α, IL-6, IL-1β, ROS, MDA, SOD, and GSH-Px. Dex protects WRL-68 cells against OGD/R-induced injury by inhibiting inflammation, oxidative stress, and cell apoptosis via the activation of Nrf2/HO-1 signaling pathway, suggesting that Dex may be a potential protector against hepatic injury.
    Keywords:  Dexmedetomidine; Nrf2/HO-1 signaling pathway; hepatic injury; inflammation; oxidative stress
    DOI:  https://doi.org/10.1684/ecn.2019.0431
  215. Environ Pollut. 2020 Jan 14. pii: S0269-7491(19)36308-0. [Epub ahead of print]260 113949
    The endoplasmic reticulum stress and related signal pathway mediated the glyphosate-induced testosterone synthesis inhibition in TM3 cells.
    Xia Y, Yang X, Lu J, Xie Q, Ye A, Sun W.
      Glyphosate is the most widely used herbicide in the world. In recent years, many studies have demonstrated that exposure to glyphosate-based herbicides (GHBs) was related to the decrease of serum testosterone and the decline in semen quality. However, the molecular mechanism of glyphosate-induced testosterone synthesis disorders is still unclear. In the present study, the effects of glyphosate on testosterone secretion and the role of endoplasmic reticulum (ER) stress in the process were investigated in TM3 cells. The effects of glyphosate at different concentrations on the viability of TM3 cells were detected by CCK8 method. The effect of glyphosate exposure on testosterone secretion was determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of testosterone synthases and ER stress-related proteins were detected by Western blot and Immunofluorescence stain. Results showed that exposure to glyphosate at concentrations below 200 mg/L had no effect on cell viability, while the glyphosate above 0.5 mg/L could inhibit the testosterone secretion in TM3 cells. Treatment TM3 cells with glyphosate at 5 mg/L not only reduced the protein levels of testosterone synthase StAR and CYP17A1, inhibited testosterone secretion, but also increased the protein level of ER stress molecule Bip and promoted the phosphorylation of PERK and eIF2α. Pretreatment cells with PBA, an inhibitor of ER stress, alleviated glyphosate-induced increase in Bip, p-PERK and p-eIF2α protein levels, meanwhile rescuing glyphosate-induced testosterone synthesis disorders. When pretreatment with GSK2606414, a PERK inhibitor, the glyphosate-induced phosphorylation of PERK and eIF2α was blocked, and the glyphosate-inhibited testosterone synthesis and secretion was also restored. Overall, our findings suggest that glyphosate can interfere with the expression of StAR and CYP17A1 and inhibit testosterone synthesis and secretion via ER stress-mediated the activation of PERK/eIF2α signaling pathway in Leydig cells.
    Keywords:  Endoplasmic reticulum stress; Glyphosate; Leydig cell; PERK/eIF2α pathway; Testosterone
    DOI:  https://doi.org/10.1016/j.envpol.2020.113949
  216. J Thorac Cardiovasc Surg. 2020 Jan 17. pii: S0022-5223(19)37103-X. [Epub ahead of print]
    Commentary: The A, C, G, and Ts of differentiating stage I and stage IV lung cancer.
    Wiesel O, Burt BM.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.12.003
  217. Medicine (Baltimore). 2020 Jan;99(4): e18543
    High ubiquitin conjugating enzyme E2 T mRNA expression and its prognostic significance in lung adenocarcinoma: A study based on the TCGA database.
    Wu ZH, Zhang YJ, Sun HY.
      Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer with a high mortality disease which has been positioned the first and second cancer morbidity of men and women in China, separately. Our study was to assess the prognostic meaningful of ubiquitin conjugating enzyme E2 T (UBE2T) expression in LUAD dependent on data acquired from The Cancer Genome Atlas (TCGA) and so as to increase further knowledge into the biological pathways involved in LUAD pathogenesis related to UBE2T.Information on gene expression and comparing clinical data were recognized and downloaded from TCGA. Gene set enrichment analysis (GSEA) created an arranged list of all genes s indicated by their connection with UBE2T expression.Our study cohort included 265 (54.5%) female and 221 (36.0%) male patients. The scatter plot and paired plot showed the difference of UBE2T expression between normal and tumor samples (P < .01). Overall survival (OS) analysis demonstrated that LUAD with UBE2T-high had a more terrible prognosis than that with UBE2T-low (P < .01). Multivariate analysis with the cox proportional hazards model indicated that the expression of UBE2T (hazard ratio [HR]: 1.28; 95% Confidence Interval (CI): 1.06-1.56; P = .011) and stage (HR: 2.02; 95% CI: 1.27-3.21; P = .003) were independent prognostic factors for patients with LUAD. The GSEA results showed that cell cycle, DNA replication, RNA degradation, oxidative phosphorylation, pathogenic Escherichia coli infection, citrate cycle tricarboxylic acid cycle, Alzheimer's disease, P53 signaling pathway, and purine metabolism are differentially enriched in UBE2T high expression phenotype.Our study found that the expression of UBE2T was significantly increased in LUAD patients and associated with several clinical features. UBE2T may be a potentially useful prognostic molecular biomarker of bad survival in LUAD, while further experimental ought to be performed to demonstrate the biologic effect of UBE2T.
    DOI:  https://doi.org/10.1097/MD.0000000000018543
  218. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jan 18. pii: S0278-5846(19)30833-4. [Epub ahead of print] 109869
    Glycine transporter type 1 (GlyT1) inhibition improves conspecific-provoked immobility in Balb/c mice: Analysis of corticosterone response and glucocorticoid gene expression in cortex and hippocampus.
    Burket JA, Pickle JC, Rusk AM, Haynes BA, Sharp JA, Deutsch SI.
      Stress reactivity and glucocorticoid signaling alterations are reported in mouse models of autism spectrum disorder (ASD). Balb/c mice display decreased locomotor activity in the presence of stimulus mice and spend less time exploring enclosed stimulus mice; this mouse strain has been validated as an ASD model. VU0410120, a glycine type 1 transporter (GlyT1) inhibitor, improved sociability in Balb/c mice, consistent with data that NMDA Receptor (NMDAR) activation regulates sociability, and the endogenous tone of NMDAR-mediated neurotransmission is altered in this strain. Effects of a prosocial dose of VU0410120 on conspecific-provoked immobility, and relationships between conspecific-provoked immobility and corticosterone response were explored. VU0410120-treated Balb/c mice showed reduced immobility in the presence of conspecifics and increased the conspecific-provoked corticosterone response. However, the intensity of conspecific-provoked immobility in VU0410120-treated Balb/c mice did not differ as a function of corticosterone response. Expression profiles of 88 glucocorticoid signaling associated genes within frontal cortex and hippocampus were examined. Balb/c mice resistant to prosocial effects of VU0410120 had increased mRNA expression of Ddit4, a negative regulator of mTOR signaling. Dysregulated mTOR signaling activity is a convergent finding in several monogenic syndromic forms of ASD. Prosocial effects of VU0410120 in the Balb/c strain may be related to regulatory influences of NMDAR-activation on mTOR signaling activity. Because corticosterone response is a marker of social stress, the current data suggest that the stressfulness of a social encounter alone may not be the sole determinant of increased immobility in Balb/c mice; this strain may also display an element of social disinterest.
    Keywords:  Autism Spectrum disorder; Balb/c; Glucocorticoid signaling; GlyT1 inhibition; Immobility; NMDA receptor
    DOI:  https://doi.org/10.1016/j.pnpbp.2020.109869
  219. Wellcome Open Res. 2019 ;4 150
    A CRISPR/Cas9 genome editing pipeline in the EndoC-βH1 cell line to study genes implicated in beta cell function.
    Grotz AK, Abaitua F, Navarro-Guerrero E, Hastoy B, Ebner D, Gloyn AL.
      Type 2 diabetes (T2D) is a global pandemic with a strong genetic component, but most causal genes influencing the disease risk remain unknown. It is clear, however, that the pancreatic beta cell is central to T2D pathogenesis. In vitro gene-knockout (KO) models to study T2D risk genes have so far focused on rodent beta cells. However, there are important structural and functional differences between rodent and human beta cell lines. With that in mind, we have developed a robust pipeline to create a stable CRISPR/Cas9 KO in an authentic human beta cell line (EndoC-βH1). The KO pipeline consists of a dual lentiviral sgRNA strategy and we targeted three genes ( INS, IDE, PAM) as a proof of concept. We achieved a significant reduction in mRNA levels and complete protein depletion of all target genes. Using this dual sgRNA strategy, up to 94 kb DNA were cut out of the target genes and the editing efficiency of each sgRNA exceeded >87.5%. Sequencing of off-targets showed no unspecific editing. Most importantly, the pipeline did not affect the glucose-responsive insulin secretion of the cells. Interestingly, comparison of KO cell lines for NEUROD1 and SLC30A8 with siRNA-mediated knockdown (KD) approaches demonstrate phenotypic differences. NEUROD1-KO cells were not viable and displayed elevated markers for ER stress and apoptosis. NEUROD1-KD, however, only had a modest elevation, by 34%, in the pro-apoptotic transcription factor CHOP and a gene expression profile indicative of chronic ER stress without evidence of elevated cell death. On the other hand, SLC30A8-KO cells demonstrated no reduction in K ATP channel gene expression in contrast to siRNA silencing. Overall, this strategy to efficiently create stable KO in the human beta cell line EndoC-βH1 will allow for a better understanding of genes involved in beta cell dysfunction, their underlying functional mechanisms and T2D pathogenesis.
    Keywords:  CRISPR/Cas9; EndoC-βH1; NEUROD1; Type 2 Diabetes; gene knockout; human beta cells; insulin secretion
    DOI:  https://doi.org/10.12688/wellcomeopenres.15447.1
  220. Cancer. 2020 Jan 24.
    Associations between nutritional factors and chemotherapy toxicity in older adults with solid tumors.
    Dotan E, Tew WP, Mohile SG, Ma H, Kim H, Sun CL, Caan B, Dale W, Gajra A, Klepin HD, Owusu C, Gross C, Muss H, Chapman A, Katheria V, Hurria A.
      BACKGROUND: Nutritional status can directly affect morbidity and mortality in older adults with cancer. This study evaluated the association between pretreatment body mass index (BMI), albumin level, and unintentional weight loss (UWL) in the prior 6 months and chemotherapy toxicity among older adults with solid tumors.METHODS: This was a secondary analysis of a prospective, multicenter study involving chemotherapy-treated patients 65 years old or older. Geriatric assessment, BMI, albumin level, and UWL data were collected before treatment. Multivariable logistic regression models evaluated the associations between nutritional factors and the risk of grade 3 or higher (grade 3+) chemotherapy toxicity.
    RESULTS: Seven hundred fifty patients with a median age of 72 years (range, 65-94 years) and mostly stage IV disease were enrolled. The median pretreatment BMI and albumin values were 26 kg/m2 (range, 15.1-52.1 kg/m2 ) and 3.9 mg/dL (range, 1.0-5.0 mg/dL), respectively. Nearly 50% of the patients reported UWL, with 17.6% reporting >10% UWL. Multivariable analysis revealed no association between >10% UWL and a risk for grade 3+ chemotherapy toxicity (adjusted odds ratio [AOR], 0.87; P = .58). Multivariable analysis showed a trend toward an association between a BMI ≥ 30 kg/m2 and a decreased risk of grade 3+ chemotherapy toxicity (AOR, 0.65; P = .06), whereas a low albumin level (≤3.6 mg/dL) was associated with a higher risk of grade 3+ chemotherapy toxicity (AOR, 1.50; P = .03). An analysis of the joint effect of BMI and albumin demonstrated the lowest risk of grade 3+ chemotherapy toxicity among patients with high BMIs (≥30 kg/m2 ) and normal albumin levels (AOR, 0.41; P = .008).
    CONCLUSIONS: Among older adults with solid tumors, higher BMIs and normal albumin levels are associated with a lower risk of grade 3+ chemotherapy toxicity. Additional research is warranted to define the clinical significance of nutritional markers and to inform future interventions.
    Keywords:  albumin; body mass index (BMI); chemotherapy tolerance; nutritional status; older patients
    DOI:  https://doi.org/10.1002/cncr.32718
  221. Nat Biotechnol. 2020 Jan 20.
    Reconstructing kinase network topologies from phosphoproteomics data reveals cancer-associated rewiring.
    Hijazi M, Smith R, Rajeeve V, Bessant C, Cutillas PR.
      Understanding how oncogenic mutations rewire regulatory-protein networks is important for rationalizing the mechanisms of oncogenesis and for individualizing anticancer treatments. We report a chemical phosphoproteomics method to elucidate the topology of kinase-signaling networks in mammalian cells. We identified >6,000 protein phosphorylation sites that can be used to infer >1,500 kinase-kinase interactions and devised algorithms that can reconstruct kinase network topologies from these phosphoproteomics data. Application of our methods to primary acute myeloid leukemia and breast cancer tumors quantified the relationship between kinase expression and activity, and enabled the identification of hitherto unknown kinase network topologies associated with drug-resistant phenotypes or specific genetic mutations. Using orthogonal methods we validated that PIK3CA wild-type cells adopt MAPK-dependent circuitries in breast cancer cells and that the kinase TTK is important in acute myeloid leukemia. Our phosphoproteomic signatures of network circuitry can identify kinase topologies associated with both phenotypes and genotypes of cancer cells.
    DOI:  https://doi.org/10.1038/s41587-019-0391-9
  222. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30083-0. [Epub ahead of print]49(1): 57-67
    Benefits and Challenges of Diabetes Technology Use in Older Adults.
    Toschi E, Munshi MN.
      With successful aging of adults with type 1 diabetes, there is an increased opportunity to use technology for diabetes management. Technology can ease the burden of self-care and provide a sense of security. However, age-related cognitive and physical decline can make technology use difficult. Guidelines using technology in the aging population are urgently needed, along with educational material for the clinicians and caregivers. In this article, we review the evidence supporting the use of diabetes-related technologies in the older population and discuss recommendations based on current data and the authors' clinical knowledge and experience.
    Keywords:  Continuous glucose monitoring; Older adults; Subcutaneous continuous insulin infusion; Technology; Type 1 diabetes mellitus; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.001
  223. Animals (Basel). 2020 Jan 16. pii: E156. [Epub ahead of print]10(1):
    Effects of Birth Weight and Postnatal Nutritional Restriction on Skeletal Muscle Development, Myofiber Maturation, and Metabolic Status of Early-Weaned Piglets.
    Hu L, Peng X, Han F, Wu F, Chen D, Wu , Feyera T, Zhang K, Che L.
      Piglets with light weaning weight commonly have a slow post-weaning growth rate due to impaired skeletal muscle development. Therefore, the present study aimed to investigate the impact of birth weight and nutrient intake on skeletal muscle development, myofiber maturation, and metabolic status of early-weaned piglets. Twelve pairs of normal birth weight and intrauterine growth-retarded (IUGR) piglets (seven days old) were randomly assigned to receive adequate nutrient intake or restricted nutrient intake for 21 days. Serum and muscle samples were collected for further analysis. The results indicated that muscle weight, cross-sectional areas, and muscular glycogen were lower (p < 0.05) in both IUGR and restricted fed piglets. Nutrient restriction decreased the contents of RNA, the RNA to DNA ratio, and the percentages of myosin heavy chain (MyHC) IIx (p < 0.05), whereas increased the activity of β-hydroxy-acyl-CoA-dehydrogenase (HAD), the ratio of HAD to citrate synthase, as well as the percentages of MyHC I (p < 0.05). In addition, nutrient restriction significantly decreased muscular glycogen, mRNA levels of fatty acid transport protein 1, cationic amino acid transporter 1, and glucose transporter 4 in IUGR piglets compared with the other groups (p < 0.05). The results of the present study showed that IUGR impaired skeletal muscle growth and disturbed the hormone and mRNA expression of genes related to energy metabolism, which led to a more severe energy deficit when receiving postnatal nutritional restriction. Postnatal nutritional restriction resulted in delayed myofiber maturation of the piglets, which may be associated with the transformation of MyHC isoform and the change of metabolic status.
    Keywords:  light weaning weight; nutrient intake; piglets; skeletal muscle; suckling
    DOI:  https://doi.org/10.3390/ani10010156
  224. J Breath Res. 2020 Jan 24. 14(2): 028001
    Comment on 'volatile biomarker in breath predicts lung cancer and pulmonary nodules'.
    Modak AS, Ruzsanyi V, Mochalski P, Mayhew CA.
      
    DOI:  https://doi.org/10.1088/1752-7163/ab6416
  225. Chempluschem. 2018 May;83(5): 320-333
    Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.
    Kahremany S, Babaev I, Hasin P, Tamir TY, Ben-Zur T, Cohen G, Jiang Z, Weintraub S, Offen D, Rahimipour S, Major MB, Senderowitz H, Gruzman A.
      The design and synthesis of a novel nuclear factor erythroid 2-related factor 2 (Nrf2) enhancer is reported. Using a structure-based virtual screening approach, several commercially available compounds were identified as having high probability to interact with the Nrf2-binding pocket in the Kelch-like ECH-associated protein 1 (Keap1). Keap1 is an adaptor protein that recruits Nrf2 to a cullin-3-dependent ubiquitin ligase complex. The identified compounds were tested against rat pheochromocytoma PC-12 cells for their cytoprotective activity, and one compound (SKT359126) demonstrated an Nrf2-mediated cell-protective effect. Based on the structure of SKT359126, 23 novel derivatives were synthesized and evaluated. Of the screened derivatives, 1-{4-[(3,4-dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic acid demonstrated better activity than the parent molecules in activating the Nrf2 transduction pathway in a dose- and time-dependent manner. This compound represents a promising starting point for the development of therapeutics for the treatment of oxidative-stress-related diseases.
    Keywords:  Nrf2; medicinal chemistry; oxidative stress; oxopyrrolidine derivatives; virtual screening
    DOI:  https://doi.org/10.1002/cplu.201700539
  226. Nat Commun. 2020 Jan 23. 11(1): 453
    Controlled release of H2S and NO gases through CO2-stimulated anion exchange.
    Ishihara S, Iyi N.
      Difficulties related to handling gases are a common bottleneck for applications. Although solid materials that release gas molecules under external stimuli exist, they require an external energy or a device for reliable operation. Herein, we report a CO2 stimulus for controlled release of p.p.m.-level functional gases from solid materials. A CO2-preferential anion-exchange property of layered double hydroxides and redox reactions in gas molecules are combined to release various gases (including H2S and NO) under ambient air from HS- and NO2--incorporated layered double hydroxides, respectively. The profiles of gas release are mainly governed by the difference of pKa between H2CO3 and resulting acids (formed through protonation of interlayer anions), and are not so susceptible to the variation of relative humidity in air. Moreover, structural modulation of solid materials enables fine control of the gas release profiles. The use of safe, ubiquitous, and nearly constant (~400 p.p.m. in atmosphere) CO2 stimulus offers broad applications for functional gases.
    DOI:  https://doi.org/10.1038/s41467-019-14270-3
  227. Biochem Biophys Res Commun. 2020 Jan 16. pii: S0006-291X(20)30058-9. [Epub ahead of print]
    Salinomycin and dichloroacetate synergistically inhibit Lewis lung carcinoma cell proliferation, tumor growth and metastasis.
    Skeberdytė A, Sarapinienė I, Krasko JA, Barakauskienė A, Žilionytė K, Prokarenkaitė R, Sužiedėlis K, Bukelskienė V, Jarmalaitė S.
      Drug combination is considered to be the cornerstone of cancer treatment. Simultaneous administration of two or more drugs but at lower doses not only increases cytotoxic effects on tumor cells, but also reduces side effects and possibly overcomes drug resistance. Salinomycin is a well-known cancer stem cell killer, and dichloroacetate is a pyruvate dehydrogenase kinase inhibitor that exclusively targets cells with altered mitochondrial activity, a characteristic being common to most of the cancer cells. In our recent study, we have demonstrated that salinomycin exerted a cytotoxic effect on colorectal carcinoma cells in the 2D and 3D cultures and provided evidence that the mechanism of their synergy was mediated by dichloroacetate-dependent inhibition of the activity of multidrug resistance proteins. In the current work, we confirmed the synergistic cytotoxic properties of salinomycin and dichloroacetate in the 2D and 3D cultures of Lewis lung carcinoma (LLC1) cells. To verify if a synergistic effect of these compounds persisted in vivo, we performed series of experiments using a syngeneic LLC1-C57BL/6 mouse model and demonstrated that combination therapy with salinomycin and DCA increased the survival rate of allografted mice, inhibited metastatic site formation and reduced the populations of cancer stem cells as well as cells that underwent the epithelial-to-mesenchymal transition. Our results demonstrate that a synergistic effect of salinomycin and dichloroacetate exists not only in vitro but also in vivo and suggest their benefits in the treatment of metastatic cancers.
    Keywords:  Cancer stem cells; Dichloroacetate; Metastasis; Salinomycin
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.107
  228. Cancers (Basel). 2020 Jan 23. pii: E279. [Epub ahead of print]12(2):
    Metabolism of Estrogens: Turnover Differs Between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells.
    Poschner S, Wackerlig J, Castillo-Tong DC, Wolf A, Decken IV, Rižner TL, Pavlič R, Meshcheryakova A, Mechtcheriakova D, Fritzer-Szekeres M, Thalhammer T, Jäger W.
      High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to "platinum-sensitive", exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.
    Keywords:  LC-HRMS; carboplatin resistance; high-grade serous ovarian cancer; interleukin-6; metabolomics; steroid hormones
    DOI:  https://doi.org/10.3390/cancers12020279
  229. Fa Yi Xue Za Zhi. 2019 Dec;35(6): 651-656
    Statistical Analysis of the Heart and Lung Mass in Forensic Anatomical Cases and Its Forensic Significance.
    Xue JJ, Wang TQ, Jia YQ, Xiao Y, Tian MH, Guan DW, Zhang GH, Wu X, Li RB, Zhao R, Cao ZP, Zhu BL.
      Abstract: Objective To investigate the differences of heart mass and lung mass in forensic autopsy cases and to explore their application value in forensic identification. Methods The data from 1 614 autopsy cases accepted by center of Medico-legal Investigation of China Medical University between 2007 to 2016 were collected. The correlation of heart and lung mass with age, height, body weight, and body mass index （BMI）, as well as differences in different causes of death were analyzed by GraphPad Prism 6.0 software. Results The heart mass and lung mass of males were higher than those of females （P<0.05）. The heart mass of males and females was positively correlated with age, height, body weight and body mass index （BMI） （P<0.05）. The heart mass of patients dying from sudden cardiac death （SCD） was significantly higher than those dying from other causes of death. The lung mass of patients dying from drowning and delayed treatment was higher than those dying from other causes of death （P<0.05）. Conclusion In forensic practice, measurement of the heart mass and lung mass has certain significance for differential diagnosis and diagnosis of different causes of death.
    Keywords:  forensic pathology; heart; lung; body mass index; cause of death
    DOI:  https://doi.org/10.12116/j.issn.1004-5619.2019.06.002
  230. Oncol Lett. 2020 Feb;19(2): 1331-1337
    Evaluation of heavy metals and metabolites in the urine of patients with breast cancer.
    Men Y, Li L, Zhang F, Kong X, Zhang W, Hao C, Wang G.
      Epidemiologic studies demonstrated that the environment serves a crucial role in cancer development. Heavy metals, including arsenic (As), cadmium (cd), chromium (Cr), lead and mercury, are considered to be carcinogens or co-carcinogens. Furthermore, Cd has been detected in breast cancer (BC) tissue at high concentrations. The present study aimed to investigate the correlation between heavy metals detected in urine and urine metabolome of patients with BC, and their association with cancer development. Nuclear magnetic resonance was used to determine urine metabolites and an inductively coupled plasma mass spectrometry system was used to detect heavy metals in urine samples. The results demonstrated that Cd was markedly increased in the urine of patients with BC compared with the control population (approximately 2-fold). Cr and As were also increased in the urine of patients with BC. In addition, numerous small molecule metabolites were altered in the urine of patients with BC compared with the control population. This study also demonstrated that alterations in small molecule metabolites in the urine of patients with BC were very similar to results from a previous report. These findings indicated that environmental exposure to Cd, As, or Cr could influence the urine levels of metabolites, which may be involved in BC development. Further investigation is therefore required to examine a larger range of samples from different countries or areas in order to understand the impact of heavy metals on metabolism and BC development.
    Keywords:  breast cancer; heavy metals; metabolome; urine
    DOI:  https://doi.org/10.3892/ol.2019.11206
  231. Thorac Cancer. 2020 Jan 22.
    Recommendation for the diagnosis and management of immune checkpoint inhibitor related infections.
    Lu M, Zhang L, Li Y, Wang H, Guo X, Zhou J, Duan L, Si X, Xu Y, Zhang L.
      Immune checkpoint inhibitors (ICIs) have been widely used in the management of malignant tumors. Programmed death 1 (PD-1)/PD-1 ligand (PD-L1) inhibitors have been introduced to treat non-small cell lung cancer (NSCLC) in recent years. Currently, PD-1/PD-L1 inhibitors are considered to have minor side effects and do not independently increase the risk of infection. However, they may cause immune-related adverse events (irAEs) that require immunosuppressive therapy with corticosteroids and/or immunosuppressants, leading to opportunistic infections. Furthermore, there have been reports describing reactivation of chronic/latent infections without irAEs or having received immunosuppressants. Thus, immune checkpoint inhibitor related infections have received more attention worldwide. In this paper, we review available clinical data, describe the potential mechanism, and propose recommendations for the diagnosis and clinical management of PD-1/PD-L1 inhibitor-related infections.
    Keywords:  Immune checkpoint; PD-1/PD-L1 inhibitors; immune-related adverse events; infections
    DOI:  https://doi.org/10.1111/1759-7714.13313
  232. Int J Radiat Biol. 2020 Jan 24. 1-21
    The Russian Radiobiological Human Tissue Repository: Characteristics of biological specimens donated by nuclear workers with lung cancer.
    Zhuntova G, Loffredo C, Grigoryeva E, Sychugov G, Kazachkov E, Kirillova E, Azizova T.
      Purpose. Characteristics of biological specimens donated by nuclear workers with lung cancer.Materials and Methods. Biological specimens were identified at the Radiobiological Human Tissue Repository (RHTR). It was established at the Southern Urals Biophysics Institute in Russia and has been developed and supported within the bilateral US-Russian Agreement on International Cooperation for Minimization of the Effects of Prolonged Radiation Exposure. Biological specimens were collected from workers of the Russian nuclear production facility Mayak PA who were exposed to gamma radiation and/or alpha particles. To determine a histologic type of lung cancer, immunohistochemistry was used.Results and Conclusions. Today biological specimens donated by 343 registrants with lung cancer are available at the RHTR. Among them, 255 donors (74%) are Mayak PA workers hired at the main facilities (reactors, plutonium production and radiochemical plants) in 1948-1982. These workers donated about 6024 specimens of lung tissues (tumor and tumor-free) stored mostly as formalin-fixed paraffin-embedded tissue blocks (31%) and histology slides (64%); in addition they donated 1800 specimens of blood/blood components, buccal epithelium cells and sputum. Among histologic types identified for these lung cancer cases, adenocarcinoma and small cell carcinoma were prevalent. Information about individual doses from external and internal radiation exposure, data on quantitative smoking characteristics and diseases is available for all workers with lung cancer. Complete information on radiation exposure, health status and non-radiation factors annotated to RHTR registrants and the high quality of the available biological specimens are a unique resource for studying biological mechanisms of radiation-induced lung cancer.
    Keywords:  Mayak PA workers; biorepository; ionizing radiation; lung cancer
    DOI:  https://doi.org/10.1080/09553002.2020.1721596
  233. Semin Roentgenol. 2020 Jan;pii: S0037-198X(19)30081-1. [Epub ahead of print]55(1): 70-78
    Advances in Lung Cancer Imaging.
    Kahn J, Kocher MR, Waltz J, Ravenel JG.
      
    DOI:  https://doi.org/10.1053/j.ro.2019.10.007
  234. Molecules. 2020 Jan 21. pii: E452. [Epub ahead of print]25(3):
    Proteomic Analysis of Saccharomyces cerevisiae Response to Oxidative Stress Mediated by Cocoa Polyphenols Extract.
    Peláez-Soto A, Roig P, Martínez-Culebras PV, Fernández-Espinar MT, Gil JV.
      The present study addressed the protective effects against oxidative stress (OS) of a cocoa powder extract (CPEX) on the protein expression profile of S. cerevisiae. A proteomic analysis was performed after culture preincubation with CPEX either without stress (-OS) or under stress conditions (+OS) (5 mM of H2O2). LC-MS/MS identified 33 differentially expressed proteins (-OS: 14, +OS: 19) that were included By Gene Ontology analysis in biological processes: biosynthesis of amino acids, carbohydrate metabolism and reactive oxygen species metabolic process. In a gene-knockout strains study, eight proteins were identified as putative candidates for being involved in the protective mechanism of cocoa polyphenols against OS induced by H2O2. CPEX was able to exert its antioxidant activity in yeast mainly through the regulation of: (a) amino acids metabolism proteins by modulating the production of molecules with known antioxidant roles; (b) stress-responsive protein Yhb1, but we were unable to fully understand its down-regulation; (c) protein Prb1, which can act by clipping Histone H3 N-terminal tails that are related to cellular resistance to DNA damaging agents.
    Keywords:  Saccharomyces cerevisiae; amino acid metabolism; antioxidant activity; cocoa polyphenols; deletion mutants; oxidative stress; protein identification
    DOI:  https://doi.org/10.3390/molecules25030452
  235. J Stroke Cerebrovasc Dis. 2020 Jan 20. pii: S1052-3057(19)30727-X. [Epub ahead of print] 104618
    Potential Metabolite Biomarkers for Acute Versus Chronic Stage of Ischemic Stroke: A Pilot Study.
    Sidorov E, Bejar C, Xu C, Ray B, Reddivari L, Chainakul J, Vanamala JKP, Sanghera DK.
      BACKGROUND: Metabolome profiling is used to identify biomarkers for acute ischemic stroke (AIS). Previous studies compared metabolite profiles in AIS and healthy controls, which did not account for factors that affect metabolome (genetics, medications). This pilot project evaluates the change in metabolite concentrations between the acute and chronic stage of stroke in the same cohort in order to minimize other factors impact.METHODS: We performed global metabolome profile on serum of 20 and urine of 12 stroke patients in acute (72 hours) and chronic (3-5.2 months) stage and compared relative peak values using Wilcoxon and orthogonal partial least squares discriminant analysis methods. Chronic stage metabolite concentrations were considered baseline. We performed analysis to identify significantly overrepresented pathways using MetaboAnalyst.
    RESULTS: Three serum metabolites asparagine (P = .045), tyrosine (P = .015), and xylose (P = .003) had significantly higher concentrations in acute stage. Seven out of top 10 serum metabolites ranked by Wilcoxon test P value were related to amino acid (AA) metabolism. Two urine metabolites glycine (P = .03) and acetylcarnitine (P = .05) had significantly different concentrations in the acute stage. Five of the top 10 urine metabolites related to AA metabolism. We identified 6 significant pathways after false discovery rate correction that were upregulated in the acute stage: (1) Aminoacyl-tRNA synthesis, (2) nitrogen, (3) alanine, aspartate, and glutamate, (4) branched-chain AA, (5) arginine and proline, and (6) phenylalanine metabolism.
    CONCLUSION: Longitudinal study design confirms that AA metabolism heavily involved in the pathophysiology of acute brain ischemia. Prospective longitudinal studies with a higher number of participants are needed to establish useful stroke biomarkers.
    Keywords:  Metabolome; amino acids; biomarkers; cerebral ischemia; stroke
    DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104618
  236. Cells. 2020 Jan 20. pii: E257. [Epub ahead of print]9(1):
    Regulation of Autophagy Is a Novel Tumorigenesis-Related Activity of Multifunctional Translationally Controlled Tumor Protein.
    Lee JS, Jang EH, Woo HA, Lee K.
      Translationally controlled tumor protein (TCTP) is highly conserved in eukaryotic organisms and plays multiple roles regulating cellular growth and homeostasis. Because of its anti-apoptotic activity and its role in the regulation of cancer metastasis, TCTP has become a promising target for cancer therapy. Moreover, growing evidence points to its clinical role in cancer prognosis. How TCTP regulates cellular growth in cancer has been widely studied, but how it regulates cellular homeostasis has received relatively little attention. This review discusses how TCTP is related to cancer and its potential as a target in cancer therapeutics, including its novel role in the regulation of autophagy. Regulation of autophagy is essential for cell recycling and scavenging cellular materials to sustain cell survival under the metabolic stress that cancer cells undergo during their aggressive proliferation.
    Keywords:  TCTP; autophagy; cancer
    DOI:  https://doi.org/10.3390/cells9010257
  237. Trends Biochem Sci. 2020 Jan 16. pii: S0968-0004(19)30263-4. [Epub ahead of print]
    Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo.
    Fernández-García J, Altea-Manzano P, Pranzini E, Fendt SM.
      Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field.
    Keywords:  in vivo metabolism; metabolic models; stable-isotope tracers; tracer analysis
    DOI:  https://doi.org/10.1016/j.tibs.2019.12.002
  238. J Clin Invest. 2020 Jan 21. pii: 131126. [Epub ahead of print]
    Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.
    O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, Fink YA, Kapuria D, Cassimatis TM, Kelsey N, Cero C, Abdul-Sater Z, Piccinini F, Baskin AS, Leitner BP, Cai H, Millo CM, Dieckmann W, Walter M, Javitt NB, Rotman Y, Walter PJ, Ader M, Bergman RN, Herscovitch P, Chen KY, Cypess AM.
      BACKGROUND: Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODS: We treated 14 healthy women of diverse ethnicity, 27.5 ± 1.1 y, BMI 25.4 ± 1.2 kg/m2, with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for four weeks, open-label. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by frequently sampled intravenous glucose tolerance test.
    RESULTS: Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers high-density lipoprotein (HDL) and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has anti-diabetic and anti-inflammatory capabilities, increased with acute treatment and was 35% higher at study completion. Finally, an intravenous glucose tolerance test demonstrated higher insulin sensitivity, glucose effectiveness, and insulin secretion.
    CONCLUSION: These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.
    TRIAL REGISTRATION: Clinicaltrials.gov NCT03049462.
    FUNDING: This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), DK075112, DK075116, DK071013, and DK071014.
    Keywords:  Adipose tissue; Cholesterol; Endocrinology; Glucose metabolism; Metabolism
    DOI:  https://doi.org/10.1172/JCI131126
  239. Exp Dermatol. 2020 Jan 20.
    Melanoma - time to fast or time to feast? An interplay between PPARs, metabolism and immunity.
    Grabacka M, Plonka PM, Reiss K.
      Development and progression of melanoma can be accelerated by intensification of particular metabolic pathways, such as aerobic glycolysis and avid amino acid catabolism, and is accompanied by aberrant immune responses within the tumor microenvironment. Contrary to other cancer types, melanoma reveals some unique tissue-specific features, such as melanogenesis, which is intertwined with metabolism. Nuclear peroxisome proliferator-activated receptors (PPARs) take part in regulation of systemic and cellular metabolism, inflammation and melanogenesis. They appear as a focal regulatory point for these three distinct processes by occupying the intersection among AMP-dependent protein kinase (AMPK), mammalian target of rapamycin (mTOR) and PPAR gamma coactivator 1-alpha (PGC-1α) signaling pathways. When deregulated, they may accelerate melanoma malignant growth. Presenting the contribution of PPARα and PPARγ in melanoma biology, we attempt to ask how two contrasting metabolic states: obesity and fasting can change progression of the disease and possible outcome of the treatment. This short essay is aimed to provoke a discussion about some practical implications for melanoma prevention and treatment, especially: how metabolic manipulation may be exploited to overcome immunosuppression and support immune checkpoint blockade efficacy.
    Keywords:  AMP-dependent protein kinase (AMPK); inflammasome; ketone bodies; mammalian target of rapamycin (mTOR); signal transducer and activator of transcription (STAT)
    DOI:  https://doi.org/10.1111/exd.14072
  240. Curr Pharm Des. 2020 Jan 22.
    DLEU1: A functional long noncoding RNA in tumorigenesis.
    Song C, Zhang J, Zhao Z, Yang Y, Meng D, Wang J, Guo C, Yuan C.
      BACKGROUND: LncRNA DLEU1 participates in various biological processes, playing an indispensable role in the pathophysiological of human diseases, especially in tumorigenesis and processes. Besides, it may represent as a promising target for biotherapy in numerous tumors. The aim of this review is to reveal the pathophysiological functions and mechanisms of lncRNA DLEU1 in sorts of cancers.METHODS: In this review, current studies concerning the biological functions and mechanisms of DLEU1 in tumor development are summarized and analyzed; the related researches are collected through a systematic retrieval of PubMed.
    RESULTS: DLEU1 is a novel cancer-associated lncRNA that has been proved to be abnormally elevated in various malignancies, containing osteosarcoma, glioma, glioblastoma multiforme, hepatocellular carcinoma, bladder cancer, cervical cancer, non-small cell lung cancer, pancreatic ductal adenocarcinoma, colorectal cancer, oral squamous cell carcinoma, endometrial cancer, gastric cancer, Burkitt lymphoma and ovarian carcinoma. Besides, lncRNA LDEU1 has been demonstrated involving in the procession of proliferation, migration, invasion and inhibition of apoptosis of cancer cells.
    CONCLUSION: Long non-coding RNA DLEU1 is likely to represent an available biomarker or a potential therapeutic target in multiple tumors.
    Keywords:  Biomarker; DLEU1; Long Non-Coding RNA; Multiple Tumors; Potential Therapeutic Target; Tumorigenesis
    DOI:  https://doi.org/10.2174/1381612826666200122145305
  241. Toxicol Lett. 2020 Jan 18. pii: S0378-4274(20)30023-0. [Epub ahead of print]
    Acetoacetate Enhances Oxidative Metabolism and Response to Toxicants of Cultured Kidney Cells.
    Denoon T, Sunilkumar S, Ford SM.
      Cultured kidney cells maintained in conventional growth media with high glucose levels exhibit increased glycolytic activity compared to the cells in vivo. In contrast, renal proximal tubules utilize substrates such as ketone bodies and rely on mitochondrial oxidative phosphorylation. LLC-PK1 cells maintain many features of the proximal tubule but are exposed to glucose concentrations ranging from 17-25 mM. This may impact their reliability in predicting mitochondrial toxicity. This study is designed to test the impact of the ketone body acetoacetate on metabolic characteristics of LLC-PK1 cells. Basal respiration, maximal respiration, spare respiratory capacity and ATP-linked respiration were significantly increased in cells grown in growth medium supplemented with 5 mM acetoacetate. In contrast, glycolytic capacity, as well as glycolytic reserve were significantly reduced in the acetoacetate group. There was an increased expression in biomarkers of mitochondrial biogenesis, and an increase in mitochondrial protein expression. Cells grown in medium complemented with acetoacetate displayed a significantly lower LC50 when treated with clotrimazole and diclofenac. There was a marked increase in uncoupled respiration in the presence of diclofenac, while clotrimazole and ciprofibrate significantly decreased respiration in the acetoacetate. The results indicate that acetoacetate complemented media can alter cellular metabolism and increase sensitization to toxicants.
    Keywords:  acetoacetate; cell culture; glucose; in vitro toxicity screening; metabolic reprogramming; mitochondrial toxicants
    DOI:  https://doi.org/10.1016/j.toxlet.2020.01.015
  242. Arch Physiol Biochem. 2020 Jan 24. 1-9
    Can gallic acid potentiate the antihyperglycemic effect of acarbose and metformin? Evidence from streptozotocin-induced diabetic rat model.
    Oboh G, Ogunbadejo MD, Ogunsuyi OB, Oyeleye SI.
      This study investigated the influence of dietary phenolic acid- Gallic acid (GA) on the antihyperglycemic properties of acarbose (ACA) and metformin (MET). Streptozotocin-induced diabetic rats were treated (p.o) with ACA, MET, GA and their combinations for 14 days. The effects of the treatments on blood glucose and insulin levels, pancreas α-amylase and intestinal α-glucosidase activities, as well as thiobarbituric acid reactive species (TBARS), thiol and reactive oxygen species (ROS) levels, including antioxidant enzyme activities were investigated. A significant increase in blood glucose, insulin, ROS and TBARS levels, and impaired antioxidant status, as well as elevation in the activities of α-amylase and α-glucosidase observed in diabetic rats were ameliorated in the treatment groups. Hpwever, GA had varying effects on the antidiabetic properties of the drugs. Nevertheless, GA showed more potentiating effects on the antidiabetic effect of MET and these effects were better observed at the lower dose of GA.
    Keywords:  Antihyperglycemic; acarbose; food-drug interaction; gallic acid; metformin
    DOI:  https://doi.org/10.1080/13813455.2020.1716014
  243. WMJ. 2019 Dec;118(4): 155
    Striving to Reduce Radon-Induced Lung Cancer in Wisconsin.
    Schrager S.
      
  244. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19913. [Epub ahead of print]24(1): 213-221
    Circ0021205 aggravates the progression of non-small cell lung cancer by targeting miRNA-16-5p/VEGFA.
    Yang Y, Huang XJ.
      OBJECTIVE: To uncover the role of circ0021205 in the progression of non-small cell lung cancer (NSCLC) and its molecular mechanism.PATIENTS AND METHODS: The expression level of circ0021205 in NSCLC tissues and cells was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The relationship between circ0021205 level and the pathological indexes of NSCLC was analyzed by the Chi-square test. The Kaplan-Meier curves were depicted for evaluating the influence of circ0021205 on the survival of NSCLC patients. After altering circ0021205 level in A549 and PC9 cells, the changes in the proliferative, migratory, and invasive abilities were assessed. The interaction among circ0021205, miRNA-16-5p, and the vascular endothelial growth factor A (VEGFA) was verified by Dual-Luciferase Reporter Gene Assay and the Spearman correlation test. At last, the role of circ0021205/miRNA-16-5p/VEGFA axis in regulating the progression of NSCLC was identified.
    RESULTS: Circ0021205 was upregulated in NSCLC tissues and cells. Its level was positively correlated to tumor size, tumor node metastasis (TNM) staging, and distant metastasis of NSCLC. Upregulation of circ0021205 predicted worse prognosis of NSCLC patients. The overexpression of circ0021205 in A549 and PC9 cells accelerated proliferative, migratory, and invasive abilities. Moreover, circ0021205 could bind to miRNA-16-5p to further mediate VEGFA level. The overexpression of miRNA-16-5p or knockdown of VEGFA could reverse the role of the overexpressed circ0021205 in regulating the cellular behaviors of NSCLC.
    CONCLUSIONS: Circ0021205 aggravates the malignant progression of NSCLC by binding to miRNA-16-5p to regulate the VEGFA level.
    DOI:  https://doi.org/10.26355/eurrev_202001_19913
  245. J Cancer. 2020 ;11(5): 1288-1298
    Identification of a Sixteen-gene Prognostic Biomarker for Lung Adenocarcinoma Using a Machine Learning Method.
    Ma B, Geng Y, Meng F, Yan G, Song F.
      Objectives: Lung adenocarcinoma (LUAD) accounts for a majority of cancer-related deaths worldwide annually. The identification of prognostic biomarkers and prediction of prognosis for LUAD patients is necessary. Materials and Methods: In this study, LUAD RNA-Seq data and clinical data from the Cancer Genome Atlas (TCGA) were divided into TCGA cohort I (n = 338) and II (n = 168). The cohort I was used for model construction, and the cohort II and data from Gene Expression Omnibus (GSE72094 cohort, n = 393; GSE11969 cohort, n = 149) were utilized for validation. First, the survival-related seed genes were selected from the cohort I using the machine learning model (random survival forest, RSF), and then in order to improve prediction accuracy, the forward selection model was utilized to identify the prognosis-related key genes among the seed genes using the clinically-integrated RNA-Seq data. Second, the survival risk score system was constructed by using these key genes in the cohort II, the GSE72094 cohort and the GSE11969 cohort, and the evaluation metrics such as HR, p value and C-index were calculated to validate the proposed method. Third, the developed approach was compared with the previous five prediction models. Finally, bioinformatics analyses (pathway, heatmap, protein-gene interaction network) have been applied to the identified seed genes and key genes. Results and Conclusion: Based on the RSF model and clinically-integrated RNA-Seq data, we identified sixteen key genes that formed the prognostic gene expression signature. These sixteen key genes could achieve a strong power for prognostic prediction of LUAD patients in cohort II (HR = 3.80, p = 1.63e-06, C-index = 0.656), and were further validated in the GSE72094 cohort (HR = 4.12, p = 1.34e-10, C-index = 0.672) and GSE11969 cohort (HR = 3.87, p = 6.81e-07, C-index = 0.670). The experimental results of three independent validation cohorts showed that compared with the traditional Cox model and the use of standalone RNA-Seq data, the machine-learning-based method effectively improved the prediction accuracy of LUAD prognosis, and the derived model was also superior to the other five existing prediction models. KEGG pathway analysis found eleven of the sixteen genes were associated with Nicotine addiction. Thirteen of the sixteen genes were reported for the first time as the LUAD prognosis-related key genes. In conclusion, we developed a sixteen-gene prognostic marker for LUAD, which may provide a powerful prognostic tool for precision oncology.
    Keywords:  Forward selection model; Lung adenocarcinoma; Prognosis prediction; RNA-Seq data; Random survival forest
    DOI:  https://doi.org/10.7150/jca.34585
  246. Mol Pharm. 2020 Jan 24.
    L-type Calcium Channel Blocker Enhances Cellular Delivery and Gene Silencing Potency of Cell-Penetrating Asymmetric siRNAs.
    Choe JY, Son DS, Kim Y, Lee JK, Shin H, Kim WJ, Kang YG, Dua P, Hong SW, Park JH, Lee DK.
      The efficient delivery of small interfering RNAs (siRNAs) to the target cells is critical for the pharmaceutical success of RNA interference (RNAi) drugs. One of the possible strategies to improve siRNA delivery is to identify auxiliary molecules that augment their cellular uptake. Herein, we performed a chemical library screening, in an effort to discover small molecules that enhance the potency of cholesterol-conjugated, cell-penetrating asymmetric siRNA (cp-asiRNA). Interestingly, three compounds identified from the screen share a common dihydropyridine (DHP) core and function as L-type calcium channel blockers (CCBs). Using confocal microscopy and quantitative analysis of small RNAs, we demonstrated that the L-type CCBs increased the endocytic cellular uptake of cp-asiRNA. Furthermore, these small molecules substantially improved the potency of cp-asiRNA, not only in vitro but also in vivo on rat skin. Collectively, our study provides an alternative pharmacological approach for the identification of small molecules that potentiate the effects of therapeutic siRNAs.
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.9b00942
  247. Trends Plant Sci. 2020 Jan 18. pii: S1360-1385(19)30337-1. [Epub ahead of print]
    GORK Channel: A Master Switch of Plant Metabolism?
    Adem GD, Chen G, Shabala L, Chen ZH, Shabala S.
      Potassium regulates a plethora of metabolic and developmental response in plants, and upon exposure to biotic and abiotic stresses a substantial K+ loss occurs from plant cells. The outward-rectifying potassium efflux GORK channels are central to this stress-induced K+ loss from the cytosol. In the mammalian systems, signaling molecules such as gamma-aminobutyric acid, G-proteins, ATP, inositol, and protein phosphatases were shown to operate as ligands controlling many K+ efflux channels. Here we present the evidence that the same molecules may also regulate GORK channels in plants. This mechanism enables operation of the GORK channels as a master switch of the cell metabolism, thus adjusting intracellular K+ homeostasis to altered environmental conditions, to maximize plant adaptive potential.
    Keywords:  ATP; G-protein; GABA; cyclic nucleotide; molecular evolution; potassium efflux channel
    DOI:  https://doi.org/10.1016/j.tplants.2019.12.012
  248. Sci Rep. 2020 Jan 23. 10(1): 1047
    First in man study of [18F]fluoro-PEG-folate PET: a novel macrophage imaging technique to visualize rheumatoid arthritis.
    Verweij NJF, Yaqub M, Bruijnen STG, Pieplenbosch S, Ter Wee MM, Jansen G, Chen Q, Low PS, Windhorst AD, Lammertsma AA, Hoekstra OS, Voskuyl AE, van der Laken CJ.
      Non-invasive imaging of arthritis activity in rheumatoid arthritis (RA) patients using macrophage PET holds promise for early diagnosis and therapeutic response monitoring. Previously obtained results with macrophage tracer (R)-[11C]PK11195 were encouraging, but the imaging signal could be further improved by reduction of background uptake. Recently, the novel macrophage tracer [18F]fluoro-PEG-folate was developed. This tracer showed excellent targeting of the folate receptor β on activated macrophages in synovial tissue in a preclinical arthritic rat model. We performed three substudies to investigate the biodistribution, potential for imaging arthritis and kinetic properties of [18F]fluoro-PEG-folate in RA patients. Firstly, biodistribution demonstrated fast clearance of [18F]fluoro-PEG-folate from heart and blood vessels and no dose limiting uptake in organs. Secondly, [18F]fluoro-PEG-folate showed uptake in arthritic joints with significantly lower background and hence significantly higher target-to-background ratios as compared to reference macrophage tracer (R)-[11C]PK11195. Lastly, dynamic scanning demonstrated fast tracer uptake in affected joints, reaching a plateau after 1 minute, co-existing with a rapid blood clearance. In conclusion, this first in man study demonstrates the potential of [18F]fluoro-PEG-folate to image arthritis activity in RA with favourable imaging characteristics of rapid clearance and low background uptake, that allow for detection of inflammatory activity in the whole body.
    DOI:  https://doi.org/10.1038/s41598-020-57841-x
  249. Am J Physiol Lung Cell Mol Physiol. 2020 Jan 22.
    Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar development.
    Blaskovic S, Donati Y, Zanetti F, Ruchonnet-Métrailler I, Lemeille S, Cremona TP, Schittny JC, Barazzone-Argiroffo C.
      Harmful consequences of cigarette smoke (CS) exposure during lung development can already manifest in infancy. In particular, early life exposure to nicotine, the main component of CS, was shown to affect lung development in animal models. We aimed to characterize the effect of nicotine on alveoli formation. We analyzed the kinetics of normal alveolar development during the alveolarization phase and then looked at the effect of nicotine in a mouse model of gestational and early life exposure. Immunohistochemical staining revealed that the wave of cell proliferation (i.e. vascular endothelial cells, alveolar epithelial cells (AEC) type II and mesenchymal cell) occurs at pnd8 in control and nicotine-exposed lungs. However, FACS analysis of individual epithelial alveolar cells revealed nicotine-induced transient increase of AEC type I proliferation and decrease of vascular endothelial cell proliferation at pnd8. Furthermore, nicotine increased the percentage of endothelial cells at pnd2. Transcriptomic data also showed significant changes in nicotine samples compared to the controls on cell cycle associated genes at pnd2, but not anymore at pnd16. Accordingly, the expression of survivin, involved in cell cycle regulation, also follows a different kinetics in nicotine lung extracts. These changes resulted in an increased lung size detected by stereology at pnd16, but no longer in adult age, suggesting that nicotine can act on the pace of lung maturation. Taken together, our results indicate that early life nicotine exposure could be harmful to alveolar development independently from other toxicants contained in CS.
    Keywords:  alveolarization; developmental kinetics; lung development; nicotine
    DOI:  https://doi.org/10.1152/ajplung.00228.2019
  250. J Biosci. 2020 ;pii: 17. [Epub ahead of print]45
    When histones are under glucose starvation.
    Lee J, Oh S, Abmayr SM, Workman JL.
      Under nutritional stress, cells undergo metabolic rewiring that results in changes of various cellular processes that include gene transcription. This transcriptional regulation requires dynamic chromatin remodeling that involves histone post-translational modifications. There are several histone marks that may act as switches upon starvation for stress-response pathways.
  251. Eur J Cancer Care (Engl). 2020 Jan 21. e13206
    Does progress achieved in the treatment of patients with metastatic non-small-cell lung cancer reach the elderly population? A cohort study from a cancer centre from Eastern Switzerland.
    Schmid S, Suipyte J, Herrmann C, Mousavi M, Hitz F, Früh M.
      OBJECTIVE: Treatment options for non-small-cell lung cancer (NSCLC) have been evolving. The goal of our study was to evaluate whether novel therapeutics are used in the elderly population and improve outcomes to a similar extent as in young patients.METHODS: We enrolled patients registered in the Cancer Registry of Eastern Switzerland and grouped them into four cohorts: Elderly patients aged ≥70 years diagnosed 2005-2007 and 2015-2016 (elderly cohorts 1,2) were compared to cohorts of patients < 70 years diagnosed during the same time periods (young cohorts 1,2).
    RESULTS: 499 individuals were analysed. Median cancer-specific survival in the elderly cohorts 1 and 2 was 3.9 months and 6.3 months, respectively, and 8.0 and 12.7 months in the young cohorts 1 and 2. 12-month survival significantly improved over ten years only in younger patients (35.6% and 54.9%), however not in the elderly cohorts (20% vs. 35%). Proportion of patients receiving any line of systemic treatment remained lower in the elderly cohorts (53% vs. 78%).
    CONCLUSION: Despite the increase in median cancer-specific survival in both cohorts, a significant and clinically meaningful improvement of 12-month cancer-specific survival was only seen in young patients. The adoption of novel treatment approaches is lagging behind in the elderly population.
    Keywords:  advanced NSCLC; elderly; immunotherapy; targeted treatment; treatment advances; undertreatment
    DOI:  https://doi.org/10.1111/ecc.13206
  252. Curr Dev Nutr. 2020 Jan;4(1): nzz102
    Evidence of a Role for One-Carbon Metabolism in Blood Pressure: Can B Vitamin Intervention Address the Genetic Risk of Hypertension Owing to a Common Folate Polymorphism?
    McNulty H, Strain JJ, Hughes CF, Pentieva K, Ward M.
      Hypertension in adulthood is recognized as the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease, whereas hypertension in pregnancy leads to serious adverse fetal and maternal outcomes. This article explores the under-recognized role of one-carbon metabolism in blood pressure (BP) and the potential for folate-related B vitamins to protect against hypertension. Genome-wide association studies and clinical studies provide evidence linking the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with BP and increased risk of hypertension and hypertension in pregnancy. A novel role for riboflavin (the MTHFR cofactor) has recently emerged, however, with evidence from randomized trials that supplemental riboflavin can lower BP specifically in adults with the variant MTHFR 677TT genotype. Further studies are required to elucidate the biological mechanisms linking one-carbon metabolism with BP and explore the effect of riboflavin in modulating the genetic risk of hypertension in early and later life.
    Keywords:  MTHFR; blood pressure; folate; gene–nutrient interaction; hypertension; hypertension in pregnancy; one-carbon metabolism; personalized nutrition; riboflavin; single nucleotide polymorphism
    DOI:  https://doi.org/10.1093/cdn/nzz102
  253. Nanoscale. 2020 Jan 23.
    A MSN-based tumor-targeted nanoplatform to interfere with lactate metabolism to induce tumor cell acidosis for tumor suppression and anti-metastasis.
    Chen ZX, Liu MD, Guo DK, Zou MZ, Wang SB, Cheng H, Zhong Z, Zhang XZ.
      Lactate, the main contributor to the acidic tumor microenvironment, not only promotes the proliferation of tumor cells, but also closely relates to tumor invasion and metastasis. Here, a tumor targeting nanoplatform, designated as Me&Flu@MSN@MnO2-FA, was fabricated for effective tumor suppression and anti-metastasis by interfering with lactate metabolism of tumor cells. Metformin (Me) and fluvastatin sodium (Flu) were incorporated into MnO2-coated mesoporous silicon nanoparticles (MSNs), the synergism between Me and Flu can modulate the pyruvate metabolic pathway to produce more lactate, and concurrently inhibit lactate efflux to induce intracellular acidosis to kill tumor cells. As a result of the restricted lactate efflux, the extracellular lactate concentration is reduced, and the ability of the tumor cells to migrate is also weakened. This ingenious strategy based on Me&Flu@MSN@MnO2-FA showed an obvious inhibitory effect on tumor growth and resistance to metastasis.
    DOI:  https://doi.org/10.1039/c9nr10344a
  254. J Chemother. 2020 Jan 20. 1-5
    Relationship between epidermal growth factor receptor mutations and skin rash in non-small cell lung cancer patients.
    Tanaka H, Atagi K, Tatsumichi T, Yamaguchi K, Takahashi K, Kaji M, Kosaka S, Houchi H.
      Several reports have investigated relationships between epidermal growth factor receptor (EGFR) mutations and the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer; however, there have been insufficient analyses of relationships between EGFR mutations and adverse reactions. This study investigated the relationships between EGFR mutations and skin rash. We first compared skin rash grades between different mutations, then tested factors possibly affecting skin rash by multivariate analysis. The main outcome measure was the significant difference in incidence of skin rash between each group with different mutations. Our study suggested that the risk of skin rash is low in patients with exon 19 deletion mutations who are taking EGFR-TKIs, whereas it is high in those with exon 21 point mutations. These results will be useful indicators for instructions regarding daily examinations, skin care, and use of oral antibiotics or topical steroids in patients taking EGFR-TKIs with skin rash.
    Keywords:  Epidermal growth factor receptor; exon 19 deletion mutation; exon 21 point mutation; non-small cell lung cancer; skin rash; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1080/1120009X.2020.1711647
  255. Sci Rep. 2020 Jan 20. 10(1): 643
    Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.
    Hwang S, Kwon AY, Jeong JY, Kim S, Kang H, Park J, Kim JH, Han OJ, Lim SM, An HJ.
      Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes.
    DOI:  https://doi.org/10.1038/s41598-019-57218-9
  256. J Breath Res. 2020 Jan 24. 14(2): 028002
    Reply to Comment on 'Volatile biomarker in breath predicts lung cancer and pulmonary nodules'.
    Phillips M, Bauer TL, Pass HI.
      
    DOI:  https://doi.org/10.1088/1752-7163/ab6417
  257. J Cell Biol. 2020 Feb 03. pii: e202001006. [Epub ahead of print]219(2):
    Neuronal GDPGP1 and glycogen metabolism: friend or foe?
    Singhal NS, Lee EM, Ma DK.
      The adult brain consumes glucose for energy needs and stores glucose as glycogen mainly in astrocytes. Schulz et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.201807127) identify the stress-regulated metabolic enzyme GDPGP1 that promotes neuronal survival likely through glycogen reserves in mouse and C. elegans neurons.
    DOI:  https://doi.org/10.1083/jcb.202001006
  258. Schizophr Res. 2020 Jan 17. pii: S0920-9964(19)30612-7. [Epub ahead of print]
    Cardiac left ventricular ejection fraction in men and women with schizophrenia on long-term antipsychotic treatment.
    Andreou D, Saetre P, Fors BM, Nilsson BM, Kullberg J, Jönsson EG, Ebeling Barbier C, Agartz I.
      Patients with schizophrenia exhibit a higher cardiovascular mortality compared to the general population which has been attributed to life-style factors, genetic susceptibility and antipsychotic medication. Recent echocardiographic studies have pointed to an association between clozapine treatment and reduced left ventricular ejection fraction (LVEF), a measure that has been inversely associated with adverse outcomes including all-cause mortality. Cardiovascular magnetic resonance (CMR) is considered the reference method for LVEF measurement. The aim of the present study was to investigate the LVEF in patients with schizophrenia on long-term treatment with antipsychotics and healthy controls. Twenty-nine adult patients with schizophrenia on long-term medication with antipsychotics and 27 age-, sex- and body mass index-matched healthy controls (mean ages 44 and 45 years, respectively) were recruited from outpatient psychiatric clinics in Uppsala, Sweden. The participants were interviewed and underwent physical examination, biochemical analyses, electrocardiogram and CMR. Men with schizophrenia on long-term antipsychotic treatment showed significantly lower LVEF than controls (p = 0.0076), whereas no such difference was evident among women (p = 0.44). Specifically, clozapine-treated male patients had 10.6% lower LVEF than male controls (p = 0.0064), whereas the LVEF was 5.5% below that of controls among male patients treated with non-clozapine antipsychotics (p = 0.047). Among medicated men with schizophrenia, we found significantly lower LVEF compared to healthy individuals, suggesting the need of routine cardiac monitoring in this patient group. This is the first study showing a significant negative association between treatment with non-clozapine antipsychotics and LVEF.
    Keywords:  Antipsychotics; Cardiovascular magnetic resonance; Clozapine; Left ventricular ejection fraction; Schizophrenia
    DOI:  https://doi.org/10.1016/j.schres.2019.12.042
  259. Eur J Paediatr Neurol. 2020 Jan 07. pii: S1090-3798(19)30441-6. [Epub ahead of print]
    The mitochondrial epilepsies.
    Lim A, Thomas RH.
      Mitochondria are vital organelles within cells that undertake many important metabolic roles, the most significant of which is to generate energy to support organ function. Dysfunction of the mitochondrion can lead to a wide range of clinical features, predominantly affecting organs with a high metabolic demand such as the brain. One of the main neurological manifestations of mitochondrial disease is metabolic epilepsies. These epileptic seizures are more frequently of posterior quadrant and occipital lobe onset, more likely to present with non-convulsive status epilepticus which may last months and be more resistant to treatment from the onset. The onset of can be of any age. Childhood onset epilepsy is a major phenotypic feature in mitochondrial disorders such as Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies, and Leigh syndrome. Meanwhile, adults with classical mitochondrial disease syndrome such as MELAS, MERFF or POLG-related disorders could present with either focal or generalised seizures. There are no specific curative treatments for mitochondrial epilepsy. Generally, the epileptic seizures should be managed by specialist neurologist with appropriate use of anticonvulsants. As a general rule, especially in disorders associated with mutation in POLG, sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal.
    DOI:  https://doi.org/10.1016/j.ejpn.2019.12.021
  260. Nucleic Acids Res. 2020 Jan 20. pii: gkz1237. [Epub ahead of print]
    Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3.
    De Troyer L, Zhao P, Pastor T, Baietti MF, Barra J, Vendramin R, Dok R, Lechat B, Najm P, Van Haver D, Impens F, Leucci E, Sablina AA.
      Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINC02657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors. LASTR is upregulated in several types of epithelial cancers due to the activation of the stress-induced JNK/c-JUN pathway. Using a mass-spectrometry based approach, we identified the RNA-splicing factor SART3 as a LASTR-interacting partner. We found that LASTR promotes splicing efficiency by controlling SART3 association with the U4 and U6 small nuclear ribonucleoproteins (snRNP) during spliceosome recycling. Intron retention induced by LASTR depletion downregulates expression of essential genes, ultimately decreasing the fitness of cancer cells.
    DOI:  https://doi.org/10.1093/nar/gkz1237
  261. Curr Biol. 2020 Jan 10. pii: S0960-9822(19)31615-X. [Epub ahead of print]
    UBAP2L Forms Distinct Cores that Act in Nucleating Stress Granules Upstream of G3BP1.
    Cirillo L, Cieren A, Barbieri S, Khong A, Schwager F, Parker R, Gotta M.
      Stress granules (SGs) are membraneless organelles that form in eukaryotic cells after stress exposure [1] (reviewed in [2-4]). Following translation inhibition, polysome disassembly releases 48S preinitiation complexes (PICs). mRNA, PICs, and other proteins coalesce in SG cores [1, 5-7]. SG cores recruit a dynamic shell, whose properties are dominated by weak interactions between proteins and RNAs [8-10]. The structure and assembly of SGs and how different components contribute to their formation are not fully understood. Using super-resolution and expansion microscopy, we find that the SG component UBAP2L [11, 12] and the core protein G3BP1 [5, 11-13] occupy different domains inside SGs. UBAP2L displays typical properties of a core protein, indicating that cores of different compositions coexist inside the same granule. Consistent with a role as a core protein, UBAP2L is required for SG assembly in several stress conditions. Our reverse genetic and cell biology experiments suggest that UBAP2L forms granules independent of G3BP1 and 2 but does not interfere with stress-induced translational inhibition. We propose a model in which UBAP2L is an essential SG nucleator that acts upstream of G3BP1 and 2 and facilitates G3BP1 core formation and SG assembly and growth.
    Keywords:  G3BP; UBAP2L; stress granule core; stress granule nucleation; stress granules
    DOI:  https://doi.org/10.1016/j.cub.2019.12.020
  262. Clin Biochem. 2020 Jan 20. pii: S0009-9120(19)30839-2. [Epub ahead of print]
    Identification and implementation of hemolysis interference thresholds in serum ionized calcium measurement.
    Robinson JL, Seiden-Long I, de Koning L.
      
    Keywords:  hemolysis; interference; ionized calcium; pre-analytical error
    DOI:  https://doi.org/10.1016/j.clinbiochem.2020.01.004
  263. J Mater Chem B. 2020 Jan 20.
    Reactive oxygen species-activatable camptothecin polyprodrug based dextran enhances chemotherapy efficacy by damaging mitochondria.
    Zhang T, Ma X, Bai S, Wang Y, Zhang X, Lu Y, Wen F, Xue P, Kang Y, Xu Z.
      Low loading capacity, poor accumulation rate and weak permeability at tumor sites have been identified as the critical barriers for anti-cancer nanomedicines (ANMs). We herein reported a reactive oxygen species (ROS)-activatable ANM of dextran-b-P(CPTMA-co-OEGMA) (DCPT). It aimed to meet the above challenges for improving the therapeutic efficiency of chemotherapy. In this system, camptothecin (CPT) was selected as a chemotherapy drug and poly(ethylene glycol)methyl ether methacrylate (OEGMA) played the role of a hydrophilic block to enhance the water solubility of polyprodrug micelles. At high ROS levels in the tumor microenvironment, the micelles could be disassembled, and simultaneously, the anti-cancer drug of CPT would be released from the DCPT micelles. The 4T1-tumor growth would be greatly inhibited by these two DCPT polyprodrugs, with outstanding in vivo biosafety. The results of both in vitro and in vivo studies indicated the superior therapeutic effects of DCPT. The rational design of polyprodrug nanomedicines may serve as a promising strategy for the development of tumor microenvironment-responsive ANMs, thus improving chemotherapy efficacy.
    DOI:  https://doi.org/10.1039/c9tb02199j
  264. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30088-X. [Epub ahead of print]49(1): 37-55
    Diabetes Technology Use in Adults with Type 1 and Type 2 Diabetes.
    Kravarusic J, Aleppo G.
      In the last 2 decades, diabetes technology has emerged as a branch of diabetes management thanks to the advent of continuous glucose monitoring (CGM) and increased availability of continuous subcutaneous insulin infusion systems, or insulin pumps. These tools have progressed from rudimentary instruments to sophisticated therapeutic options for advanced diabetes management. This article discusses the available CGM and insulin pump systems and the clinical benefits of their use in adults with type 1 diabetes, intensively insulin-treated type 2 diabetes, and pregnant patients with preexisting diabetes.
    Keywords:  Continuous glucose monitoring (CGM); Continuous subcutaneous insulin infusion (CSII); Hybrid closed loop; Patch pump; Sensor-augmented pump (SAP)
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.006
  265. FASEB J. 2020 Jan 20.
    Metabolic changes related to the IDH1 mutation in gliomas preserve TCA-cycle activity: An investigation at the protein level.
    Dekker LJM, Wu S, Jurriëns C, Mustafa DAN, Grevers F, Burgers PC, Sillevis Smitt PAE, Kros JM, Luider TM.
      The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA cycle are associated with IDH1 mut. Here, we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism, and the TCA cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate, and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine, and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA-cycle activity in IDH1 mut gliomas.
    Keywords:  IDH1 mutation; TCA cycle; glioma; glutaminolysis; metabolism; proteomics
    DOI:  https://doi.org/10.1096/fj.201902352R
  266. Endocr Relat Cancer. 2020 Jan 01. pii: ERC-19-0482.R1. [Epub ahead of print]
    Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer.
    Lee WK, Kim WG, Fozzatti L, Park S, Zhao L, Willingham M, Lonard D, O'Malley BW, Cheng SY.
      Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy without effective therapeutic options to improve survival. Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator whose amplification and/or overexpression has been identified in many cancers. In this study, we explored the expression of SRC-3 in ATCs and the effects of a new class of SRC-3 inhibitor-2 (SI-2) in human ATC cells (THJ-11T and -16T cells) and mouse xenograft models to assess therapeutic potential of SI-2 for the treatment of ATC. SRC-3 protein abundance was significantly higher in human ATC tissue samples and ATC cells than in differentiated thyroid carcinomas or normal controls. SI-2 treatment effectively reduced the SRC-3 expression in both ATC cells and ATC xenograft tumors induced by these cells. Cancer cell survival in ATC cells and tumor growth in xenograft tumors were significantly reduced by SI-2 treatment through induction of cancer cell apoptosis and cell cycle arrest. SI-2 also reduced cancer stem-like cells as shown by an inhibition of tumorsphere formation, ALDH activity and expression of stem cell markers in ATC. These findings indicate that SRC-3 is a potential therapeutic target for treatment of ATC patients, and that SI-2 is a potent and promising candidate for a new therapeutic agent.
    DOI:  https://doi.org/10.1530/ERC-19-0482
  267. Mol Aspects Med. 2020 Jan 16. pii: S0098-2997(19)30119-0. [Epub ahead of print] 100838
    Macrophage activation as an archetype of mitochondrial repurposing.
    Jones AE, Divakaruni AS.
      Mitochondria are metabolic organelles essential not only for energy transduction, but also a range of other functions such as biosynthesis, ion and metal homeostasis, maintenance of redox balance, and cell signaling. A hallmark example of how mitochondria can rebalance these processes to adjust cell function is observed in macrophages. These innate immune cells are responsible for a remarkable breadth of processes including pathogen elimination, antigen presentation, debris clearance, and wound healing. These diverse, polarized functions often include similarly disparate alterations in the metabolic phenotype associated with their execution. In this chapter, mitochondrial bioenergetics and signaling are viewed through the lens of macrophage polarization: both classical, pro-inflammatory activation and alternative, anti-inflammatory activation are associated with substantive changes to mitochondrial metabolism. Emphasis is placed on recent evidence that aims to clarify the essential - rather than associative - mitochondrial alterations, as well as accumulating data suggesting a degree of plasticity within the metabolic phenotypes that can support pro- and anti-inflammatory functions.
    DOI:  https://doi.org/10.1016/j.mam.2019.100838
  268. Int J Obes (Lond). 2020 Jan 21.
    Glucose metabolism in brown adipose tissue determined by deuterium metabolic imaging in rats.
    Riis-Vestergaard MJ, Laustsen C, Mariager CØ, Schulte RF, Pedersen SB, Richelsen B.
      BACKGROUND/OBJECTIVES: Brown adipose tissue (BAT) has gained growing interest as a potential target for treatment of obesity. Currently, the most widely used technique/method for in vivo measurements of BAT activity in humans is 18FDG PET/CT. To supplement these investigations novel radiation-free methods are warranted. Deuterium metabolic imaging (DMI) is a novel modality that combines magnetic resonance spectroscopic (MRS) imaging with deuterium-labelled glucose (2H-glucose). This allows for spatio-temporal and metabolic imaging beyond glucose uptake. We aimed to evaluate if DMI could discriminate glucose metabolism in BAT of cold-acclimatised and thermoneutral rats.SUBJECTS/METHODS: Male Sprague-Dawley rats were housed in a cold environment (9 °C, n = 10) or at thermoneutrality (30 °C, n = 11) for 1 week. For imaging rats were anaesthetized, received a 2H-glucose (1 M, 1.95 g/kg) bolus and DMI was acquired at baseline followed by 20 min time intervals up to 2 h. Furthermore, Dixon MRI was performed for anatomical determination of the interscapular BAT (iBAT) depot along with dynamic contrast enhanced (DCE) MRI to evaluate perfusion.
    RESULTS: 2H-glucose signal was higher in cold-acclimatised rats compared with thermoneutral rats (p ≤ 0.001) indicating an overall increase in glucose uptake and metabolism. This was in line with a lower fat/water threshold, higher perfusion and increased UCP1 mRNA expression in iBAT (ninefold increment) of cold-acclimatised rats compared with thermoneutral rats.
    CONCLUSIONS: We find that DMI can discriminate cold-acclimatised and thermoneutral BAT in rats. This is the first study to evaluate BAT activity by DMI, which may open up for the use of the non-radioactive DMI method for BAT measurements in humans.
    DOI:  https://doi.org/10.1038/s41366-020-0533-7
  269. Sci Rep. 2020 Jan 23. 10(1): 1064
    Potential effect of non-thermal plasma for the inhibition of scar formation: a preliminary report.
    Wang XF, Fang QQ, Jia B, Hu YY, Wang ZC, Yan KP, Yin SY, Liu Z, Tan WQ.
      Non-thermal plasma (NTP) is a promising biomedical tool for application to wound healing. However, there is limited scientific evidence that confirms its efficacy to inhibit scar formation. This study aims to investigate the role of non-thermal plasma in scar formation. Two full-thickness dorsal cutaneous wounds of rats were treated with either a non-thermal helium plasma jet or helium. It was determined that the non-thermal plasma jet accelerated the wound healing process from 5 days after surgery (day 5: 41.27% ± 2.351 vs 54.7% ± 5.314, p < 0.05; day 7: 56.05% ± 1.881 vs 75.28% ± 3.914, p < 0.01; day 14: 89.85% ± 2.991 vs 98.07% ± 0.839, p < 0.05). The width of the scars for the NTP group was narrower than those of control group (4.607 ± 0.416 mm vs 3.260 ± 0.333 mm, p < 0.05). In addition, a lower level of TGF-β1, p-Smad2 and p-Smad3 were detected in the NTP treated wounds (p < 0.05, p < 0.01 and p < 0.01). As expected, α-SMA was also significantly decreased in the NTP treatment group (p < 0.01). Moreover, the expression of type I collagen and the proportion of type I to III collagen were lower in the NTP group (p < 0.05). The results of the study suggest that NTP may play a potential role in scar formation by inhibiting the TGF β1 signal pathway and reducing the levels of α-SMA and type I collagen, and may have clinical utility in the future.
    DOI:  https://doi.org/10.1038/s41598-020-57703-6
  270. Blood Adv. 2020 Jan 28. 4(2): 266-273
    P-selectin-deficient mice to study pathophysiology of sickle cell disease.
    Bennewitz MF, Tutuncuoglu E, Gudapati S, Brzoska T, Watkins SC, Monga SP, Pradhan-Sundd T, Sundd P.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2019000603
  271. Biochem Biophys Res Commun. 2020 Jan 15. pii: S0006-291X(20)30031-0. [Epub ahead of print]
    Identification of a selective DDX3X inhibitor with newly developed quantitative high-throughput RNA helicase assays.
    Nakao S, Nogami M, Iwatani M, Imaeda T, Ito M, Tanaka T, Tawada M, Endo S, Cary DR, Ohori M, Imaeda Y, Kawamoto T, Aparicio S, Nakanishi A, Araki S.
      The DEAD-box family of RNA helicases plays essential roles in both transcriptional and translational mRNA degradation; they unwind short double-stranded RNA by breaking the RNA-RNA interactions. Two DEAD-box RNA helicases, eukaryotic translation initiation factor 4A3 (eIF4A3) and DEAD-box helicase 3 (DDX3X), show high homology in the ATP-binding region and are considered key molecules for cancer progression. Several small molecules that target eIF4A3 and DDX3X have been reported to inhibit cancer cell growth; however, more potent compounds are required for cancer therapeutics, and there is a critical need for high-throughput assays to screen for RNA helicase inhibitors. In this study, we developed novel fluorescence resonance energy transfer-based high-throughput RNA helicase assays for eIF4A3 and DDX3X. Using these assays, we identified several eIF4A3 allosteric inhibitors whose inhibitory effect on eIF4A3 ATPase showed a strong correlation with inhibitory effect on helicase activity. From 102 compounds that exhibited eIF4A3 ATPase inhibition, we identified a selective DDX3X inhibitor, C1, which showed stronger inhibition of DDX3X than of eIF4A3. Small-molecule helicase inhibitors can be valuable for clarifying the molecular machinery of DEAD-box RNA helicases. The high-throughput quantitative assays established here should facilitate the evaluation of the helicase inhibitory activity of compounds.
    Keywords:  DDX3X; RNA helicase; RNA helicase inhibitor; eIF4A3
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.094
  272. Autophagy. 2020 Jan 22. 1-15
    Loss of HSPA9 induces peroxisomal degradation by increasing pexophagy.
    Jo DS, Park SJ, Kim AK, Park NY, Kim JB, Bae JE, Park HJ, Shin JH, Chang JW, Kim PK, Jung YK, Koh JY, Choe SK, Lee KS, Cho DH.
      Quality control of peroxisomes is essential for cellular homeostasis. However, the mechanism underlying pexophagy is largely unknown. In this study, we identified HSPA9 as a novel pexophagy regulator. Downregulation of HSPA9 increased macroautophagy/autophagy but decreased the number of peroxisomes in vitro and in vivo. The loss of peroxisomes by HSPA9 depletion was attenuated in SQSTM1-deficient cells. In HSPA9-deficient cells, the level of peroxisomal reactive oxygen species (ROS) increased, while inhibition of ROS blocked pexophagy in HeLa and SH-SY5Y cells. Importantly, reconstitution of HSPA9 mutants found in Parkinson disease failed to rescue the loss of peroxisomes, whereas reconstitution with wild type inhibited pexophagy in HSPA9-depleted cells. Knockdown of Hsc70-5 decreased peroxisomes in Drosophila, and the HSPA9 mutants failed to rescue the loss of peroxisomes in Hsc70-5-depleted flies. Taken together, our findings suggest that the loss of HSPA9 enhances peroxisomal degradation by pexophagy.
    Keywords:  Drosophila; HSPA9; Parkinson disease; ROS; peroxisome; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2020.1712812
  273. Biomed Chromatogr. 2020 Jan 22. e4795
    Non-targeted urine metabolomics analysis the protective and therapeutic effects of Citri Reticulatae Chachiensis Pericarpium on high-fat feed induced hyperlipidemia in rats.
    Zeng W, Huang KE, Luo Y, Li DX, Chen W, Yu XQ, Ke XH.
      In this study, we focused on studying the changes of urine metabolites in hyperlipidemia rats by using ultra performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC-Q-TOF/MS) and Metabolomics, as well as the effect of Citri Reticulatae Chachiensis Pericarpium (CRCP) on hyperlipidemia. These urine samples were examined by UPLC-Q-TOF/MS to obtain MS data. The MS data were analyzed by principal component analysis (PCA) and partial least squares-discriminant analysis (OPLS-DA) to identify the differential metabolites. CRCP could reduce the levels of the body weight, TC, TG, HDL-C and LDL-C of hyperlipidemia rats which were significantly raised by high-fat diet. 27 potential biomarkers were identified within complex sample matrix of urine. Thereinto, 14 biomarkers increased in the rats of hyperlipidemia Compared to the normal rats. Meanwhile, 13 biomarkers decreased. The CRCP could reverse the abnormal changes of the biomarkers, including 5-L-Glutamyl-taurine, 5-aminopentanoic acid, cis-4-Octenedioic acid and 2-Octenedioic acid. These biomarkers show that hyperlipidemia is related to the metabolic pathways of Taurine and hypotaurine metabolism, Fatty acid biosynthesis and Arginine and proline metabolism. The CRCP mainly prevents hyperlipidemia by intervening these metabolic pathways.
    Keywords:  Citri Reticulatae Chachiensis Pericarpium; Metabolomics; UPLC-Q-TOF/MS; hyperlipidemia; urine
    DOI:  https://doi.org/10.1002/bmc.4795
  274. Cells. 2020 Jan 16. pii: E223. [Epub ahead of print]9(1):
    Zinc Finger Transcription Factor MZF1-A Specific Regulator of Cancer Invasion.
    Brix DM, Bundgaard Clemmensen KK, Kallunki T.
      Over 90% of cancer deaths are due to cancer cells metastasizing into other organs. Invasion is a prerequisite for metastasis formation. Thus, inhibition of invasion can be an efficient way to prevent disease progression in these patients. This could be achieved by targeting the molecules regulating invasion. One of these is an oncogenic transcription factor, Myeloid Zinc Finger 1 (MZF1). Dysregulated transcription factors represent a unique, increasing group of drug targets that are responsible for aberrant gene expression in cancer and are important nodes driving cancer malignancy. Recent studies report of a central involvement of MZF1 in the invasion and metastasis of various solid cancers. In this review, we summarize the research on MZF1 in cancer including its function and role in lysosome-mediated invasion and in the expression of genes involved in epithelial to mesenchymal transition. We also discuss possible means to target it on the basis of the current knowledge of its function in cancer.
    Keywords:  EMT; MZF1; PAK4; SUMOylation; cancer therapy; lysosome; lysosome-mediated invasion; phosphorylation; transcription factor; zinc finger
    DOI:  https://doi.org/10.3390/cells9010223
  275. Cancer Invest. 2020 Jan 24. 1-22
    Discriminant Analysis of Lung Cancer using Nonlinear Clustering of Copy Numbers.
    Kachouie NN, Shutaywi M, Christiani DC.
      Background: Patient survival is not optimal for non-small cell lung cancer (NSCLC) patients, recurrence rate is high, and hence, early detection is crucial to increase the patient's survival. Gene-cancer mapping intends to discover associated genes with cancers and due to advances in high-throughput genotyping, screening for disease loci on a genome-wide scale is now possible. DNA copy numbers can potentially be used to identify cancer from normal cells in early detection of cancer.Methods: We use a nonlinear clustering method, so called kernel K-means to separate cancer from normal samples. Kernel K-means is applied to the copy numbers obtained for each chromosome to cluster 63 paired cancer-blood samples (total of 126 samples) into two groups. Clustering performance is evaluated using true and false positive rates, true and false negative rates, and a nonlinear criterion, normalized mutual information (NMI).Results: Copy numbers of paired cancer-blood samples for 63 non-small cell lung cancer patients are used in this study. Kernel K-means was applied to cluster 126 samples in two groups using copy numbers on each chromosome separately. The clustering results for 22 chromosomes are evaluated and discriminant power of them in identifying cancer is computed. We identified top five and bottom five chromosomes based on their discriminant power.Conclusions: The results reveal high discriminant power of chromosomes 8, 5, 1, 3, and 19 for identifying cancer with the highest sensitivity of 75% yielded by chromosome 5. Bottom 5 chromosomes 9, 6, 4, 13, and 21 show low discriminant power with accuracy of below 54% where true cancer and normal samples are grouped into substantially overlapping groups using copy numbers. This indicates the similarities of copy numbers obtained for cancer and normal samples on these chromosomes.
    Keywords:  Clustering; DNA Copy Numbers; Discriminant Analysis; Kernel K-Means; Lung Cancer; Normalized Mutual Information
    DOI:  https://doi.org/10.1080/07357907.2020.1719501
  276. Br J Nurs. 2020 Jan 23. 29(2): 111-117
    Assessment of cancer-related fatigue among Jordanian patients: a cross-sectional survey.
    Abu-Taha OM, Al Qadire MI, Maharmeh M, Alyami MS.
      BACKGROUND: Cancer-related fatigue (CRF) is considered to be one of the most common symptoms reported by cancer patients. However, little information is available regarding the variables associated with CRF among Jordanian patients.AIMS: To assess the prevalence of CRF and explore its predictors among Jordanian patients.
    METHODS: A cross-sectional survey design was used.
    FINDINGS: Of the 240 patients surveyed, 210 (87.5%) had fatigue at the time of the survey. The total mean fatigue score was 6.2 (SD=1.7) out of a maximum possible score of 10. The results also showed that being unemployed, with longer hospitalisation, low haemoglobin, and having lung cancer seem to predict higher levels of CRF.
    CONCLUSION: Several variables and factors associated with CRF were identified. In response to these results, healthcare providers should pay more attention to CRF, which needs to be assessed on a regular basis and to be managed with the available pharmacological and non-pharmacological interventions.
    Keywords:  Cancer; Cancer-related fatigue; Fatigue; Jordan; Oncology; Palliative care
    DOI:  https://doi.org/10.12968/bjon.2020.29.2.111
  277. Int J Mol Sci. 2020 Jan 22. pii: E735. [Epub ahead of print]21(3):
    Disparate Phenotypes Resulting from Mutations of a Single Histidine in Switch II of Geobacillus stearothermophilus Translation Initiation Factor IF2.
    Tomsic J, Smorlesi A, Caserta E, Giuliodori AM, Pon CL, Gualerzi CO.
      The conserved Histidine 301 in switch II of Geobacillus stearothermophilus IF2 G2 domain was substituted with Ser, Gln, Arg, Leu and Tyr to generate mutants displaying different phenotypes. Overexpression of IF2H301S, IF2H301L and IF2H301Y in cells expressing wtIF2, unlike IF2H301Q and IF2H301R, caused a dominant lethal phenotype, inhibiting in vivo translation and drastically reducing cell viability. All mutants bound GTP but, except for IF2H301Q, were inactive in ribosome-dependent GTPase for different reasons. All mutants promoted 30S initiation complex (30S IC) formation with wild type (wt) efficiency but upon 30S IC association with the 50S subunit, the fMet-tRNA reacted with puromycin to different extents depending upon the IF2 mutant present in the complex (wtIF2 to IF2H301Q > IF2H301R >>> IF2H301S, IF2H301L and IF2H301Y) whereas only fMet-tRNA 30S-bound with IF2H301Q retained some ability to form initiation dipeptide fMet-Phe. Unlike wtIF2, all mutants, regardless of their ability to hydrolyze GTP, displayed higher affinity for the ribosome and failed to dissociate from the ribosomes upon 50S docking to 30S IC. We conclude that different amino acids substitutions of His301 cause different structural alterations of the factor, resulting in disparate phenotypes with no direct correlation existing between GTPase inactivation and IF2 failure to dissociate from ribosomes.
    Keywords:  GTP hydrolysis; IF2 recycling; IF2 structure; protein synthesis; switch II mutations; translation initiation
    DOI:  https://doi.org/10.3390/ijms21030735
  278. Lancet Respir Med. 2020 Jan 17. pii: S2213-2600(20)30008-4. [Epub ahead of print]
    Reducing stigma around smoking would encourage more early lung cancer screening.
    Kirby T.
      
    DOI:  https://doi.org/10.1016/S2213-2600(20)30008-4
  279. J Cell Mol Med. 2020 Jan 22.
    Vitamin B6 inhibits macrophage activation to prevent lipopolysaccharide-induced acute pneumonia in mice.
    Shan MR, Zhou SN, Fu CN, Song JW, Wang XQ, Bai WW, Li P, Song P, Zhu ML, Ma ZM, Liu Z, Xu J, Dong B, Liu C, Guo T, Zhang C, Wang SX.
      Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP-activated protein kinase (AMPK) produces anti-inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin-1 beta (IL-1β), IL-6 and tumour necrosis factor alpha (TNF-α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP-activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose-dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL-1β, IL-6 and TNF-α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS-induced macrophage activation if AMPK was in deficient through siRNA-mediated approaches. Further, the anti-inflammatory effects produced by VitB6 or AICAR in LPS-treated macrophages were abolished in DOK3 gene knockout (DOK3-/- ) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS-induced both systemic inflammation and acute pneumonia in wild-type mice, but not in DOK3-/- mice. VitB6 prevents LPS-induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.
    Keywords:  AMP-activated protein kinase; inflammation; lung; macrophage; vitamin B6
    DOI:  https://doi.org/10.1111/jcmm.14983
  280. Neural Regen Res. 2020 Jul;15(7): 1360-1367
    Temporal changes in the spinal cord transcriptome after peripheral nerve injury.
    Weng J, Li DD, Jiang BG, Yin XF.
      Peripheral nerve injury may trigger changes in mRNA levels in the spinal cord. Finding key mRNAs is important for improving repair after nerve injury. This study aimed to investigate changes in mRNAs in the spinal cord following sciatic nerve injury by transcriptomic analysis. The left sciatic nerve denervation model was established in C57BL/6 mice. The left L4-6 spinal cord segment was obtained at 0, 1, 2, 4 and 8 weeks after severing the sciatic nerve. mRNA expression profiles were generated by RNA sequencing. The sequencing results of spinal cord mRNA at 1, 2, 4, and 8 weeks after severing the sciatic nerve were compared with those at 0 weeks by bioinformatic analysis. We identified 1915 differentially expressed mRNAs in the spinal cord, of which 4, 1909, and 2 were differentially expressed at 1, 4, and 8 weeks after sciatic nerve injury, respectively. Sequencing results indicated that the number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury. These mRNAs were associated with the cellular response to lipid, ATP metabolism, energy coupled proton transmembrane transport, nuclear transcription factor complex, vacuolar proton-transporting V-type ATPase complex, inner mitochondrial membrane protein complex, tau protein binding, NADH dehydrogenase activity and hydrogen ion transmembrane transporter activity. Of these mRNAs, Sgk1, Neurturin and Gpnmb took part in cell growth and development. Pathway analysis showed that these mRNAs were mainly involved in aldosterone-regulated sodium reabsorption, oxidative phosphorylation and collecting duct acid secretion. Functional assessment indicated that these mRNAs were associated with inflammation and cell morphology development. Our findings show that the number and type of spinal cord mRNAs involved in changes at different time points after peripheral nerve injury were different. The number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury. These results provide reference data for finding new targets for the treatment of peripheral nerve injury, and for further gene therapy studies of peripheral nerve injury and repair. The study procedures were approved by the Ethics Committee of the Peking University People's Hospital (approval No. 2017PHC004) on March 5, 2017.
    Keywords:  RNA sequencing; deep sequencing; expression profile; gene therapy; mRNAs; nerve regeneration; peripheral nerve injury; sciatic nerve injury; spinal cord; transcriptome
    DOI:  https://doi.org/10.4103/1673-5374.272618
  281. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19915. [Epub ahead of print]24(1): 230-237
    Effects of lncRNA SNHG20 on proliferation and apoptosis of non-small cell lung cancer cells through Wnt/β-catenin signaling pathway.
    Wang ZX, Zhao Y, Yu Y, Liu N, Zou QX, Liang FH, Cheng KP, Lin FW.
      OBJECTIVE: To investigate the influence of long non-coding ribonucleic acid (lncRNA) small nucleolar host gene 20 (SNHG20) on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) cells through the Wnt/β-catenin signaling pathway.PATIENTS AND METHODS: The human NSCLC cells were cultured and lncRNA SNHG20 was inhibited using si-SNHG20 and overexpressed using SNHG20-OE. Then, flow cytometry was used to detect the apoptotic rate. The targets of lncRNA SNHG20 were detected via dual-luciferase reporter gene assay, and the changes in the protein level were detected via Western blotting.
    RESULTS: LncRNA SNHG20 was highly expressed in the cancer tissues and serum of patients with NSCLC. LncRNA SNHG20 could promote the proliferation and inhibit the apoptosis of NSCLC cells. LncRNA SNHG20 could bind to micro RNA (miR)-197 in a targeted manner. Besides, nuclear translocation of β-catenin was significantly enhanced after transfection of miR-197. After the down-regulation of miR-197 by small interfering RNA (siRNA), the key molecules TCF and LEF1 of the Wnt/β-catenin pathway were significantly down-regulated.
    CONCLUSIONS: LncRNA SNHG20 promotes the proliferation and inhibits the apoptosis of NSCLC cells by targeting miR-197 through the Wnt/β-catenin signaling pathway.
    DOI:  https://doi.org/10.26355/eurrev_202001_19915
  282. Sci Rep. 2020 Jan 22. 10(1): 923
    VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake.
    Ning FC, Jensen N, Mi J, Lindström W, Balan M, Muhl L, Eriksson U, Nilsson I, Nyqvist D.
      Type 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.
    DOI:  https://doi.org/10.1038/s41598-020-57599-2
  283. Cell. 2020 Jan 23. pii: S0092-8674(19)31379-0. [Epub ahead of print]180(2): 278-295.e23
    FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle.
    Cader MZ, de Almeida Rodrigues RP, West JA, Sewell GW, Md-Ibrahim MN, Reikine S, Sirago G, Unger LW, Inglesias-Romero AB, Ramshorn K, Haag LM, Saveljeva S, Ebel JF, Rosenstiel P, Kaneider NC, Lee JC, Lawley TD, Bradley A, Dougan G, Modis Y, Griffin JL, Kaser A.
      Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.
    Keywords:  C13orf31; Crohn's disease; FAMIN; LACC1; Still's disease; immunometabolism; pH homeostasis; purine metabolism; purine nucleotide cycle; redox homeostasis
    DOI:  https://doi.org/10.1016/j.cell.2019.12.017
  284. Gut. 2020 Jan 21. pii: gutjnl-2019-319620. [Epub ahead of print]
    Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery.
    West KA, Kanu C, Maric T, McDonald JAK, Nicholson JK, Li JV, Johnson MR, Holmes E, Savvidou MD.
      OBJECTIVE: Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development.DESIGN: A parallel metabonomic (molecular phenotyping based on proton nuclear magnetic resonance spectroscopy) and gut bacterial (16S ribosomal RNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared with women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed.
    RESULTS: Previous malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p-cresol sulfate, indoxyl sulfate and p-hydroxyphenylacetate), and a shift in the gut microbiota. The urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (p=0.001) and was also elevated in urine of neonates born from these mothers (p=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight.
    CONCLUSION: Metabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.
    Keywords:  colonic bacteria; colonic fermentation; enteric bacterial microflora; gastric surgery; obesity surgery
    DOI:  https://doi.org/10.1136/gutjnl-2019-319620
  285. GE Port J Gastroenterol. 2020 Jan;27(1): 29-32
    A Rare Pancreatic Tail Metastasis from Squamous Cell Lung Carcinoma Diagnosed by EUS-FNB and a Small Review of the Literature.
    Stoupis I, Voudoukis E, Mastorakis E, Kazamias G, Ieromonachou P, Pappas C.
      Differential diagnosis of pancreatic lesions is really challenging, especially when the patient is diagnosed with primary cancer at another site. In this case report, we managed to histologically confirm pancreatic metastasis from squamous cell lung carcinoma, which is a very rare entity, using endoscopic ultrasound fine needle biopsy.
    Keywords:  EUS-FNB; Lung cancer; Pancreatic metastasis; Squamous cell
    DOI:  https://doi.org/10.1159/000497387
  286. PLoS One. 2020 ;15(1): e0227260
    The Brazilian TP53 mutation (R337H) and sarcomas.
    Volc SM, Ramos CRN, Galvão HCR, Felicio PS, Coelho AS, Berardineli GN, Campacci N, Sabato CDS, Abrahao-Machado LF, Santana IVV, Campanella N, Lengert AVH, Vidal DO, Reis RM, Dantas CF, Coelho RC, Boldrini E, Serrano SV, Palmero EI.
      Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.
    DOI:  https://doi.org/10.1371/journal.pone.0227260
  287. Cancers (Basel). 2020 Jan 21. pii: E259. [Epub ahead of print]12(2):
    Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer.
    Gopal Krishnan PD, Golden E, Woodward EA, Pavlos NJ, Blancafort P.
      The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.
    Keywords:  PI3K-AKT-mTOR; Rab GTPase; apoptosis; cancer
    DOI:  https://doi.org/10.3390/cancers12020259
  288. Mini Rev Med Chem. 2020 Jan 22.
    Micro-RNA and the Features of Metabolic Syndrome: A Narrative Review.
    Das S, Mohamed IN, Teoh SL, Thevaraj T, Ku Ahmad Nasir KN, Zawawi A, Salim HH, Zhou DK.
      The incidence of metabolic syndrome (MetS) is one the rise globally. MetS includes a combination of features, i.e. blood glucose impairment, excess abdominal/body fat dyslipidemia and elevated blood pressure. Other than conventional treatment with drugs, the main preventive approaches include lifestyle changes, weight loss, diet control and adequate exercise also prove to be beneficial. MicroRNAs (miRNAs) are small non-coding RNAs that play critical regulatory roles in most biological and pathological processes. In the present review, we discuss various miRNAs which are related to MetS by targeting various organs, including the pancreas, liver, skeletal muscles and adipose tissues. These miRNAs have the effect on insulin production and secretion (miR-9, miR-124a, miR-130a,b, miR152, miR-335, miR-375), insulin resistance (miR-29), adipogenesis (miR-143, miR148a) and lipid metabolism (miR-192). We also discuss the miRNAs as potential biomarkers and future therapeutic targets. This review may be beneficial for molecular biologists and clinicians dealing with MetS.
    Keywords:  Biomarker; Metabolic syndrome; Therapeutic; miRNA
    DOI:  https://doi.org/10.2174/1389557520666200122124445
  289. Br J Radiol. 2020 Jan 23. 20190147
    Chemoradiation and granulocyte-or granulocyte macrophage-colony stimulating factors (G-CSF or GM-CSF): Time to think out of the box?
    Benna M, Guy JB, Bosacki C, Jmour O, Ben Mrad M, Ogorodniitchouk O, Soltani S, Lan M, Daguenet E, Mery B, Sotton S, Magné N, Vallard A.
      Concerns have been raised about potential toxic interactions when colony-stimulating factors (CSFs) and chemoradiation are concurrently performed. In 2006, the ASCO guidelines advised against their concomitant use. Nevertheless, with the development of modern radiotherapy techniques and supportive care, the therapeutic index of combined chemotherapy, radiotherapy and CSFs is worth reassessing. Recent clinical trials testing chemoradiation in lung cancer let investigators free to decide the use of concomitant CSFs or not. No abnormal infield event was reported after the use of modern radiotherapy techniques and concomitant chemotherapy regimens. These elements call for further investigation to set new recommendations in favor of the association of chemoradiation and CSFs. Moreover, radiotherapy could induce anticancer systemic effects mediated by the immune system in vitro and in vivo. With combined CSFs, this effect was reinforced in preclinical and clinical trials introducing innovative radioimmunotherapy models. So far, the association of radiation with CSfs has not been combined with immunotherapy. However, it might play a major role in triggering an immune response against cancer cells, leading to abscopal effects. The present article re-assesses the therapeutic index of the combination CSFs-chemoradiation through an updated review on its safety and efficacy. It also provides a special focus on radioimmunotherapy.
    DOI:  https://doi.org/10.1259/bjr.20190147
  290. Expert Opin Ther Targets. 2020 Jan 23.
    The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease.
    Zou H, Zhu N, Li S.
      Introduction: Dipeptidyl-peptidase-4 (DPP-4) is a surface bound ectopeptidase that is commonly known as CD26 or adenosine deaminase binding protein. DPP-4 is membrane anchored but it can be cleaved by numerous proteases including matrix-metalloproteinases (MMPs). DPP-4 is expressed by endothelial and epithelial cells, the kidney, intestine and cells of the immune system; it has a broad spectrum of biological functions in immune regulation, cancer biology and glucose metabolism.Areas covered: This article sheds light on the functions of DPP-4, the molecular mechanisms that govern its expression, it's role in the pathogenesis of common respiratory illnesses and potential as a therapeutic target.Expert opinion: DPP-4 has a deleterious role in respiratory disease. Its biological functions, key molecular pathways, interactions and associations are slowly being elucidated. Progressing our knowledge of the role of this multi-faceted molecule may yield vital and novel therapies for respiratory diseases such as lung cancer, asthma, and chronic obstructive pulmonary disease (COPD).
    Keywords:  Asthma; Chronic Obstructive Pulmonary Disease (COPD); Cluster Of Differentiation 26 (CD26); Dipeptidyl-Peptidase-4 (DPP-4)
    DOI:  https://doi.org/10.1080/14728222.2020.1721468
  291. PLoS One. 2020 ;15(1): e0228444
    Retraction: Immunoglobulin G Expression in Lung Cancer and Its Effects on Metastasis.
    .
      
    DOI:  https://doi.org/10.1371/journal.pone.0228444
  292. Mol Psychiatry. 2020 Jan 20.
    An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder.
    Pu J, Liu Y, Zhang H, Tian L, Gui S, Yu Y, Chen X, Chen Y, Yang L, Ran Y, Zhong X, Xu S, Song X, Liu L, Zheng P, Wang H, Xie P.
      Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of L-acetylcarnitine, creatinine, L-asparagine, L-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, L-serine, oleic acid, myo-inositol, dodecanoic acid, L-methionine, hypoxanthine, palmitic acid, L-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. L-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of L-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan-kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased L-tryptophan and kynurenic acid levels, and alterations in the tryptophan-kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.
    DOI:  https://doi.org/10.1038/s41380-020-0645-4
  293. South Asian J Cancer. 2020 Jan-Mar;9(1):9(1): 59-61
    Role of Cresp® in the management of chemotherapy-induced anemia in cancer patients: A real-world clinical practice audit.
    Biswas G, Pandey A, Ghadyalpatil N, Lokeshwar N, Thomas B, Ramesh A, Arora Y, Dodagoudar C, Naik V, Joshi A, Ghosh I, Roy R, Kunjahari M, Singh T, Satya PD, Hingmire S, Parikh PM.
      Introduction: Anemia is a common, underestimated problem in cancer patients receiving myelosuppressive chemotherapy and has significant adverse effect on the quality of life and outcome. Darbepoetin has been shown to be effective in this setting, but controversy surrounds it actual use.Methods: We analyzed prospectively collected clinical practice data of patients receiving darbepoetin in a real-world setting for this retrospective audit. Patients with baseline hemoglobin (Hb) of <11 g/dl were included in this analysis. Their medical records were audited using a predetermined 35-point pro forma.
    Results: There were a total of 274 patients with advanced cancer receiving myelosuppressive chemotherapy who had baseline Hb <11 g/dl and who were given darbepoetin. Head-and-neck squamous cell carcinoma, lung cancer, and breast cancer were the most common cancers. Their median baseline Hb was 8.9 g/dl which rose to 11.2 g/dl at the end of commenced therapy, along with improved symptomatology. There were no new toxicities, and only two patients required discontinuation of darbepoetin due to toxicity.
    Conclusion: Darbepoetin is safe and effective in the prevention and management of anemia among patients receiving myelosuppressive chemotherapy.
    Keywords:  Hemoglobin; India; prophylaxis; quality of life; supportive care
    DOI:  https://doi.org/10.4103/sajc.sajc_246_19
  294. Chembiochem. 2020 Jan 21.
    Terminal Alkynes as Raman Probes of α-Synuclein in Solution and in Cells.
    Flynn JD, Gimmen MY, Dean DN, Lacy SM, Lee JC.
      Conformational changes of α-synuclein (α-syn) are central to its biological function and Parkinson's disease pathology. Here, terminal alkynes (homopropargylglycine) were employed as environmentally sensitive Raman probes at residues 1, 5, 116, and 127, to characterize soluble (disordered), micelle-bound (α-helical), and fibrillar (β-sheet) α-syn. Along with the full-length protein, a disease-related C-terminal truncation (1-115) was also studied. For the first time, β-sheet α-syn amyloid structure was detected by the amide-I band in N27 dopaminergic rat cells, where a reciprocal relationship between levels of fibrils and lipids was seen. Site-specific spectral features of the terminal alkynes also revealed heterogeneity of the cellular environment. This work shows the versatility of Raman microspectroscopy and the power of unnatural amino acids in providing structural and residue-level insights in solution and in cells.
    Keywords:  C-terminal truncations; Parkinson's disease; Raman spectroscopy; amyloid; homopropargylglycine
    DOI:  https://doi.org/10.1002/cbic.202000026
  295. Support Care Cancer. 2020 Jan 24.
    Pain, fatigue and depression symptom cluster in survivors of prostate cancer.
    Baden M, Lu L, Drummond FJ, Gavin A, Sharp L.
      PURPOSE: Pain, fatigue and depression are common sequelae of a cancer diagnosis. The extent to which these occur together in prostate cancer survivors is unknown. We (i) investigated prevalence of the pain-fatigue-depression symptom cluster and (ii) identified factors associated with experiencing the symptom cluster among prostate cancer survivors.METHODS: Men in Ireland diagnosed with prostate cancer 2-18 years previously were identified from population-based cancer registries and sent postal questionnaires. Cancer-related pain and fatigue were measured using the EORTC QLQ-C30 and depression using the DASS-21. Cut-offs to define 'caseness' were pain ≥ 25, fatigue ≥ 39 and depression ≥ 10. Associations between survivor-related factors, clinical variables and specific prostate cancer physical symptoms and the symptom cluster were assessed using multivariate logistic regression.
    RESULTS: A total of 3348 men participated (response rate = 54%). Twenty-four percent had clinically significant pain, 19.7% had clinically significant fatigue, and 14.4% had depression; 7.3% had all three symptoms. In multivariate analysis, factors significantly associated with the symptom cluster were living in Northern Ireland, experiencing back pain at diagnosis and being affected by incontinence, loss of sexual desire, bowel problems, gynecomastia and hot flashes post-treatment. There was a strong association between the cluster and health-related quality of life.
    CONCLUSIONS: The pain-fatigue-depression symptom cluster is present in 1 in 13 prostate cancer survivors. Physical after-effects of prostate cancer treatment are associated with this cluster. More attention should be paid to identifying and supporting survivors who experience multiple symptoms; this may help health-related quality of life improve among the growing population of prostate cancer survivors.
    Keywords:  Depression; Fatigue; Pain; Prostate cancer; Symptom cluster
    DOI:  https://doi.org/10.1007/s00520-019-05268-0
  296. Cancer Med. 2020 Jan 20.
    Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.
    Dilly A, Honick BD, Lee YJ, Bartlett DL, Choudry HA.
      Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co-therapy. Co-treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)-induced synergistic cytotoxicity and intrinsic mitochondrial-mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)-associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock-down assays demonstrated that mitochondrial-mediated apoptosis in LS174T cells was not ERS-dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post-translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient-derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK-PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co-treatment based on their unique phenotypic and genotypic characteristics.
    Keywords:  MUC2; mucinous colon/appendix cancer; MEK; PI3K; colonoids; xenograft
    DOI:  https://doi.org/10.1002/cam4.2847
  297. Elife. 2020 Jan 20. pii: e50770. [Epub ahead of print]9
    YAP1 and TAZ negatively control bone angiogenesis by limiting hypoxia-inducible factor signaling in endothelial cells.
    Sivaraj KK, Dharmalingam B, Mohanakrishnan V, Jeong HW, Kato K, Schröder S, Adams S, Koh GY, Adams RH.
      Blood vessels are integrated into different organ environments with distinct properties and physiology (Augustin and Koh, 2017). A striking example of organ-specific specialization is the bone vasculature where certain molecular signals yield the opposite effect as in other tissues (Glomski et al., 2011; Kusumbe et al., 2014; Ramasamy et al., 2014). Here, we show that the transcriptional coregulators Yap1 and Taz, components of the Hippo pathway, suppress vascular growth in the hypoxic microenvironment of bone, in contrast to their pro-angiogenic role in other organs. Likewise, the kinase Lats2, which limits Yap1/Taz activity, is essential for bone angiogenesis but dispensable in organs with lower levels of hypoxia. With mouse genetics, RNA sequencing, biochemistry, and cell culture experiments, we show that Yap1/Taz constrain hypoxia-inducible factor 1α (HIF1α) target gene expression in vivo and in vitro. We propose that crosstalk between Yap1/Taz and HIF1α controls angiogenesis depending on the level of tissue hypoxia, resulting in organ-specific biological responses.
    Keywords:  Hippo signaling; angiogenesis; bone; cell biology; developmental biology; endothelial cells; hypoxia; mouse
    DOI:  https://doi.org/10.7554/eLife.50770
  298. Autophagy. 2020 Jan 23.
    Atg11 is required for initiation of glucose starvation-induced autophagy.
    Yao W, Li Y, Wu L, Wu C, Zhang Y, Liu J, He Z, Wu X, Lu C, Wang L, Zhong H, Hong Z, Xu S, Liu W, Yi C.
      How energy deprivation induces macroautophagy/autophagy is not fully understood. Here, we show that Atg11, a receptor protein for cargo recognition in selective autophagy, is required for the initiation of glucose starvation-induced autophagy. Upon glucose starvation, Atg11 facilitates the interaction between Snf1 and Atg1, thus is required for Snf1-dependent Atg1 activation. Phagophore assembly site (PAS) formation requires Atg11 via its control of the association of Atg17 with Atg29-Atg31. The binding of Atg11 with Atg9 is crucial for recruiting Atg9 vesicles to the PAS and, thus, glucose starvation-induced autophagy. We propose Atg11 as a key initiation factor controlling multiple key steps in energy deprivation-induced autophagy.
    Keywords:  Atg11; Atg9; PAS; Snf1; glucose starvation-induced autophagy
    DOI:  https://doi.org/10.1080/15548627.2020.1719724
  299. J Pediatr Endocrinol Metab. 2020 Jan 18. pii: /j/jpem.ahead-of-print/jpem-2019-0329/jpem-2019-0329.xml. [Epub ahead of print]
    Novel associations of serum adropin and lipopolysaccharide-binding protein versus lipid profiles in childhood obesity.
    Yuan X, Chen R, Ouyang Q, Lin X, Ai Z, Zhang Y, Yang X.
      Background The relationship between cytokines and lipid metabolism has garnered attention given their potential metabolic interaction. However, the relationship between adropin and lipopolysaccharide-binding protein (LBP) and obesity-related inflammation has not been reported, as well as their relationship with serum lipid profiles. Objective This study analyzed the association of serum adropin, leptin, LBP levels and lipid profiles in obese children ranging from 5 to 14 years old. Methods Plasma lipid measurements included total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) by standard methods, and serum adropin, leptin and LBP levels was measured by enzyme-linked immunosorbent assay (ELISA). Results One hundred and twenty-four children (9.25 ± 1.59 years) with obesity and 42 controls (8.81 ± 1.94 years) were assessed. Compared with the control group, the serum adropin concentrations in the obesity group were significantly lower, whereas the serum leptin and LBP levels were significantly higher. Pearson's correlation analysis showed that serum adropin levels negatively correlated with TG, waist to hip ratio (WHR) and body mass index (BMI), and positively correlated with HDL-c. Serum LBP levels positively correlated with LDL-c and WHR. After adjusting for LBP, the correlation coefficients of adropin with TG, HDL-c and leptin were more robust. Also, after adjusting for serum LBP, the correlation coefficient of leptin with TG was attenuated, yet remained statistically significant, and the correlation coefficient of leptin with HDL-c was enhanced. Conclusions Children with obesity have decreased serum adropin levels and elevated leptin and LBP levels. Each of the three serum cytokines were associated with lipid metabolism, and this association warrants further study.
    Keywords:  adropin; children; lipid characteristics; lipopolysaccharide-binding protein; obesity
    DOI:  https://doi.org/10.1515/jpem-2019-0329
  300. Food Res Int. 2020 Feb;pii: S0963-9969(19)30682-9. [Epub ahead of print]128 108796
    Metabolic analysis of salicylic acid-induced chilling tolerance of banana using NMR.
    Chen L, Zhao X, Wu J, He Y, Yang H.
      Banana is highly susceptible to low temperature and salicylic acid (SA) can effectively improve the chilling tolerance. The metabolic changes of SA induced chilling responses of banana were studied. Bananas normally ripened under 15 °C and dramatic metabolic difference compared with other groups was recorded. Accumulation of glucose (>1.5 folds) and consumption of unsaturated fatty acids (11.0-16.5%) were observed. The glycolysis was induced to compensate the decreased energy charge. Low temperature (6 °C) caused chilling damage and metabolites including glutamine, serine, and glucose were related to chilled bananas. Various physiological changes such as sugar metabolism and consumption of reducing substances occurred to adapt the cold stress. SA released the cold injury and the disaccharides were increased by 18.1-21.4%. Further analysis revealed the synthesis of unsaturated fatty acids, amino acids such as proline, and enhanced energy charge. Thus, SA increased the chilling tolerance via a number of different metabolic mechanisms.
    Keywords:  Cold injury; Energy status; Fruit; Metabolomics; Omics; Pathway; Principal component analysis; Salicylic acid
    DOI:  https://doi.org/10.1016/j.foodres.2019.108796
  301. J Diabetes Res. 2019 ;2019 4875421
    Scutellarin Prevents Angiogenesis in Diabetic Retinopathy by Downregulating VEGF/ERK/FAK/Src Pathway Signaling.
    Long L, Li Y, Yu S, Li X, Hu Y, Long T, Wang L, Li W, Ye X, Ke Z, Xiao H.
      Background: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. This study demonstrates the antiangiogenic effects of scutellarin (SCU) on high glucose- and hypoxia-stimulated human retinal endothelial cells (HRECs) and on a diabetic rat model by oral administration. The antiangiogenic mechanisms of SCU in vitro and in vivo were investigated.Method: HRECs were cultured in high glucose- (30 mM D-glucose) and hypoxia (cobalt chloride-treated)-stimulated diabetic condition to evaluate the antiangiogenic effects of SCU by CCK-8 test, cell migration experiment (wound healing and transwell), and tube formation experiment. A streptozotocin-induced type II diabetic rat model was established to measure the effects of oral administration of SCU on protecting retinal microvascular dysfunction by Doppler waveforms and HE staining. We further used western blot, luciferase reporter assay, and immunofluorescence staining to study the antiangiogenic mechanism of SCU. The protein levels of phospho-ERK, phospho-FAK, phospho-Src, VEGF, and PEDF were examined in HRECs and retina of diabetic rats.
    Result: Our results indicated that SCU attenuated diabetes-induced HREC proliferation, migration, and tube formation and decreased neovascularization and resistive index in the retina of diabetic rats by oral administration. SCU suppressed the crosstalk of phospho-ERK, phospho-FAK, phospho-Src, and VEGF in vivo and in vitro.
    Conclusions: These results suggested that SCU can be an oral drug to alleviate microvascular dysfunction of DR and exerts its antiangiogenic effects by inhibiting the expression of the crosstalk of VEGF, p-ERK, p-FAK, and p-Src.
    DOI:  https://doi.org/10.1155/2019/4875421
  302. Antioxid Redox Signal. 2020 Jan 22.
    Mitophagy and its contribution to metabolic and aging associated disorders.
    Liu L, Liao X, Wu H, Li Y, Zhu Y, Chen Q.
      Mitochondria are the cellular powerhouses for ATP synthesis through oxidative phosphorylation (OXPHOS), and the centers for fatty acid β-oxidation, metabolite synthesis, ROS production, innate immunity and apoptosis. To fulfill these critical functions, mitochondrial quality and homeostasis must be well maintained to avoid potential damage to the cell. Abnormal mitochondrial quality contributes to aging and age-related disorders, such as metabolic syndrome, cancers and neurodegenerative diseases. Mitophagy is a cellular process that selectively removes damaged or superfluous mitochondria by autolysosomal degradation and is regarded as one of the major mechanisms responsible for mitochondrial quality control. To date, distinct mitophagy pathways have been discovered, including receptor-mediated mitophagy and ubiquitin-dependent mitophagy, of which the PINK1/Parkin-dependent mechanism is the best characterized to date. Emerging knowledge of these pathways shows that they play important roles in sensing mitochondrial stress and signaling for metabolic adaptations. Here, we provide a review on the molecular mechanisms for mitophagy and its interplay with cellular metabolism, with a particular focus on its role in metabolic and aging related disorders.
    DOI:  https://doi.org/10.1089/ars.2019.8013
  303. Nat Immunol. 2020 Feb;21(2): 221-231
    Transcriptomic and epigenetic mechanisms underlying myeloid diversity in the lung.
    Sajti E, Link VM, Ouyang Z, Spann NJ, Westin E, Romanoski CE, Fonseca GJ, Prince LS, Glass CK.
      The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.
    DOI:  https://doi.org/10.1038/s41590-019-0582-z
  304. Biosci Rep. 2020 Jan 22. pii: BSR20193524. [Epub ahead of print]
    The pro- and anti-cancer effects of oxycodone are associated with epithelial growth factor receptor level in cancer cells.
    Yu Y, Li D, Duan J, Xu H, Li L, Tan D, Yan H.
      BACKGROUND: Oxycodone is an opioid medication used for the treatment of pain in cancer patients. However, little is known on the direct effects of oxycodone on cancer cells.AIM: To determine the effects and mechanisms of oxycodone in cancer cells.
    MATERIALS AND METHODS: Proliferation, survival and migration assays were performed on multiple types of cancer cells. Epithelial growth factor receptor (EGFR)/ERK/Akt pathway and oxidative stress were investigated after oxycodone treatment.
    RESULTS: Oxycodone can either stimulates growth and migration without affecting survival in MDA-468 cells or inhibits growth and survival without affecting migration in SKBR3 and Caco2 cells. In addition, oxycodone can either attenuate or stimulate efficacy of chemotherapeutic drugs in cancer, depending on the type of cancer cells and nature of action of oxycodone as single drug alone. Our mechanism studies suggest that the stimulatory and inhibitory effects of oxycodone are associated with EGFR expression levels in cancer cells. In cancer cells with high EGFR level, oxycodone activates EGFR signaling in cancer cells, leading to stimulatory effects in multiple biological activities, and this is dependent on opioid receptor. In cancer cells with low EGFR level, oxycodone induces mitochondria-mediated caspase activity and oxidative stress and damage, leading to cell death.
    CONCLUSIONS: Our work is the first to demonstrate systematic analysis of oxycodone's effects and mechanism of action in cancer. The activation of EGFR signaling by oxycodone may provide a new guide in the clinical use of oxycodone, in particular for cancer patients with high EGFR levels.
    Keywords:  EGFR; cancer; opioids receptor; oxidative stress; oxycodone
    DOI:  https://doi.org/10.1042/BSR20193524
  305. J Dairy Sci. 2020 Jan 15. pii: S0022-0302(20)30025-4. [Epub ahead of print]
    Postruminal infusions of amino acids or glucose affect metabolisms of splanchnic, mammary, and other peripheral tissues and drive amino acid use in dairy cows.
    Omphalius C, Lemosquet S, Ouellet DR, Bahloul L, Lapierre H.
      Effects of AA and glucose infusions on efficiency of use of essential AA (EAA) were studied according to a 2 × 2 factorial using 5 multicatheterized cows in a 4 × 4 Latin square plus one cow, with 2-wk periods. The diet provided 87% of energy and 70% of metabolizable protein requirements, and the 4 treatments were abomasal infusions of (1) water, (2) an AA mixture with a casein profile (695 g/d), (3) glucose (1,454 g/d), or (4) a combination of AA and glucose infusions. Milk samples were collected on the last 6 milkings. On d 14, 6 blood samples were collected from arterial, and portal, hepatic, and mammary venous vessels. Splanchnic plasma flow was calculated by dilution of p-aminohippurate and mammary flow by the Fick principle using Phe + Tyr. The net flux of AA across tissues [splanchnic, i.e., portal drained viscera (PDV) + liver, and mammary gland] was calculated as the efflux minus the influx across that tissue. The efficiency of EAA was calculated as the sum of exported true proteins [milk protein yield (MPY), scurf, and metabolic fecal protein] multiplied by their respective AA profile and divided by the predicted AA supply minus AA endogenous urinary loss. In addition, catabolism was estimated for each tissue: AA supply - (portal net flux + metabolic fecal protein) for the PDV; -hepatic net flux for the liver; splanchnic net flux - (-mammary net flux + scurf) for the other peripheral tissues; and -mammary net flux - milk for the mammary gland. The MIXED procedure (SAS Institute Inc., Cary, NC) was used with cow as a random effect. No AA × glucose interaction existed for most of the measured parameters. With infusions of AA and glucose, MPY increased by 17 and 14%, respectively. The decreased efficiency of EAA-N with AA infusion resulted from increased EAA-N in MPY smaller than the increased EAA-N supply and was accompanied by increased liver catabolism of His + Met + Phe (representing group 1 AA) and increased mammary and PDV catabolisms of group 2 AA-N (Ile, Leu, Lys, and Val). In contrast, the increased efficiency of EAA-N with glucose infusion, resulting from increased EAA-N in MPY with no change in EAA-N supply, was accompanied by decreased mammary catabolism of group 2 AA-N and hepatic catabolism of His + Met + Phe. No mammary catabolism of His, Met, and Phe existed in all treatments, as indicated by the mammary uptake to milk output ratio close to one for these EAA. Therefore, the mammary gland contributes significantly to variations of efficiency of group 2 AA-N through variations of AA catabolism, in response to both AA and glucose supplies, whereas additional PDV catabolism was observed with increased AA supply. Partition of AA use between tissues allows to delineate their anabolic or catabolic fate across tissues and better understand changes of efficiency of EAA in response to protein and energy supplies.
    Keywords:  catabolism; efficiency; energy; net flux; protein
    DOI:  https://doi.org/10.3168/jds.2019-17249
  306. Sci Rep. 2020 Jan 23. 10(1): 1309
    Author Correction: Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells.
    Hung JJ, Kao YS, Huang CH, Hsu WH.
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    DOI:  https://doi.org/10.1038/s41598-020-57957-0
  307. Rheumatol Int. 2020 Jan 20.
    Is biological therapy in systemic sclerosis the answer?
    Misra DP, Ahmed S, Agarwal V.
      Systemic sclerosis is a systemic fibrosing disorder associated with significant morbidity and mortality, with no universally accepted disease-modifying therapy. Significant advances in the understanding of systemic sclerosis in recent years have guided the exploration of biological drugs in systemic sclerosis. In this narrative review, we summarize the published literature on biologic therapies in systemic sclerosis. A double-blind randomized trial, and an open label trial of tocilizumab (which antagonizes the interleukin 6 receptor), identified potential benefits in skin and lung fibrosis in systemic sclerosis; however, these differences failed to attain statistical significance. Two open-label trials compared rituximab (which depletes B lymphocytes) to conventional treatment/ cyclophosphamide in systemic sclerosis-associated interstitial lung disease (ILD), and revealed significant improvements in lung functions and skin disease with rituximab. Significant observational data also support the use of rituximab in skin, lung, muscle and joint manifestations of systemic sclerosis. Abatacept (which blocks T lymphocyte activation) has demonstrated utility for skin and joint disease in systemic sclerosis; a recent clinical trial failed to demonstrate benefits in improving skin thickness compared to placebo. Agents targeting type I interferons, interleukin 17 pathway, CD19 and plasma cells hold promise in systemic sclerosis; however, high-quality evidence is lacking. The results of different ongoing clinical trials targeting B lymphocytes, T lymphocytes, various cytokines (interleukins 6, 17, 4, 13, IL-1α), platelet-derived growth factor receptor, proteasome, integrins or oncostatin M may help guide future therapeutic regimens with biological agents in systemic sclerosis.
    Keywords:  B lymphocyte; Biological therapy; Interleukin 17; Interleukin 6; Rituximab; Scleroderma
    DOI:  https://doi.org/10.1007/s00296-020-04515-6
  308. Cancers (Basel). 2020 Jan 19. pii: E244. [Epub ahead of print]12(1):
    Resistance to MET/VEGFR2 Inhibition by Cabozantinib Is Mediated by YAP/TBX5-Dependent Induction of FGFR1 in Castration-Resistant Prostate Cancer.
    Koinis F, Corn P, Parikh N, Song J, Vardaki I, Mourkioti I, Lin SH, Logothetis C, Panaretakis T, Gallick G.
      The overall goal of this study was to elucidate the role of FGFR1 induction in acquired resistance to MET and VEGFR2 inhibition by cabozantinib in prostate cancer (PCa) and leverage this understanding to improve therapy outcomes. The response to cabozantinib was examined in mice bearing patient-derived xenografts in which FGFR1 was overexpressed. Using a variety of cell models that reflect different PCa disease states, the mechanism underpinning FGFR1 signaling activation by cabozantinib was investigated. We performed parallel investigations in specimens from cabozantinib-treated patients to confirm our in vitro and in vivo data. FGFR1 overexpression was sufficient to confer resistance to cabozantinib. Our results demonstrate transcriptional activation of FGF/FGFR1 expression in cabozantinib-resistant models. Further analysis of molecular pathways identified a YAP/TBX5-driven mechanism of FGFR1 and FGF overexpression induced by MET inhibition. Importantly, knockdown of YAP and TBX5 led to decreased FGFR1 protein expression and decreased mRNA levels of FGFR1, FGF1, and FGF2. This association was confirmed in a cohort of hormone-naïve patients with PCa receiving androgen deprivation therapy and cabozantinib, further validating our findings. These findings reveal that the molecular basis of resistance to MET inhibition in PCa is FGFR1 activation through a YAP/TBX5-dependent mechanism. YAP and its downstream target TBX5 represent a crucial mediator in acquired resistance to MET inhibitors. Thus, our studies provide insight into the mechanism of acquired resistance and will guide future development of clinical trials with MET inhibitors.
    Keywords:  FGFR1; TBX5; YAP; c-MET; cabozantinib; prostate cancer; resistance
    DOI:  https://doi.org/10.3390/cancers12010244
  309. Front Pharmacol. 2019 ;10 1503
    Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells.
    Si Y, Wang J, Liu X, Zhou T, Xiang Y, Zhang T, Wang X, Feng T, Xu L, Yu Q, Zhao H, Liu Y.
      Ethoxysanguinarine (Eth) is a benzophenanthridine alkaloid extracted from Macleaya cordata (Willd) R. Br. It possesses antibacterial and antiviral activities and offers therapeutic benefits for the treatment of respiratory syndrome virus-induced cytopathic effects. However, the effect of Eth on human tumors and its pharmacological effects remain to be elucidated, together with its cellular target. Here, we examined the effects of Eth on breast cancer (BC) cells. We found that at low doses, Eth strongly inhibited the viability of BC cell lines and induced autophagy. Mechanistic studies showed that Eth induced autophagy by upregulating the activity of the AMP-activated protein kinase (AMPK). The AMPK inhibitor compound C significantly attenuated Eth-induced autophagy and inhibited proliferation. Meanwhile, the AMPK activator metformin significantly enhanced Eth-induced autophagy and inhibited proliferation. Computational docking and affinity assays showed that Eth directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. AMPK was less activated in tumor samples compared to normal breast tissues and was inversely associated with the prognosis of the patients. Moreover, Eth exhibited potent anti-BC activity in nude mice and favorable pharmacokinetics in rats. These characteristics render Eth as a promising candidate drug for further development and for designing new effective AMPK activators.
    Keywords:  AMP-activated protein kinase; autophagy; breast cancer; ethoxysanguinarine; molecular docking; pharmacokinetic
    DOI:  https://doi.org/10.3389/fphar.2019.01503
  310. J Assoc Physicians India. 2020 Jan;68(1): 82
    Association of Serum Ferritin Levels with Smoking and Lung Function in COPD Patients of Tertiary Care Center: Mysuru.
    N T, Mg M.
      
  311. Sci Signal. 2020 Jan 21. pii: eaba1302. [Epub ahead of print]13(615):
    Genetic basis of oxygen sensing in the carotid body: HIF2α and an isoform switch in cytochrome c oxidase subunit 4.
    Bishop T, Ratcliffe PJ.
      The mechanistic basis of the marked oxygen sensitivity of glomus cells in the carotid body has long puzzled physiologists. In this issue of Science Signaling, Moreno-Domínguez et al. show the critical importance of high levels of hypoxia-inducible factor, HIF2α/EPAS1, and the nuclear-encoded mitochondrial cytochrome c oxidase subunit, COX4I2, in glomus cell sensitivity to hypoxia.
    DOI:  https://doi.org/10.1126/scisignal.aba1302
  312. J Mol Endocrinol. 2020 Jan 01. pii: JME-19-0235.R2. [Epub ahead of print]
    Glucocorticoid Signalling Drives Reduced Versican Levels in the Fetal Mouse Lung.
    Short KL, Bird AD, Seow BKL, Ng J, McDougall ARA, Wallace M, Hooper SB, Cole T.
      Glucocorticoid (GC) signalling via the glucocorticoid receptor (GR) is essential for lung maturation in mammals. Previous studies using global or conditional mouse model knockouts of the GR gene have established that GR-mediated signalling in the interstitial mesenchyme of the fetal lung is critical for normal lung development. Screens for downstream GC-targets in conditional mesenchymal GR deficient mouse lung (GRmesKO) identified Versican (Vcan), an important extracellular matrix component and cell proliferation regulator, as a potential GR-regulated target. We show that of the five major VCAN isoforms, the VCAN-V1 isoform, containing the GAG domain is the predominant VCAN isoform in the fetal mouse lung distal mesenchyme at both E16.5 and E18.5, whereas the GAG-specific VCAN-V2 isoform was only localized to the smooth muscle surrounding proximal airways. Both Vcan-V1 mRNA and protein levels were strongly overexpressed in the GRmesKO lung at E18.5. Finally, we investigated the GC regulation of the ECM protease ADAMTS 12 and show that Adamts 12 mRNA levels were markedly reduced at E18.5 in GRmesKO fetal mouse lung and were strongly induced by both cortisol and betamethasone in cultures of primary rat fetal lung fibroblasts. ADAMTS12 protein immunoreactivity was also strongly increased in the distal lung at E18.5 following dexamethasone treatment in utero. In summary, glucocorticoid signalling via GR represses GAG domain-containing VCAN isoforms in distal lung mesenchyme in vivo by repressing Vcan gene expression and in part by induction of the ECM protease ADAMTS12, thereby contributing to the control of ECM remodelling and lung cell proliferation prior to birth.
    DOI:  https://doi.org/10.1530/JME-19-0235
  313. Toxicol In Vitro. 2020 Jan 18. pii: S0887-2333(19)30800-8. [Epub ahead of print] 104777
    Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells.
    Siqueira RP, Caetano MMM, de Souza LÂ, Dos Passos PMS, Simaroli NB, Barros MVA, de Souza APM, de Oliveira LL, Júnior AS, Fietto JLR, Teixeira RR, Teixeira FR, Bressan GC.
      The serine/arginine protein kinases respond to the EGFR-PI3K-AKT signaling module in the context of pre-mRNA alternative splicing regulation. These enzymes (notably SRPK1 and SRPK2) have been found dysregulated in a variety of cancers, which suggests them as promising drug targets in oncology. SRPK2 has been related to leukemia cells proliferation and found preferentially overexpressed in T-cell acute lymphoblastic leukemia (T-ALL). Previously, synergistic combination between vincristine and SRPK inhibitors has been observed in leukemia cells in vitro. Herein we sought to evaluate the in vitro combinatory effects of inhibiting SRPK and multiple other kinase targets from the EGFR pathway in T-ALL, a hematological malignancy with a still poor prognosis. We found that the combined SRPK and AKT pharmacological inhibition is synergistic in Jurkat, CCRF-CEM, and TALL-1 (all T-ALL) but not in HL60, an acute myelogenous leukemia cell lineage. Combined treatments also impaired SR proteins phosphorylation in accordance with an improved suppression of SRPK activity. Furthermore, the synergism of treatments seemed associated with apoptosis triggering, as revealed by flow cytometry analyses. Taken together, these results suggest the therapeutic potential of the combined SRPK and AKT pharmacological inhibition against T-ALL.
    Keywords:  AKT inhibitor; GSK-699603; Jurkat; Lymphoblastic leukemia; SRPIN340; SRPK inhibitor
    DOI:  https://doi.org/10.1016/j.tiv.2020.104777
  314. Antioxidants (Basel). 2020 Jan 19. pii: E83. [Epub ahead of print]9(1):
    Cytoprotective Effects of Delphinidin for Human Chondrocytes against Oxidative Stress through Activation of Autophagy.
    Lee DY, Park YJ, Song MG, Kim DR, Zada S, Kim DH.
      Antioxidant enzymes are decreased in osteoarthritis (OA) patients, implying the role of oxidative stress in osteoarthritis pathogenesis. The aim of this study was to evaluate the cytoprotective effects of delphinidin, a potent antioxidant, in human chondrocytes and the underlying mechanisms. The cytoprotective mechanism induced by delphinidin against oxidative stress (H2O2) in human chondrocytes was investigated. Cell viability and death were evaluated using proapoptotic and antiapoptotic markers such as cleaved caspase-3 (c-caspase-3), cleaved poly(ADP-ribose) polymerase N-acetylcysteine (c-PARP), Bcl-XL, and transcription factors associated with redox and inflammation regulation, including nuclear factor kappa B (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Induction of autophagy was assessed by formation of LC3-II and autophagosome-(LC3 punctate, monodansylcadaverine (MDC) and acridine orange staining) in the presence or absence of an autophagy inhibitor. Treatment with delphinidin itself at concentration below 50 µM for 24 h did not affect viability of chondrocytes. Delphinidin inhibited reactive oxygen species (ROS)-induced apoptosis by significantly decreasing apoptosis markers such as c-caspase-3 and c-PARP while increasing antiapoptotic marker Bcl-XL and antioxidant response NF-κB and Nrf2 pathways. Delphinidin also activated cytoprotective autophagy to protect chondrocytes during oxidative stresses. Activation of autophagy with autophagy inducer rapamycin also inhibited ROS-induced cell death and decreased proapoptotic proteins but increased antiapoptotic protein Bcl-XL, NF-κB, and Nrf2. Delphinidin can protect chondrocytes against H2O2-induced apoptosis via activation of Nrf2 and NF-κB and protective autophagy. Thus, it can inhibit OA with protection of chondrocytes. Delphinidin can protect chondrocytes against H2O2-induced ROS with maintenance of homeostasis and redox. These results suggest that delphinidin could be used to protect chondrocytes against age-related oxidative stress and other oxidative stresses in the treatment of OA. Thus, delphinidin may play a critical role in preventing the development and progression of OA.
    Keywords:  Nrf2; apoptosis; autophagy; delphinidin; osteoarthritis; oxidative stress
    DOI:  https://doi.org/10.3390/antiox9010083
  315. Biotechnol Bioeng. 2020 Jan 20.
    Overexpression of transcription factor Foxa1 and target genes remediates therapeutic protein production bottlenecks in Chinese hamster ovary cells.
    Berger A, Le Fourn V, Masternak J, Regamey A, Bodenmann I, Mermod N.
      Despite extensive research conducted to increase protein production from Chinese hamster ovary (CHO) cells, cellular bottlenecks often remain, hindering high yields. In this study, a transcriptomic analysis led to the identification of 32 genes that are consistently upregulated in high producer clones, and thus might mediate a high productivity. Candidate genes were associated to functions such as signaling, protein folding, cytoskeleton organization and cell survival. We focused on two engineering targets, Erp27, which binds unfolded proteins and the Erp57 disulfide isomerase in the endoplasmic reticulum, and Foxa1, a pioneering transcription factor involved in organ development. Erp27 moderate overexpression increased production of an easy-to-express antibody, while Erp27 and Erp57 co-overexpression increased cell density, viability, and the yield of difficult-to-express proteins. Foxa1 overexpression increased cell density, cell viability, and easy- and difficult-to-express protein yields, whereas it decreased reactive oxygen species late in fed-batch cultures. Foxa1 overexpression upregulated two other candidate genes that increased the production of difficult- and/or easy-to-express proteins, namely Ca3, involved in protecting cells from oxidative stress, and Tagap, involved in signaling and cytoskeleton remodeling. Overall, several genes allowing to overcome CHO cell bottlenecks were identified, including Foxa1 which mediated multiple favorable metabolic changes that improve therapeutic protein yields. This article is protected by copyright. All rights reserved.
    Keywords:  CHO cells; Foxa1 transcription factor; cell viability; protein folding; recombinant protein production
    DOI:  https://doi.org/10.1002/bit.27274
  316. J Med Food. 2020 Jan 22.
    The Effects of Carob (Ceratonia siliqua L.) on Emotional Behavior Impairment and Metabolic Disorders Induced by Estrogen Deficiency in Rats.
    Ammari M, Othman H, Rtibi K, Sakly M, Abdelmelek H.
      Carob (Ceratonia siliqua L.) contains a wide variety of polyphenols with high antioxidant properties. In this study, we investigated the effects of aqueous extract of carob pods (AECP) on emotional behavior impairments and metabolic disorders in ovariectomized (OVX) rats. Female Wistar rats were assigned to three groups: group 1, control non-OVX rats; group 2, OVX rats; and group 3, OVX rats orally treated with AECP (500 mg/kg) for15 days after ovariectomy. Elevated plus-maze and open-field tests were performed on the 26th and 27th post-ovariectomy days, respectively. Afterwards, the rats were anesthetized and their serums were collected for biochemical analysis. We found that AECP improved emotional behavior impairments revealed by elevated plus-maze and open-field tests in OVX rats. Moreover, ovariectomy significantly increased triglyceride, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels in the serum. AECP administration significantly reversed ovariectomy-induced biochemical alterations. Thus, we suggest that the AECP may have an anxiolytic-like effect and prevent biochemical disorders associated with menopause or ovariectomy.
    Keywords:  anxiety; aqueous extract of carob pods; neuroprotective; ovariectomy; rat
    DOI:  https://doi.org/10.1089/jmf.2019.0187
  317. Biochem Pharmacol. 2020 Jan 20. pii: S0006-2952(20)30025-3. [Epub ahead of print] 113815
    Salvianolic acid B protects against oxLDL-induced endothelial dysfunction under high-glucose conditions by downregulating ROCK1-mediated mitophagy and apoptosis.
    Shin Ko Y, Jin H, Won Park S, Jung Kim H.
      Diabetes is related to alterations in glucose and lipid metabolism, which are linked to endothelial cell (EC) dysfunction. Salvianolic acid B (Sal B), one of the major ingredient of Danshen (Salvia miltiorrhiza), possesses many of the biological activities. However, protective effect of Sal B against oxLDL induced ECs dysfunction under high glucose condition (high Glu) is not well known. Thus, in this study, we investigated the protective effects of Sal B against EC dysfunction induced by oxLDL and high Glu and examined the associated mechanisms. Our results showed that Sal B significantly and dose-dependently decreased oxLDL- and high Glu-mediated induction of lectin-like oxLDL receptor-1 and significantly decreased oxLDL- and high Glu-induced mitochondrial ROS (mtROS) production and mitochondrial DNA (mtDNA) expression. In addition, oxLDL stimulation under high-Glu conditions activated the intrinsic apoptosis pathway in ECs. These effects were abolished by Sal B through reductions in mtROS and mtDNA. Furthermore, Sal B inhibited oxLDL- and high Glu-induced increases in fission protein (p-DRP 1 and FIS 1) levels. OxLDL and high Glu activated the ROCK1 pathway, which is involved in apoptosis and mitophagy, while Sal B significantly reduced ROCK1 protein levels. The protective effects of Sal B against oxLDL- and high Glu-induced endothelial dysfunction may be mediated by reductions in apoptosis-related proteins and fission proteins through suppression of the ROCK1-mediated pathway.
    Keywords:  Salvianolic acid B; apoptosis; endothelial cells; high glucose; mitophagy; oxLDL
    DOI:  https://doi.org/10.1016/j.bcp.2020.113815
  318. Front Pharmacol. 2019 ;10 1485
    Systemic Evaluation on the Pharmacokinetics of Platinum-Based Anticancer Drugs From Animal to Cell Level: Based on Total Platinum and Intact Drugs.
    Qin Z, Ren G, Yuan J, Chen H, Lu Y, Li N, Zhang Y, Chen X, Zhao D.
      Cisplatin, carboplatin, and oxaliplatin are the common platinum-based anticancer drugs widely used in the chemotherapeutic treatment of solid tumors in clinic. However, the comprehensive pharmacokinetics of platinum-based anticancer drugs has not been fully understood yet. This leads to many limitations for the further studies on their pharmacology and toxicology. In this study, we conduct a systemic evaluation on the pharmacokinetics of three platinum analogues at animal and cell levels, with quantification of both total platinum and intact drugs. A detailed animal study to address and compare the different pharmacokinetic behaviors of three platinum analogues has been conducted in three biological matrices: blood, plasma, and ultrafiltrate plasma. Carboplatin showed an obviously different pharmacokinetic characteristic from cisplatin and oxaliplatin. On the one hand, carboplatin has the highest proportion of Pt distribution in ultrafiltrate plasma. On the other hand, carboplatin has the highest intact drug exposure and longest intact drug elimination time in blood, plasma, and ultrafiltrate plasma, which may explain its high hematotoxicity. Additionally, the cellular and subcellular pharmacokinetics of oxaliplatin in two colon cancer HCT-116/LOVO cell lines has been elucidated for the first time. The biotransformation of intact oxaliplatin in cells was rapid with a fast elimination, however, the generated platinum-containing metabolites still exist within cells. The distribution of total platinum in the cytosol is higher than in the mitochondria, followed by the nucleus. Enrichment of platinum in mitochondria may affect the respiratory chain or energy metabolism, and further lead to cell apoptosis, which may indicate mitochondria as another potential target for efficacy and toxicity of oxaliplatin.
    Keywords:  carboplatin; cisplatin; oxaliplatin; pharmacokinetics; total platinum
    DOI:  https://doi.org/10.3389/fphar.2019.01485
  319. Thorax. 2020 Jan 20. pii: thoraxjnl-2019-214076. [Epub ahead of print]
    Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency.
    O'Brien ME, Fee L, Browne N, Carroll TP, Meleady P, Henry M, McQuillan K, Murphy MP, Logan M, McCarthy C, McElvaney OJ, Reeves EP, McElvaney NG.
      INTRODUCTION: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy.METHODS: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5).
    RESULTS: Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001).
    DISCUSSION: Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD.
    Keywords:  alpha1 antitrypsin deficiency; emphysema; rare lung diseases
    DOI:  https://doi.org/10.1136/thoraxjnl-2019-214076
  320. mSystems. 2020 Jan 21. pii: e00770-19. [Epub ahead of print]5(1):
    A Complex Interplay between Nitric Oxide, Quorum Sensing, and the Unique Secondary Metabolite Tundrenone Constitutes the Hypoxia Response in Methylobacter.
    Yu Z, Pesesky M, Zhang L, Huang J, Winkler M, Chistoserdova L.
      Methylobacter species, members of the Methylococcales, have recently emerged as some of the globally widespread, cosmopolitan species that play a key role in the environmental consumption of methane across gradients of dioxygen tensions. In this work, we approached the question of how Methylobacter copes with hypoxia, via laboratory manipulation. Through comparative transcriptomics of cultures grown under high dioxygen partial pressure versus cultures exposed to hypoxia, we identified a gene cluster encoding a hybrid cluster protein along with sensing and regulatory functions. Through mutant analysis, we demonstrated that this gene cluster is involved in the hypoxia stress response. Through additional transcriptomic analyses, we uncovered a complex interconnection between the NO-mediated stress response, quorum sensing, the secondary metabolite tundrenone, and methanol dehydrogenase functions. This novel and complex hypoxia stress response system is so far unique to Methylobacter species, and it may play a role in the environmental fitness of these organisms and in their cosmopolitan environmental distribution.IMPORTANCE Here, we describe a novel and complex hypoxia response system in a methanotrophic bacterium that involves modules of central carbon metabolism, denitrification, quorum sensing, and a secondary metabolite, tundrenone. This intricate stress response system, so far unique to Methylobacter species, may be responsible for the persistence and activity of these species across gradients of dioxygen tensions and for the cosmopolitan distribution of these organisms in freshwater and soil environments in the Northern Hemisphere, including the fast-melting permafrosts.
    Keywords:  Methylobacter tundripaludum ; hybrid cluster protein; hypoxia; nitric oxide; quorum sensing; tundrenone
    DOI:  https://doi.org/10.1128/mSystems.00770-19
  321. Oncogene. 2020 Jan 24.
    Targeting MEK5 impairs nonhomologous end-joining repair and sensitizes prostate cancer to DNA damaging agents.
    Broustas CG, Duval AJ, Chaudhary KR, Friedman RA, Virk RK, Lieberman HB.
      Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that nonhomologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.
    DOI:  https://doi.org/10.1038/s41388-020-1163-1
  322. Exp Gerontol. 2020 Jan 17. pii: S0531-5565(19)30803-4. [Epub ahead of print] 110836
    Cell senescence and fibrotic lung diseases.
    Liu RM, Liu G.
      Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disorder with an unknown etiology and very limited therapeutic options. The incidence and severity of IPF increase with advanced age, suggesting that aging is a major risk factor for IPF. The mechanism underlying the aging-related susceptibility to IPF, however, remains unclear. Cellular senescence, a permanent arrest of cell growth, has been increasingly recognized as an important contributor to aging and aging-related diseases, including IPF. Senescent cells have been identified in IPF lungs and in experimental lung fibrosis models. Removal of senescent cells pharmacologically or genetically improves lung function and reverses pulmonary fibrosis induced by different stimuli in experimental fibrosis models. Treatment with senolytic drugs also improves clinical symptoms in IPF patients. These intriguing findings suggest that cellular senescence contributes importantly to the pathogenesis of fibrotic lung diseases and targeting senescent cells may represent a novel approach for the treatment of fibrotic lung disorders. In this mini review, we summarize the recent advance in the field regarding the role of cellular senescence in fibrotic lung diseases, with a focus on IPF.
    Keywords:  Aging; Cell senescence; Lung fibrosis
    DOI:  https://doi.org/10.1016/j.exger.2020.110836
  323. Asia Pac J Clin Oncol. 2020 Jan 19.
    Cost-effectiveness of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.
    Li W, Bai R, Qian L, Chen N, Zhao Y, Han F, Bai L, Li J, Yu Y, Cui J.
      PURPOSE: Nonsmall cell lung cancer (NSCLC) patients with brain metastases (BM) have a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with whole-brain irradiation (WBI) with or without chemotherapy for NSCLC patients with BM.MATERIALS AND METHODS: A Markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]) from the Chinese healthcare perspective.
    RESULTS: When considering progression as intracranial progression and overall progression, respectively, the incremental cost-effectiveness ratio was $14 882.64/QALY and $13 484.21/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (ACER) and net benefit showed advantage of icotinib (ACER: $34 521.42/QALY for intracranial progression and $36 562.63/QALY for overall progression; net benefit: -$8407.36 for intracranial progression and -$9836.41 for overall progression). One-way sensitivity analyses demonstrated that no thresholds were encountered. The probabilistic sensitivity analyses showed even at a WTP under $18 000/QALY, icotinib could be cost-effective.
    CONCLUSION: Icotinib was cost-effective compared with WBI with or without chemotherapy.
    Keywords:  cost-effectiveness analysis; icotinib; nonsmall cell lung cancer
    DOI:  https://doi.org/10.1111/ajco.13291
  324. Bioorg Chem. 2020 Jan 11. pii: S0045-2068(19)31631-1. [Epub ahead of print]96 103570
    Search for non-acidic ALR2 inhibitors: Evaluation of flavones as targeted agents for the management of diabetic complications.
    Vyas B, Choudhary S, Singh PK, Kumar M, Verma H, Singh M, Malik AK, Silakari O.
      Diabetic complications (DC) follow multiple pathophysiological pathways and one of the key pathways is the polyol pathway which involves the metabolism of glucose via aldose reductase (ALR2) and sorbitol dehydrogenase (SDH). ALR2 inhibitors such as epalrestat has already been established as promising candidates for the management of DC. On the basis of pathophysiological understanding of polyol pathway, simultaneous inhibition of ALR2 and SDH may be expected to provide synergistic outcomes in the treatment strategies for DC. Thus, in this study, dual inhibitors of ALR2 and SDH were identified using pharmacophore-based virtual screening. For this purpose, the pharmacophore model for SDH (model ID: AAADH.343) was generated and validated. For screening against ALR2, the pharmacophore model (model ID: AADRR.1109) which was previously reported by our group was applied. Initially, flavones reported by our research group were screened by those two pharmacophore models to obtain hits with an optimum affinity for the catalytic domain of both ALR2 and SDH. Inhibitory potential of identified hits for ALR2 and SDH were then experimentally determined using enzymatic assays reported in the literature. Additional focus was laid on the selectivity of the designed molecules towards ALR2 over ALR1, thus evaluation against ALR1 was also performed. Overall, four molecules FLV-2, FLV-11, FLV-12, and FLV-15 were found to possess significant dual inhibitory activity against ALR2 and SDH, with selectivity over ALR1. Among them, FLV-2 displayed significant dual inhibitory potential with an IC50 value of 0.689 ± 0.018 µM and 0.174 ± 0.003 µM against ALR2 and SDH respectively with a selectivity index of 52.902 to ALR2 over ALR1.
    Keywords:  Aldose reductase; Flavones; In-silico analysis; Sorbitol dehydrogenase
    DOI:  https://doi.org/10.1016/j.bioorg.2020.103570
  325. Appl Biochem Biotechnol. 2020 Jan 20.
    SNHG3 Functions as miRNA Sponge to Promote Breast Cancer Cells Growth Through the Metabolic Reprogramming.
    Li Y, Zhao Z, Liu W, Li X.
      Cancer-associated fibroblasts (CAFs) are important ingredient in tumor microenvironment. The dynamic interplay between CAFs and cancer cells plays essential roles during tumor development and progression. However, the mechanisms of intercellular communication between CAFs and cancer cells remain largely unknown. We characterized exosomes secreted from breast cancer patient-derived CAFs by transmission electron microscopy. The expression of SNHG3, miR-330-5p, and PKM (Pyruvate Kinase M1/M2) was examined by real-time QPCR and immunoblot. The function of SNHG3 on the growth and metabolism of tumor cells was used by CCK8 and mitochondrial oxygen consumption assays. The binding between SNHG3, miR-330-5p, and PKM was examined by dual luciferase reporter assays. Orthotopical xenograft of breast tumor experiments was performed to determine the function of SNHG3 in vivo. We demonstrated that exosomes secreted from CAFs reprogram the metabolic pathways after tumor cells uptake the exosomes. CAF-secreted exosomal lncRNA SNHG3 served as a molecular sponge for miR-330-5p in breast cancer cells. Moreover, PKM could be targeted by miR-330-5p and was controlled by SNHG3 in breast cancer cells. Mechanistically, SNHG3 knockdown in CAF-secreted exosomes suppressed glycolysis metabolism and cell proliferation by the increase of miR-330-5p and decrease of PKM expression in tumor cells. SNHG3 functions as a miR-330-5p sponge to positively regulate PKM expression, inhibit mitochondrial oxidative phosphorylation, increase glycolysis carboxylation, and enhance breast tumor cell proliferation. Overall, SNHG3 could play a major role in the development and progression of breast cancer and support the therapeutic potential of targeting communication between cancer cells and tumor microenvironment.
    Keywords:  Breast cancer; Cancer-associated; Fibroblasts; Metabolism reprogram; SNHG3; miR-330
    DOI:  https://doi.org/10.1007/s12010-020-03244-7
  326. Respir Res. 2020 Jan 20. 21(1): 28
    The impact of COPD on polyneuropathy: results from the German COPD cohort COSYCONET.
    Kahnert K, Föhrenbach M, Lucke T, Alter P, Trudzinski FT, Bals R, Lutter JI, Timmermann H, Söhler S, Förderreuther S, Nowak D, Watz H, Waschki B, Behr J, Welte T, Vogelmeier CF, Jörres RA.
      BACKGROUND: Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects.METHODS: We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters.
    RESULTS: 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same.
    CONCLUSION: We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.
    Keywords:  Ankle-brachial-index; Base excess; COPD; Peripheral neuropathy
    DOI:  https://doi.org/10.1186/s12931-020-1293-6
  327. Am J Cardiol. 2020 Jan 09. pii: S0002-9149(20)30010-2. [Epub ahead of print]
    Relation of Plasma Xanthine Oxidoreductase Activity to Coronary Lipid Core Plaques Assessed by Near-Infrared Spectroscopy Intravascular Ultrasound in Patients With Stable Coronary Artery Disease.
    Mori N, Saito Y, Saito K, Matsuoka T, Tateishi K, Kadohira T, Kitahara H, Fujimoto Y, Kobayashi Y.
      Previous studies reported that elevated serum uric acid level was associated with greater coronary lipid plaque. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine metabolism and is believed to play important roles in coronary atherosclerosis. However, the relation between XOR and coronary lipid plaque is unclear. Patients with stable coronary artery disease who underwent elective percutaneous coronary intervention under near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) guidance were prospectively included. They were divided into 3 groups according to plasma XOR activities based on a previous report: low, normal, and high. Quantitative coronary angiography and gray-scale IVUS were analyzed. The primary end point was coronary lipid plaques in a nontarget vessel assessed by NIRS-IVUS with lipid core burden index (LCBI) and maximum LCBI in 4 mm (maxLCBI4mm). Out of 68 patients, 26, 31, and 11 patients were classified as low, normal, and high XOR activity groups. Quantitative coronary angiography demonstrated that the high XOR activity group had longer lesion length, smaller minimum lumen diameter, and higher percentage of diameter stenosis in a nontarget vessel among the 3 groups. Gray-scale IVUS analysis also showed smaller lumen area in the high XOR activity group than the others. LCBI (102.1 ± 56.5 vs 65.6 ± 48.5 vs 55.6 ± 37.8, p = 0.04) and maxLCBI4mm (474.4 ± 171.6 vs 347.4 ± 181.6, 294.0 ± 155.9, p = 0.04) in a nontarget vessel were significantly higher in the high XOR group than in the normal and low groups. In conclusion, elevated XOR activity was associated with coronary lipid-rich plaque in a nontarget vessel in patients with stable coronary artery disease.
    DOI:  https://doi.org/10.1016/j.amjcard.2019.12.043
  328. J Trace Elem Med Biol. 2020 Jan 13. pii: S0946-672X(19)30689-3. [Epub ahead of print]59 126467
    Association between trace elements in serum from bipolar disorder and schizophrenia patients considering treatment effects.
    Santa Cruz EC, Madrid KC, Arruda MAZ, Sussulini A.
      BACKGROUND: Imbalances in metal concentrations have been suggested to contribute to the pathophysiology of different brain disorders, such as bipolar disorder (BD) and schizophrenia (SCZ).OBJECTIVES: The aim of this exploratory study is to evaluate the association between the concentrations of macro/trace elements in serum from BD and SCZ patients considering the effects from different treatments.
    METHODS: Eleven subjects with SCZ, seven with BD treated with lithium (BDL) and eight subjects with BD treated with other medications except lithium (BDN) were recruited for the study, as well as eleven healthy controls (HC). Serum concentrations of eleven macro/trace elements (Se, Zn, Fe, K, Ca, Mg, P, Al, Cu, Mn, and Ni) were determined using inductively coupled plasma mass spectrometry (ICP-MS).
    RESULTS: Se and Zn concentrations were significantly lower for patients with SCZ and BD in comparison to HC by one-way ANOVA test. Moreover, serum concentrations for Fe were significantly higher (p < 0.05) in BDN (548 ± 92 μg L-1) and SCZ (632 ± 279 μg L-1) in comparison to HC (421 ± 121 μg L-1). A significant negative correlation was reported between Se and Fe in BDL group (r = -0.935, p < 0.05). In addition, a significantly higher Cu/Zn ratio was determined in SCZ group against HC (ratio = 2.4, p = 0.028).
    CONCLUSIONS: The obtained results suggest that the imbalance in Fe concentrations is an effect of BD treatment. Lithium is supposed to have an antagonist effect for Se in BDL patients. A negative correlation reported between Fe and BMI in SCZ group could be related to antipsychotic treatment and the Cu/Zn ratio reported could be considered as a suggesting parameter to relate oxidative stress to SCZ. Future studies including larger number of patients with SCZ and BD before and after treatment are necessary to confirm the investigative results presented herein.
    Keywords:  Bipolar disorder; ICP-MS; Iron; Schizophrenia; Selenium; Zinc
    DOI:  https://doi.org/10.1016/j.jtemb.2020.126467
  329. Med Hypothesis Discov Innov Ophthalmol. 2020 ;9(1): 7-14
    Pazopanib Selectively Inhibits Choroidal Vascular Endothelial Cell Proliferation and Promotes Apoptosis.
    Mynampati B, Enghelberg M, Chalam KV.
      Exudative age related macular degeneration (AMD) is related to active choroidal neovascularization (CNV) and formation of disciform scars. Vascular endothelial growth factor (VEGF) mediated choroidal vascular endothelial cell (CVECs) proliferation is characteristic of CNV. Intravitreal injections of bevacizumab, ranibizumab and aflibercept (anti-VEGF monoclonal antibodies) are used to treat exudative AMD. Pazopanib, a tyrosine kinase inhibitor, inhibits neovascularization through blockade of intracellular tyrosine kinase VEGF receptor and platelet-derived growth factor receptor. In this in vitro investigation, we evaluated the inhibitory consequences of escalating doses of pazopanib on proliferation of VEGF-enriched CVECs to establish a safe dosage range. VEGF (50 ng/mL) enriched CVECs were treated with escalating doses of pazopanib (10, 50,100 and 250 µM). Cell proliferation rates (WST-1 assay), cell viability (trypan blue exclusion assay), and reactive oxygen species (ROS) levels were measured at 48 hours (h), 72h and 1 week. Intracellular caspase 3 levels and morphological changes were recorded. VEGF enriched CVECs showed a significant decrease in cell proliferation rates after one week of treatment with increasing doses of pazopanib (10, 50,100 and 250 µM) treatment i.e. 87.8%, 43.0%, 38.1% and 9.3% compared to controls (p<0.001). Similarly, trypan blue exclusion assay revealed a decrease in cell viability as 81.8%, 81.0%, 53.4% and 8.7%, respectively (p<0.05). Further, pazopanib actively inhibited proliferation of VEGF-enriched CVECs, with 1.32, 1.92, 1.92 and 4.1-fold increase (p<0.01) in intracellular caspase 3 levels. VEGF-enriched CVECs treated with escalating doses of pazopanib decreased cell viability and increased caspase 3 levels in a time and dose dependent manner.
    Keywords:  Aflibercept; Age Related Macular Degeneration; Bevacizumab; Choroidal Vascular Endothelial Cell; In vitro; Pazopanib; Ranibizumab; Vacular Endothelial Growth Factor
  330. Medicine (Baltimore). 2020 Jan;99(4): e18395
    Meta-analysis of modified Stoppa approach and ilioinguinal approach in anterior pelvic ring and acetabular fractures.
    Wu H, Zhang L, Guo X, Jiang X.
      BACKGROUND: The purpose of this meta-analysis was to compare the efficacy of the modified Stoppa approach (MSA) and ilioinguinal approach (IA) in the treatment of anterior pelvic ring and acetabular fractures.METHODS: A literature search was conducted using PubMed, Embase, and Cochrane database for articles that compared MSA and IA in the treatment of anterior pelvic ring and acetabular fractures. All the included articles were evaluated by 2 trained reviewers in accordance with the Cochrane Collaboration Handbook for potential risk. The Jadad decision algorithm and Downs and Black scores were also used to assess the quality of the included studies. The extracted data included operative time, intraoperative blood loss, reduction quality, clinical outcome, and complications.
    RESULTS: Five articles were included in this meta-analysis, with 186 patients in the MSA group and 219 patients in the IA group. Compared with IA, MSA significantly shortened the operative time (P = .0002), decreased intraoperative blood loss (P = .002), and provided better reduction quality (P = .03). Meanwhile, this meta-analysis suggests no significant difference between MSA and IA regarding clinical outcomes (P = .63) and complications (P = .34). The subgroup analysis of complications also showed no statistically significant difference between the 2 groups (including infection, and vascular and nerve injuries).
    CONCLUSION: According to this meta-analysis, the currently available evidence suggests that MSA can significantly shorten operative time, decrease intraoperative blood loss, and provide better reduction quality than IA in the treatment of anterior pelvic ring and acetabular fractures. In addition, in terms of clinical outcomes and complications, no significant differences were found between the 2 groups.
    LEVEL OF EVIDENCE: Level IV, meta-analysis.
    DOI:  https://doi.org/10.1097/MD.0000000000018395
  331. PLoS One. 2020 ;15(1): e0227577
    Dissection of flag leaf metabolic shifts and their relationship with those occurring simultaneously in developing seed by application of non-targeted metabolomics.
    Hu C, Rao J, Song Y, Chan SA, Tohge T, Cui B, Lin H, Fernie AR, Zhang D, Shi J.
      Rice flag leaves are major source organs providing more than half of the nutrition needed for rice seed development. The dynamic metabolic changes in rice flag leaves and the detailed metabolic relationship between source and sink organs in rice, however, remain largely unknown. In this study, the metabolic changes of flag leaves in two japonica and two indica rice cultivars were investigated using non-targeted metabolomics approach. Principal component analysis (PCA) revealed that flag leaf metabolomes varied significantly depending on both species and developmental stage. Only a few of the metabolites in flag leaves displayed the same change pattern across the four tested cultivars along the process of seed development. Further association analysis found that levels of 45 metabolites in seeds that are associated with human nutrition and health correlated significantly with their levels in flag leaves. Comparison of metabolomics of flag leaves and seeds revealed that some flavonoids were specific or much higher in flag leaves while some lipid metabolites such as phospholipids were much higher in seeds. This reflected not only the function of the tissue specific metabolism but also the different physiological properties and metabolic adaptive features of these two tissues.
    DOI:  https://doi.org/10.1371/journal.pone.0227577
  332. Thorac Cancer. 2020 Jan 24.
    Environmental pollutants damage airway epithelial cell cilia: Implications for the prevention of obstructive lung diseases.
    Cao Y, Chen M, Dong D, Xie S, Liu M.
      Mucociliary epithelium lining the upper and lower respiratory tract constitutes the first line of defense of the airway and lungs against inhaled pollutants and pathogens. The concerted beating of multiciliated cells drives mucociliary clearance. Abnormalities in both the structure and function of airway cilia have been implicated in obstructive lung diseases. Emerging evidence reveals a close correlation between lung diseases and environmental stimuli such as sulfur dioxide and tobacco particles. However, the underlying mechanism remains to be described. In this review, we emphasize the importance of airway cilia in mucociliary clearance and discuss how environmental pollutants affect the structure and function of airway cilia, thus shedding light on the function of airway cilia in preventing obstructive lung diseases and revealing the negative effects of environmental pollutants on human health.
    Keywords:  Airway epithelium; environmental pollutant; lung disease; mucociliary clearance
    DOI:  https://doi.org/10.1111/1759-7714.13323
  333. Redox Biol. 2019 Dec 16. pii: S2213-2317(19)31207-8. [Epub ahead of print]30 101403
    Superoxide induced inhibition of death receptor signaling is mediated via induced expression of apoptosis inhibitory protein cFLIP.
    Hirpara JL, Subramaniam K, Bellot G, Qu J, Seah S, Loh T, Tucker-Kellogg L, Clement MV, Pervaiz S.
      The death inhibitory proteins, cFLIP and Bcl-2, canonically act at different steps to regulate receptor-mediated apoptosis in cancer cells. Here we report that pharmacological or genetic means to effect an increase in intracellular superoxide result in cFLIP upregulation. Interestingly, Bcl-2 overexpression is associated with a concomitant increase in cFLIP, and reducing superoxide sensitizes Bcl-2 overexpressing cancer cells to receptor-mediated apoptosis via downregulation of cFLIP. Moreover, inhibiting glycolytic flux overcomes apoptosis resistance by superoxide-dependent downregulation of cFLIP. Superoxide-induced upregulation of cFLIP is a function of enhanced transcription, as evidenced by increases in cFLIP promoter activity and mRNA abundance. The positive effect of superoxide on cFLIP is mediated through its reaction with nitric oxide to generate peroxynitrite. Corroborating these findings in cell lines, subjecting primary cells derived from lymphoma patients to glucose deprivation ex vivo, as a means to decrease superoxide, not only reduced cFLIP expression but also significantly enhanced death receptor sensitivity. Based on this novel mechanistic insight into the redox regulation of cancer cell fate, modulation of intracellular superoxide could have potential therapeutic implications in cancers in which these two death inhibitory proteins present a therapeutic challenge.
    Keywords:  Apoptosis; Bcl-2; Cancer; Superoxide; cFLIP
    DOI:  https://doi.org/10.1016/j.redox.2019.101403
  334. Food Funct. 2020 Jan 23.
    Trehalose and alginate oligosaccharides increase the stability of muscle proteins in frozen shrimp (Litopenaeus vannamei).
    Zhang B, Yao H, Qi H, Zhang XL.
      Muscle proteins in whiteleg shrimp (Litopenaeus vannamei) are susceptible to denaturation and are affected by freezing and frozen storage. Cryoprotective trehalose (TR) and alginate oligosaccharides (AOs) can slow the degradation of myofibrillar proteins and reduce mechanical damage to shrimp muscle tissues. We conducted label-free based proteomic analysis to study the stability of proteins in TR- and AO-treated shrimp after 30 d of frozen storage at -18 °C. A total of 2155 peptides and 626 proteins were identified and quantified in shrimp muscle. The most common 95 differentially abundant proteins (DAPs) were down-regulated and detected in distilled water (DW), TR, and AO, especially the down-regulated DAPs including actin, calcium-transporting ATPase, myosin heavy and light chains, paramyosin, tropomyosin, and troponin. Most of the above DAPs were up-regulated in TR/AO compared to DW. This was most likely due to the incorporation of TR/AO molecules into the muscle tissues, resulting in decreased protein degradation and reduced damage from ice crystal growth. Gene Ontology (GO) analysis indicated that these DAPs were mainly involved in binding, catalytic activity, cell, cell parts, cellular process, and metabolic process items, which were associated with the protein structure, function, and metabolism. Kyoto Encyclopedia of Genes and Genomes (KEGG) results suggested alteration of many pathways, including metabolic pathways, carbon metabolism, phototransduction, phagosome and ribosome pathways, which are involved with arginine kinase, l-lactate dehydrogenase, malate dehydrogenase, phosphoglycerate mutase, and ribosomal proteins. The TR/AO treatment maintained the natural conformation, structure, and function of the DAPs and delayed the degradation of muscle proteins. Here, this study provided a deeper insight into the protein changes in shrimp muscle during frozen storage and could be a valuable foundation for future investigations.
    DOI:  https://doi.org/10.1039/c9fo02016k
  335. Thromb Res. 2020 Jan 15. pii: S0049-3848(20)30012-8. [Epub ahead of print]187 91-102
    Hyper-coagulability in obese patients accurately identified by combinations of global coagulation assay parameters.
    Bertaggia Calderara D, Aliotta A, Zermatten MG, Kröll D, Stirnimann G, Alberio L.
      BACKGROUND: Routine laboratory methods are insensitive to hyper-coagulation, which may be detected by global hemostasis tests. Calibrated Automated Thrombogram (CAT) is a gold standard method to measure thrombin generation and coagulation potential. Thrombodynamics (TD) is a new global assay that monitors the spatio-temporal propagation of blood coagulation, separating initiation from amplification/propagation phases of coagulation and visualizing fibrin clot formation.AIM: We investigated whether CAT and/or TD can identify hyper- and hypo-coagulable states in patients with well-characterized phenotypes and which parameters could be used as potential predictors of thrombotic risk.
    METHODS: Blood was collected from: (1) forty healthy volunteers; (2) twelve obese patients scheduled for bariatric surgery (BMI ≥ 35 kg/m2); (3) nine patients under therapy with vitamin K-antagonists (median INR 2.7); (4) eight patients treated with low molecular weight heparins (anti-Xa activity between 0.5 and 0.7 U anti-Xa/ml); (5) ten patients with hemophilia A or B. Tissue factor induced thrombin generation was measured with CAT. Propagation of thrombin generation and clot growth from a tissue factor coated surface were monitored with TD.
    RESULTS: Thrombin generation and fibrin clot formation parameters were significantly higher in obese patients compared to healthy volunteers and anticoagulated or hemophilic patients. ROC analysis of combined CAT or CAT/TD parameters (integrating thrombin generation and fibrin clot formation) demonstrated an excellent accuracy in detecting hyper-coagulability.
    CONCLUSION: Combinations of CAT assay parameters and of parameters of thrombin generation burst with final fibrin clot properties allow recognizing accurately hyper-coagulable plasma and may represent predictive markers for thrombotic events.
    Keywords:  Global hemostasis test; Hyper-coagulation; Thrombin generation; Thrombodynamics; Thrombotic risk
    DOI:  https://doi.org/10.1016/j.thromres.2020.01.012
  336. Chem Commun (Camb). 2020 Jan 23.
    An octopus-mimic PEGylated peptide as a specific integrin αvβ3 inhibitor for preventing tumor progression.
    Shan X, Zhang L, Xu Y, Sun L, Guo L, Feng S, Ge H, Gu T, Ning X.
      We have developed a multivalent PEGylated RWrNR, named octopus-R, which exhibits good water solubility, biostability, biocompatibility and cancer targeting ability, endowing it with high anticancer potential. Octopus-R represents a promising theranostic agent and holds great potential for improving the management of malignant tumors.
    DOI:  https://doi.org/10.1039/c9cc09496b
  337. AACE Clin Case Rep. 2019 Sep-Oct;5(5):5(5): e316-e320
    BISPHOSPHONATES FOR THE TREATMENT OF CALCITRIOL-INDUCED HYPERCALCEMIA.
    Mateo RCI, Ortiz R, Rosen HN.
      Objective: Calcitriol excess is a less common cause of hypercalcemia than hyperparathyroidism. Hypercalcemia due to calcitriol excess is usually managed acutely with intravenous (IV) fluid administration and dietary calcium restriction. Steroids and ketoconazole are second-line agents. There is evidence supporting the role of bone resorption in the genesis of hypercalcemia in vitamin D intoxication and for a rapid response of hypercalcemia to treatment with bisphosphonates. We seek to demonstrate the utility of bisphosphonates in calcitriol-induced hypercalcemia (CIH).Methods: We present the case of a patient with recurrent CIH from a follicular lymphoma who achieved normalization and subsequent stabilization of serum calcium levels following bisphosphonate administration.
    Results: A 77-year-old woman with a history of non-small cell lung cancer was admitted with dry mouth, polyuria, weight loss, and fatigue. She was found to have a calcium level of 14.7 mg/dL (normal range is 8.5 to 10.2 mg/dL), 25-hydroxyvitamin D of 47 ng/mL (normal range is 30 to 60 ng/mL), 1,25-dihydroxyvitamin D of 89 pg/mL (normal range is 18 to 72 pg/mL), and parathyroid hormone of 19 pg/mL (normal range is 15 to 65 pg/mL), which recurred despite treatment with IV fluids and strict low-calcium diet. She received 5 mg of IV zoledronic acid and normocalcemia was maintained thereafter, without any diagnosis-specific treatment for >3 months. Positron emission tomography with computed tomography eventually showed new innumerable foci of increased uptake in the skeleton and lymph node biopsy revealed grade 3A follicular lymphoma.
    Conclusion: The first choice for CIH is treating the underlying cause. Bisphosphonates are, however, useful until a diagnosis is made, as they may be safer than steroids and can provide rapid relief even with a single treatment with minimal side effects.
    DOI:  https://doi.org/10.4158/ACCR-2019-0101
  338. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31715-2. [Epub ahead of print]30(3): 807-819.e4
    Multi-lineage Lung Regeneration by Stem Cell Transplantation across Major Genetic Barriers.
    Hillel-Karniel C, Rosen C, Milman-Krentsis I, Orgad R, Bachar-Lustig E, Shezen E, Reisner Y.
      Induction of lung regeneration by transplantation of lung progenitor cells is a critical preclinical challenge. Recently, we demonstrated that robust lung regeneration can be achieved if the endogenous stem cell niches in the recipient's lung are vacated by sub-lethal pre-conditioning. However, overcoming MHC barriers is an additional requirement for clinical application of this attractive approach. We demonstrate here that durable tolerance toward mis-matched lung progenitors and their derivatives can be achieved without any chronic immune suppression, by virtue of co-transplantation with hematopoietic progenitors from the same donor. Initial proof of concept of this approach was attained by transplantation of fetal lung cells comprising both hematopoietic and non-hematopoietic progenitors. Furthermore, an even higher rate of blood and epithelial lung chimerism was attained by using adult lung cells supplemented with bone marrow hematopoietic progenitors. These results lay the foundation for repair of lung injury through a procedure akin to bone marrow transplantation.
    Keywords:  adult mouse lung; allogeneic transplantation; fetal mouse lung; lung chimerism; mouse bone marrow; tolerance induction
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.058
  339. Medicine (Baltimore). 2020 Jan;99(4): e18607
    Preoperative platelet-lymphocyte ratio is a superior prognostic biomarker to other systemic inflammatory response markers in non-small cell lung cancer.
    Huang Q, Diao P, Li CL, Peng Q, Xie T, Tan Y, Lang JY.
      Systemic inflammatory response markers are associated with poor survival in many types of malignances. This study aimed to evaluate the prognostic value of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC).We retrospectively evaluated 254 NSCLC patients who underwent radical surgery between January 2012 and April 2014 in the Sichuan Provincial Cancer Hospital. The cut-off values of NLR, PLR, LMR, and CRP were determined according to the receiver operating characteristic curve, and the correlation of NLR, PLR, LMR, and CRP with prognosis was analyzed based on the cut-off value.The cut-off value for NLR, PLR, LMR, and CRP were 3.18, 122, 4.04, and 8.8, respectively. Univariate analysis showed that age (P = .022), tumor-node-metastasis (TNM) stage (P < .001), T stage (P = .001), and N stage (P < .001) were significantly correlated with disease-free survival (DFS), while age (P = .011), TNM stage (P < .001), T stage (P = .008), N stage (P < .001), and PLR (P = .001) were significantly correlated with overall survival (OS). In multivariate analysis, age (hazard ratio [HR]: 1.564, 95% confidence interval [CI]: 1.087-2.252, P = .016) and TNM stage (HR: 1.704, 95% CI: 1.061-2.735, P = .027) remained independent risk factors affecting DFS, while age (HR: 1.721, 95% CI: 1.153-2.567, P = .008), TNM stage (HR: 2.198, 95% CI: 1.263-3.824, P = .005), and PLR (HR: 1.850, 95% CI: 1.246-2.746, P = .002) were independent risk factors affecting OS.The preoperative PLR is superior to NLR, LMR, and CRP as a biomarker for evaluating the prognosis of patients undergoing curative surgery for NSCLC.
    DOI:  https://doi.org/10.1097/MD.0000000000018607
  340. Acta Biochim Biophys Sin (Shanghai). 2020 Jan 21. pii: gmz153. [Epub ahead of print]
    Gene expression profiling of cells of origin of squamous cell carcinomas in head-and-neck, esophagus, and lung.
    Qu N, Huang D, Xu Q, Wang J, Chen C, Ji Q, Wu W, Zhu Y, Xu M.
      
    DOI:  https://doi.org/10.1093/abbs/gmz153
  341. Chest. 2020 Jan 17. pii: S0012-3692(20)30032-5. [Epub ahead of print]
    Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial.
    Noronha V, Bhattacharjee A, Patil VM, Joshi A, Menon N, Shah S, Kannan S, Mukadam SA, Maske K, Ishi S, Prabhash K.
      BACKGROUND: Although cough is a common and distressing symptom in lung cancer patients, there is almost no evidence to guide management. Aprepitant, a centrally acting neurokinin-1 inhibitor, significantly decreased cough frequency in a pilot study.METHODS: Patients with advanced lung cancer and cough lasting over two weeks despite a cough suppressant, were randomized 1:1 to aprepitant 125 mg orally on day one then 80 mg orally on days two to seven with physician's choice of antitussive; or to physician's choice of antitussive alone. Evaluation was at baseline and on days three, seven, nine and twelve. Primary endpoint was subjective cough improvement on day nine, measured by the Visual Analog Scale (VAS) and Manchester Cough in Lung Cancer Scale (MCLCS). Secondary endpoints included quality of life (QoL) as measured by the EORTC QLQ-C30 and QLQ-LC13 and toxicity.
    RESULTS: Between 2017 and 2018, 128 patients were randomized. Median baseline cough duration was 90 days. Mean VAS scores (in mm) at baseline and day nine were 68 and 39 in the aprepitant arm and 62 and 49 in the control arm respectively, P<0.001; Mean MCLCS scores at baseline and day nine were 33 and 23 in aprepitant arm and 30 and 25 in control arm, P<0.001. Overall QoL was not significantly different between the two arms, however aprepitant led to a significant improvement in the cough-specific QoL domain, P=0.017. Aprepitant did not increase severe adverse events.
    CONCLUSIONS: Aprepitant led to a significant improvement in cough in advanced lung cancer, without increasing severe side-effects.
    Keywords:  Antitussive; Cough; MCLCS; NSCLC; Repurposing; neurokinin,
    DOI:  https://doi.org/10.1016/j.chest.2019.11.048
  342. Lancet Respir Med. 2020 Jan 15. pii: S2213-2600(19)30267-X. [Epub ahead of print]
    Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study.
    Tan DS, Leighl NB, Riely GJ, Yang JC, Sequist LV, Wolf J, Seto T, Felip E, Aix SP, Jonnaert M, Pan C, Tan EY, Ko J, Moody SE, Kim DW.
      BACKGROUND: Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50-60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC.METHODS: This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB-IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov (NCT02108964); enrolment to phase 1 is complete and the study is ongoing.
    FINDINGS: By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52-69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1-2. Any-cause grade 3-4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients.
    INTERPRETATION: Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions.
    FUNDING: Novartis Pharmaceuticals Corporation.
    DOI:  https://doi.org/10.1016/S2213-2600(19)30267-X
  343. Cell Stem Cell. 2020 Jan 23. pii: S1934-5909(19)30572-7. [Epub ahead of print]
    Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration.
    Kathiriya JJ, Brumwell AN, Jackson JR, Tang X, Chapman HA.
      Lung injury activates specialized adult epithelial progenitors to regenerate the epithelium. Depending on the extent of injury, both remaining alveolar type II cells (AEC2s) and distal airway stem/progenitors mobilize to cover denuded alveoli and restore normal barriers. The major source of airway stem/progenitors other than basal-like cells remains uncertain. Here, we define a distinct subpopulation (∼5%) of club-like lineage-negative epithelial progenitors (LNEPs) marked by high H2-K1 expression critical for alveolar repair. Quiescent H2-K1high cells account for virtually all in vitro regenerative activity of airway lineages. After bleomycin injury, H2-K1 cells expand and differentiate in vivo to alveolar lineages. However, injured H2-K1 cells eventually develop impaired self-renewal with features of senescence, limiting complete repair. Normal H2-K1high cells transplanted into injured lungs differentiate into alveolar cells and rescue lung function. These findings indicate that small subpopulations of specialized stem/progenitors are required for effective lung regeneration and are a potential therapeutic adjunct after major lung injury.
    Keywords:  MHC(high) airway progenitors; alveolar injury and regeneration; bleomycin injury; dedifferentiation; lung epithelial stem cells; oxygenation; single cell transcriptomics; transplantation
    DOI:  https://doi.org/10.1016/j.stem.2019.12.014
  344. J Steroid Biochem Mol Biol. 2020 Jan 15. pii: S0960-0760(19)30655-7. [Epub ahead of print] 105591
    Impact of Maternal Smoking Associated Lyso-phosphatidylcholine 20:3 on Offspring Brain Development.
    Yong-Ping L, Reichetzeder C, Prehn C, Yin LH, Chu C, Elitok S, Krämer BK, Adamski J, Hocher B.
      Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analyzed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p <  0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75～-0.41 cm, p =  2.45×10-11). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68～39.88 cm, p =  4.62×10-4) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring's development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.
    Keywords:  biomarker; head circumference; lyso-phosphatidylcholine 20:3; male offspring; maternal smoking
    DOI:  https://doi.org/10.1016/j.jsbmb.2020.105591
  345. Nat Commun. 2020 Jan 23. 11(1): 437
    Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.
    Imbert C, Montfort A, Fraisse M, Marcheteau E, Gilhodes J, Martin E, Bertrand F, Marcellin M, Burlet-Schiltz O, Peredo AG, Garcia V, Carpentier S, Tartare-Deckert S, Brousset P, Rochaix P, Puisset F, Filleron T, Meyer N, Lamant L, Levade T, Ségui B, Andrieu-Abadie N, Colacios C.
      Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-019-14218-7
  346. Neoplasma. 2020 Jan 21. pii: 190417N346. [Epub ahead of print]
    Patient-derived organoids of non-small cells lung cancer and their application for drug screening.
    Li YF, Gao Y, Liang BW, Cao XQ, Sun ZJ, Yu JH, Liu ZD, Han Y.
      Patient-derived organoids (PDOs) are emerging as preclinical models with promising values in personalized cancer therapy. The purpose of this study was to establish a living biobank of PDOs from patients with non-small cell lung cancer (NSCLC) and study the responses of PDOs to drugs. PDOs derived from NSCLC were cultured in vitro, and then treated with nature compounds including chelerythrine chloride, cantharidin, harmine, berberine and betaine with series concentrations (0.5 ~ 30 μM) for drug screening. Phenotypic feature and treatment responses of established PDOs were reported. Cell lines (H1299, H460 and H1650) were used for drug screening. We successfully established a living NSCLC organoids biobank of 10 patients, which showed similar pathological features with primary tumors. Nine of the 10 patients showed mutations in EGFR. Natural compounds chelerythrine chloride, cantharidin and harmine showed anticancer activity on PDOs and cell lines. There was no significant difference in the 95% confidence interval (CI) for the IC50 value of chelerythrine chloride between PDOs (1.56 ~ 2.88 μM) and cell lines (1.45 ~ 3.73 μM, P > 0.05). PDOs were sensitive to berberine (95% CI, 0.092 ~ 1.55 μM), whereas cell lines showed resistance (95% CI, of 46.57 ~ 2275 μM, p < 0.0001). PDOs had a higher IC50 value of cantharidin, and lower IC50 value of harmine than cell lines (P < 0.05, 7.50 ~ 10.45 μM and 4.27 ~ 6.50 μM in PDOs, 3.07 ~ 4.44 μM and 4.69 ~ 544.99 μM in cell lines, respectively). Both PDOs and cell lines were resistant to betaine. Chelerythrine chloride showed the highest inhibitory effect on both models. Our study established a living biobank of PDOs from NSCLC patients, which might be used for high-throughput drug screening and for promising personalized therapy design.
    DOI:  https://doi.org/10.4149/neo_2020_190417N346
  347. Biomaterials. 2020 Jan 06. pii: S0142-9612(20)30007-7. [Epub ahead of print]234 119761
    ROS-augmented and tumor-microenvironment responsive biodegradable nanoplatform for enhancing chemo-sonodynamic therapy.
    An J, Hu YG, Cheng K, Li C, Hou XL, Wang GL, Zhang XS, Liu B, Zhao YD, Zhang MZ.
      Nanocarrier for augmenting the efficacy of reactive oxygen species (ROS) by tumor microenvironment (TME) has become an emerging strategy for cancer treatment. Herein, a smart biodegradable drug delivery nanoplatform with mitochondrial-targeted ability, pH-responsive drug release and enzyme-like catalytic function is designed. This efficient ROS-generating platform uses ultrasound with deeper penetration capability as excitation source for combined chemotherapy and sonodynamic therapy (SDT) of tumor. In vitro experiments show that the nanoplatform can co-load Ce6 and DOX and be degraded in slight acid environment, and the DOX release rate is 63.91 ± 1.67%. In vivo experiments show that the nanoplatform has extremely biosafety and can be enriched in tumor site and excluded from body after 24 h. More significantly, after combined treatment, the tumors are eliminated and the mice still survive healthily without recurrence after 60 d. This is because not only it can achieve mitochondrial targeting and use platinum particle to increase oxygen content in TME to enhance the effect of SDT, but also it can use weak acidic TME to accelerate drug release to achieve the combination of chemotherapy and SDT. The probe provides a new strategy for designing ROS-based nanoplatform for the treatment of malignant tumor.
    Keywords:  Chemotherapy; Mitochondria targeting; Sonodynamic therapy; Tumor hypoxia; pH-responsive
    DOI:  https://doi.org/10.1016/j.biomaterials.2020.119761
  348. Am J Physiol Endocrinol Metab. 2020 Jan 21.
    Enoyl Coenzyme A Hydratase 1 Combats Obesity and Related Metabolic Disorders by Promoting Adipose Tissue Browning.
    Mao X, Huang D, Rao C, Du M, Liang M, Li F, Liu B, Huang K.
      Browning of white adipose tissue (WAT) has been recognized as an important strategy for the treatment of obesity, insulin resistance, and diabetes. Enoyl coenzyme A hydratase 1 (ECH1) is a widely known enzyme involved in lipid metabolism. However, whether and how ECH1 is implicated in browning of WAT remains obscure. Adeno-associated virus-mediated genetic engineering of ECH1 in adipose tissue was used in investigations in mouse models of obesity induced by a high-fat diet (HFD) or browning induced by cold exposure. Metabolic parameters showed that ECH1 overexpression decreased weight gain and improved insulin sensitivity and lipid profile after 8 weeks of HFD. Further work revealed that these changes were associated with enhanced energy expenditure and increased appearance of brown-like adipocytes in inguinal WAT, as verified by a remarkable increase in UCP1 and thermogenic gene expression. In vitro, ECH1 induced brown fat-related gene expression in adipocytes differentiated from primary stromal vascular fractions, whereas knockdown of ECH1 reversed this effect. Mechanistically, ECH1 regulated the thermogenic program by inhibiting mTOR signaling, which may partially explain the potential mechanism for ECH1 regulating adipose browning. In summary, ECH1 may participate in the pathology of obesity by regulating browning of WAT, which probably provides us with a new therapeutic strategy for combating obesity.
    Keywords:  ECH1; UCP1; adipose browning; mTOR; obesity
    DOI:  https://doi.org/10.1152/ajpendo.00424.2019
  349. Sci Rep. 2020 Jan 21. 10(1): 888
    Profiling of human lymphocytes reveals a specific network of protein kinases modulated by endurance training status.
    Alack K, Weiss A, Krüger K, Höret M, Schermuly R, Frech T, Eggert M, Mooren FC.
      To date, the effects of endurance exercise training on lymphocyte physiology at the kinome level are largely unknown. Therefore, the present study used a highly sensitive peptide-based kinase activity profiling approach to investigate if the basal activity of tyrosine (Tyr) and serine/threonine (Ser/Thr) kinases of human lymphocytes is affected by the aerobic endurance training status. Results revealed that the activity of various tyrosine kinases of the FGFR family and ZAP70 was increased, whereas the activity of multiple Ser/Thr kinases such as IKKα, CaMK4, PKAα, PKCα+δ (among others) was decreased in lymphocytes of endurance trained athletes (ET). Moreover, functional associations between several differentially regulated kinases in ET-derived lymphocytes were demonstrated by phylogenetic mapping and network analysis. Especially, Ser/Thr kinases of the AGC-kinase (protein kinase A, G, and C) family represent exercise-sensitive key components within the lymphocytes kinase network that may mediate the long-term effects of endurance training. Furthermore, KEGG (Kyoto Encyclopedia of Genes and Genomes) and Reactome pathway analysis indicate that Ras as well as intracellular signaling by second messengers were found to be enriched in the ET individuals. Overall, our data suggest that endurance exercise training improves the adaptive immune competence by modulating the activity of multiple protein kinases in human lymphocytes.
    DOI:  https://doi.org/10.1038/s41598-020-57676-6
  350. MDM Policy Pract. 2020 Jan-Jun;5(1):5(1): 2381468319891452
    Brief Education and a Conjoint Valuation Survey May Reduce Decisional Conflict Regarding Lung Cancer Screening.
    Studts JL, Thurer RJ, Brinker K, Lillie SE, Byrne MM.
      Background. Recent data and policy decisions have led to the availability of lung cancer screening (LCS) for individuals who are at increased risk of developing lung cancer. In establishing implementation policies, the US Preventive Services Task Force recommended and the Centers for Medicare and Medicaid Services required that individuals who meet eligibility criteria for LCS receive a patient counseling and shared decision-making consultation prior to LCS. Methods. This study evaluated the potential of a values clarification/preference elicitation exercise and brief educational intervention to reduce decisional conflict regarding LCS. Participants (N = 210) completing a larger online survey responded to a measure of decisional conflict prior to and following administration of a conjoint survey and brief educational narrative about LCS. The conjoint survey included 22 choice sets (two of which were holdout cards), incorporating 5 attributes with 17 levels. Results. Results pertaining to changes in decisional conflict showed that participants reported statistically significantly and clinically meaningful reductions in decisional conflict following administration of the brief educational narrative and conjoint survey across the total score (Δ = 29.30; d = 1.09) and all four decisional conflict subscales: Uncertainty (Δ = 27.75; d = 0.73), Informed (Δ = 35.32; d = 1.11), Values Clarity (Δ = 31.82; d = 0.85), and Support (Δ = 18.78; d = 0.66). Discussion. While the study design precludes differentiating the effects of the brief educational narrative and the conjoint survey, data suggest that these tools offer a reasonable approach to clarifying personal beliefs and perspectives regarding LCS participation. Given the complicated nature of LCS decisions and recent policies advocating informed and shared decision-making approaches, conjoint surveys should be evaluated as one of the tools that could help individuals make choices about LCS participation.
    Keywords:  conjoint analysis; decision making; lung cancer screening; patient preferences
    DOI:  https://doi.org/10.1177/2381468319891452
  351. Scand J Surg. 2020 Jan 20. 1457496919900406
    The Occurrence of Lung Cancer and Non-Pulmonary Malignancies After Pleural Infections.
    Khan J, Ala-Seppälä H, Lehtomäki A, Toikkanen V, Pohja E, Laurikka J, Ukkonen M.
      BACKGROUND AND AIMS: Patients who develop infections of the pleura have several risk factors for malignancies, particularly lung cancer, and the infections might even be caused by undiagnosed intra-thoracic neoplasms. The aim of the study was to compare the occurrence of lung cancer and other malignancies between patients treated for pleural infections and controls during long-term follow-up.MATERIALS AND METHODS: All consecutive patients treated for pleural infections between January 2000 and June 2016 at the Tampere University Hospital were included. Ten matched controls and data regarding later cancer diagnoses were requested from national registries. The cancer types and rates, the diagnostic delays, as well as survival were compared between patients and controls.
    RESULTS: The material comprised 506 patients and 5022 controls (78% was male and median age was 60 years in both groups) with a median follow-up time of 69 months. In total, 74% of pleural infections were related to pneumonia. The occurrence of lung cancer during follow-up was 3.0% in all patients, 2.2% in pneumonia-related cases, and 0.6% in controls, p < 0.001 when compared with controls. The overall rate of non-pulmonary malignancies did not differ. Lung cancer was diagnosed within 3 months in 73% of patients versus in 6.9% of controls, p < 0.001. The survival in patients with later lung cancers or other malignancies was inferior to that of controls with similar neoplasms.
    CONCLUSION: The rate of lung cancer diagnoses was significantly increased in patients treated for pleural infections when compared with matched controls and the prognosis of patients with subsequent malignancies was impacted.
    Keywords:  Empyema; infection; lung; neoplasms; pleura
    DOI:  https://doi.org/10.1177/1457496919900406
  352. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Jan 21. pii: S1388-1981(19)30240-9. [Epub ahead of print] 158589
    Molecular and cellular insights into the role of SND1 in lipid metabolism.
    Navarro-Imaz H, Ochoa B, García-Arcos I, Martínez MJ, Chico Y, Fresnedo O, Rueda Y.
      Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an evolutionarily conserved protein present in eukaryotic cells from protozoa to mammals. SND1 has gained importance because it is overexpressed in aggressive cancer cells and diverse primary tumors. Indeed, it is regarded as a marker of cancer malignity. A broad range of molecular functions and the participation in many cellular processes have been attributed to SND1, mostly related to the regulation of gene expression. An increasing body of evidence points to a relevant relationship between SND1 and lipid metabolism. In this review, we summarize the knowledge about SND1 and its molecular and functional relationship with lipid metabolism. We highlight that SND1 plays a direct role in the regulation of cholesterol metabolism by affecting the activation of sterol response element-binding protein 2 (SREBP2) and we propose that that might have implications in the response of lipid homeostasis to stress situations.
    Keywords:  Cancer; Cholesterol; Lipid metabolism; SND1; SREBP2; Stress response
    DOI:  https://doi.org/10.1016/j.bbalip.2019.158589
  353. J Agric Food Chem. 2020 Jan 22.
    Plasma-polymerized phlorotannins and their enhanced biological activities.
    Kim HJ, Yong HI, Lee BW, Park S, Baek KH, Kim TH, Jo C.
      Here, we investigated the effect of cold plasma (CP) on the biological activities of phloroglucinol. Phloroglucinol (7.92 and 15.84 mM in methanol) was treated with air dielectric barrier discharge plasma at 250 W. In vitro 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and Ferrous reducing antioxidant power (FRAP) values of phloroglucinol increased in a plasma treatment time-dependent manner. CP treatment of phloroglucinol decreased the lipid oxidation of oil emulsion during storage and increased the antimicrobial activity against Bacillus cereus, Escherichia coli O157:H7, and Staphylococcus aureus. Angiotensin-converting enzyme (ACE) inhibitory activity of phloroglucinol increased and total phenolic content decreased based on CP treatment. CP-induced polymerization of phloroglocinol to phlorotannin derivatives was identified using high performance liquid chromatography with UV detector and electrospray ionization/mass spectrometry (HPLC-UV-ESI/MS) method. Consequently, the polymer structure of phloroglucinol was found in CP-treated phloroglucinol. In addition, CP enhances the biological activity of phloroglucinol and could be applied to bioactive materials in food and related industries.
    DOI:  https://doi.org/10.1021/acs.jafc.9b07077
  354. FASEB J. 2020 Jan 19.
    Blood contains circulating cell-free respiratory competent mitochondria.
    Al Amir Dache Z, Otandault A, Tanos R, Pastor B, Meddeb R, Sanchez C, Arena G, Lasorsa L, Bennett A, Grange T, El Messaoudi S, Mazard T, Prevostel C, Thierry AR.
      Mitochondria are considered as the power-generating units of the cell due to their key role in energy metabolism and cell signaling. However, mitochondrial components could be found in the extracellular space, as fragments or encapsulated in vesicles. In addition, this intact organelle has been recently reported to be released by platelets exclusively in specific conditions. Here, we demonstrate for the first time, that blood preparation with resting platelets, contains whole functional mitochondria in normal physiological state. Likewise, we show, that normal and tumor cultured cells are able to secrete their mitochondria. Using serial centrifugation or filtration followed by polymerase chain reaction-based methods, and Whole Genome Sequencing, we detect extracellular full-length mitochondrial DNA in particles over 0.22 µm holding specific mitochondrial membrane proteins. We identify these particles as intact cell-free mitochondria using fluorescence-activated cell sorting analysis, fluorescence microscopy, and transmission electron microscopy. Oxygen consumption analysis revealed that these mitochondria are respiratory competent. In view of previously described mitochondrial potential in intercellular transfer, this discovery could greatly widen the scope of cell-cell communication biology. Further steps should be developed to investigate the potential role of mitochondria as a signaling organelle outside the cell and to determine whether these circulating units could be relevant for early detection and prognosis of various diseases.
    Keywords:  blood; circulating DNA; mitochondria; mitochondrial genome; respiratory competent
    DOI:  https://doi.org/10.1096/fj.201901917RR
  355. Med Phys. 2020 Jan 18.
    Spatially-guided non-local mean approach for denoising of PET images.
    Arabi H, Zaidi H.
      PURPOSE: Non-local mean (NLM) filtering proved to be an effective tool for noise reduction in natural and medical imaging. The technique relies on existing redundant information in the input image to discriminate the genuine signal from noise. However, due to the prohibitively long computation time, the search for finding similar information is confined by a predefined search window, which may hamper the performance of this filter. In this work, a spatially-guided non-local mean (SG-NLM) approach is proposed to overcome this issue. The proposed method was evaluated on whole-body PET images presenting with high noise levels, which adversely affect lesion detectability and quantitative accuracy.METHODS: In the SG-NLM method, as opposed to the conventional NLM method, where a predefined search window is defined to confine exhaustive search for finding similar patterns, the information about similar patterns is extracted from the clustered version (created based on signal intensity levels) of the input image as well as information about prominent edges. The performance of the SG-NLM was evaluated against post-reconstruction NLM, Gaussian, bilateral and BayesShrink Wavelet denoising approaches. A digital phantom containing three small spheres mimicking lesions in the lung, experimental study using the Jaszczak phantom and whole-body PET/CT clinical studies were utilized to assess the performance of abovementioned denoising approaches.
    RESULTS: The SG-NLM method led to a signal-to-noise (SNR) increase from 21.3 (unfiltered PET image) to 30.1 in computer simulations of small lesions while the NLM mean filer resulted in an SNR of 29.4 (p<0.05). The experimental Jaszczak phantom study demonstrated that the contrast-to-noise ratio (CNR) increased from 11.3 when using the Gaussian filter to 18.6 and 19.5 when using NLM and SG-NLM filters (p<0.05), respectively. The superior performance of the SG-NLM approach was confirmed by the clinical studies where the bias in malignant lesions decreased to -2.3±1.1% compared to -11.7±2.4 and -2.9±1.1 achieved by the Gaussian and NLM methods (p<0.05), respectively.
    CONCLUSIONS: The proposed SG-NLM achieves promising compromise between noise reduction and signal preservation compared to the conventional NLM method. The superior performance of the SG-NLM method was accomplished without adding extra burden to the computational complexity of the conventional NLM filter, which makes it attractive for denoising PET images.
    Keywords:  PET; curvelet transform; filtering; image quality; non-local means
    DOI:  https://doi.org/10.1002/mp.14024
  356. J Cell Physiol. 2020 Jan 24.
    The effect of lncRNA-ARAP1-AS2/ARAP1 on high glucose-induced cytoskeleton rearrangement and epithelial-mesenchymal transition in human renal tubular epithelial cells.
    Li L, Xu L, Wen S, Yang Y, Li X, Fan Q.
      The epithelial-mesenchymal transition (EMT) plays an important role in diabetic renal fibrosis. The ARAP1 gene is located near risk alleles for Type 2 diabetes, and its function has been linked to cytoskeleton rearrangement, Golgi apparatus remodeling, and endocytic trafficking of membrane receptors. The role of ARAP1 and its antisense RNA, ARAP1-AS2, in the pathogenesis of diabetes is unclear. To clarify the roles of ARAP1 and its antisense RNA in diabetes and related complications, we examined if the expression of these transcripts changed under high glucose (HG) conditions. To do this, we examined transcript levels in HK-2 cells, and explored the roles of ARAP1 and ARAP1-AS2 in the EMT process in HK-2 cells. We found increased expression of ARAP1-AS2 and ARAP1 in HK-2 cells under HG condition, and observed that the overexpression of ARAP1-AS2 significantly increased the EMT process. In addition, HG upregulated Cdc42-GTP levels in HK-2 cells, and increased cytoskeleton rearrangement, cell viability, and migration. After knockdown of ARAP1, the level of Cdc42-GTP was decreased; cytoskeleton reorganization, cell viability, and migration processes were decreased; and EMT and expression of fibrosis marker protein. Overall, our results indicated that ARAP1-AS2/ARAP1 may participate in cytoskeleton rearrangement and EMT processes in HK-2 cells through increased Cdc42-GTP levels.
    Keywords:  ARAP1; Cdc42; EMT; antisense lncRNA; diabetic nephropathy
    DOI:  https://doi.org/10.1002/jcp.29512
  357. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30091-X. [Epub ahead of print]49(1): 1-18
    Evolution of Diabetes Technology.
    Dovc K, Battelino T.
      Technological innovations have fundamentally changed diabetes care. Insulin pump use and continuous glucose monitoring are associated with improved glycemic control along with a better quality of life; automated insulin-dosing advisors facilitate and improve decision making. Glucose-responsive automated insulin delivery enables the highest targets for time in range, lowest rate and duration of hypoglycemia, and favorable quality of life. Clear targets for time in ranges and a standard visualization of the data will help the diabetes technology to be used more efficiently. Decision support systems within and integrated cloud environment will further simplify, unify, and improve modern routine diabetes care.
    Keywords:  Artificial pancreas; Closed loop; Continuous glucose monitoring; Insulin pump; Multiple daily injections; Self-monitoring of blood glucose; Technology; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.009
  358. Biochem Pharmacol. 2020 Jan 16. pii: S0006-2952(20)30024-1. [Epub ahead of print] 113814
    Pathway analysis of glutamate-mediated, calcium-related signaling in glioma progression.
    Pei Z, Lee KC, Khan A, Erisnor G, Wang HY.
      Brain tumors, particularly high-grade glioblastomas, are a crucial public health issue due to poor prognosis and an extremely low survival rate. The glioblastoma multiforme (GBM) grows rapidly within its unique microenvironment that is characterized by active neural communications. Therefore, diverse neurotransmitters not only maintain normal brain functions but also influence glioma progression. To fully appreciate the relationship between neurotransmitters and glioma progression, we reviewed potential neurotransmitter contributors in human GBM and the much less aggressive Low-grade glioma (LGG) by combining previously published data from gene-mutation/mRNA sequencing databases together with protein-protein interaction (PPI) network analysis results. The summarized results indicate that glutamatergic and calcium signaling may provide positive feedback to promote glioma formation through 1) metabolic reprogramming and genetic switching to accelerate glioma duplication and progression; 2) upregulation of cytoskeleton proteins and elevation of intracellular Ca2+ levels to increase glutamate release and facilitate formation of synaptic-like connections with surrounding cells in their microenvironment. The upregulated glutamatergic neuronal activities in turn stimulate glioma growth and signaling. Importantly, the enhanced electrical and molecular signals from both neurons and glia propagate out to enable glioma symptoms such as epilepsy and migraine. The elevated intracellular Ca2+ also activates nitric oxide synthase to produce nitric oxide (NO) that can either promote or inhibit tumorigenesis. By analyzing the network effects for complex interaction among neurotransmitters such as glutamate, Ca2+ and NO in brain tumor progression, especially GBM, we identified the glutamatergic signaling as the potential therapeutic targets and suggest manipulation of glutamatergic signaling may be an effective treatment strategy for this aggressive brain cancer.
    Keywords:  Glutamate; N-methyl-D-aspartate (NMDA) receptor; Nitric Oxide synthesize (NOS); Transmitters; calcium waives; gamma-Aminobutyric acid (GABA) receptor; metabolic reprogramming; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor
    DOI:  https://doi.org/10.1016/j.bcp.2020.113814
  359. Cancer Cell. 2020 Jan 22. pii: S1535-6108(19)30583-5. [Epub ahead of print]
    Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.
    Sudhan DR, Guerrero-Zotano A, Won H, González Ericsson P, Servetto A, Huerta-Rosario M, Ye D, Lee KM, Formisano L, Guo Y, Liu Q, Kinch LN, Red Brewer M, Dugger T, Koch J, Wick MJ, Cutler RE, Lalani AS, Bryce R, Auerbach A, Hanker AB, Arteaga CL.
      We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.
    Keywords:  HER2 mutations; TORC1; drug resistance; neratinib; precision oncology
    DOI:  https://doi.org/10.1016/j.ccell.2019.12.013
  360. Bioorg Chem. 2020 Jan 10. pii: S0045-2068(19)32091-7. [Epub ahead of print]96 103575
    Design, synthesis and biological evaluation of erythrina derivatives bearing a 1,2,3-triazole moiety as PARP-1 inhibitors.
    Li S, Li XY, Zhang TJ, Zhu J, Xue WH, Qian XH, Meng FH.
      Inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer, and many researchers are interested in the development of new PARP-1 inhibitors. Herein, we designed and synthesized 44 novel erythrina derivatives bearing a 1,2,3-triazole moiety as PARP-1 inhibitors. MTT assay results indicated that compound 10b had the most potent anti-proliferative activity against A549 cells among five cancer cells. The enzyme inhibitory activity in vitro of compound 10b was also significantly better than rucaparib. Furthermore, the selectivity index of compound 10b was higher than rucaparib for lung cancer cells. Flow cytometry analysis showed that compound 10b induced apoptosis of A549 cells by the mitochondrial pathway. Western blot analysis indicated that compound 10b was able to inhibit the biosynthesis of PAR effectively, and it was more potent than rucaparib. Also, compound 10b was able to up-regulate the ratio of bax/bcl-2, activate caspase-3, and ultimately induced apoptosis of A549 cells. The combined results revealed that the discovery of novel non-amide based PARP-1 inhibitors have great research significance and provide a better choice for the future development of drugs.
    Keywords:  1,2,3-Triazole; Apoptosis; Erythrina; PARP-1 inhibitor
    DOI:  https://doi.org/10.1016/j.bioorg.2020.103575
  361. Curr Opin Cell Biol. 2020 Jan 20. pii: S0955-0674(19)30117-6. [Epub ahead of print]63 57-67
    Novel roles of phosphoinositides in signaling, lipid transport, and disease.
    Hammond GRV, Burke JE.
      Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad cellular processes and multiple human diseases mediated by misregulation of PPIn signaling. This review will present a timely summary of recent discoveries in PPIn biology, specifically their role in regulating unexpected signaling pathways, modification of signaling outcomes downstream of integral membrane proteins, and novel roles in lipid transport. This has revealed new roles of PPIns in regulating membrane trafficking, immunity, cell polarity, and response to extracellular signals. A specific focus will be on novel opportunities to target PPIn metabolism for treatment of human diseases, including cancer, pathogen infection, developmental disorders, and immune disorders.
    Keywords:  Flippases; GPCR; Ion channels; Lipid kinases; Lipid signaling; Lipid transfer proteins; Membrane contact sites; Membrane trafficking; PI3P; PI4KB; PI4P; PIK3CA; PIP2; PIP3; Phosphatidylinositol; Phosphoinositide kinases; Phosphoinositides
    DOI:  https://doi.org/10.1016/j.ceb.2019.12.007
  362. Fitoterapia. 2020 Jan 16. pii: S0367-326X(20)30064-2. [Epub ahead of print] 104482
    A review on osteoclast diseases and osteoclastogenesis inhibitors recently developed from natural resources.
    Wang X, Yamauchi K, Mitsunaga T.
      Natural products have been investigated as potential candidates of novel therapeutics and play a crucial role in advanced medicinal drugs. Natural resources, including local medicinal plants (especially folk medicinal plants), animals, bacteria, and fungi have been used for more than a century, and are precious gifts from nature, providing potential medicines with high safety. Osteoclast-related diseases, such as osteoporosis, rheumatoid arthritis, Paget's disease, osteoclastoma, and periprosthetic osteolysis, are currently the most common reasons for bone inflammation, pain and fractures, resulting in low quality of life. However, the curative effects of current therapeutic drugs for these osteoclast-related diseases are limited, and long-term treatment is needed. Further, in severe cases, surgical treatments are necessary, which may cause unaffordable expenses and subsequent influences such as neuralgia, mental stress, and even development of cancer. Thus, safer inhibitors and potential drugs with enhanced curative effects and quick relief are needed to treat patients with osteoclast diseases. This review aims to introduce the main osteoclast-related diseases and some of the recently developed naturally sourced inhibitors against osteoclastogenesis, also it is desired to attract people's attention on using widely available natural resources for the evolution of new types of osteoclast inhibitors with minimal or no side-effects upon long-term treatments.
    Keywords:  Inhibitors; Natural resources; Osteoclast-related diseases; Osteoclastogenesis
    DOI:  https://doi.org/10.1016/j.fitote.2020.104482
  363. Expert Opin Drug Discov. 2020 Jan 20. 1-14
    New directions in antimalarial target validation.
    Batista FA, Gyau B, Vilacha JF, Bosch SS, Lunev S, Wrenger C, Groves MR.
      Introduction: Malaria is one of the most prevalent human infections worldwide with over 40% of the world's population living in malaria-endemic areas. In the absence of an effective vaccine, emergence of drug-resistant strains requires urgent drug development. Current methods applied to drug target validation, a crucial step in drug discovery, possess limitations in malaria. These constraints require the development of techniques capable of simplifying the validation of Plasmodial targets.Areas covered: The authors review the current state of the art in techniques used to validate drug targets in malaria, including our contribution - the protein interference assay (PIA) - as an additional tool in rapid in vivo target validation.Expert opinion: Each technique in this review has advantages and disadvantages, implying that future validation efforts should not focus on a single approach, but integrate multiple approaches. PIA is a significant addition to the current toolset of antimalarial validation. Validation of aspartate metabolism as a druggable pathway provided proof of concept of how oligomeric interfaces can be exploited to control specific activity in vivo. PIA has the potential to be applied not only to other enzymes/pathways of the malaria parasite but could, in principle, be extrapolated to other infectious diseases.
    Keywords:  Protein oligomerisation; drug target validation; malaria; phenotypic mapping
    DOI:  https://doi.org/10.1080/17460441.2020.1691996
  364. J Allergy Clin Immunol. 2020 Jan 16. pii: S0091-6749(20)30037-3. [Epub ahead of print]
    Vagal sensory neurons drive mucous cell metaplasia.
    Talbot S, Doyle B, Huang J, Wang JC, Ahmadi M, Roberson DP, Yekkirala A, Foster SL, Browne LE, Bean BP, Levy BD, Woolf CJ.
      Airway sensory neuron-produced Substance P heightens allergy-induced goblet cell hyperplasia and hypersecretion of Muc5AC, electrically silencing these overreactive neurons reduced these components of lung type 2 allergic inflammatory response.
    Keywords:  Asthma; Goblet cell hyperplasia; Muc5AC; Muc5B; Mucous metaplasia; Optogenetic; QX-314; Substance P; TRPV1; Vagal sensory neurons
    DOI:  https://doi.org/10.1016/j.jaci.2020.01.003
  365. Arch Gynecol Obstet. 2020 Jan 21.
    Altered growth trajectory in children born to mothers with gestational diabetes mellitus and preeclampsia.
    Huang Y, Zhang W, Go K, Tsuchiya KJ, Hu J, Skupski DW, Sie SY, Nomura Y.
      PURPOSE: Gestational diabetes mellitus (GDM) and preeclampsia are leading causes of mortality and morbidity in mothers and children. High childhood body mass index (BMI) is among their myriad of negative outcomes. However, little is known about the trajectory of the child BMI exposed to GDM and co-occurring preeclampsia from early to mid-childhood. This study examined the independent and joint impact of GDM and preeclampsia on childhood BMI trajectory.METHODS: A population-based sample of 356 mothers were recruited from OB/GYN clinics in New York. Their children were then followed annually from 18 to 72 months. Maternal GDM and preeclampsia status were obtained from medical records. Child BMI was calculated based on their height and weight at annual visits.
    RESULTS: Hierarchical Linear Modeling was used to evaluate the trajectories of child BMI exposed to GDM and preeclampsia. BMI trajectory by GDM decreased (t ratio = - 2.24, [Formula: see text]0.45, 95% CI - 0.05-0.95, p = 0.07), but the trajectory by preeclampsia increased over time (t ratio = 3.153,[Formula: see text]0.65, 95% CI 0.11-1.18, p = 0.002). Moreover, there was a significant interaction between the two (t ratio = -2.24, [Formula: see text]- 1.244, 95% CI 0.15-2.33, p = 0.02), such that the BMI of children born to mothers with both GDM and preeclampsia showed consistent increases over time.
    CONCLUSIONS: GDM and preeclampsia could be used as a marker for childhood obesity risk and the identification of a high-risk group, providing potential early intervention. These findings highlight the importance of managing obstetric complications, as an effective method of child obesity prevention.
    Keywords:  Body mass index; Childhood obesity; Gestational diabetes mellitus; Growth trajectory; Preeclampsia; Prenatal origin of childhood obesity
    DOI:  https://doi.org/10.1007/s00404-020-05436-2
  366. Plant Physiol Biochem. 2020 Jan 07. pii: S0981-9428(20)30005-X. [Epub ahead of print]148 122-132
    Energy conversion processes and related gene expression in a sunflower mutant with altered salicylic acid metabolism.
    Scartazza A, Fambrini M, Mariotti L, Picciarelli P, Pugliesi C.
      Salicylic acid (SA) is involved in several responses associated with plant development and defence against biotic and abiotic stress, but its role on photosynthetic regulation is still under debate. This work investigated energy conversion processes and related gene expression in the brachytic mutant of sunflower lingering hope (linho). This mutant was characterized by a higher ratio between the free SA form and its conjugate form SA O-β-D-glucoside (SAG) compared to wild type (WT), without significant changes in the endogenous level of abscisic acid and hydrogen peroxide. The mutant showed an inhibition of photosynthesis due to a combination of both stomatal and non-stomatal limitations, although the latter seemed to play a major role. The reduced carboxylation efficiency was associated with a down-regulation of the gene expression for both the large and small subunits of Rubisco and the Rubisco activase enzyme. Moreover, linho showed an alteration of photosystem II (PSII) functionality, with reduced PSII photochemistry, increased PSII excitation pressure and decreased thermal energy dissipation of excessive light energy. These responses were associated with a lower photosynthetic pigments concentration and a reduced expression of genes encoding for light-harvesting chlorophyll a/b binding proteins (i.e. HaLhcA), chlorophyll binding subunits of PSII proteins (i.e. HaPsbS and HaPsbX), phytoene synthase enzyme and a different expression level for genes related to PSII repair cycle, such as HaPsbA and HaPsbD. The concomitant stimulation of respiratory metabolism, suggests that linho activated a coordinate modulation of chloroplast and mitochondria activities to compensate the energy imbalance and regulate energy conversion processes.
    Keywords:  Carboxylation efficiency; Electron transport rate; Light energy dissipation; Photosynthetic pigments; Plant hormones; Real-time quantitative PCR
    DOI:  https://doi.org/10.1016/j.plaphy.2020.01.005
  367. Cell Signal. 2020 Jan 17. pii: S0898-6568(20)30020-6. [Epub ahead of print] 109543
    E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer.
    Jin J, Lu Z, Wang X, Liu Y, Han T, Wang Y, Wang T, Gan M, Xie C, Wang J, Yu B.
      The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer.
    Keywords:  Degradation; GNIP1; NF-κB; NSCLC; TRIM7; Tumor suppressor
    DOI:  https://doi.org/10.1016/j.cellsig.2020.109543
  368. Ann Oncol. 2020 Feb;pii: S0923-7534(19)36083-1. [Epub ahead of print]31(2): 191-201
    Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.
    Park K, Vansteenkiste J, Lee KH, Pentheroudakis G, Zhou C, Prabhash K, Seto T, Voon PJ, Tan DSW, Yang JCH, Wang J, Babu KG, Nakayama Y, Alip A, Chua KLM, Cheng JC, Senan S, Ahn YC, Kim TY, Ahn HK, Peters S, Yoshino T, Douillard JY.
      The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.
    Keywords:  ESMO guidelines; NSCLC; Pan-Asian; consensus; locally-advanced; unresectable
    DOI:  https://doi.org/10.1016/j.annonc.2019.10.026
  369. Chem Biol Interact. 2020 Jan 19. pii: S0009-2797(19)31858-7. [Epub ahead of print] 108947
    Immunological axis of berberine in managing inflammation underlying chronic respiratory inflammatory diseases.
    Tew XN, Xin Lau NJ, Chellappan DK, Madheswaran T, Zeeshan F, Tambuwala MM, Aljabali AA, Balusamy SR, Perumalsamy H, Gupta G, Oliver BG, Hsu A, Wark P, Reddy K, Wadhwa R, Hansbro PM, Dua K.
      Inflammatory responses play a remarkable role in the mechanisms of acute and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and lung cancer. Currently, there is a resurgence in the use of drugs from natural sources for various ailments as potent therapeutics. Berberine, an alkaloid prominent in the Chinese traditional system of medicine has been reported to exert therapeutic properties in various diseases. Nevertheless, the number of studies focusing on the curative potential of berberine in inflammatory diseases involving the respiratory system is limited. In this review, we have attempted to discuss the reported anti-inflammatory properties of berberine that function through several pathways such as, the NF-κB, ERK1/2 and p38 MAPK pathways which affect several pro-inflammatory cytokines in the pathophysiological processes involved in chronic respiratory diseases. This review would serve to provide valuable information to researchers who work in this field and a new direction in the field of drug discovery with respect to respiratory diseases.
    Keywords:  Asthma; Berberine; COPD; Inflammatory diseases; Lung cancer; Pulmonary fibrosis; Respiratory diseases
    DOI:  https://doi.org/10.1016/j.cbi.2020.108947
  370. J Cell Physiol. 2020 Jan 24.
    Mechanical stretch activates glycometabolism-related enzymes via estrogen in C2 C12 myoblasts.
    Feng Y, Zhang J, Tian X, Wu J, Lu J, Shi R.
      Moderate exercise improves glycometabolic disorder and type 2 diabetes mellitus in menopausal females. So far, the effect of exercise-induced estrogen on muscular glycometabolism is not well defined. The current study was designed to explore the effect of mechanical stretch-induced estrogen on glycometabolism in mouse C2 C12 myoblasts. The mouse C2 C12 myoblasts in vitro were assigned randomly to the control (C), stretch (S), and stretch plus aromatase inhibitor anastrozole (SA) groups. Cells in the S group were stretched by the Flexcell FX-5000™ system (15% magnitude, 1 Hz frequency, and 6-hr duration) whereas those in the SA group were treated with 400 μg/ml anastrozole before the same stretching. Glucose uptake, estradiol levels, PFK-1 levels, and oxygen consumption rate were determined, and the expression of HK, PI3K, p-AKT, AKT, and GLUT4 proteins were semiquantified with western blot analysis. Compared to the control, the estradiol level, oxygen consumption rate, expression of HK, PI3K, and PFK-1 proteins, the ratio of p-AKT to AKT, and the ratio of GLUT4 in the cell membrane to that in the whole cell were higher in the S group. On the other hand, the estradiol level, glucose uptake, expression of PFK-1 and GLUT4 proteins, oxygen consumption rate, expression of HK protein, and the ratio of p-AKT/AKT were lower in the myoblasts in the SA group than those in the S group. The level of estradiol was positively correlated with glucose uptake (p < .01, r = .818). Therefore, mechanical stretch-induced estrogen increased the expression of glycometabolism-related enzymes and proteins in the mouse C2 C12 myoblasts.
    Keywords:  C2C12 myoblasts; GLUT4; estrogen; glycometabolism
    DOI:  https://doi.org/10.1002/jcp.29502
  371. J Biosci. 2020 ;pii: 3. [Epub ahead of print]45
    Hypoxia-induced changes in intragenic DNA methylation correlate with alternative splicing in breast cancer.
    Pant D, Narayanan SP, Vijay N, Shukla S.
      The tumor microenvironment is marked by gradients in the level of oxygen and nutrients, with oxygen levels reaching a minimum at the core of the tumor, a condition known as tumor hypoxia. Mediated by members of the HIF family of transcription factors, hypoxia leads to a more aggressive tumor phenotype by transactivation of several genes as well as reprogramming of pre-mRNA splicing. Intragenic DNA methylation, which is known to affect alternative splicing in cancer, could be one of several reasons behind the changes in splicing patterns under hypoxia. Here, we have tried to establish a correlation between intragenicDNA methylation and alternative usage of exons in tumor hypoxia. First, we have generated a customhypoxia signature consisting of 34 genes that are upregulated under hypoxia and are direct targets of HIF-1α. Using this gene expression signature, we have successfully stratified publicly available breast cancer patient samples into hypoxia positive and hypoxia negative groups followed by mining of differentially spliced isoforms between these groups. The Hypoxia Hallmark signature from MSigDB was also used independently to stratify the same tumor samples into hypoxic and normoxic.We found that 821 genes were showing differential splicing between samples stratified using a custom signature, whereas, 911 genes were showing differential splicing between samples stratified using the MSigDB signature. Finally, we performed multiple correlation tests between the methylation levels (β) of microarray probes located within 1 kilo base pairs of isoform-specific exons using those exons' expression levels in the same patient samples in which the methylation level was recorded. We found that the expression level of one of the exons ofDHX32 and BICD2 significantly correlated with the methylation levels, and we were also able to predict patient survival (p-value: 0.02 for DHX32 and 0.0024 for BICD2). Our findings provide new insights into the potential functional role of intragenic DNA methylation in modulating alternative splicing during hypoxia.
  372. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Jan 15. pii: S1388-1981(20)30023-8. [Epub ahead of print]1865(4): 158631
    The regulation of p53, p38 MAPK, JNK and XBP-1s by sphingosine kinases in human embryonic kidney cells.
    Alsanafi M, Kelly SL, McNaughton M, Merrill AH, Pyne NJ, Pyne S.
      Since inhibitors of sphingosine kinases (SK1, SK2) have been shown to induce p53-mediated cell death, we have further investigated their role in regulating p53, stress activated protein kinases and XBP-1s in HEK293T cells. Treatment of these cells with the sphingosine kinase inhibitor, SKi, which fails to induce apoptosis, promoted the conversion of p53 into two proteins with molecular masses of 63 and 90 kDa, and which was enhanced by over-expression of ubiquitin. The SKi induced conversion of p53 to p63/p90 was also enhanced by siRNA knockdown of SK1, but not SK2 or dihydroceramide desaturase (Degs1), suggesting that SK1 is a negative regulator of this process. In contrast, another sphingosine kinase inhibitor, ABC294640 only very weakly stimulated formation of p63/p90 and induced apoptosis of HEK293T cells. We have previously shown that SKi promotes the polyubiquitination of Degs1, and these forms positively regulate p38 MAPK/JNK pathways to promote HEK293T cell survival/growth. siRNA knockdown of SK1 enhanced the activation of p38 MAPK/JNK pathways in response to SKi, suggesting that SK1 functions to oppose these pro-survival pathways in HEK293T cells. SKi also enhanced the stimulatory effect of the proteasome inhibitor, MG132 on the expression of the pro-survival protein XBP-1s and this was reduced by siRNA knockdown of SK2 and increased by knockdown of p53. These findings suggest that SK1 and SK2 have opposing roles in regulating p53-dependent function in HEK293T cells.
    Keywords:  Dihydroceramide desaturase; ER stress; Proteasome; Sphingosine 1-phosphate; Sphingosine kinase
    DOI:  https://doi.org/10.1016/j.bbalip.2020.158631
  373. Fish Shellfish Immunol. 2020 Jan 19. pii: S1050-4648(20)30026-7. [Epub ahead of print]
    Arginine, ornithine and citrulline supplementation in rainbow trout: Free amino acid dynamics and gene expression responses to bacterial infection.
    Clark TC, Tinsley J, Sigholt T, Macqueen DJ, Martin SAM.
      Supplementing the diet with functional ingredients is a key strategy to improve fish performance and health in aquaculture. The amino acids of the urea and nitric oxide (NO) cycles - arginine, ornithine and citrulline - perform crucial roles in the immune response through the generation of NO and the synthesis of polyamine used for tissue repair. We previously found that citrulline supplementation improves and maintains circulating free arginine levels in rainbow trout more effectively than arginine supplementation. Here, to test whether supplementation of urea cycle amino acids modulates the immune response in rainbow trout (Oncorhynchus mykiss), we supplemented a commercial diet with high levels (2% of total diet) of either arginine, ornithine or citrulline during a 7-week feeding trial, before challenging fish with the bacterium Aeromonas salmonicida. We carried out two separate experiments to investigate fish survival and 24 h post-infection to investigate the immediate response of free amino acid levels, and transcriptional changes in genes encoding urea cycle, NO cycle and polyamine synthesis enzymes. There were no differences in percentage fish mortality between diets, however there were numerous highly significant changes in free amino acid levels and gene expression to both dietary supplementation and infection. Out of 26 amino acids detected in blood plasma, 8 were significantly changed by infection and 9 by dietary supplementation of either arginine, ornithine or citrulline. Taurine, glycine and aspartic acid displayed the largest decreases in circulating levels in infected fish, while ornithine and isoleucine were the only amino acids that increased in concentration. We investigated transcriptional responses of the enzymes involved in arginine metabolism in liver and head kidney; transcripts for polyamine synthesis enzymes showed highly significant increases in both tissues across all diets following infection. The paralogous arginase-encoding genes, Arg1a, Arg1b, Arg2a and Arg2b, displayed complex responses across tissues and also due to diet and infection. Overall, these findings improve our understanding of amino acid metabolism following infection and suggests new potential amino acid targets for improving the immune response in salmonids.
    Keywords:  Arginine; Citrulline; Functional amino acids; Health; Ornithine; Polyamine; Salmonids; Urea cycle
    DOI:  https://doi.org/10.1016/j.fsi.2020.01.026
  374. Stem Cell Res Ther. 2020 Jan 23. 11(1): 36
    Mesenchymal stem cell-derived exosomes ameliorate cardiomyocyte apoptosis in hypoxic conditions through microRNA144 by targeting the PTEN/AKT pathway.
    Wen Z, Mai Z, Zhu X, Wu T, Chen Y, Geng D, Wang J.
      BACKGROUND: A growing body of evidence suggests that stem cell-derived exosomal microRNAs (miRNAs) could be a promising cardioprotective therapy in the context of hypoxic conditions. The present study aims to explore how miRNA-144 (miR-144), a miRNA contained in bone marrow mesenchymal stem cell (MSC)-derived exosomes, exerts a cardioprotective effect on cardiomyocyte apoptosis in the context of hypoxic conditions and identify the underlying mechanisms.METHODS: MSCs were cultured using the whole bone marrow adherent method. MSC-derived exosomes were isolated using the total exosome isolation reagent and confirmed by nanoparticle trafficking analysis as well as western blotting using TSG101 and CD63 as markers. The hypoxic growth conditions for the H9C2 cells were established using the AnaeroPack method. Treatment conditions tested included H9C2 cells pre-incubated with exosomes, transfected with miR-144 mimics or inhibitor, or treated with the PTEN inhibitor SF1670, all under hypoxic growth conditions. Cell apoptosis was determined by flow cytometry using 7-ADD and Annexin V together. The expression levels of the miRNAs were detected by real-time PCR, and the expression levels of AKT/p-AKT, Bcl-2, caspase-3, HIF-1α, PTEN, and Rac-1 were measured by both real-time PCR and western blotting.
    RESULTS: Exosomes were readily internalized by H9C2 cells after co-incubation for 12 h. Exosome-mediated protection of H9C2 cells from apoptosis was accompanied by increasing levels of p-AKT. MiR-144 was found to be highly enriched in MSC-derived exosomes. Transfection of cells with a miR-144 inhibitor weakened exosome-mediated protection from apoptosis. Furthermore, treatment of cells grown in hypoxic conditions with miR-144 mimics resulted in decreased PTEN expression, increased p-AKT expression, and prevented H9C2 cell apoptosis, whereas treatment with a miR-144 inhibitor resulted in increased PTEN expression, decreased p-AKT expression, and enhanced H9C2 cell apoptosis in hypoxic conditions. We also validated that PTEN was a target of miR-144 by using luciferase reporter assay. Additionally, cells treated with SF1670, a PTEN-specific inhibitor, resulted in increased p-AKT expression and decreased H9C2 cell apoptosis.
    CONCLUSIONS: These findings demonstrate that MSC-derived exosomes inhibit cell apoptotic injury in hypoxic conditions by delivering miR-144 to cells, where it targets the PTEN/AKT pathway. MSC-derived exosomes could be a promising therapeutic vehicle to facilitate delivery of miRNA therapies to ameliorate ischemic conditions.
    Keywords:  Cell apoptosis; Exosomes; Mesenchymal stem cells; PTEN/AKT pathway; microRNA-144
    DOI:  https://doi.org/10.1186/s13287-020-1563-8
  375. J Pak Med Assoc. 2020 Jan;70(1): 17-23
    Balance disorder, falling risks and fear of falling in obese individuals: cross-sectional clinical research in Isparta.
    Ercan S, Baskurt Z, Baskurt F, Cetin C.
      OBJECTIVE: To examine the effect of obesity according to gender on balance, posture, the risk of falling and the fear of falling.METHODS: The cross-sectional study was conducted at the Department of Sports Medicine, Suleyman Demirel University, Isparta, Turkey, from December 2016 to June 2017, and comprised individuals aged 40-60 years who were divided into obese and non-obese groups based on their body mass index values. Demographic data was recorded before collecting target data using Tinetti Falls Efficacy Scale, Activities-Specific Balance Confidence Scale, History of Falls Scale, Single Leg Stance Test, Functional Reach Test and the New York Posture Rating Test. SPSS 20 was used for data analysis.
    RESULTS: Of the 251 subjects, 129(51.4%) were females and 122(48.6%) were males. The obese group had 125(49.8%) subjects. There was a significant difference between the history of stumbling in obese males and the history of stumbling and falls in obese females (p<0.05). A high restriction in activity was determined in obese females because of fear of falling (p<0.05). There was impaired posture in all 125(100%) obese individuals and they had all experienced loss of balance. Despite loss of balance and impaired posture in obese males, they did not experience fear of falling and no difference was determined in confidence (p>0.05). Fear of falling was high in obese females and confidence in daily activities was low (p<0.05). Significant negative relationship was found among body mass index, loss of balance and poor posture (p<0.05). No significant relationship was determined in males between obesity and Tinetti Falls Efficacy Scale and Activities-Specific Balance Confidence Scale scores (p>0.05).
    CONCLUSIONS: Obesity causes loss of balance and posture. However, despite functional losses in obese males, as there was no fear of falling and a deceptive sense of confidence, this prevented prediction of the risk of falling.
    Keywords:  Obesity, Balance, Posture, Risk of fall, Fear of fall
    DOI:  https://doi.org/10.5455/JPMA.293668
  376. Biochim Biophys Acta Biomembr. 2020 Jan 20. pii: S0005-2736(20)30026-2. [Epub ahead of print] 183200
    Photo-controlled delivery of very long chain fatty acids to cell membranes and modulation of membrane protein function.
    Kong L, Dawkins E, Campbell F, Winkler E, Derks RJE, Giera M, Kamp F, Steiner H, Kros A.
      The biophysical properties and biological functions of membranes are highly dependent on lipid composition. Supplementing cellular membranes with very long chain fatty acids (vlcFAs) is notoriously difficult given the extreme insolubility of vlcFAs in aqueous solution. Herein, we report a solvent-free, photochemical approach to enrich target membranes with vlcFA. To prevent aggregation of vlcFA, we created light-sensitive micelles composed exclusively of poly-ethylene-glycol-nervonic acid amphiphiles (NA-PEG), which spontaneously disassemble in the presence of lipid bilayers. Once embedded within a membrane, UV light is used to cleave off PEG, leaving free nervonic acid (NA, i.e. FA24:1) in the target membrane. When applied to living cells, free NA was processed by the cell to generate various species of membrane and other lipids with incorporated vlcFAs. In this way, we were able to alter the membrane lipid composition of cellular membranes and modulate the enzymatic activity of γ-secretase, an intramembrane protease whose dysfunction has been implicated in the onset and progression of Alzheimer's disease.
    Keywords:  Alzheimer's disease; Cell membranes; Light activation; Lipidomics; Nervonic acid; Very long chain fatty acids; γ-Secretase
    DOI:  https://doi.org/10.1016/j.bbamem.2020.183200
  377. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30103-0. [Epub ahead of print]
    PRMT2 inhibits the formation of foam cell induced by ox-LDL in RAW 264.7 macrophage involving ABCA1 mediated cholesterol efflux.
    Li YY, Zhou SH, Chen SS, Zhong J, Wen GB.
      OBJECTIVES: Protein arginine methyltransferase 2 (PRMT2) is closely related to the occurrence and development of atherosclerosis. However, its underlying mechanisms remain to be elucidated. The purpose of this study is to observe the effect of overexpression of PRMT2 on the formation of foam cells and to explore its possible mechanism in RAW 264.7 macrophage.METHODS: Lentivirus vector of overexpression PRMT2 (LV-PRMT2) was constructed. LV-PRMT2 and lentivirus vector GV492 were transfected into RAW 264.7 macrophages, positive clone cells were screened by treatment with 4.0 μg/mL puromycin for 4 weeks. The macrophages were treated with ox-LDL (50 μg/mL) for 48 h to induce foaming. The lipid accumulation of macrophages was observed by oil red O staining. The levels of cellular total cholesterol (TC), free cholesterol (FC) and cholesteryl ester (CE) were measured by high performance liquid chromatography (HPLC) assays. The cholesterol efflux of macrophages was tested by the [3H] labeled cholesterol. The expressions of ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1), CD36 and scavenger receptor A1 (SR-A1) in macrophages were measured by Western Blot.
    RESULTS: The results showed that LV-PRMT2 and lentivirus vector has been successfully transfected into RAW 264.7 macrophage. Compared with the Vector group, the mRNA and protein expressions of PRMT2 were significantly up-regulated (P < 0.05). Compared with Control group, the expression of PRMT2 was significantly down-regulated in ox-LDL group (P < 0.05). A large number of red lipid droplets appeared in the cells in Vector group. Compared with Vector group, lipid droplets, the levels of TC, FC and CE and CE/TC, cholesterol efflux rate and expression of ABCA1 in RAW 264.7 macrophage was significantly decreased in LV-PRMT2 group (all P < 0.05). There was no significant difference about the expressions of ABCG1, CD36 and SR-A1 between LV-PRMT2 group and Vector group (all P > 0.05).
    CONCLUSIONS: Overexpression of PRMT2 inhibits the formation of foam cell induced by ox-LDL in RAW 264.7 macrophage, and the mechanism may be related to the increase of ABCA1 expression and ABCA1 mediated cholesterol efflux.
    Keywords:  ATP binding cassette transporter A1; Atherosclerosis; Cholesterol efflux; Foam cell; Protein arginine methyltransferase 2
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.040
  378. J Anim Physiol Anim Nutr (Berl). 2020 Jan 23.
    Dietary thymol supplementation promotes skeletal muscle fibre type switch in longissimus dorsi of finishing pigs.
    Luo P, Luo L, Zhao W, Wang L, Sun L, Wu H, Li Y, Zhang R, Shu G, Wang S, Gao P, Zhu X, Xi Q, Zhang Y, Wang L, Jiang Q.
      As one of the key points related to meat quality, skeletal muscle fibre type is determined by energy metabolism and genetic factors, but its transformation could be also greatly influenced by many factors. Thymol, the primary effective ingredients of thyme, is well known for its anti-oxidation and anti-inflammatory, while little is known about its effect on skeletal muscle oxidative metabolism and fibre type switch. Therefore, in order to investigate its effects and possibility to be applied in livestock production, 36 150-day-old fattening Pigs were fed with different diet for six-week experiment. As a result, the drip loss ratio of longissimus dorsi (LD) was significantly reduced (p < .05). Oxidative metabolism-related enzyme activity, the mRNA levels and protein expression of COX5B and PGC1α, mRNA level of myosin heavy chain I (MyHC I) and protein level of MyHC IIa were significantly upregulated (p < .05). While compared with control group, the protein expression of MyHC IIb was significantly decreased (p < .05). The result revealed that thymol could promote the oxidative metabolism in the muscle of pigs and improve the meat quality to a certain extent.
    Keywords:  muscle fibre type; oxidative metabolism; pigs; thymol
    DOI:  https://doi.org/10.1111/jpn.13269
  379. Lancet Respir Med. 2020 Jan 15. pii: S2213-2600(19)30361-3. [Epub ahead of print]
    Nazartinib in EGFR Thr790Met-mutant non-small-cell lung cancer.
    Jassem J, Dziadziuszko R.
      
    DOI:  https://doi.org/10.1016/S2213-2600(19)30361-3
  380. South Asian J Cancer. 2020 Jan-Mar;9(1):9(1): 67-68
    Lorlatinib in anaplastic lymphoma kinase-positive non-small cell lung cancer: Indian experience.
    Talreja VT, Noronha V, Patil VM, Joshi A, Prabhash K.
      
    DOI:  https://doi.org/10.4103/sajc.sajc_364_19
  381. Semin Roentgenol. 2020 Jan;pii: S0037-198X(19)30079-3. [Epub ahead of print]55(1): 4
    Letter From the Guest Editor: Lung Cancer-From Diagnosis to Imaging to Management.
    Mohammed TL.
      
    DOI:  https://doi.org/10.1053/j.ro.2019.10.005
  382. Cell Rep. 2020 Jan 21. pii: S2211-1247(20)30036-X. [Epub ahead of print]30(3): 599-601
    A LIGHTning Strike to the Metastatic Niche.
    Martinez-Usatorre A, De Palma M.
      Tumor-induced vascular alterations in distant organs have been linked to the spreading of cancer. In this issue of Cell Reports, He et al. (2019) show that targeting the cytokine LIGHT to the pulmonary vasculature prevents the establishment of lung metastasis in mice.
    DOI:  https://doi.org/10.1016/j.celrep.2020.01.027
  383. Sci Rep. 2020 Jan 24. 10(1): 1110
    Neutrophils do not impact viral load or the peak of disease severity during RSV infection.
    Kirsebom F, Michalaki C, Agueda-Oyarzabal M, Johansson C.
      Lung and airway neutrophils are a hallmark of severe disease in infants with respiratory syncytial virus (RSV)-induced lower respiratory tract infections. Despite their abundance in the lungs during RSV infection of both mice and man, the role of neutrophils in viral control and in immune pathology is not clear. Here, antibody mediated neutrophil depletion was used to investigate the degree to which neutrophils impact the lung immune environment, the control of viral replication and the peak severity of disease after RSV infection of mice. Neutrophil depletion did not substantially affect the levels of inflammatory mediators such as type I interferons, IL-6, TNF-α or IL-1β in response to RSV. In addition, the lack of neutrophils did not change the viral load during RSV infection. Neither neutrophil depletion nor the enhancement of lung neutrophils by administration of the chemoattractant CXCL1 during RSV infection affected disease severity as measured by weight loss. Therefore, in this model of RSV infection, lung neutrophils do not offer obvious benefits to the host in terms of increasing anti-viral inflammatory responses or restricting viral replication and neutrophils do not contribute to disease severity.
    DOI:  https://doi.org/10.1038/s41598-020-57969-w
  384. Nat Commun. 2020 Jan 23. 11(1): 465
    Chaperone mediated detection of small molecule target binding in cells.
    Cho KF, Ma TP, Rose CM, Kirkpatrick DS, Yu K, Blake RA.
      The ability to quantitatively measure a small molecule's interactions with its protein target(s) is crucial for both mechanistic studies of signaling pathways and in drug discovery. However, current methods to achieve this have specific requirements that can limit their application or interpretation. Here we describe a complementary target-engagement method, HIPStA (Heat Shock Protein Inhibition Protein Stability Assay), a high-throughput method to assess small molecule binding to endogenous, unmodified target protein(s) in cells. The methodology relies on the change in protein turnover when chaperones, such as HSP90, are inhibited and the stabilization effect that drug-target binding has on this change. We use HIPStA to measure drug binding to three different classes of drug targets (receptor tyrosine kinases, nuclear hormone receptors, and cytoplasmic protein kinases), via quantitative fluorescence imaging. We further demonstrate its utility by pairing the method with quantitative mass spectrometry to identify previously unknown targets of a receptor tyrosine kinase inhibitor.
    DOI:  https://doi.org/10.1038/s41467-019-14033-0
  385. Biochem Biophys Res Commun. 2020 Jan 20. pii: S0006-291X(20)30061-9. [Epub ahead of print]
    Zinc induces iron egress from intestinal Caco-2 cells via induction of Hephaestin: A role for PI3K in intestinal iron absorption.
    Kondaiah P, Sharp PA, Pullakhandam R.
      In previous studies we demonstrated that zinc stimulates iron uptake in intestinal Caco-2 cells via Zinc-PI3K-IRP2-DMT1 axis. In the current study we investigated the effect of zinc on basolateral iron release and characterized the associated mechanisms. In Caco-2 cells grown on permeable supports, zinc induced iron transport and expression of DMT1, HEPH mRNA and protein, but not that of FPN1. LY294002, an inhibitor of PI3K, inhibited the zinc-induced iron transport, DMT1, HEPH mRNA and protein expression. In addition, LY294002 also inhibited the basal expression of HEPH and FPN1 resulting in blockade of iron egress from cells. In addition, siRNA-silencing of HEPH led to inhibition of both zinc-induced and basal iron transport. Conversely, TPEN, a chelator of zinc, inhibited iron uptake, DMT1, HEPH and FPN1 mRNA and protein expression. These results suggest that intestinal cell zinc status is a critical determinant of iron absorption and effects are mediated via activation of PI3K. Further, PI3K pathway appears to selectively modulate the expression of iron transporters and iron absorption, therefore this might serve as a therapeutic target in iron overload disorders.
    Keywords:  Caco-2 cells; Hephaestin; Interactions; Iron; Iron transporters; PI3K; Zinc; siRNA
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.023
  386. Biomolecules. 2020 Jan 17. pii: E152. [Epub ahead of print]10(1):
    Retinoic Acid: A Key Regulator of Lung Development.
    Fernandes-Silva H, Araújo-Silva H, Correia-Pinto J, Moura RS.
      Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA levels that assures the formation of a fully functional organ. RA signaling influences lung specification, branching morphogenesis, and alveolarization by regulating the expression of particular target genes. Moreover, cooperation with other developmental pathways is essential to shape lung organogenesis. This review focuses on the events regulated by retinoic acid during lung developmental phases and pulmonary vascular development; also, it aims to provide a snapshot of RA interplay with other well-known regulators of lung development.
    Keywords:  alveologenesis; branching morphogenesis; lung specification; respiratory system; retinol; vitamin A
    DOI:  https://doi.org/10.3390/biom10010152
  387. Mol Genet Metab. 2020 Jan 09. pii: S1096-7192(19)31323-X. [Epub ahead of print]
    The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes.
    Welsink-Karssies MM, van Weeghel M, Hollak CEM, Elfrink HL, Janssen MCH, Lai K, Langendonk JG, Oussoren E, Ruiter JPN, Treacy EP, de Vries M, Ferdinandusse S, Bosch AM.
      BACKGROUND: The high variability in clinical outcome of patients with Classical Galactosemia (CG) is poorly understood and underlines the importance of prognostic biomarkers, which are currently lacking. The aim of this study was to investigate if residual galactose metabolism capacity is associated with clinical and biochemical outcomes in CG patients with varying geno- and phenotypes.METHODS: Galactose Metabolite Profiling (GMP) was used to determine residual galactose metabolism in fibroblasts of CG patients. The association between the galactose index (GI) defined as the ratio of the measured metabolites [U13C]Gal-1-P/ [13C6]UDP-galactose, and both intellectual and neurological outcome and galactose-1-phosphate (Gal-1-P) levels was investigated.
    RESULTS: GMP was performed in fibroblasts of 28 patients and 3 control subjects. The GI of the classical phenotype patients (n = 22) was significantly higher than the GI of four variant patients detected by newborn screening (NBS) (p = .002), two homozygous p.Ser135Leu patients (p = .022) and three controls (p = .006). In the classical phenotype patients, 13/18 (72%) had a poor intellectual outcome (IQ < 85) and 6/12 (50%) had a movement disorder. All the NBS detected variant patients (n = 4) had a normal intellectual outcome (IQ ≥ 85) and none of them has a movement disorder. In the classical phenotype patients, there was no significant difference in GI between patients with a poor and normal clinical outcome. The NBS detected variant patients had significantly lower GI levels and thus higher residual galactose metabolism than patients with classical phenotypes. There was a clear correlation between Gal-1-P levels in erythrocytes and the GI (p = .001).
    CONCLUSIONS: The GI was able to distinguish CG patients with varying geno- and phenotypes and correlated with Gal-1-P. The data of the NBS detected variant patients demonstrated that a higher residual galactose metabolism may result in a more favourable clinical outcome. Further research is needed to enable individual prognostication and treatment in all CG patients.
    Keywords:  Classical Galactosemia; Fibroblasts; GALT deficiency; Inborn error of metabolism; Residual galactose metabolism
    DOI:  https://doi.org/10.1016/j.ymgme.2020.01.002
  388. Aging (Albany NY). 2020 Jan 21. 12
    Effect of antioxidants on the H2O2-induced premature senescence of human fibroblasts.
    Pieńkowska N, Bartosz G, Pichla M, Grzesik-Pietrasiewicz M, Gruchala M, Sadowska-Bartosz I.
      The study was aimed at evaluation of the role of secondary oxidative stress in the stress-induced premature senescence (SIPS) of human fibroblasts induced by H2O2. Two fibroblast lines were used: lung MRC-5 and ear H8F2p25LM fibroblasts. The lines differed considerably in sensitivity to H2O2 (IC50 of 528 and 33.5 μM, respectively). The cells were exposed to H2O2 concentrations corresponding to IC50 and after 24 h supplemented with a range of antioxidants. Most of antioxidants studied slightly augmented the survival of fibroblasts at single concentrations or in a narrow concentration range, but the results were not consistent among the cell lines. Chosen antioxidants (4-amino-TEMPO, curcumin, caffeic acid and p-coumaric acid) did not restore the level of glutathione decreased by H2O2. Hydrogen peroxide treatment did not induce secondary production of H2O2 and even decreased it, decreased mitochondrial potential in both cell lines and induced changes in the mitochondrial mass inconsistent between the lines. Antioxidant protected mitochondrial potential only in H8F2p25LM cells, but attenuated changes in mitochondrial mass. These results speak against the intermediacy of secondary oxidative stress in the SIPS induced by H2O2 and suggest that the small protective action of antioxidants is due to their effects on mitochondria.
    Keywords:  antioxidants; fibroblasts; hydrogen peroxide; stress-induced premature senescence
    DOI:  https://doi.org/10.18632/aging.102730
  389. Eur J Cancer. 2020 Jan 20. pii: S0959-8049(19)30856-1. [Epub ahead of print]
    Tumour infiltrating lymphocytes and correlation with response to intensified platinum-based chemotherapy in BRCA-like tumours.
    Criscitiello C, Curigliano G.
      
    DOI:  https://doi.org/10.1016/j.ejca.2019.12.004
  390. Ann Am Thorac Soc. 2020 Jan 22.
    Early Age at Natural Menopause Is Related to Lower Post-Bronchodilator Lung Function: A Longitudinal Population-based Study.
    Campbell B, Bui DS, Simpson JA, Lodge CJ, Lowe AJ, Bowatte G, Leynaert B, Gómez Real F, Thomas PS, Giles GG, Johns DP, Garcia-Aymerich J, Hopper JL, Jarvis D, Abramson MJ, Walters EH, Perret JL, Dharmage SC.
      RATIONALE: Poor lung function, a significant predictor of mortality, has been observed in post-menopausal women when compared to those still menstruating. Menopausal age is a risk factor for several adverse health outcomes, but little evidence exists on the impact of menopausal age on lung function impairments, especially on post-bronchodilator lung function measures.OBJECTIVES: Investigate the association between age at menopause and pre- and post-bronchodilator lung function outcomes.
    METHODS: During the 6th decade follow-up of the Tasmanian Longitudinal Health Study (TAHS) cohort (mean age 53 years), information was collected on most recent menstrual period and menopausal status. Lung function was measured at age 7 and again at 53 years. Multiple linear regression was performed to determine the association between age at menopause and pre- and post-bronchodilator spirometry controlling for early and adult life confounders.
    RESULTS: Women reporting an early age at natural menopause (<45 years) had lower post-bronchodilator forced expiratory volume in one second (-168mL; 95%Confidence Interval [CI] -273, -63) and forced vital capacity (-186mL; 95%CI -302, -70) compared with post-menopausal women who experienced menopause at a later age (≥45 years). No association was observed with FEV1/FVC ratio. Adjustment for early life confounders strengthened these associations.
    CONCLUSIONS: This study provides new evidence that early menopause is associated with reduced lung function that is suggestive of restriction, but not obstruction, even after adjustment for early life confounders. Given the important link between poor lung function and mortality, clinicians should be aware of the risk of diminished lung function in post-menopausal women who experience menopause at an early age.
    DOI:  https://doi.org/10.1513/AnnalsATS.201902-180OC
  391. Asian J Surg. 2020 Jan 17. pii: S1015-9584(19)30832-2. [Epub ahead of print]
    Lung metastases, triple receptor negativity, multiple organ metastases and no adjuvant radiotherapy as predictors of poorer survival after palliative mastectomy.
    Tan HCL, Tan JH, Sikin SM, Arulanantham S.
      
    DOI:  https://doi.org/10.1016/j.asjsur.2019.11.001
  392. Bioresour Technol. 2020 Jan 12. pii: S0960-8524(20)30061-4. [Epub ahead of print]301 122792
    Long-term alkaline conditions inhibit the relative abundances of tetracycline resistance genes in saline 4-chlorophenol wastewater treatment.
    Li Y, Zhao J, Li Y, Jin B, Zhang K, Zhang H.
      Considering the occurrence and spread of antibiotic resistance genes (ARGs) pose significant risks to public health, the effects of long-term exposure to alkaline conditions on the relative abundances of tetracycline resistance genes (TRGs) were studied in saline 4-chlorophenol (4-CP) wastewater treatment. Alkaline conditions were maintained by supplying the co-metabolic carbon source of sodium acetate. Results showed that except for the 4-CP, the removal of pollutants was significantly inhibited, and the relative abundances of the most TRGs were repressed. In addition, the removal of pollutants and the relative abundances of TRGs were moderately affected by the NaCl addition. The proteins in the extracellular polymeric substances (EPS) played key roles in reducing the relative abundances of TRGs, which were altered by the microbial diversity. In conclusion, for the pollutants removal and ARGs reduction in refractory industrial wastewater treatment, alkaline conditions should be maintained by selecting suitable co-metabolic carbon sources.
    Keywords:  Alkaline conditions; EPS; Microbial diversity; Saline 4-chlorophenol wastewater; Tetracycline resistance genes
    DOI:  https://doi.org/10.1016/j.biortech.2020.122792
  393. Cancers (Basel). 2020 Jan 20. pii: E253. [Epub ahead of print]12(1):
    Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers.
    Prusinkiewicz MA, Gameiro SF, Ghasemi F, Dodge MJ, Zeng PYF, Maekebay H, Barrett JW, Nichols AC, Mymryk JS.
      Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive HNSCC influences patient survival. The Cancer Genome Atlas RNA-seq data from primary HNSCC patient samples were categorized as 73 HPV-positive, 442 HPV-negative, and 43 normal-adjacent control tissues. We analyzed 229 metabolic genes and identified numerous differentially expressed genes between HPV-positive and negative HNSCC patients. HPV-positive carcinomas exhibited lower expression levels of genes involved in glycolysis and higher levels of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and β-oxidation than the HPV-negative carcinomas. Importantly, reduced expression of the metabolism-related genes SDHC, COX7A1, COX16, COX17, ELOVL6, GOT2, and SLC16A2 were correlated with improved patient survival only in the HPV-positive group. This work suggests that specific transcriptional alterations in metabolic genes may serve as predictive biomarkers of patient outcome and identifies potential targets for novel therapeutic intervention in HPV-positive head and neck cancers.
    Keywords:  TCGA; cancer metabolism; cellular respiration; glycolysis; head and neck cancer; human papillomavirus
    DOI:  https://doi.org/10.3390/cancers12010253
  394. Nutr Res. 2019 Dec 23. pii: S0271-5317(19)31004-8. [Epub ahead of print]75 1-14
    Postischemic supplementation of folic acid improves neuronal survival and regeneration in vitro.
    Davis CK, Gk R.
      Supplementation of folic acid (FA) is beneficial to several neurological diseases because it promotes notch signaling and neurogenesis and reduces blood homocysteine levels. We hypothesized that postischemic supplementation of FA is beneficial for neuronal survival and regeneration. The objective of the present study was to determine the postischemic neuroprotective and neuroregenerative efficacy of FA supplementation and its effects on various cellular processes in vitro. This work benefited from the use of FA and glucose-free media to better assess the ischemic neuroprotection provided by FA supplementation. The postischemic supplementation of FA significantly improved cell viability, and the improvement was primarily by obstructing the oxygen-glucose deprivation (OGD)-activated apoptosis. Furthermore, postischemic treatment with FA significantly reduced the mitochondrial membrane depolarization and the formation of acidic organelles triggered by OGD. Moreover, FA's effect on neuroregeneration following OGD was evaluated by measuring the cell proliferation and neurite outgrowth length. Treatment with FA enhanced cell proliferation and neurite outgrowth significantly. Thus, these results revealed some of the mechanisms by which FA supplementation provided neuroprotection and neuroregeneration following ischemic injury and highlighted the need for further research into the potential of folic acid as a clinical drug for ischemic stroke.
    Keywords:  Folic acid; Ischemic stroke; Neuroprotection; Neuroregeneration; Oxygen-glucose deprivation
    DOI:  https://doi.org/10.1016/j.nutres.2019.12.007
  395. EJNMMI Res. 2020 Jan 23. 10(1): 5
    Low-dose 18F-FDG TOF-PET/MR for accurate quantification of brown adipose tissue in healthy volunteers.
    Ter Voert EEGW, Svirydenka H, Müller J, Becker AS, Balaz M, Efthymiou V, Maushart CI, Gashi G, Wolfrum C, Betz MJ, Burger IA.
      BACKGROUND: Positron emission tomography (PET) is increasingly applied for in vivo brown adipose tissue (BAT) research in healthy volunteers. To limit the radiation exposure, the injected 18F-FDG tracer dose should be as low as possible. With simultaneous PET/MR imaging, the radiation exposure due to computed tomography (CT) can be avoided, but more importantly, the PET acquisition time can often be increased to match the more extensive magnetic resonance (MR) imaging protocol. The potential gain in detected coincidence counts, due to the longer acquisition time, can then be applied to decrease the injected tracer dose. The aim of this study was to investigate the minimal 18F-FDG dose for a 10-min time-of-flight (TOF) PET/MR acquisition that would still allow accurate quantification of supraclavicular BAT volume and activity.METHODS: Twenty datasets from 13 volunteers were retrospectively included from a prospective clinical study. PET emission datasets were modified to simulate step-wise reductions of the original 75 MBq injected dose. The resulting PET images were visually and quantitatively assessed and compared to a 4-min reference scan. For the visual assessment, the image quality and artifacts were scored using a 5-point and a 3-point Likert scale. For the quantitative analysis, image noise and artifacts, BAT metabolic activity, BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were investigated.
    RESULTS: The visual assessment showed still good image quality for the 35%, 30%, and 25% activity reconstructions with no artifacts. Quantitatively, the background noise was similar to the reference for the 35% and 30% activity reconstructions and the artifacts started to increase significantly in the 25% and lower activity reconstructions. There was no significant difference in supraclavicular BAT metabolic activity, BMV, and TBG between the reference and the 35% to 20% activity reconstructions.
    CONCLUSIONS: This study indicates that when the PET acquisition time is matched to the 10-min MRI protocol, the injected 18F-FDG tracer dose can be reduced to approximately 19 MBq (25%) while maintaining image quality and accurate supraclavicular BAT quantification. This could decrease the effective dose from 1.4 mSv to 0.36 mSv.
    Keywords:  18F-FDG; Brown adipose tissue; Clinical; Dose optimization; PET/MR; Supraclavicular region
    DOI:  https://doi.org/10.1186/s13550-020-0592-8
  396. Life Sci. 2020 Jan 16. pii: S0024-3205(20)30076-X. [Epub ahead of print]244 117329
    MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress.
    Ashrafizadeh M, Ahmadi Z, Samarghandian S, Mohammadinejad R, Yaribeygi H, Sathyapalan T, Sahebkar A.
      MicroRNAs (miRs) are small non-coding pieces of RNA that are involved in a variety of physiologic processes such as apoptosis, cell proliferation, cell differentiation, cell cycle and cell survival. These multifunctional nucleotides are also capable of preventing oxidative damages by modulating antioxidant defense systems in a variety of milieu, such as in diabetes. Although the exact molecular mechanisms by which miRs modulate the antioxidant defense elements are unclear, some evidence suggests that they may exert these effects via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intracellular mechanism is crucial in the maintenance of the physiologic redox balance by regulating the expression and activity of various cellular antioxidative defense elements and thereby plays a pivotal role in the development of oxidative stress. Any impairment in the Nrf2 signaling pathway may result in oxidative damage-dependent complications such as various diabetic complications, neurological disorders and cancer. In the current review, we discuss the modulatory effects of miRs on the Nrf2 signaling pathway, which can potentially be novel therapeutic targets.
    Keywords:  Diabetes mellitus; Free radicals; MicroRNAs; Nrf2 signaling pathway; Oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2020.117329
  397. Metabolites. 2020 Jan 21. pii: E42. [Epub ahead of print]10(2):
    Dexamethasone-Induced Perturbations in Tissue Metabolomics Revealed by Chemical Isotope Labeling LC-MS analysis.
    Dahabiyeh LA, Malkawi AK, Wang X, Colak D, Mujamammi AH, Sabi EM, Li L, Dasouki M, Abdel Rahman AM.
      Dexamethasone (Dex) is a synthetic glucocorticoid (GC) drug commonly used clinically for the treatment of several inflammatory and immune-mediated diseases. Despite its broad range of indications, the long-term use of Dex is known to be associated with specific abnormalities in several tissues and organs. In this study, the metabolomic effects on five different organs induced by the chronic administration of Dex in the Sprague-Dawley rat model were investigated using the chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS) platform, which targets the amine/phenol submetabolomes. Compared to controls, a prolonged intake of Dex resulted in significant perturbations in the levels of 492, 442, 300, 186, and 105 metabolites in the brain, skeletal muscle, liver, kidney, and heart tissues, respectively. The positively identified metabolites were mapped to diverse molecular pathways in different organs. In the brain, perturbations in protein biosynthesis, amino acid metabolism, and monoamine neurotransmitter synthesis were identified, while in the heart, pyrimidine metabolism and branched amino acid biosynthesis were the most significantly impaired pathways. In the kidney, several amino acid pathways were dysregulated, which reflected impairments in several biological functions, including gluconeogenesis and ureagenesis. Beta-alanine metabolism and uridine homeostasis were profoundly affected in liver tissues, whereas alterations of glutathione, arginine, glutamine, and nitrogen metabolism pointed to the modulation of muscle metabolism and disturbances in energy production and muscle mass in skeletal muscle. The differential expression of multiple dipeptides was most significant in the liver (down-regulated), brain (up-regulation), and kidney tissues, but not in the heart or skeletal muscle tissues. The identification of clinically relevant pathways provides holistic insights into the tissue molecular responses induced by Dex and understanding of the underlying mechanisms associated with their side effects. Our data suggest a potential role for glutathione supplementation and dipeptide modulators as novel therapeutic interventions to mitigate the side effects induced by Dex therapy.
    Keywords:  amino acids; dexamethasone; glucocorticoids; mass spectrometry; metabolomics; rats; side effects
    DOI:  https://doi.org/10.3390/metabo10020042
  398. Int J Cosmet Sci. 2020 Jan 20.
    A combination of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol stabilizes hypoxic inducible factor 1 alpha and improves hair density in female volunteers.
    Juchaux F, Sellathurai T, Perrault V, Boirre F, Delannoy P, Bakkar K, Albaud J, Guenich A, Cheniti A, Dal Belo S, Souverain L, Le Balch M, Commo S, Thibaut S, Michelet JF.
      Alopecia can affect 50% of women during their life causing a fall of their self-esteem and quality of life. Besides surgical solutions and treatments with potential detrimental side effects, there is a need to improve the efficacy of cosmetics preventing hair loss while maintaining the safety of patients. Here, we selected a combination of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol to favor biological pathways associated with hair growth. We first showed, in vitro, that the combination of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol stabilize HIF-1α protein leading to a synergistic effect on the expression of HIF-1α related genes. Results also showed that resveratrol significantly reduced the oxygen peroxide-induced oxidative stress in hair follicle and hair matrix cells cultured in vitro. Finally, a randomized clinical study on hair density conducted on 79 Caucasian female subjects showed that a topical treatment containing 5% of pyridine-2, 4-dicarboxylic acid diethyl ester and 0.25% resveratrol significantly increased the hair density on women from 1.5 months. In conclusion, these results demonstrated the interest to sustain the HIF-1α pathway combined to a strategy aimed at to prevent hair follicle and scalp from oxidative stress to improve hair growth in women.
    DOI:  https://doi.org/10.1111/ics.12600
  399. Proc Natl Acad Sci U S A. 2020 Jan 21. pii: 201913841. [Epub ahead of print]
    Imaging breast cancer using hyperpolarized carbon-13 MRI.
    Gallagher FA, Woitek R, McLean MA, Gill AB, Manzano Garcia R, Provenzano E, Riemer F, Kaggie J, Chhabra A, Ursprung S, Grist JT, Daniels CJ, Zaccagna F, Laurent MC, Locke M, Hilborne S, Frary A, Torheim T, Boursnell C, Schiller A, Patterson I, Slough R, Carmo B, Kane J, Biggs H, Harrison E, Deen SS, Patterson A, Lanz T, Kingsbury Z, Ross M, Basu B, Baird R, Lomas DJ, Sala E, Wason J, Rueda OM, Chin SF, Wilkinson IB, Graves MJ, Abraham JE, Gilbert FJ, Caldas C, Brindle KM.
      Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.
    Keywords:  breast cancer; cancer metabolism; magnetic resonance imaging; metabolic imaging
    DOI:  https://doi.org/10.1073/pnas.1913841117
  400. Heart Lung Circ. 2019 Dec 18. pii: S1443-9506(19)31525-2. [Epub ahead of print]
    How Patient Perceptions Shape Responses and Outcomes in Inherited Cardiac Conditions.
    O'Donovan C, Ingles J, Broadbent E, Skinner JR, Kasparian NA.
      At least one-third of adults living with an inherited cardiac condition report clinically-significant levels of psychological distress. Poorer health-related quality of life compared with population norms is also consistently reported. These outcomes are associated with younger patient age, having an implantable cardioverter defibrillator, and receipt of uncertain clinical test results, and can influence self-management behaviours, such as adherence to potentially critical life-preserving medications. According to the Common Sense Model of Illness, people use information from multiple sources to 'make sense' of their health condition, and how they conceptualise the condition can strongly influence adaptation and coping responses. Previous studies with people with inherited cardiac conditions show that illness perceptions, such as greater perceived consequences and a poorer understanding of the condition, are associated with greater psychological distress and poorer adherence to medication. The Common Sense Model provides one potential framework for identifying patients who may be more vulnerable to adverse health outcomes, and for developing early interventions to reduce the physical and psychosocial burden of these conditions. Interventions based on the Common Sense Model have successfully improved physical and psychosocial outcomes associated with other cardiac conditions, and could be tailored for use with patients with an inherited cardiac condition (ICC).
    Keywords:  Anxiety; Common Sense Model of Illness; Depression; Health-related quality of life; Illness perceptions; Inherited cardiac conditions
    DOI:  https://doi.org/10.1016/j.hlc.2019.11.003
  401. Curr Pharm Des. 2020 Jan 14.
    Treatment with the Ketone Body D-β-hydroxybutyrate Attenuates Autophagy Activated by NMDA and Reduces Excitotoxic Neuronal Damage in the Rat Striatum in Vivo.
    Montiel T, Montes-Ortega LA, Flores-Yáñez S, Massieu L.
      BACKGROUND: The ketone bodies (KB), β-hydroxybutyrate (BHB) and acetoacetate, have been proposed for the treatment of acute and chronic neurological disorders, however, the molecular mechanisms involved in KB protection are not well understood. KB can substitute for glucose and support mitochondrial metabolism increasing cell survival. We have reported that the D-isomer of BHB (D-BHB) stimulates autophagic degradation during glucose deprivation in cultured neurons increasing cell viability. Autophagy is a lysosomal degradation process of damaged proteins and organelles activated during nutrient deprivation to obtain building blocks and energy. However, impaired or excessive autophagy can contribute to neuronal death.OBJECTIVE: The aim of the present study was to test whether D-BHB can preserve autophagic function in an in vivo model of excitotoxic damage induced by the administration of the glutamate receptor agonist, N-methyl-D-aspartate (NMDA), in the rat striatum.
    METHODS: D-BHB was administered through an intravenous injection followed by either an intraperitoneal injection (i.v+i.p) or a continuous epidural infusion (i.v+pump), or through a continuous infusion of D-BHB alone. Changes in the autophagy proteins ATG7, ATG5, BECLIN 1 (BECN1), LC3, Sequestrosome1/p62 (SQSTM1/p62) and the lysosomal membrane protein LAMP2, were evaluated by immunoblot. The lesion volume was measured in cresyl violet-stained brain sections.
    RESULTS: Autophagy is early activated after NMDA injection but autophagic degradation is impaired due to the cleavage of LAMP2. Twenty-four h after NMDA intrastriatal injection the autophagic flux is reestablished, but LAMP2 cleavage is still observed. The administration of D-BHB through the i.v+pump protocol reduced the content of autophagic proteins and the cleavage of LAMP2, suggesting decreased autophagosome formation and lysosomal membrane preservation, improving autophagic degradation. D-BHB also reduced brain injury. The i.v+i.p administration protocol and the infusion of D-BHB alone showed no effect on autophagy activation or degradation.
    Keywords:  Autophagic flux; Excitotoxicity; Ketone bodies; Lysosomal degradation; Neuronal death ; Striatum
    DOI:  https://doi.org/10.2174/1381612826666200115103646
  402. J Inherit Metab Dis. 2020 Jan 18.
    Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency.
    Bleeker JC, Visser G, Clarke K, Ferdinandusse S, de Haan FH, Houtkooper RH, IJlst L, Kok IL, Langeveld M, van der Pol WL, de Sain-van der Velden MGM, Sibeijn-Kuiper A, Takken T, Wanders RJA, van Weeghel M, Wijburg FA, van der Woude LH, Wüst RCI, Cox PJ, Jeneson JAL.
      BACKGROUND: A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesized that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long-Chain acyl-CoA Dehydrogenase (VLCAD).METHODS: Five patients (range 17-45 y; 4M/1F) patients were included in an investigator-initiated, randomized, blinded, placebo-controlled, 2-way cross-over study. Patients drank either a KE+CHO mix or an isocaloric CHO equivalent and performed 35 min upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; ~40% VO2 max). The protocol was repeated after a one-week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31 P-MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings.
    RESULTS: Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD-specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE+CHO than CHO.
    CONCLUSION: These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. This article is protected by copyright. All rights reserved.
    Keywords:  VLCADD; fatty acid oxidation; in vivo 31P MRS; ketone ester; mitochondrial energy transduction; muscle; nutritional ketosis; very long-chain acyl-CoA dehydrogenase
    DOI:  https://doi.org/10.1002/jimd.12217
  403. Neurochem Res. 2020 Jan 24.
    Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur.
    Barros LF, Ruminot I, San Martín A, Lerchundi R, Fernández-Moncada I, Baeza-Lehnert F.
      Information processing is onerous. Curiously, active brain tissue does not fully oxidize glucose and instead generates a local surplus of lactate, a phenomenon termed aerobic glycolysis. Why engage in inefficient ATP production by glycolysis when energy demand is highest and oxygen is plentiful? Aerobic glycolysis is associated to classic biochemical effects known by the names of Pasteur, Warburg and Crabtree. Here we discuss these three interdependent phenomena in brain cells, in light of high-resolution data of neuronal and astrocytic metabolism in culture, tissue slices and in vivo, acquired with genetically-encoded fluorescent sensors. These sensors are synthetic proteins that can be targeted to specific cell types and subcellular compartments, which change their fluorescence in response to variations in metabolite concentration. A major site of acute aerobic glycolysis is the astrocyte. In this cell, a Crabtree effect triggered by K+ coincides with a Warburg effect mediated by NO, superimposed on a slower longer-lasting Warburg effect caused by glutamate and possibly by NH4+. The compounded outcome is that more fuel (lactate) and more oxygen are made available to neurons, on demand. Meanwhile neurons consume both glucose and lactate, maintaining a strict balance between glycolysis and respiration, commanded by the Na+ pump. We conclude that activity-dependent Warburg and Crabtree effects in brain tissue, and the resulting aerobic glycolysis, do not reflect inefficient energy generation but the marshalling of astrocytes for the purpose of neuronal ATP generation. It remains to be seen whether neurons contribute to aerobic glycolysis under physiological conditions.
    Keywords:  Ammonium; Astrocytes; Glucose; Glutamate; Lactate; Neuron; Nitric oxide; Oxygen; Potassium
    DOI:  https://doi.org/10.1007/s11064-020-02964-w
  404. Metabolomics. 2020 Jan 24. 16(2): 20
    Serum metabolomics reveals metabolic profiling for women with hyperandrogenism and insulin resistance in polycystic ovary syndrome.
    Zhang Z, Hong Y, Chen M, Tan N, Liu S, Nie X, Zhou W.
      INTRODUCTION: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder. Hyperandrogenism (HA) and insulin resistance (IR) are two important pathogenic factors.OBJECTIVE: We aimed to investigate the inherent disturbed metabolic profiles for women with HA or IR in PCOS as well as discover diagnostic biomarkers.
    METHODS: A total of 286 subjects were recruited for the study. They constituted the following groups: healthy women (C), those with HA (B1), those with IR but not obese (B2) and obese women with IR (B3) in PCOS. Nine cross-comparisons with PCOS were performed to characterize metabolic disturbances. Serum metabolomic profiles were determined by gas chromatography-mass spectrometry.
    RESULTS AND CONCLUSION: We found a total of 59 differential metabolites. 28 metabolites for B1 vs C, 32 for B2 vs C and 25 for B3 vs C were discovered. Among them, palmitic acid, cholesterol, myo-inositol, D-allose, 1,5-anhydro-D-sorbitol, 1-monopalmitin, 1-monostearin, glycerol 1-phosphate, malic acid and citric acid, were the common differential metabolites among B1 vs C, B2 vs C and B3 vs C, which related to biosynthesis of unsaturated fatty acids, citrate cycle etc. Besides, 9-biomarker panel can diagnose well between HA and IR in PCOS. They provided areas under the receiver operating characteristic curve of 0.8511 to 1.000 in the discovery phase, and predictive values of 90% to 92% in the validation set. The result indicated that the differential metabolites can reflect the underlying mechanism of PCOS and serve as biomarkers for complementary diagnosis of HA and IR in PCOS.
    Keywords:  Biomarkers; Hyperandrogenism; Insulin resistance; Metabolomics; Polycystic ovary syndrome
    DOI:  https://doi.org/10.1007/s11306-020-1642-y
  405. J Cell Mol Med. 2020 Jan 22.
    Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAFV600E by synergistically decreasing global trimethylation of H3K27.
    Fu H, Cheng L, Sa R, Jin Y, Chen L.
      Clinical efficacy of differentiation therapy with mitogen-activated protein kinase inhibitors (MAPKi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAFV600E -MAPK-induced cancer dedifferentiation and drug resistance. Therefore, dual inhibition of MAPK and histone methyltransferase (EZH2) may produce more favourable treatment effects. In this study, BRAFV600E -mutant (BCPAP and K1) and BRAF-wild-type (TPC-1) PTC cells were treated with MAPKi (dabrafenib or selumetinib) or EZH2 inhibitor (tazemetostat), or in combination, and the expression of iodine-metabolizing genes, radioiodine uptake, and toxicity were tested. We found that tazemetostat alone slightly increased iodine-metabolizing gene expression and promoted radioiodine uptake and toxicity, irrespective of the BRAF status. However, MAPKi induced these effects preferentially in BRAFV600E mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi-induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAFV600E -mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAFV600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.
    Keywords:  EZH2 inhibitor; H3K27me3; MAPK inhibitor; differentiation therapy; thyroid cancer
    DOI:  https://doi.org/10.1111/jcmm.15007
  406. J Biol Chem. 2020 Jan 23. pii: jbc.RA120.012533. [Epub ahead of print]
    Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation.
    Moonira T, Chachra SS, Ford BE, Marin S, Alshawi A, Adam-Primus NS, Arden C, Al-Oanzi ZH, Foretz M, Viollet B, Cascante M, Agius L.
      The chronic effects of metformin on liver gluconeogenesis involve repression of the G6pc gene, which is regulated by the Carbohydrate response element binding protein through raised cellular intermediates of glucose metabolism.   In this study we determined the candidate mechanisms by which metformin lowers glucose 6-phosphate (G6P) in mouse and rat hepatocytes challenged with high glucose or gluconeogenic precursors.   Cell metformin loads in the therapeutic range lowered cell G6P but not ATP and decreased G6pc mRNA at high glucose.  The G6P lowering by metformin was mimicked by a Complex 1 inhibitor (rotenone), an uncoupler (dinitrophenol) and by overexpression of mGPDH, which lowers glycerol 3-phosphate and G6P and also mimics the G6pc repression by metformin.  In contrast, direct allosteric activators of AMPK (A-769662, 991, C13) had opposite effects from metformin on glycolysis, gluconeogenesis and cell G6P. The G6P lowering by metformin which also occurs in hepatocytes from AMPK-knock-out mice, is best explained by allosteric regulation of phosphofructokinase-1 (PFK-1) and/or fructose bisphosphatase-1, as supported by: increased metabolism of [3-3H]glucose relative to [2-3H]glucose;  an increase in lactate m2/m1 isotopologue ratio from [1,2-13C2]glucose, by lowering of glycerol 3-phosphate an allosteric inhibitor of phosphofructokinase-1  and by marked G6P elevation by selective inhibition of phosphofructokinase-1 but not by a more reduced cytoplasmic NADH/NAD redox state.   We conclude that therapeutically relevant doses of metformin lower G6P in hepatocytes challenged with high glucose by stimulation of glycolysis by an AMPK-independent mechanism through changes in allosteric effectors of PFK-1 and fructose bisphosphatase-1, including AMP, inorganic phosphate and glycerol 3-phosphate.
    Keywords:  glucose 6-phosphate; glycolysis; hepatocyte; liver; metformin; phosphofructokinase
    DOI:  https://doi.org/10.1074/jbc.RA120.012533
  407. EBioMedicine. 2020 Jan 20. pii: S2352-3964(20)30004-9. [Epub ahead of print]52 102629
    Corrigendum to 'Inhibition of HDACs-EphA2 signaling axis with WW437 demonstrates promising preclinical antitumor activity in breast cancer' [EBioMedicine 31 (2018) 276-286].
    Zhang T, Li J, Ma X, Yang Y, Sun W, Jin W, Wang L, He Y, Yang F, Yi Z, Hua Y, Liu M, Chen Y, Cai Z.
      
    DOI:  https://doi.org/10.1016/j.ebiom.2020.102629
  408. Int Immunopharmacol. 2020 Jan 15. pii: S1567-5769(19)32143-5. [Epub ahead of print]80 106198
    Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma).
    Sun Y, Luo J, Chen Y, Cui J, Lei Y, Cui Y, Jiang N, Jiang W, Chen L, Chen Y, Kuang Y, Tang K, Ke Z.
      The interaction between CD155 and its high-affinity ligand TIGIT is being increasingly investigated in various solid tumors. However, the prognostic significance of CD155 and TIGIT in lung adenocarcinoma (LUAD) remains unclear. In this study, immunohistochemistry was applied in 334 LUAD cases to evaluate the expression of CD155 and TIGIT. Western blotting was conducted in 5 paired primary LUAD and adjacent normal lung tissues. Our results reveal that CD155 and TIGIT are overexpressed in LUAD tissues and that aberrant overexpression is closely correlated with poor clinical outcomes (P < 0.01). The multivariate model also shows that CD155 expression is an independent risk factor for LUAD (RR, 1.34; P = 0.036). Moreover, patients expressing high CD155 and TIGIT simultaneously presented shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01). These findings suggest that CD155 and TIGIT can make up a prognosticating tool to predict clinical outcomes, thereby contributing to personalized medical care in LUAD.
    Keywords:  CD155; Immune checkpoint; LUAD; TIGIT
    DOI:  https://doi.org/10.1016/j.intimp.2020.106198
  409. Food Chem Toxicol. 2020 Jan 19. pii: S0278-6915(20)30022-3. [Epub ahead of print] 111135
    New grapefruit cultivars exhibit low cytochrome P4503A4-Inhibition activity.
    Guttman Y, Yedidia I, Nudel A, Zhmykhova Y, Kerem Z, Carmi N.
      Furanocoumarins are the main compounds responsible for the food-drug interactions known as the grapefruit effect, which is caused by the inhibition of CYP3A4-mediated drug metabolism. We evaluated the effects of two new, low-furanocoumarin grapefruit cultivars on CYP3A4 activity and the roles of different furanocoumarins, individually and together with other juice compounds, in the inhibition of CYP3A4 by grapefruit. Whereas a standard grapefruit cultivar inhibited CYP3A4 activity in a dose-dependent manner, neither of the two examined low-furanocoumarin cultivars had an inhibitory effect. Despite the fact that bergamottin and 6',7'-dihydroxybergamottin are weak inhibitors of CYP3A4, their relatively high levels in grapefruit make them the leading cause of the grapefruit effect. We found that furanocoumarins together with other juice compounds inhibit CYP3A4 in an additive manner. In silico docking simulation was employed, and differentiated between high- and low-potency inhibitors, suggesting that modeling may be useful for identifying potentially harmful food-drug interactions.
    Keywords:  CYP3A4; Docking; Food–drug interactions; Furanocoumarins; Grapefruit juice
    DOI:  https://doi.org/10.1016/j.fct.2020.111135
  410. Gynecol Oncol. 2020 Jan 16. pii: S0090-8258(20)30020-2. [Epub ahead of print]
    Quantitative proteomic analysis identifies novel regulators of methotrexate resistance in choriocarcinoma.
    Jun F, Peng Z, Zhang Y, Shi D.
      OBJECTIVE: Although methotrexate (MTX) is commonly used for the treatment of choriocarcinoma, chemoresistance to MTX may occur in a considerable fraction of patients. Further understanding on the mechanisms of MTX resistance would help to develop more effective therapy for choriocarcinoma.METHODS: Quantitative proteomic approach involving TMT labeling and LC-MS/MS was used to identify MTX resistance-related proteomic profiles in choriocarcinoma cell models. Pathway and process enrichment analysis were conducted to identify MTX resistance-related biological processes/molecular pathways. CCK-8 viability assay, clonogenic survival assay, and BrdU incorporation analysis were used to examine the chemosensitivity to MTX in choriocarcinoma cells.
    RESULTS: In total, 5704 protein groups were identified, among which 4997 proteins were quantified. Bioinformatic analysis revealed that multiple biological processes/molecular pathways might be associated with MTX resistance in JEG3/JEG3/MTX cell systems. DPP4 and METTL7A were selected for further investigation. Increased expression of DPP4 or METTL7A was observed in MTX-resistant cancer cell lines and choriocarcinoma tissues. Knockdown of DPP4 or METTL7A significantly decreased cell viability, impaired clonogenesis, and increased apoptosis after MTX treatment in JEG3/MTX and JAR/MTX cells; while over-expression of DPP4 or METTL7A promoted cell viability and reduced apoptosis following exposure to MTX in JEG3, JAR and BEWO cells. Further, DPP4 and METTL7A differentially activated prosurvival signaling pathways including PI3K/AKT, ERK1/2 and STAT3, and attenuated the accumulation of reactive oxygen species (ROS) in choriocarcinoma cell lines.
    CONCLUSIONS: DPP4 and METTL7A might promote MTX resistance through activating pro-survival signaling pathways and attenuating the accumulation of ROS in choriocarcinoma cells. Targeting DPP4 and METTL7A might be useful to sensitize choriocarcinoma cells to MTX-based chemotherapy.
    Keywords:  Chemoresistance; Choriocarcinoma; DPP4; METTL7A; Methotrexate; Quantitative proteomics
    DOI:  https://doi.org/10.1016/j.ygyno.2020.01.013
  411. J Biol Chem. 2020 Jan 20. pii: jbc.RA119.011596. [Epub ahead of print]
    Von Hippel-Lindau tumor suppressor (VHL) stimulates TOR signaling by interacting with phosphoinositide 3-kinase (PI3K).
    Hwang SH, Bang S, Kim W, Chung J.
      Cell growth is positively controlled by phosphoinositide 3-kinase (PI3K)-TOR signaling pathway under conditions of abundant growth factors and nutrients. To discover additional mechanisms that regulate cell growth, here we performed RNAi-based mosaic analyses in the Drosophila fat body, the primary metabolic organ in the fly. Unexpectedly, the knockdown of the Drosophila von Hippel-Lindau (VHL) gene markedly decreased cell size and body size. These cell growth phenotypes induced by VHL loss-of-function were recovered by activation of TOR signaling in Drosophila Consistent with the genetic interactions between VHL and the signaling components of PI3K-TOR pathway in Drosophila, we observed that VHL loss-of-function in mammalian cells causes decreased phosphorylation of ribosomal protein S6 kinase (S6K) and Akt, which represent the main activities of this pathway. We further demonstrate that VHL activates TOR signaling by directly interacting with the p110 catalytic subunit of PI3K. On the basis of the evolutionarily conserved regulation of PI3K-TOR signaling by VHL observed here, we propose that VHL plays an important role in the regulation and maintenance of proper cell growth in metazoans.
    Keywords:  Akt PKB; S6 kinase; cell size; metabolic regulation; nutrient sensing; p110; phosphatidylinositide 3-kinase (PI 3-kinase); target of rapamycin (TOR); von Hippel-Lindau (VHL)
    DOI:  https://doi.org/10.1074/jbc.RA119.011596
  412. Nat Commun. 2020 Jan 23. 11(1): 440
    Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake.
    Jakobi AJ, Huber ST, Mortensen SA, Schultz SW, Palara A, Kuhm T, Shrestha BK, Lamark T, Hagen WJH, Wilmanns M, Johansen T, Brech A, Sachse C.
      p62/SQSTM1 is an autophagy receptor and signaling adaptor with an N-terminal PB1 domain that forms the scaffold of phase-separated p62 bodies in the cell. The molecular determinants that govern PB1 domain filament formation in vitro remain to be determined and the role of p62 filaments inside the cell is currently unclear. We here determine four high-resolution cryo-EM structures of different human and Arabidopsis PB1 domain assemblies and observed a filamentous ultrastructure of p62/SQSTM1 bodies using correlative cellular EM. We show that oligomerization or polymerization, driven by a double arginine finger in the PB1 domain, is a general requirement for lysosomal targeting of p62. Furthermore, the filamentous assembly state of p62 is required for autophagosomal processing of the p62-specific cargo KEAP1. Our results show that using such mechanisms, p62 filaments can be critical for cargo uptake in autophagy and are an integral part of phase-separated p62 bodies.
    DOI:  https://doi.org/10.1038/s41467-020-14343-8
  413. Lung. 2020 Jan 24.
    Falsely Accused? Insufficient Evidence to Conclude that Sitagliptin is a Cause of Chronic Cough.
    Dicpinigaitis P, Satia I, Ferguson N.
      
    DOI:  https://doi.org/10.1007/s00408-020-00329-2
  414. Cancer Lett. 2020 Jan 18. pii: S0304-3835(20)30023-9. [Epub ahead of print]474 53-62
    Preclinical models for neuroblastoma: Advances and challenges.
    Nolan JC, Frawley T, Tighe J, Soh H, Curtin C, Piskareva O.
      Neuroblastoma is a paediatric cancer of the sympathetic nervous system and the most common solid tumour of infancy, contributing to 15% of paediatric oncology deaths. Current therapies are not effective in the long-term treatment of almost 80% of patients with this clinically aggressive disease. The primary challenge in the identification and validation of new agents for paediatric drug development is the accurate representation of tumour biology and diversity. In addition to this limitation, the low incidence of neuroblastoma makes the recruitment of eligible patients for early phase clinical trials highly challenging and highlights the need for robust preclinical testing to ensure that the best treatments are selected. The research field requires new preclinical models, technologies, and concepts to tackle these problems. Tissue engineering offers attractive tools to assist in the development of three-dimensional (3D) cell models using various biomaterials and manufacturing approaches that recreate the geometry, mechanics, heterogeneity, metabolic gradients, and cell communication of the native tumour microenvironment. In this review, we discuss current experimental models and assess their abilities to reflect the structural organisation and physiological conditions of the human body, in addition to current and new techniques to recapitulate the tumour niche using tissue-engineered platforms. Finally, we will discuss the possible use of novel 3D in vitro culture systems to address open questions in neuroblastoma biology.
    Keywords:  2D cell models; 3D cell models; ECM; Neuroblastoma; Scaffolds; Tissue-engineering; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2020.01.015
  415. Thorac Cancer. 2020 Jan 22.
    Long non-coding RNA XIST expedites lung adenocarcinoma progression through upregulating MDM2 expression via binding to miR-363-3p.
    Rong H, Chen B, Wei X, Peng J, Ma K, Duan S, He J.
      BACKGROUND: Lung adenocarcinoma (LAD) is a highly aggressive malignant tumor which threatens the health and life of the population. Long non-coding RNA X-inactive specific transcript (XIST) and mouse double minute clone 2 (MDM2) are connected with the tumorigenesis of LAD. Nevertheless, whether MDM2 is regulated by XIST has not previously been reported in LAD.METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of XIST, microRNA-363-3p (miR-363-3p) and MDM2 in LAD tissues and cells. The proliferation, migration, invasion and apoptosis of LAD cells were determined by 3-(4, 5-dimethylthiazol-2-YI)-2, 5-diphenyltetrazolium bromide (MTT), transwell or flow cytometry assay, respectively. MDM2 protein level was detected using western blot analysis. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pulldown assay were performed to determine the interaction among XIST, miR-363-3p and MDM2. A xenograft tumor model was constructed to validate the effect of XIST on LAD cells in vivo.
    RESULTS: We found that XIST and MDM2 were remarkably elevated while miR-363-3p was reduced in LAD tissues and cells. Both XIST and MDM2 downregulation restrained proliferation, migration and invasion, and facilitated apoptosis of LAD cells in vitro. Importantly, XIST bound to miR-363-3p to modulate MDM2 expression in LAD cells. Moreover, miR-363-3p knockdown or MDM2 elevation reversed the effects of XIST downregulation on the proliferation, migration, invasion and apoptosis of LAD cells. Furthermore, XIST knockdown constrained tumor growth on LAD cells in vivo.
    CONCLUSIONS: XIST knockdown repressed proliferation, migration and invasion, and accelerated apoptosis of LAD cells by downregulating MDM2 expression via binding to miR-363-3p.
    KEY POINTS: Significant findings of the study XIST and MDM2 were abnormally enhanced in LAD tissues and cells. Both downregulation of XIST and MDM2 repressed proliferation, migration and invasion, and boosted apoptosis of LAD cells in vitro. XIST bound to miR-363-3p to regulate MDM2 expression in LAD cells. Downregulation of XIST impeded tumor growth on LAD cells in vivo. What this study adds This study confirmed that XIST was a potential target for inhibiting the development of LAD, and affords a possible strategy for the treatment of LAD in the future.
    Keywords:  LAD; MDM2; XIST; miR-363-3p
    DOI:  https://doi.org/10.1111/1759-7714.13310
  416. Pain. 2020 Feb;161(2): 446-458
    Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice.
    Zhang X, Kanter K, Chen J, Kim S, Wang Y, Adeyemi C, OʼBuckley SC, Nackley AG.
      Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.
    DOI:  https://doi.org/10.1097/j.pain.0000000000001734
  417. Am J Cardiol. 2019 Dec 26. pii: S0002-9149(19)31503-6. [Epub ahead of print]
    Impact of Hyperglycemia on Long-Term Outcome in Patients With ST-Segment Elevation Myocardial Infarction.
    Kojima T, Hikoso S, Nakatani D, Suna S, Dohi T, Mizuno H, Okada K, Kitamura T, Kida H, Oeun B, Sunaga A, Kurakami H, Yamada T, Sakata Y, Sato H, Hori M, Komuro I, Sakata Y, .
      In patients with ST-segment elevation myocardial infarction (STEMI), the association between stress-induced hyperglycemia (SIH) and long-term outcomes, as well as the effects of baseline diabetic status on this association remain elusive. To clarify the association between SIH and long-term outcomes, and the effects of baseline diabetic status on this association, we studied 6,287 STEMI patients who were discharged alive. SIH was estimated using the stress hyperglycemia ratio (SHR), which is defined as [(admission glucose (mg/dl))/(28.7 × HbA1c (%) - 46.7)]. End points were all-cause death and admission for heart failure (HF). We compared prognosis between patients in the highest SHR quartile and those in other quartiles of the nondiabetic and diabetic population. Over a follow-up of 5 years (median 1,522 days), 464 (7.4%) and 401 (6.4%) cases of all-cause death and HF admission were observed. In the nondiabetic population, the highest SHR quartile (Q4) group was significantly associated with worse long-term outcomes (adjusted hazard ratio [HR] (95% confidence interval [CI]), all-cause death; 1.45 (1.06 to 1.98), p = 0.021, HF admission; 1.48 (1.04 to 2.10), p = 0.031). However, in the diabetic population, SHR Q4 group was not significantly associated with worse long-term outcomes (adjusted HR (95% CI), all-cause death; 1.00 (0.68 - 1.48), p = 0.996, HF admission; 1.31 (0.90 to 1.89), p = 0.154). In conclusion, in STEMI patients discharged alive, high SHR was significantly associated with worse long-term prognosis in the nondiabetic population. In contrast, high SHR was not significantly associated with worse long-term prognosis in the diabetic population.
    DOI:  https://doi.org/10.1016/j.amjcard.2019.12.034
  418. Domest Anim Endocrinol. 2019 Nov 21. pii: S0739-7240(19)30097-9. [Epub ahead of print]72 106418
    A negative energy balance during the peri-implantational period reduces dam IGF-1 but does not alter progesterone or pregnancy-specific protein B (PSPB) or fertility in suckled cows.
    Noya A, Casasús I, Rodríguez-Sánchez JA, Ferrer J, Sanz A.
      The aim of this study was to evaluate the effect of a negative energy balance during the first third of gestation on metabolic, endocrine, and pregnancy recognition parameters in 2 beef cattle breeds adapted to semiextensive conditions. Seventy-five lactating Parda de Montaña and 40 Pirenaica multiparous cows rearing calves were synchronized and timed artificial inseminated (TAI) on day 76 postpartum. Cows were assigned to one of 2 diets (CONTROL or SUBNUT; 100% or 65% of their requirements supplied) until day 82 of gestation. Pregnancy was diagnosed 37 d post-TAI using ultrasound. Blood samples were obtained to determine metabolic (glucose, NEFA, β-hydroxybutyrate, cholesterol, and urea) and endocrine (IGF-1) status throughout the first third of gestation and to determine the concentrations of progesterone and pregnancy-specific protein B (PSPB) in the peri-implantational period. Undernutrition affected both cow and calf performance. The CONTROL cows maintained BCS and BW, whereas SUBNUT cows had negative daily gains. The CONTROL lactating calves had higher BW gains than SUBNUT. These negative effects were more evident in the Pirenaica breed, which was more sensitive to undernutrition. The negative energy balance was reflected in the cows' metabolic profiles, with higher NEFA values and lower IGF-1 concentrations in SUBNUT cows. However, undernutrition did not affect dam pregnancy/TAI or pregnancy recognition and maintenance, confirming that during periods of undernourishment pregnant dams prioritize the allocation of dietary energy toward reproductive functions. Progesterone concentration on day 21 post-TAI (with a 4.8 ng/mL cut-off value) and PSPB on day 26 post-TAI (with a 0.57 ng/mL cut-off value) were determined as the earliest indicators to accurately establish dam pregnancy status, regardless of breed or nutrition treatment. In summary, early undernutrition affected cow performance and metabolic profiles and impaired lactating calf growth, but did not affect progesterone or PSPB concentrations or the pregnancy/TAI rate in suckled cows.
    Keywords:  Calf performance; Early gestation; Malnutrition; Metabolism; Pregnancy diagnosis
    DOI:  https://doi.org/10.1016/j.domaniend.2019.106418
  419. J Cell Mol Med. 2020 Jan 20.
    CPF impedes cell cycle re-entry of quiescent lung cancer cells through transcriptional suppression of FACT and c-MYC.
    Bi L, Xie C, Jiao L, Jin S, Hnit SST, Mu Y, Wang Y, Wang Q, Ge G, Wang Y, Zhao X, Shi X, Kang Y, De Souza P, Liu T, Zhou J, Xu L, Dong Q.
      Blockade of cell cycle re-entry in quiescent cancer cells is a strategy to prevent cancer progression and recurrence. We investigated the action and mode of action of CPF mixture (Coptis chinensis, Pinellia ternata and Fructus trichosanthis) in impeding a proliferative switch in quiescent lung cancer cells. The results indicated that CPF impeded cell cycle re-entry in quiescent lung cancer cells by reduction of FACT and c-MYC mRNA and protein levels, with concomitant decrease in H3K4 tri-methylation and RNA polymerase II occupancy at FACT and c-MYC promoter regions. Animals implanted with quiescent cancer cells that had been exposed to CPF had reduced tumour volume/weight. Thus, CPF suppresses proliferative switching through transcriptional suppression of FACT and the c-MYC, providing a new insight into therapeutic target and intervention method in impeding cancer recurrence.
    Keywords:  G0 cell cycle re-entry; c-MYC; lung cancer; structure-specific recognition protein 1; suppressor of Ty homolog-16
    DOI:  https://doi.org/10.1111/jcmm.14897
  420. Oncogene. 2020 Jan 23.
    Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis.
    Gu L, Zhu Y, Lin X, Tan X, Lu B, Li Y.
      Metabolic alteration for adaptation of the local environment has been recognized as a hallmark of cancer. GNPAT dysregulation has been implicated in hepatocellular carcinoma (HCC). However, the precise posttranslational regulation of GNPAT is still undiscovered. Here we show that ACAT1 is upregulated in response to extra palmitic acid (PA). ACAT1 acetylates GNPAT at K128, which represses TRIM21-mediated GNPAT ubiquitination and degradation. Conversely, GNPAT deacetylation by SIRT4 antagonizes ACAT1's function. GNPAT represses TRIM21-mediated FASN degradation and promotes lipid metabolism. Furthermore, shRNA-mediated ACAT1 ablation and acetylation deficiency of GNPAT repress lipid metabolism and tumor progression in xenograft and DEN/CCl4-induced HCC. Otherwise, ACAT1 inhibitor combination with sorafenib enormously retards tumor formation in mice. Collectively, we demonstrate that stabilization of FASN by ACAT1-mediated GNPAT acetylation plays a critical role in hepatocarcinogenesis.
    DOI:  https://doi.org/10.1038/s41388-020-1156-0
  421. Biom J. 2020 Jan 20.
    Generalized parametric cure models for relative survival.
    Jakobsen LH, Bøgsted M, Clements M.
      Cure models are used in time-to-event analysis when not all individuals are expected to experience the event of interest, or when the survival of the considered individuals reaches the same level as the general population. These scenarios correspond to a plateau in the survival and relative survival function, respectively. The main parameters of interest in cure models are the proportion of individuals who are cured, termed the cure proportion, and the survival function of the uncured individuals. Although numerous cure models have been proposed in the statistical literature, there is no consensus on how to formulate these. We introduce a general parametric formulation of mixture cure models and a new class of cure models, termed latent cure models, together with a general estimation framework and software, which enable fitting of a wide range of different models. Through simulations, we assess the statistical properties of the models with respect to the cure proportion and the survival of the uncured individuals. Finally, we illustrate the models using survival data on colon cancer, which typically display a plateau in the relative survival. As demonstrated in the simulations, mixture cure models which are not guaranteed to be constant after a finite time point, tend to produce accurate estimates of the cure proportion and the survival of the uncured. However, these models are very unstable in certain cases due to identifiability issues, whereas LC models generally provide stable results at the price of more biased estimates.
    Keywords:  cure models; parametric models; relative survival; splines
    DOI:  https://doi.org/10.1002/bimj.201900056
  422. Sci Rep. 2020 Jan 22. 10(1): 980
    Tannic acid inhibits lipid metabolism and induce ROS in prostate cancer cells.
    Nagesh PKB, Chowdhury P, Hatami E, Jain S, Dan N, Kashyap VK, Chauhan SC, Jaggi M, Yallapu MM.
      Prostate cancer (PCa) cells exploit the aberrant lipid signaling and metabolism as their survival advantage. Also, intracellular storage lipids act as fuel for the PCa proliferation. However, few studies were available that addressed the topic of targeting lipid metabolism in PCa. Here, we assessed the tannic acid (TA) lipid-targeting ability and its capability to induce endoplasmic reticulum (ER) stress by reactive oxygen species (ROS) in PCa cells. TA exhibited dual effects by inhibiting lipogenic signaling and suppression of lipid metabolic pathways. The expression of proteins responsible for lipogenesis was down regulated. The membrane permeability and functionality of PCa were severely affected and caused nuclear disorganization during drug exposure. Finally, these consolidated events shifted the cell's survival balance towards apoptosis. These results suggest that TA distinctly interferes with the lipid signaling and metabolism of PCa cells.
    DOI:  https://doi.org/10.1038/s41598-020-57932-9
  423. Mol Ther Nucleic Acids. 2019 Dec 20. pii: S2162-2531(19)30408-1. [Epub ahead of print]19 804-813
    N6-Methyladenosine: A Potential Breakthrough for Human Cancer.
    Liu L, Wang Y, Wu J, Liu J, Qin Z, Fan H.
      Among more than 100 types of identified RNA modification, N6-methyladenosine (m6A) modification is the predominant mRNA modification, which regulates RNA splicing, translocation, stability, and translation. m6A modification plays critical roles in the growth, differentiation, and metabolism of cells. As a dynamic and reversible modification, m6A is catalyzed by "writers" (RNA methyltransferases), removed by "erasers" (demethylases), and interacts with "readers" (m6A-binding proteins). With more advanced technology applied to research, the molecular mechanisms of RNA methyltransferase, demethylase, and m6A-binding protein have been revealed. An increasing number of studies have implicated the correlation between m6A modification and human cancers. In this review, we summarize that the occurrence and development of various human cancers are associated with aberrant m6A modification. We also discuss the progress in research related to m6A modification, providing novel therapeutic insight and potential breakthrough in anticancer therapy.
    Keywords:  cancer; epigenetics; m(6)A; tumor suppressor
    DOI:  https://doi.org/10.1016/j.omtn.2019.12.013
  424. Proc Natl Acad Sci U S A. 2020 Jan 21. pii: 201916748. [Epub ahead of print]
    Coordination of host and symbiont gene expression reveals a metabolic tug-of-war between aphids and Buchnera.
    Smith TE, Moran NA.
      Symbioses between animals and microbes are often described as mutualistic, but are subject to tradeoffs that may manifest as shifts in host and symbiont metabolism, cellular processes, or symbiont density. In pea aphids, the bacterial symbiont Buchnera is confined to specialized aphid cells called bacteriocytes, where it produces essential amino acids needed by hosts. This relationship is dynamic; Buchnera titer varies within individual aphids and among different clonal aphid lineages, and is affected by environmental and host genetic factors. We examined how host genotypic variation relates to host and symbiont function among seven aphid clones differing in Buchnera titer. We found that bacteriocyte gene expression varies among individual aphids and among aphid clones, and that Buchnera gene expression changes in response. By comparing hosts with low and high Buchnera titer, we found that aphids and Buchnera oppositely regulate genes underlying amino acid biosynthesis and cell growth. In high-titer hosts, both bacteriocytes and symbionts show elevated expression of genes underlying energy metabolism. Several eukaryotic cell signaling pathways are differentially expressed in bacteriocytes of low- versus high-titer hosts: Cell-growth pathways are up-regulated in low-titer genotypes, while membrane trafficking, lysosomal processes, and mechanistic target of rapamycin (mTOR) and cytokine pathways are up-regulated in high-titer genotypes. Specific Buchnera functions are up-regulated within different bacteriocyte environments, with genes underlying flagellar body secretion and flagellar assembly overexpressed in low- and high-titer hosts, respectively. Overall, our results reveal allowances and demands made by both host and symbiont engaged in a metabolic "tug-of-war."
    Keywords:  Buchnera; RNA-seq; aphids; host–symbiont interactions; symbiosis
    DOI:  https://doi.org/10.1073/pnas.1916748117
  425. J Cell Mol Med. 2020 Jan 19.
    Isoalantolactone restores the sensitivity of gram-negative Enterobacteriaceae carrying MCR-1 to carbapenems.
    Lu N, Lv Q, Sun X, Zhou Y, Guo Y, Qiu J, Zhang P, Wang J.
      Polymyxin B has been re-applied to the clinic as the final choice for the treatment of multidrug-resistant gram-negative pathogenic infections, but the use of polymyxin B has been re-assessed because of the emergence and spread of the plasmid-mediated mcr-1 gene. The purpose of this study was to search for an MCR inhibitor synergistically acting with polymyxin to treat the infection caused by this pathogen. In this study, we used the broth microdilution checkerboard method to evaluate the synergistic effect of isoalantolactone (IAL) and polymyxin B on mcr-1-positive Enterobacteriaceae. Growth curve analysis, time-killing assays and a combined disc test were used to further verify the efficacy of the combined drug. Colonization of the thigh muscle in mice, survival experiments and lung tissue section observations was used to determine the effect of synergy in vivo after Klebsiella pneumoniae and Escherichia coli infection. We screened a natural compound, IAL, which can enhance the sensitivity of polymyxin B to mcr-1-positive Enterobacteriaceae. The results showed that the combined use of polymyxin B and IAL has a synergistic effect on mcr-1-positive Enterobacteriaceae, such as K pneumoniae and E coli, not only in vitro but also in vivo. Our results indicate that IAL is a natural compound with broad application prospects that can prolong the service life of polymyxin B and make outstanding contributions to the treatment of gram-negative Enterobacteriaceae infections resistant to polymyxin B.
    Keywords:   mcr-1 ; isoalantolactone; polycolistin B; synergistic effect
    DOI:  https://doi.org/10.1111/jcmm.14936
  426. Biomolecules. 2020 Jan 16. pii: E143. [Epub ahead of print]10(1):
    Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes.
    Podkalicka P, Mucha O, Kruczek S, Biela A, Andrysiak K, Stępniewski J, Mikulski M, Gałęzowski M, Sitarz K, Brzózka K, Józkowicz A, Dulak J, Łoboda A.
      Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.
    Keywords:  fumarate hydratase; heme oxygenase-1; small-molecule inhibitors; synthetic lethality hereditary leiomyomatosis and renal cell carcinoma
    DOI:  https://doi.org/10.3390/biom10010143
  427. J Chem Neuroanat. 2020 Jan 17. pii: S0891-0618(19)30193-0. [Epub ahead of print] 101749
    LncRNA CASC2 inhibits astrocytic activation and adenosine metabolism by regulating PTEN in pentylenetetrazol-induced epilepsy model.
    Liu H.
      Growing evidence has indicated that long noncoding RNAs (lncRNAs) are closely implicated in the progress of epilepsy. However, the expression profile and potential function of long noncoding RNAs cancer susceptibility candidate 2 (lncRNA CASC2) in epilepsy are poorly studied. The aim of this study was to testify the influence of lncRNA CASC2 on epilepsy in rat and cell models of epileptic seizure. We adopted qRT-PCR on the hippocampus of rats following pentylenetetrazol (PTZ)-stimulated epilepsy. To further examine the correlation between lncRNA CASC2 and Phosphatase and tensin homolog (PTEN), we detected the effects of lncRNA CASC2 on PTEN expression. We found that lncRNA CASC2 and PTEN expression were positively correlated in PTZ-induced epileptic rat. Overexpression of lncRNA CASC2 prolonged the latency and reduced the frequency of epileptic seizure, suppressed the activation of astrocytes and the release of adenosine in epileptic rat, whereas downregulation of lncRNA CASC2 exhibited the opposite effects. Meanwhile, lncRNA CASC2 decreased the adenosine metabolism related proteins expression of p38, Equilibrative nucleoside transporter 1 (ENT1) and Adenosine Kinase (ADK). In PTZ-treated astrocytes, PTEN was found to be a direct target of lncRNA CASC2. Additionally, downregulation of PTEN attenuated the protective effect of lncRNA CASC2 overexpression in epileptic seizure. Our findings manifested the key role of lncRNA CASC2 in the occurrence of epilepsy by targeting PTEN, which provided a novel target for epilepsy therapy.
    Keywords:  PTEN; adenosine; astrocyte activation; epilepsy; lncRNA CASC2
    DOI:  https://doi.org/10.1016/j.jchemneu.2020.101749
  428. Cancer Gene Ther. 2020 Jan 20.
    RNA N6-methyladenosine modification in solid tumors: new therapeutic frontiers.
    Melstrom L, Chen J.
      Epigenetic mRNA modification is an evolving field. N6-methyladenosine (m6A) is the most frequent internal transcriptional modification in eukaryotic messenger RNAs (mRNAs). This review will discuss the functions of the m6A mRNA machinery, including its "writers" that are components of the methyltransferase complex, its "readers" and its "erasers" (specifically FTO and ALKBH5) in cancer. The writers deposit the m6A and include METTL3, METTL14, WTAP, VIRMA, and RBM15. M6A methylation is removed by the m6A demethylases (FTO and ALKBH5). Lastly, the most diverse members are the readers that can contribute to mRNA splicing, stability, translation, and nuclear export. Many of these functions continue to be elucidated. The dysregulation of this machinery in various malignancies and the associated impact on tumorigenesis and drug response will be discussed herein with a focus on solid tumors. It is clear that, by contributing to either mRNA stability or translation, there are downstream targets that are impacted, contributing to cancer progression and the self-renewal ability of cancer stem cells.
    DOI:  https://doi.org/10.1038/s41417-020-0160-4
  429. Anal Bioanal Chem. 2020 Jan 22.
    In silico MS/MS spectra for identifying unknowns: a critical examination using CFM-ID algorithms and ENTACT mixture samples.
    Chao A, Al-Ghoul H, McEachran AD, Balabin I, Transue T, Cathey T, Grossman JN, Singh RR, Ulrich EM, Williams AJ, Sobus JR.
      High-resolution mass spectrometry (HRMS) enables rapid chemical annotation via accurate mass measurements and matching of experimentally derived spectra with reference spectra. Reference libraries are generated from chemical standards and are therefore limited in size relative to known chemical space. To address this limitation, in silico spectra (i.e., MS/MS or MS2 spectra), predicted via Competitive Fragmentation Modeling-ID (CFM-ID) algorithms, were generated for compounds within the U.S. Environmental Protection Agency's (EPA) Distributed Structure-Searchable Toxicity (DSSTox) database (totaling, at the time of analysis, ~ 765,000 substances). Experimental spectra from EPA's Non-Targeted Analysis Collaborative Trial (ENTACT) mixtures (n = 10) were then used to evaluate the performance of the in silico spectra. Overall, MS2 spectra were acquired for 377 unique compounds from the ENTACT mixtures. Approximately 53% of these compounds were correctly identified using a commercial reference library, whereas up to 50% were correctly identified as the top hit using the in silico library. Together, the reference and in silico libraries were able to correctly identify 73% of the 377 ENTACT substances. When using the in silico spectra for candidate filtering, an examination of binary classifiers showed a true positive rate (TPR) of 0.90 associated with false positive rates (FPRs) of 0.10 to 0.85, depending on the sample and method of candidate filtering. Taken together, these findings show the abilities of in silico spectra to correctly identify true positives in complex samples (at rates comparable to those observed with reference spectra), and efficiently filter large numbers of potential false positives from further consideration. Graphical abstract.
    Keywords:  CFM-ID; DSSTox; ENTACT; High-resolution mass spectrometry; Non-targeted analysis; ToxCast
    DOI:  https://doi.org/10.1007/s00216-019-02351-7
  430. BMC Evol Biol. 2020 Jan 22. 20(1): 11
    Exploring molecular evolution of Rubisco in C3 and CAM Orchidaceae and Bromeliaceae.
    Hermida-Carrera C, Fares MA, Font-Carrascosa M, Kapralov MV, Koch MA, Mir A, Molins A, Ribas-Carbó M, Rocha J, Galmés J.
      BACKGROUND: The CO2-concentrating mechanism associated to Crassulacean acid metabolism (CAM) alters the catalytic context for Rubisco by increasing CO2 availability and provides an advantage in particular ecological conditions. We hypothesized about the existence of molecular changes linked to these particular adaptations in CAM Rubisco. We investigated molecular evolution of the Rubisco large (L-) subunit in 78 orchids and 144 bromeliads with C3 and CAM photosynthetic pathways. The sequence analyses were complemented with measurements of Rubisco kinetics in some species with contrasting photosynthetic mechanism and differing in the L-subunit sequence.RESULTS: We identified potential positively selected sites and residues with signatures of co-adaptation. The implementation of a decision tree model related Rubisco specific variable sites to the leaf carbon isotopic composition of the species. Differences in the Rubisco catalytic traits found among C3 orchids and between strong CAM and C3 bromeliads suggested Rubisco had evolved in response to differing CO2 concentration.
    CONCLUSIONS: The results revealed that the variability in the Rubisco L-subunit sequence in orchids and bromeliads is composed of coevolving sites under potential positive adaptive signal. The sequence variability was related to δ13C in orchids and bromeliads, however it could not be linked to the variability found in the kinetic properties of the studied species.
    Keywords:  C3; CAM; Carboxylation; Catalytic rate; Coevolution; Decision tree; Positive selection; Rubisco
    DOI:  https://doi.org/10.1186/s12862-019-1551-8
  431. Cell Mol Life Sci. 2020 Jan 23.
    The lung microbiota: role in maintaining pulmonary immune homeostasis and its implications in cancer development and therapy.
    Sommariva M, Le Noci V, Bianchi F, Camelliti S, Balsari A, Tagliabue E, Sfondrini L.
      Like other body districts, lungs present a complex bacteria community. An emerging function of lung microbiota is to promote and maintain a state of immune tolerance, to prevent uncontrolled and not desirable inflammatory response caused by inhalation of harmless environmental stimuli. This effect is mediated by a continuous dialog between commensal bacteria and immune cells resident in lungs, which express a repertoire of sensors able to detect microorganisms. The same receptors are also involved in the recognition of pathogens and in mounting a proper immune response. Due to its important role in preserving lung homeostasis, the lung microbiota can be also considered a mirror of lung health status. Indeed, several studies indicate that lung bacterial composition drastically changes during the occurrence of pulmonary pathologies, such as lung cancer, and the available data suggest that the modifications of lung microbiota can be part of the etiology of tumors in lungs and can influence their progression and response to therapy. These results provide the scientific rationale to analyze lung microbiota composition as biomarker for lung cancer and to consider lung microbiota a new potential target for therapeutic intervention to reprogram the antitumor immune microenvironment. In the present review, we discussed about the role of lung microbiota in lung physiology and summarized the most relevant data about the relationship between lung microbiota and cancer.
    Keywords:  Commensal microorganisms; Immune system; Immunological tolerance; Respiratory tract; Tumor
    DOI:  https://doi.org/10.1007/s00018-020-03452-8
  432. Physiol Rep. 2020 Jan;8(2): e14344
    Transcriptomic profiles reveal differences between the right and left ventricle in normoxia and hypoxia.
    Gorr MW, Sriram K, Chinn AM, Muthusamy A, Insel PA.
      Chronic hypoxia from diseases in the lung, such as pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease, can increase pulmonary vascular resistance, resulting in hypertrophy and dysfunction of the right ventricle (RV). In order to obtain insight into RV biology and perhaps uncover potentially novel therapeutic approaches for RV dysfunction, we performed RNA-sequencing (RNA-seq) of RV and LV tissue from rats in normal ambient conditions or subjected to hypoxia (10% O2 ) for 2 weeks. Gene ontology and pathway analysis of the RV and LV revealed multiple transcriptomic differences, in particular increased expression in the RV of genes related to immune function in both normoxia and hypoxia. Immune cell profiling by flow cytometry of cardiac digests revealed that in both conditions, the RV had a larger percentage than the LV of double-positive CD45+ /CD11b/c+ cells (which are predominantly macrophages and dendritic cells). Analysis of gene expression changes under hypoxic conditions identified multiple pathways that may contribute to hypoxia-induced changes in the RV, including increased expression of genes related to cell mitosis/proliferation and decreased expression of genes related to metabolic processes. Together, the findings indicate that the RV differs from the LV with respect to content of immune cells and expression of certain genes, thus suggesting the two ventricles differ in aspects of pathophysiology and in potential therapeutic targets for RV dysfunction.
    Keywords:  hypoxia; immune cells; pulmonary hypertension; remodeling; right ventricle; transcriptomics
    DOI:  https://doi.org/10.14814/phy2.14344
  433. Eur J Pharmacol. 2020 Jan 21. pii: S0014-2999(20)30035-2. [Epub ahead of print] 172943
    A novel trifluoromethyl 2-phosphonopyrrole analogue inhibits human cancer cell migration and growth by cell cycle arrest at G1 phase and apoptosis.
    Olszewska P, Cal D, Zagórski P, Mikiciuk-Olasik E.
      Pyrroles, an important class of heterocyclic compounds found in naturally occurring products, represent an interesting biologically active scaffold for drug design. Recently we have synthetized a series of five new fluorinated pyrrole derivatives for potential anticancer applications. All new compounds contain a trifluoromethyl and N-benzyl group, but are different from each other by bearing a phenyl, ethoxycarbonyl or carboxylic moiety, with two of them possessing an additional phosphonyl function. The aim of this study was to evaluate anticancer activity of the new compounds in human lung and breast cancer cells. We found that compound 3, bearing a phosphonyl and phenyl group, was the most effective in attenuating growth of A549 and MCF-7 cells in a dose dependent manner with IC50 36.5 μM ± 1.80 and 27.9 μM ± 1.68, respectively. Compound 3 inhibited cancer cell proliferation by cell cycle arrest at G1 phase as detected by flow cytometry analysis. Furthermore, compound 3 induced apoptosis of A549 cells by activation of caspase-3. Cancer cell migration rate was significantly inhibited when A549 and MCF-7 cells were cultured in the presence of the compound. These results demonstrate that a novel trifluoromethyl-functionalized phosphonopyrrole with a phenyl group might be a promising pyrrole analogue with anticancer potential.
    Keywords:  Anticancer compounds; Breast cancer; Fluorinated pyrrole derivatives; Lung cancer; Phosphonopyrrole derivatives
    DOI:  https://doi.org/10.1016/j.ejphar.2020.172943
  434. Acta Med Port. 2019 Oct 14.
    [Primary Pulmonary Tumor in an Adolescent].
    Rodrigues L, Domingues R, Amaral D, Cavaco J.
      Primary lung tumors in the pediatric age group are rare, histologically diverse and have different therapeutic approaches. The inflammatory myofibroblastic tumor of the lung accounts for 0.04% - 1.2% of all lung tumors, is more common in children and young adults and its etiology is unknown. The diagnosis is difficult as clinical and radiological findings are highly variable. We report a case of a 15-year-old adolescent who presented with a single pulmonary nodule on a chest radiograph, in the context of a respiratory infection, and whose etiological investigation revealed an inflammatory myofibroblastic tumor of the lung. Atypical resection was performed by video-assisted thoracoscopic surgery, with full recovery. We highlight the rarity of this entity, the need for a high suspicion index and the diagnostic investigation undertaken to reach a definitive diagnosis and a successful outcome.
    Keywords:  Adolescent; Granuloma, Plasma Cell; Lung Neoplasms; Myofibroma
    DOI:  https://doi.org/10.20344/amp.12690
  435. BMJ Open. 2020 Jan 21. 10(1): e031768
    Direct and indirect healthcare costs of lung cancer CT screening in Denmark: a registry study.
    Jensen MD, Siersma V, Rasmussen JF, Brodersen J.
      INTRODUCTION: A study based on the Danish Randomised Controlled Lung Cancer Screening Trial (DLCST) calculated the healthcare costs of lung cancer screening by comparing costs in an intervention group with a control group. Participants in both groups, however, experienced significantly increased negative psychosocial consequences after randomisation. Substantial participation bias has also been documented: The DLCST participants reported fewer negative psychosocial aspects and experienced better living conditions compared with the random sample.OBJECTIVE: To comprehensively analyse the costs of lung cancer CT screening and to determine whether invitations to mass screening alter the utilisation of the healthcare system resulting in indirect costs. Healthcare utilisation and costs are analysed in the primary care sector (general practitioner psychologists, physiotherapists, other specialists, drugs) and the secondary care sector (emergency room contacts, outpatient visits, hospitalisation days, surgical procedures and non-surgical procedures).
    DESIGN: To account for bias in the original trial, the costs and utilisation of healthcare by participants in DLCST were compared with a new reference group, selected in the period from randomisation (2004-2006) until 2014.
    SETTING: Four Danish national registers.
    PARTICIPANTS: DLCST included 4104 current or former heavy smokers, randomly assigned to the CT group or the control group. The new reference group comprised a random sample of 535 current or former heavy smokers in the general Danish population who were never invited to participate in a cancer screening test.
    MAIN OUTCOME MEASURES: Total healthcare costs including costs and utilisation of healthcare in both the primary and the secondary care sector.
    RESULTS: Compared with the reference group, the participants in both the CT group (offered annual CT screening, lung function test and smoking counselling) and the control group (offered annual lung function test and smoking counselling) had significantly increased total healthcare costs, calculated at 60% and 48% respectively. The increase in costs was caused by increased use of healthcare in both the primary and the secondary sectors.
    CONCLUSION: CT screening leads to 60% increased total healthcare costs. Such increase would raise the expected annual healthcare cost per participant from EUR 2348 to EUR 3756. Cost analysis that only includes costs directly related to the CT scan and follow-up procedures most likely underestimates total costs. Our data show that the increased costs are not limited to the secondary sector.
    TRIAL REGISTRATION NUMBER: NCT00496977.
    Keywords:  CT scan; cancer screening test; healthcare cost; illness perception; lung cancer; mass screening
    DOI:  https://doi.org/10.1136/bmjopen-2019-031768
  436. J Clin Endocrinol Metab. 2020 Jan 24. pii: dgaa027. [Epub ahead of print]
    HLA class II allele analyses implicate common genetic components in type 1 and non-insulin treated type 2 diabetes.
    Jacobi T, Massier L, Klöting N, Horn K, Schuch A, Ahnert P, Engel C, Löffler M, Burkhardt R, Thiery J, Tönjes A, Stumvoll M, Blüher M, Doxiadis I, Scholz M, Kovacs P.
      CONTEXT: Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type 1 diabetes, the aim of the present study was to test the association of high density imputed HLA genotypes with type 2 diabetes.OBJECTIVES AND DESIGN: Three cohorts (Ntotal=10,413) from Leipzig, Germany were included in this study: LIFE-Adult (N=4649), LIFE-Heart (N=4815) and the Sorbs (N=949) cohort. Detailed metabolic phenotyping and genome-wide SNP data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4 digit level and association tests for type 2 diabetes and related metabolic traits were conducted.
    RESULTS: In a meta-analysis including all three cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (p=0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (p=0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02 which was also associated with reduced risk of type 2 diabetes (OR=0.84, p=0.005). Contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non-insulin treated diabetes (OR=1.37, p=0.002).
    CONCLUSIONS: Genetic variation in the HLA class II locus exerts risk and protective effects on non-insulin treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.
    Keywords:  HLA class II; association; genotype imputation; haplotype; single nucleotide polymorphism; type 1 diabetes; type 2 diabetes
    DOI:  https://doi.org/10.1210/clinem/dgaa027
  437. EJNMMI Radiopharm Chem. 2020 Jan 23. 5(1): 3
    Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone.
    Wichmann CW, Goh YW, Parslow AC, Rigopoulos A, Guo N, Scott AM, Ackermann U, White JM.
      BACKGROUND: Targeted therapy of HER2 positive breast cancer has led to clinical success in some cases with primary and secondary resistance being major obstacles. Due to the substantial involvement of mTOR kinase in cell growth and proliferation pathways it is now targeted in combination treatments to counteract HER2 targeted therapy resistance. However, the selection of receptive patient populations for a specific drug combination is crucial. This work aims to develop a molecular probe capable of identifying patients with tumour populations which are receptive to RAD001 combination therapy. Based on the structure of a mTOR inhibitor specific for mTORC1, we designed, synthesised and characterised a novel benzofuran based molecular probe which suits late stage fluorination via Click chemistry.RESULTS: Synthesis of the alkyne precursor 5 proceeded in 27.5% yield over 7 linear steps. Click derivatisation gave the non-radioactive standard in 25% yield. Radiosynthesis of [18F]1-((1-(2-Fluoroethyl)-1H-1,2,3-triazol-4-yl) methyl)-4-((5-methoxy-2-phenylbenzofuran-4-yl) methyl) piperazine ([18F]mBPET-1) proceeded over two steps which were automated on an iPhase FlexLab synthesis module. In the first step, 2-[18F]fluoroethylazide ([18F]6) was produced, purified by automated distillation in 60% non-decay-corrected yield and subjected to Click conditions with 5. Semi-preparative RP-HPLC purification and reformulation gave [18F]mBPET-1 in 40% ± 5% (n = 6) overall RCY with a process time of 90 min. Radiochemical purity was ≥99% at end of synthesis (EOS) and ≥ 98% after 4 h at room temperature. Molar activities ranged from typically 24.8 GBq/μmol (EOS) to a maximum of 78.6 GBq/μmol (EOS). Lipophilicity of [18F]mBPET-1 was determined at pH 7.4 (logD7.4 = 0.89). [18F]mBPET-1 showed high metabolic stability when incubated with mouse S9 liver fractions which resulted in a 0.8% drop in radiochemical purity after 3 h. Cell uptake assays showed 1.3-1.9-fold increased uptake of the [18F]mBPET-1 in RAD001 sensitive compared to insensitive cells across a panel of 4 breast cancer cell lines.
    CONCLUSION: Molecular targeting of mTOR with [18F]mBPET-1 distinguishes mTOR inhibitor sensitive and insensitive cell lines. Future studies will explore the ability of [18F]mBPET-1 to predict response to mTOR inhibitor treatment in in vivo models.
    Keywords:  18F; Breast cancer; Everolimus therapy; Fluorine-18; Molecular targeting; PET; RAD001; mTOR
    DOI:  https://doi.org/10.1186/s41181-020-0089-9
  438. Ecol Lett. 2020 Jan 23.
    Assessing seasonal demographic covariation to understand environmental-change impacts on a hibernating mammal.
    Paniw M, Childs DZ, Armitage KB, Blumstein DT, Martin JGA, Oli MK, Ozgul A.
      Natural populations are exposed to seasonal variation in environmental factors that simultaneously affect several demographic rates (survival, development and reproduction). The resulting covariation in these rates determines population dynamics, but accounting for its numerous biotic and abiotic drivers is a significant challenge. Here, we use a factor-analytic approach to capture partially unobserved drivers of seasonal population dynamics. We use 40 years of individual-based demography from yellow-bellied marmots (Marmota flaviventer) to fit and project population models that account for seasonal demographic covariation using a latent variable. We show that this latent variable, by producing positive covariation among winter demographic rates, depicts a measure of environmental quality. Simultaneously, negative responses of winter survival and reproductive-status change to declining environmental quality result in a higher risk of population quasi-extinction, regardless of summer demography where recruitment takes place. We demonstrate how complex environmental processes can be summarized to understand population persistence in seasonal environments.
    Keywords:  Bayesian population model; carry-over effects; demography; factor-analytic models; seasonal structured population models; viability
    DOI:  https://doi.org/10.1111/ele.13459
  439. J Mol Biol. 2020 Jan 21. pii: S0022-2836(20)30066-8. [Epub ahead of print]
    Amplitude effects allow short jetlags and large seasonal phase shifts in minimal clock models.
    Ananthasubramaniam B, Schmal C, Herzel H.
      Mathematical models of varying complexity have helped shed light on different aspects of circadian clock function. In this work, we question whether minimal clock models (Goodwin models) are sufficient to reproduce essential phenotypes of the clock: a small phase response curve (PRC), fast jetlag and seasonal phase shifts. Instead of building a single best model, we take an approach where we study the properties of a set of models satisfying certain constraints; here a one-hour pulse PRC with a range of three hours and clock periods between 22h and 26h. Surprisingly, almost all these randomly parameterized models showed a four hour change in phase of entrainment between long and short days and jetlag durations of three to seven days in advance and delay. Moreover, intrinsic clock period influenced jetlag duration and entrainment amplitude and phase. Fast jetlag was realized in this model by means of an interesting amplitude effect: the association between clock amplitude and clock period termed 'twist'. This twist allows amplitude changes to speed up and slow down clocks enabling faster shifts. These findings were robust to the addition of positive feedback to the model. In summary, the known design principles of rhythm generation - negative feedback, long delay and switch-like inhibition (we review these in detail) - are sufficient to reproduce the essential clock phenotypes. Furthermore, amplitudes play a role in determining clock properties and must be always considered, although they are difficult to measure.
    Keywords:  circadian clock; design principles; mathematical model; seasonality; twist
    DOI:  https://doi.org/10.1016/j.jmb.2020.01.014
  440. Eur J Intern Med. 2020 Jan 16. pii: S0953-6205(19)30443-1. [Epub ahead of print]
    Understanding the impact of chronic obstructive pulmonary disease exacerbations on patient health and quality of life.
    Hurst JR, Skolnik N, Hansen GJ, Anzueto A, Donaldson GC, Dransfield MT, Varghese P.
      Exacerbations of chronic obstructive pulmonary disease (COPD) represent a significant clinical problem, and are associated with decreased lung function, worsening quality of life and decreased physical activity levels, with even a single exacerbation having detrimental effects. The occurrence of COPD exacerbations can also have a considerable impact on healthcare costs and mortality rates, with over one-fifth of patients hospitalized for a COPD exacerbation for the first time dying within one year of discharge. This highlights the need for COPD exacerbations to be a major focus in clinical practice. Furthermore, the substantial effect that COPD exacerbations can have on patient mental health should not be underestimated. Despite their clinical importance, COPD exacerbations are poorly recognized and reported by patients, and improving patient understanding and reporting of exacerbations to ensure prompt treatment may minimize their deleterious effects. Renewed focus on improving current clinical practice with support from evidence-based guidelines is required. This also raises a challenge to payors, healthcare systems and government policies to do more to tackle the considerable outstanding burden of COPD exacerbations.
    Keywords:  Comorbidity; Mental health; Mortality; Physical functional performance; Quality of life; Respiratory function tests
    DOI:  https://doi.org/10.1016/j.ejim.2019.12.014
  441. Brain Behav. 2020 Jan 20. e01536
    Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement.
    Fine JM, Kosyakovsky J, Baillargeon AM, Tokarev JV, Cooner JM, Svitak AL, Faltesek KA, Frey WH, Hanson LR.
      INTRODUCTION: Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of Alzheimer's and Parkinson's disease.METHODS: In order to assess the mechanism of DFO, determine its ability to improve memory from baseline in the absence of a diseased state, and assess targeting ability of intranasal delivery, we treated healthy mice with IN DFO (2.4 mg) or intraperitoneal (IP) DFO and compared behavioral and biochemical changes with saline-treated controls. Mice were treated 5 days/week for 4 weeks and subjected to behavioral tests 30 min after dosing.
    RESULTS: We found that IN DFO, but not IP DFO, significantly enhanced working memory in the radial arm water maze, suggesting that IN administration is more efficacious as a targeted delivery route to the brain. Moreover, the ability of DFO to improve memory from baseline in healthy mice suggests a non-disease-specific mechanism of memory improvement. IN DFO treatment was accompanied by decreased GSK-3β activity and increased HIF-1α activity.
    CONCLUSIONS: These pathways are suspected in DFO's ability to improve memory and perhaps represent a component of the common mechanism through which DFO enacts beneficial change in models of neurologic disease and injury.
    Keywords:  deferoxamine; glycogen synthase kinase 3β; hypoxia-inducible factor 1α; intranasal; memory enhancement; radial arm water maze
    DOI:  https://doi.org/10.1002/brb3.1536
  442. Metabolomics. 2020 Jan 24. 16(2): 19
    Association between phospholipid metabolism in plasma and spontaneous preterm birth: a discovery lipidomic analysis in the cork pregnancy cohort.
    Morillon AC, Yakkundi S, Thomas G, Gethings LA, Langridge JI, Baker PN, Kenny LC, English JA, McCarthy FP.
      INTRODUCTION: Preterm birth (PTB) is defined as birth occurring before 37 weeks' gestation, affects 5-9% of all pregnancies in developed countries, and is the leading cause of perinatal mortality. Spontaneous preterm birth (sPTB) accounts for 31-50% of all PTB, but the underlying pathophysiology is poorly understood.OBJECTIVE: This study aimed to decipher the lipidomics pathways involved in pathophysiology of sPTB.
    METHODS: Blood samples were taken from SCreening fOr Pregnancy Endpoints (SCOPE), an international study that recruited 5628 nulliparous women, with a singleton low-risk pregnancy. Our analysis focused on plasma from SCOPE in Cork. Discovery profiling of the samples was undertaken using liquid chromatography-mass spectrometry Lipidomics, and features significantly altered between sPTB (n = 16) and Control (n = 32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons.
    RESULTS: Twenty-six lipids showed lower levels in plasma of sPTB compared to controls (adjusted p < 0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls.
    CONCLUSIONS: We report reduced levels of plasma phospholipids in sPTB. Phospholipid integrity is linked to biological membrane stability and inflammation, while storage and breakdown of lipids have previously been implicated in pregnancy complications. The contribution of phospholipids to sPTB as a cause or effect is still unclear; however, our results of differential plasma phospholipid expression represent another step in advancing our understanding of the aetiology of sPTB. Further work is needed to validate these findings in independent pregnancy cohorts.
    Keywords:  Lipid profiling; Lipidomics; Metabolic profiling; Pregnancy; SCOPE study; Spontaneous preterm birth
    DOI:  https://doi.org/10.1007/s11306-020-1639-6
  443. J Cell Physiol. 2020 Jan 24.
    miR-210 is induced by hypoxia and regulates neural cell adhesion molecule in prostate cells.
    Angel CZ, Lynch SM, Nesbitt H, McKenna MM, Walsh CP, McKenna DJ.
      Hypoxia in prostate tumours has been associated with disease progression and metastasis. MicroRNAs are short noncoding RNA molecules that are important in several cell processes, but their role in hypoxic signalling is still poorly understood. miR-210 has been linked with hypoxic mechanisms, but this relationship has been poorly characterised in prostate cancer. In this report, the link between hypoxia and miR-210 in prostate cancer cells is investigated. Polymerase chain reaction analysis demonstrates that miR-210 is induced by hypoxia in prostate cancer cells using in vitro cell models and an in vivo prostate tumour xenograft model. Analysis of The Cancer Genome Atlas prostate biopsy datasets shows that miR-210 is significantly correlated with Gleason grade and other clinical markers of prostate cancer progression. Neural cell adhesion molecule (NCAM) is identified as a target of miR-210, providing a biological mechanism whereby hypoxia-induced miR-210 expression can contribute to prostate cancer. This study provides evidence that miR-210 is an important regulator of cell response to hypoxic stress and proposes that its regulation of NCAM may play an important role in the pathogenesis of prostate cancer.
    Keywords:  NCAM; hypoxia; miR-210; microRNA; prostate cancer
    DOI:  https://doi.org/10.1002/jcp.29548
  444. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2019 Dec 28. 44(12): 1353-1359
    [Effect of progesterone on the pathogenesis and development of hemangioma in nude mice].
    Shi Q, Chen X, Qiu F, Lei S.
      OBJECTIVE: To explore the role of progesterone in the pathogenesis and development of hemangioma in nude mice.
 Methods: The hemangioma model was established. Progesterone was injected intramuscularly at different doses (0.2, 0.4, and 0.8 mg/d) for one week. Camellia oil (0.4 mL/d) was injected intramuscularly as control. The size of hemangioma was observed dynamically. The subcutaneous implants were harvested on the 14th and 28th days. The expression of vascular endothelial growth factor in the tumor tissues were evaluated using immunohistochemistry and microvessel density (MVD) was counted under the microscope.
 Results: On the 14th day, the expression of vascular endothelial growth factor (P<0.01 and P<0.05, respectively) was higher, the volume of tumors (All P<0.01) and MVD (All P<0.01) were greater in the high-dose progesterone group than those in the control and low-dose progesterone group. On the 28th day, there was no significant difference in the volume of tumors among 4 groups (P>0.05). The expression of vascular endothelial growth factor (P<0.01) was lower, and MVD (All P<0.05) were less in the middle-dose and high-dose progesterone group than those in the control and low-dose progesterone group.
 Conclusion: Progesterone promotes angiogenesis via upregulation of vascular endothelial growth factor expression, promotion of hemangiomas proliferation, suggesting that excessive progesterone supplementation may be one of the initial factors for early hemangioma formation.
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2019.190123
  445. Int J Radiat Biol. 2020 Jan 24. 1-11
    Radiation metabolomics in the quest of cardiotoxicity biomarkers: the review.
    Gramatyka M, Sokół M.
      Purpose: Ionizing radiation is a risk factor to the whole organism, including the heart. Cardiac damage is considered to be a late effect of radiation exposure. While the acute cardiotoxicity of high doses is well characterized, the knowledge about nature and magnitude of the cardiac risk following lower doses exposure is incomplete. It has been shown that the cardiotoxic effects of radiation are source-, dose- and time-dependent. This paper provides an overview on these dependencies with regard to the molecular responses at the cellular and tissue levels. Main focus is put on the Nuclear Magnetic Resonance (NMR)-based and Mass Spectrometry (MS)-based metabolomic approaches in search of toxicity markers of relatively small doses of radiation.Conclusions: Available literature indicates that radiation exposure affects metabolites associated with: energy production, degradation of proteins and cell membranes, expression of proteins and stress response. Such effects are common for both animal and human studies. However, the specific metabolic response depends on several factors, including the examined organ. Radiation metabolomics can be used to explain the mechanisms of development of radiation-induced heart disease and to find an organ-specific biomarker of radiation exposure. The main aim of this review was to collect the information on the human cardiotoxicity biomarkers. In addition it also summarizes results of the studies on the metabolic responses to ionizing radiation for other organs, as well as the comparative data concerning animal studies.
    Keywords:  Ionizing radiation; biomarkers; cardiotoxicity; metabolomics
    DOI:  https://doi.org/10.1080/09553002.2020.1704299
  446. J Biol Chem. 2020 Jan 22. pii: jbc.RA119.010252. [Epub ahead of print]
    Extracellular domains I-II of cell-surface glycoprotein CD44 mediate its trans-homophilic dimerization and tumor cluster aggregation.
    Kawaguchi M, Dashzeveg N, Cao Y, Jia Y, Liu X, Shen Y, Liu H.
      CD44 molecule (CD44) is a well-known surface glycoprotein on tumor-initiating cells or cancer stem cells. However, its utility as a therapeutic target for managing metastases remains to be  evaluated. We previously demonstrated that CD44 mediates homophilic interactions for circulating tumor cell (CTC) cluster formation, which enhances cancer stemness and metastatic potential in association with an unfavorable prognosis. Furthermore, CD44 self-interactions activate the P21-activated kinase 2 (PAK2) signaling pathway. Here, we further examined the biochemical properties of CD44 in homotypic tumor cell aggregation. The standard CD44 form (CD44s) mainly assembled as intercellular homodimers (trans-dimers) in tumor clusters rather than intracellular dimers (cis-dimers) present in single cells. Machine learning-based computational modeling combined with experimental mutagenesis tests revealed that the extracellular domains I and II of CD44 are essential for its trans-dimerization and predicted high-score residues to be required for dimerization. Substitutions of 10  residues in domain I (Ser-45, Glu-48, Phe-74, Cys-77, Arg-78, Tyr-79, Ile-88, Arg-90, Asn-94, and Cys-97) or 5 residues in domain II (Ile-106, Tyr-155, Val-156, Gln-157, and Lys-158) abolished CD44 dimerization and reduced tumor cell aggregation in vitro. Importantly, the substitutions in domain II dramatically inhibited lung colonization in mice. The CD44 dimer-disrupting substitutions decreased downstream PAK2 activation without affecting the interaction between CD44 and PAK2, suggesting that PAK2 activation in tumor cell clusters is CD44 trans-dimer-dependent. These results shed critical light on the biochemical mechanisms of CD44-mediated tumor cell cluster formation and may help inform the development of therapeutic strategies to prevent tumor cluster formation and block cluster-mediated metastases.
    Keywords:  CD44; metastasis; mutagenesis; protein domain; protein-protein interaction
    DOI:  https://doi.org/10.1074/jbc.RA119.010252
  447. Clin Radiol. 2020 Jan 21. pii: S0009-9260(20)30002-7. [Epub ahead of print]
    Imaging of cerebral venous thrombosis.
    Ghoneim A, Straiton J, Pollard C, Macdonald K, Jampana R.
      The incidence of cerebral venous thrombosis (CVT) is increasing due to the widespread use of computed tomography (CT) and magnetic resonance imaging (MRI) for investigating patients with acute headaches and new onset of seizures. Alternatively referred to as cerebral venous sinus thrombosis (CVST) or dural venous sinus thrombosis (DVST), the terms encompass a broad spectrum of neurological pathologies. These include dural venous sinus thrombosis, cortical vein thrombosis, cavernous sinus thrombosis, venous infarction/haemorrhage, and the rare sequelae of intracranial hypertension or dural arteriovenous fistula. Timely and accurate diagnosis is critical; most patients are young adults and up to 15% will die in the acute phase of the condition. Imaging diagnosis using unenhanced CT or CT venography (CTV) can be readily achieved by the general radiologist. MRI or MRI venography (MRV) are powerful techniques, provided the radiologist is aware of critical diagnostic pitfalls. In selected cases, cerebral digital subtraction angiography (DSA) can facilitate both diagnosis and anticoagulant/transcatheter thrombolytic therapy improving clinical outcome. This article will outline the condition, highlighting cerebral venous anatomy, diagnostic techniques, and pitfalls pertinent to all practising radiologists.
    DOI:  https://doi.org/10.1016/j.crad.2019.12.009
  448. Clin Cancer Res. 2020 Jan 21. pii: clincanres.2803.2019. [Epub ahead of print]
    A four-chemokine signature is associated with a T cell-inflamed phenotype in primary and metastatic pancreatic cancer.
    Romero JM, Grünwald BT, Jang GH, Bavi PP, Jhaveri A, Masoomian M, Fischer SE, Zhang A, Denroche RE, Lungu IM, De Luca A, Bartlett JMS, Xu J, Li N, Dhaliwal S, Liang SB, Chadwick D, Vyas F, Bronsert P, Khokha R, McGaha TL, Notta F, Ohashi PS, Done SJ, O'Kane GM, Wilson JM, Knox JJ, Connor A, Wang Y, Zogopoulos G, Gallinger S.
      PURPOSE: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T cell infiltration in PDAC.EXPERIMENTAL DESIGN: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from TCGA and 92 PDACs from the Australian ICGC. We explored associations between immune cell counts by immunohistochemistry, chemokine expression and transcriptional hallmarks of antitumor immunity by RNAseq, and mutational burden by whole genome sequencing.
    RESULTS: Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, CXCL10) was strongly associated with CD8+ T cell infiltration (p < 0.0001). Expression of this '4-chemokine signature' positively correlated with transcriptional metrics of T cell activation (ZAP70, ITK, IL2RB), cytolytic activity (GZMA, PRF1), and immunosuppression (PD-L1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T cell activation scores (MHC I presentation, T cell/APC co-stimulation) and elevated expression of innate immune sensing pathways involved in T cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T cell-inflamed phenotype across primary PDAC and PDAC liver metastases.
    CONCLUSIONS: A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-2803
  449. Mol Ther Methods Clin Dev. 2020 Jun 12. 17 220-233
    Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency.
    Gao MH, Giamouridis D, Lai NC, Guo T, Xia B, Kim YC, Huu VAN, Skowronska-Krawczyk D, Lantier L, Bhargava R, Hammond HK.
      Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices-events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease.
    Keywords:  AMP-activated protein kinase; Akita Mouse; Akt; Diabetic retinopathy; Gene therapy; Insulin sensitivity; Intravenous AAV8; Islet insulin release; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.omtm.2019.12.002
  450. Arch Bronconeumol. 2020 Jan 20. pii: S0300-2896(19)30604-0. [Epub ahead of print]
    Diagnostic Yield and Safety of Pleural Cryobiopsy during Medical Thoracoscopy to Diagnose Pleural Effusion. A Systematic Review and Meta-Analysis.
    Botana Rial M, Lojo Rodríguez I, Mouronte Roibás C, Leiro Fernández V, Núñez Delgado M, Salgado Barreira Á, Pereira Torrado A, Fernández Villar A.
      OBJECTIVE: Current evidence on the diagnostic yield and safety of pleural cryobiopsy (CB) is based on a series of heterogeneous studies with limited cohorts. A pooled analysis of these studies could improve the evidence and contribute to a better understanding of this new technique.METHODOLOGY: We performed a systematic review and meta-analysis of published studies that included data on the yield and diagnostic safety of pleural CB compared with procedures performed using conventional flexible forceps. The heterogeneity of the analysis was evaluated by determining the I2 index, while study quality was measured with the QUADAS-2 tool.
    RESULTS: Seven studies involving 356 patients were used for the final evaluation. In 55.6%, the etiology of the pleural effusion was malignant, 61.1% of which were lung cancer. The diagnostic yield of pleural CB was 95% (95% CI 92-97) vs. 91% (95% CI 87-94) with conventional flexible forceps (P=.019). Mild bleeding was reported in 67% of CB procedures (95% CI 62-72) compared with 85% of conventional flexible forceps procedures (95% CI 79-90) (P<.001). CB specimens were larger, and fewer artifacts were detected. A pooled analysis of the detection of molecular changes could not be performed. Heterogeneity was moderate to high, although the quality of the studies was acceptable.
    CONCLUSIONS: Pleural CB is a safe technique with a high yield for etiological diagnosis of pleural effusion, and larger specimens with fewer artifacts are obtained. Molecular determinations should be investigated in more depth.
    Keywords:  Complicaciones; Complications; Criobiopsia; Cryobiopsy; Derrame pleural; Diagnostic yield; Medical thoracoscopy; Pleural effusion; Rentabilidad diagnóstica; Toracoscopia médica
    DOI:  https://doi.org/10.1016/j.arbres.2019.12.001
  451. Curr Biol. 2020 Jan 10. pii: S0960-9822(19)31693-8. [Epub ahead of print]
    Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects.
    Lakshminarayan R, Phillips BP, Binnian IL, Gomez-Navarro N, Escudero-Urquijo N, Warren AJ, Miller EA.
      Cells possess multiple mechanisms that protect against the accumulation of toxic aggregation-prone proteins. Here, we identify a pre-emptive pathway that reduces synthesis of membrane proteins that have failed to properly assemble in the endoplasmic reticulum (ER). We show that loss of the ER membrane complex (EMC) or mutation of the Sec61 translocon causes reduced synthesis of misfolded forms of the yeast ABC transporter Yor1. Synthesis defects are rescued by various ribosomal mutations, as well as by reducing cellular ribosome abundance. Genetic and biochemical evidence point to a ribosome-associated quality-control pathway triggered by ribosome collisions when membrane domain insertion and/or folding fails. In support of this model, translation initiation also contributes to synthesis defects, likely by modulating ribosome abundance on the message. Examination of translation efficiency across the yeast membrane proteome revealed that polytopic membrane proteins have relatively low ribosome abundance, providing evidence for translational tuning to balance protein synthesis and folding. We propose that by modulating translation rates of poorly folded proteins, cells can pre-emptively protect themselves from potentially toxic aberrant transmembrane proteins.
    Keywords:  endoplasmic reticulum; protein folding; protein quality control; ribosome-associated quality control; translational tuning
    DOI:  https://doi.org/10.1016/j.cub.2019.12.060
  452. Blood. 2020 Jan 24. pii: blood.2019003014. [Epub ahead of print]
    Development and Survival of MYC-driven Lymphomas Requires MYC-Antagonist MNT to Curb MYC-induced Apoptosis.
    Cory S, Nguyen HV, Vandenberg CJ, Ng AP, Anstee NS, Rimes J, Hawkins E, Robati MR.
      Deregulated over-expression of MYC is implicated in the development and malignant progression of most (~70%) human tumors. MYC drives cell growth and proliferation but also, at high levels, promotes apoptosis. Here, we report that the proliferative capacity of MYC-driven normal and neoplastic B lymphoid cells depends on MNT, a MYC-related transcriptional repressor. Our genetic data establish that MNT synergises with MYC by suppressing MYC-driven apoptosis and that it does so primarily by reducing the level of pro-apoptotic BIM. In Em-Myc mice, which model the MYC/IGH chromosome translocation in Burkitt's lymphoma, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing apoptosis and markedly decreasing premalignant B lymphoid cell populations. Strikingly, by inducing Mnt deletion within transplanted fully-malignant Em-Myc lymphoma cells, we significantly extended transplant recipient survival. The dependency of lymphomas on MNT for survival suggests that drugs inhibiting MNT could significantly boost therapy of MYC-driven tumors by enhancing intrinsic MYC-driven apoptosis.
    DOI:  https://doi.org/10.1182/blood.2019003014
  453. Mol Aspects Med. 2020 Jan 17. pii: S0098-2997(19)30082-2. [Epub ahead of print] 100844
    Integrating circulating miRNA analysis in the clinical management of lung cancer: Present or future?
    Lampignano R, Kloten V, Krahn T, Schlange T.
      Liquid biopsy holds great promise to complement traditional analysis on cancerous tissue during clinical management of cancer: screening of patients, (early) disease diagnosis, prognosis, therapy selection as well as early response to treatment and disease monitoring. Among emerging circulating biomarkers, cell-free miRNA (cfmiRNA) may have potential in detecting lung cancer and following the course of the disease. Furthermore, several studies highlighted the possibility to utilize these regulatory RNAs to obtain prognostic information as well as to verify patient's response towards treatment. However, despite these findings, cfmiRNA is not used in the clinical practice as biomarkers to date, since their clinical utility and validity has not been confirmed in prospective clinical studies yet. In addition, there is no consensus on standardized (pre)analytical procedures. In this review, we present an overview of cfmiRNA biomarker candidates for clinical management of lung cancer and we discuss the issue of assay standardization.
    Keywords:  Circulating miRNA; Liquid biopsy; Lung cancer; Standardization
    DOI:  https://doi.org/10.1016/j.mam.2020.100844
  454. J Med Chem. 2020 Jan 24.
    Identification of Parthenolide Dimers as Activators of Pyruvate Ki-nase M2 in Xenograft of Glioblastoma Multiforme in vivo.
    Ding Y, Xue Q, Liu S, Hu K, Wang D, Wang T, Li Y, Guo H, Hao X, Ge W, Zhang Y, Li A, Li J, Chen Y, Zhang Q.
      Herein we detail the discovery of a series of parthenolide dimers as activators of PKM2 and evaluation of their anti-GBM activities. The most promising compound 5 showed high potency to activate PKM2 with AC50 value of 15 nM, inhibited proliferation and metastasis, and induced apoptosis of GBM cells. Compound 5 could promote tetramer formation of PKM2 and reduce nucleus translocation of PKM2 in GBM cells while without influence on the expression of total PKM2, thereby inhibited STAT3 signal pathway in vitro and in vivo. PKM2 knockdown assay demonstrated that the anti-GBM effect of 5 mainly depended on the expression of PKM2 in vitro and in vivo. Compound 16, a prodrug of 5, markedly suppressed U118 tumor xenograft growth and reduced the weight of tumor. On the basis of these investigations, we propose that 16 might be considered as a promising lead compound for discovery of anti-GBM drug.
    DOI:  https://doi.org/10.1021/acs.jmedchem.9b01328
  455. Comput Methods Programs Biomed. 2020 Jan 13. pii: S0169-2607(19)31244-1. [Epub ahead of print]189 105337
    Bregmannian consensus clustering for cancer subtypes analysis.
    Li J, Xie L, Xie Y, Wang F.
      Cancer subtype analysis, as an extension of cancer diagnosis, can be regarded as a consensus clustering problem. This analysis is beneficial for providing patients with more accurate treatment. Consensus clustering refers to a situation in which several different clusters have been obtained for a particular data set, and it is desired to aggregate those clustering results to get a better clustering solution. In this paper, we propose to generalize the traditional consensus clustering methods in three manners: (1) We provide Bregmannian consensus clustering (BCC), where the loss between the consensus clustering result and all the input clusterings are generalized from a traditional Euclidean distance to a general Bregman loss; (2) we generalize the BCC to a weighted case, where each input clustering has different weights, providing a better solution for the final clustering result; and (3) we propose a novel semi-supervised consensus clustering, which adds some must-link and cannot-link constraints compared with the first two methods. Then, we obtain three cancer (breast, lung, colorectal cancer) data sets from The Cancer Genome Atlas (TCGA). Each data set has three data types (mRNA, mircoRNA, methylation), and each is respectively used to test the accuracy of the proposed algorithms for clusterings. The experimental results demonstrate that the highest aggregation accuracy of the weighted BCC (WBCC) on cancer data sets is 90.2%. Moreover, although the lowest accuracy is 62.3%, it is higher than other methods on the same data set. Therefore, we conclude that as compared with the competition, our method is more effective.
    Keywords:  Bregman divergence; Cancer subtypes analysis; Consensus Clustering
    DOI:  https://doi.org/10.1016/j.cmpb.2020.105337
  456. Public Health Rep. 2020 Jan 22. 33354919900889
    An Examination of Child and Adolescent Neurodevelopment Through National Institutes of Health Studies.
    Volkow ND, Gordon JA, Koob GF, Birnbaum LS, Clayton JA, Koroshetz WJ, Bianchi DW, Gibbons GH, Riley WT, Pérez-Stable EJ, Croyle RT.
      
    Keywords:  addiction; brain; environment; longitudinal; neurodevelopment
    DOI:  https://doi.org/10.1177/0033354919900889
  457. Skeletal Radiol. 2020 Jan 18.
    Qualitative and quantitative analysis of glenoid bone stock and glenoid version: inter-reader analysis and correlation with rotator cuff tendinopathy and atrophy in patients with shoulder osteoarthritis.
    Siebert MJ, Chalian M, Sharifi A, Pezeshk P, Xi Y, Lawson P, Chhabra A.
      PURPOSE: Glenoid bone stock and morphology and rotator cuff muscle quality and tendon integrity affect the outcome of total shoulder arthroplasty. We hypothesized that glenoid bone loss correlates with rotator cuff muscle fatty infiltration (FI), tendinopathy, and atrophy.DESIGN: Forty-three 3D CT scans and MRIs of 43 patients (mean age 62 years; SD 13 years; range 22-77 years) referred for primary shoulder pain were evaluated. Measurements of glenoid bone stock, version, and posterior humeral subluxation index (HSI) were assessed on an axial CT image reconstructed in the true scapular plane. Measurements utilized the Friedman line to approximate the pre-pathologic surface. Glenoid morphology was assigned by modified Walch classification. Rotator cuff FI, atrophy, and tendon integrity were assessed on corresponding MRIs.
    RESULTS: There was a very strong negative correlation between increasing glenoid version and HSI (r = - 0.908; p < 0.0001). There was a moderately negative correlation between anterior bone loss and HSI (r = - 0.562; p < 0.0001) and a moderately positive correlation between posterior bone loss and HSI (r = 0.555; p < 0.0001). Subscapularis muscle FI correlated moderately with increased anterior and central bone loss and increased humeral head medialization (r = 0.512, p = 0.0294; r = 0.479, p = 0.033; r = 0.494, p = 0.0294; respectively). Inter-observer reliability (intra-class correlation coefficient [ICC] and kappa) was good to excellent for all measurements and grading.
    CONCLUSION: Glenoid anteversion and anterior and posterior bone loss are associated with varying HSI. Subscapularis muscle FI, not tendon integrity, correlates to anterior and central glenoid erosion. The study adds evidence that neither rotator cuff tendinopathy nor muscle atrophy exhibits a significant relationship to HSI.
    Keywords:  3D; Atrophy; Bone stock; Computed tomography; Glenoid; Glenoid bone stock; Muscle atrophy; Rotator cuff; Subluxation
    DOI:  https://doi.org/10.1007/s00256-020-03377-0
  458. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31713-9. [Epub ahead of print]30(3): 755-770.e6
    Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer.
    Yomtoubian S, Lee SB, Verma A, Izzo F, Markowitz G, Choi H, Cerchietti L, Vahdat L, Brown KA, Andreopoulou E, Elemento O, Chang J, Inghirami G, Gao D, Ryu S, Mittal V.
      Epigenetic changes are increasingly being appreciated as key events in breast cancer progression. However, breast cancer subtype-specific epigenetic regulation remains poorly investigated. Here we report that EZH2 is a leading candidate of epigenetic modulators associated with the TNBC subtype and that it predicts poor overall survival in TNBC patients. We demonstrate that specific pharmacological or genetic inhibition of EZH2 catalytic activity impairs distant metastasis. We further define a specific EZH2high population with enhanced invasion, mammosphere formation, and metastatic potential that exhibits marked sensitivity to EZH2 inhibition. Mechanistically, EZH2 inhibition differentiates EZH2high basal cells to a luminal-like phenotype by derepressing GATA3 and renders them sensitive to endocrine therapy. Furthermore, dissection of human TNBC heterogeneity shows that EZH2high basal-like 1 and mesenchymal subtypes have exquisite sensitivity to EZH2 inhibition compared with the EZH2low luminal androgen receptor subtype. These preclinical findings provide a rationale for clinical development of EZH2 as a targeted therapy against TNBC metastasis.
    Keywords:  EZH2; GATA3; breast cancer; circulating tumor cells; differentiation; epigenetics; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.056
  459. Support Care Cancer. 2020 Jan 21.
    Effects of curative-intent lung cancer therapy on functional exercise capacity and patient-reported outcomes.
    Ha D, Ries AL, Lippman SM, Fuster MM.
      PURPOSE: Lung cancer treatment can lead to negative health consequences. We analyzed the effects of curative-intent lung cancer treatment on functional exercise capacity (EC) and patient-reported outcomes (PROs).METHODS: We performed a prospective, observational cohort study of consecutive patients with stage I-IIIA lung cancer undergoing curative-intent therapy and assessed functional EC (primary outcome, six-minute walk distance (6MWD)), cancer-specific quality of life (QoL) (secondary outcome, European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC-QLQ-C30) summary score), and exploratory outcomes including dyspnea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)) and fatigue Brief Fatigue Inventory (BFI)) symptoms before and at 1 to 3 months post-treatment. We analyzed the time effect of treatment on outcomes using multivariable generalized estimating equations.
    RESULTS: In 35 enrolled participants, treatment was associated with a clinically meaningful and borderline-significant decline in functional EC ((mean change, 95% CI) 6MWD = - 25.4 m (- 55.3, + 4.47), p = 0.10), clinically meaningful and statistically significant higher dyspnea (UCSD SOBQ = + 13.1 (+ 5.7, + 20.6), p = 0.001) and fatigue (BFI = + 10.0 (+ 2.9, + 17.0), p = 0.006), but no clinically meaningful or statistically significant change in cancer-specific QoL (EORTC-QLQ-C30 summary score = - 3.4 (- 9.8, + 3.0), p = 0.30).
    CONCLUSIONS: Among the first prospective analysis of the effect of curative-intent lung cancer treatment on functional EC and PROs, we observed worsening dyspnea and fatigue, and possibly a decline in functional EC but not cancer-specific QoL at 1 to 3 months post-treatment. Interventions to reduce treatment-related morbidities and improve lung cancer survivorship may need to focus on reducing dyspnea, fatigue, and/or improving functional EC.
    Keywords:  Patient-reported outcome measures; Quality of life; Survivorship; Symptom assessment; Treatment outcome
    DOI:  https://doi.org/10.1007/s00520-020-05294-3
  460. J Gene Med. 2020 Jan 21. e3163
    Insights into the expression profiles and functions of circRNAs in a newborn hyperoxia-induced rat bronchopulmonary dysplasia model.
    Cheng H, Wu B, Wang L, Hu T, Deng Z, Li D.
      BACKGROUND: Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease in preterm infants. Circular RNAs (circRNAs) are key regulators of various biological processes. This study aimed to explore the biological roles of circRNAs in BPD pathogenesis.METHODS: A newborn BPD rat model was developed to construct a circRNA library; deep sequencing was used to reveal differential expression of circRNAs in the hyperoxia-induced BPD rat models. Sanger sequencing and RT-PCR were performed to confirm circRNAs that may be related to BPD. After miRNA binding-site prediction, we constructed a network diagram of circRNA-competing endogenous RNAs (ceRNAs) related to transforming growth factor-beta (TGF-beta) and p53 pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.
    RESULTS: A total of 256 differentially expressed circRNAs were detected between the hyperoxia group and the normoxia group. Of these circRNAs, 195 were up-regulated and 61 were down-regulated. The differences of circRNA distribution between the two groups were analyzed and six circRNAs were validated in the tissue samples. GO analysis indicated that 6519 target genes were enriched in cell location and biological processes. KEGG pathway enrichment analysis showed that circRNAs involved in 242 KEGG pathways. A network diagram of circRNA-ceRNA related to TGF-beta and p53 pathways was constructed.
    CONCLUSIONS: CircRNAs are differentially expressed between the BPD model and control group. Many target genes of circRNAs are involved in the developmental process, which suggests that BPD may be associated with pathways including extracellular matrix-receptor interaction, vascular endothelial growth factor signaling, and vascular smooth muscle contraction.
    Keywords:  TGF-beta; bronchopulmonary dysplasia; ceRNA; circRNA; deep sequencing; p53
    DOI:  https://doi.org/10.1002/jgm.3163
  461. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19940. [Epub ahead of print]24(1): 418-427
    AXIN2 gene silencing reduces apoptosis through regulating mitochondria-associated apoptosis signaling pathway and enhances proliferation of ESCs by modulating Wnt/β-catenin signaling pathway.
    Fu F, Deng Q, Li R, Wang D, Yu QX, Yang X, Lei TY, Han J, Pan M, Zhen L, Li J, Li FT, Zhang YL, Li DZ, Liao C.
      OBJECTIVE: Embryonic stem cells (ESCs) mainly originate from totipotent cells in early-stage of mammalian embryo and could proliferate in a manner of un-limitation. This study aimed to investigate roles of Axin2 in proliferation of ESCs and explore the associated mechanisms.MATERIALS AND METHODS: Axis inhibition protein 2 (AXIN2) over-expression (LV5-AXIN2) and AXIN2 RNA interfere (LV3-AXIN2-RNAi) vectors were structured and transfected into H9 cells. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was used to evaluate cell proliferative activity. Flow cytometry analysis was employed to measure apoptosis of H9 cells. AXIN2, β-catenin, transcription factor 4 (TCF4), c-myc, c-jun and Cyclin D mRNA levels and protein expressions were determined using quantitative real-time PCR (qRT-PCR) and Western blotting assay.
    RESULTS: LV5-AXIN2 and LV3-AXIN2-RNAi were successfully structured with higher transfecting efficacy. AXIN2 gene silencing remarkably increased proliferative activity and AXIN2 treatment significantly induced apoptosis of H9 cells, comparing with blank vector group (p<0.05). AXIN2 gene silencing significantly enhanced B-cell lymphoma-2 (Bcl-2) expression and remarkably inhibited cleaved caspase-3 expression comparing to that in blank vector group (p<0.05). AXIN2-RNAi treatment significantly enhanced and AXIN2 over-expression significantly reduced β-catenin and TCF4 expression, comparing to that in blank vector group (p<0.05). AXIN2 gene silence activated down-stream molecules of Wnt/β-catenin signaling pathway, including c-jun, c-myc, and Cyclin D1 (p<0.05).
    CONCLUSIONS: AXIN2 gene silencing reduced apoptosis by regulating mitochondria-associated apoptosis signaling pathway and enhanced proliferation by modulating molecules in Wnt/β-catenin signaling pathway. Therefore, targeting of aberrant apoptosis and AXIN2 might be a novel clinical strategy to inhibit aging and enhance self-renewal of ESCs.
    DOI:  https://doi.org/10.26355/eurrev_202001_19940
  462. J Am Chem Soc. 2020 Jan 21.
    Dual Chalcogen-Chalcogen Bonding Catalysis.
    Wang W, Zhu H, Feng L, Yu Q, Hao JC, Zhu R, Wang Y.
      The noncovalent S•••O bonding interaction is an evolutionary force that has been smartly exploited by Nature to modulate the conformational preferences of proteins. The employment of this type of weak noncovalent force to drive chemical reactions is promising yet remains largely elusive. Herein, we describe a dual chalcogen-chalcogen bonding catalysis strategy that the distinct chalcogen atoms simultaneously interact with two chalcogen-based electron donors to give rise to the catalytic activity, thus facilitating chemical reactions. Conventional approaches to the Rauhut-Currier-type reactions require the use of strongly nucleophilic Lewis bases as essential promoters. The implementation of this dual chalcogen-chalcogen bonding catalysis strategy allows the simultaneous Se•••O bonding interaction between chalcogen-bonding donors and an enone and an alcohol, enabling the realization of the Rauhut-Currier-type reactions in a distinct way. The further implementation of a consecutive dual Se•••O bonding catalysis approach enables the achievement of an initial Rauhut-Currier-type reaction to give an enone product which further undergoes an alcohol-addition induced cyclization reaction. This work demonstrates that the nearly linear chalcogen-bonding interaction can differentiate similar alkyl groups to give rise to regioselectivity. Moreover, the new strategy shows its advantage as it not only enables less reactive substrates working efficiently but tolerates inaccessible substrates using conventional methods.
    DOI:  https://doi.org/10.1021/jacs.9b12610
  463. J Cell Physiol. 2020 Jan 21.
    CircTIMELESS regulates the proliferation and invasion of lung squamous cell carcinoma cells via the miR-136-5p/ROCK1 axis.
    Zhang W, Shi J, Cheng C, Wang H.
      Numerous studies demonstrate that circular RNAs (circRNAs) are critical regulators of the occurrence and progression of tumors. However, research on the involvement of circRNAs in lung squamous cell carcinoma (LUSC) is limited. In our study, circTIMELESS (also named hsa_circ_0000408 in the Human circRNA Database) was upregulated in both LUSC tissues and LUSC cells, and circTIMELESS expression was positively associated with the TNM stage. Moreover, circTIMELESS silencing markedly suppressed invasion in vitro and disrupted proliferation in vitro as well as in vivo. Additional investigations have shown that circTIMELESS functions as a miR-136-5p "sponge" and regulates miR-136-5p expression. Furthermore, the impact of miR-136-5p upregulation was consistent with the results of circTIMELESS silencing, both of which inhibited the proliferation and invasion of LUSC cells. Additional results showed that Rho-associated coiled-coil containing protein kinase 1 (ROCK1) is targeted by miR-136-5p. The results of recovery experiments showed that ROCK1 overexpression partly rescued the impact of circTIMELESS silencing and miR-136-5p upregulation on proliferation and invasion. Consequently, our findings confirmed that circTIMELESS exists in LUSC and acts as a tumor promoter through the miR-136-5p/ROCK1 axis. Based on these findings, circTIMELESS may be potentially utilized as a therapeutic target for LUSC.
    Keywords:  ROCK1; circTIMELESS; lung squamous cell carcinoma; miR-136-5p
    DOI:  https://doi.org/10.1002/jcp.29521
  464. J Phys Chem Lett. 2020 Jan 22.
    In Situ Light-Initiated Ligands Crosslinking Enables Efficient All-Solution-Processed Perovskite Light-Emitting Diodes.
    Wei Y, Li X, Chen Y, Cheng Z, Xiao H, Li X, Ding J, Lin J.
      Solution process has been considered to be an effective method to fabricate emitting layer (EML) in light-emitting diodes (LEDs). However, the fabrication of charge transport layer (CTL) above the perovskite EML by solution processing is challenging. Herein, we incorporated polymerizable molecules, conjugated linoleic acid (CLA), as surface ligands to passivate perovskite QDs. The polymerized CLA can create a crosslinked QD film, which allows the solution deposition of subsequent CTLs. The theoretical calculations reveal that the binding energy of polymerized CLA with QDs increased, and the strong ligands binding state can better passivate the surface and improve the stability of QDs. As a result, all-solution-processed multilayer perovskite LEDs were fabricated with performance of a max luminance of 2470 cd/m2 for CsPbBr3-based devices, and a peak EQE of 2.67% for CsPbI3-based devices. These results demonstrate that the in situ light-initiated ligands crosslinking can be an effective strategy in all-solution-processed optoelectronic devices.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03775
  465. Sci Rep. 2020 Jan 21. 10(1): 833
    The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia.
    Perekopskiy D, Afzal A, Jackson SN, Muller L, Woods AS, Kiyatkin EA.
      While it is known that opioid receptors (ORs) are densely expressed in both the brain and periphery, it is widely accepted that hypoxic effects of opioids result solely from their direct action in the CNS. To examine the role of peripheral ORs in triggering brain hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and naloxone-methiodide, the latter which is commonly believed to be peripherally restricted, affect brain oxygen responses induced by intravenous heroin at low, human-relevant doses. Similar to naloxone-HCl, naloxone-methiodide at a relatively low dose (2 mg/kg) fully blocked heroin-induced decreases in brain oxygen levels. As measured by mass spectrometry, naloxone-methiodide was found to be ~40-fold less permeable than naloxone-HCl across the blood-brain barrier, thus acting as a selective blocker of peripheral ORs. Despite this selectivity, a low but detectable amount of naloxone was found in brain tissue after naloxone-methiodide administration, potentially influencing our results. Therefore, we examined the effects of naloxone-methiodide at a very low dose (0.2 mg/kg; at which naloxone was undetectable in brain tissue) and found that this drug still powerfully attenuates heroin-induced brain oxygen responses. These data demonstrate the role of peripheral ORs in triggering heroin-induced respiratory depression and subsequent brain hypoxia.
    DOI:  https://doi.org/10.1038/s41598-020-57768-3
  466. Sci Rep. 2020 Jan 22. 10(1): 979
    Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma.
    Reese RM, Dourado M, Anderson K, Warming S, Stark KL, Balestrini A, Suto E, Lee W, Riol-Blanco L, Shields SD, Hackos DH.
      The transient receptor potential (TRP) superfamily of ion channels has garnered significant attention by the pharmaceutical industry. In particular, TRP channels showing high levels of expression in sensory neurons such as TRPV1, TRPA1, and TRPM8, have been considered as targets for indications where sensory neurons play a fundamental role, such as pain, itch, and asthma. Modeling these indications in rodents is challenging, especially in mice. The rat is the preferred species for pharmacological studies in pain, itch, and asthma, but until recently, genetic manipulation of the rat has been technically challenging. Here, using CRISPR technology, we have generated a TRPA1 KO rat to enable more sophisticated modeling of pain, itch, and asthma. We present a detailed phenotyping of the TRPA1 KO rat in models of pain, itch, and asthma that have previously only been investigated in the mouse. With the exception of nociception induced by direct TRPA1 activation, we have found that the TRPA1 KO rat shows apparently normal behavioral responses in multiple models of pain and itch. Immune cell infiltration into the lung in the rat OVA model of asthma, on the other hand, appears to be dependent on TRPA1, similar to was has been observed in TRPA1 KO mice. Our hope is that the TRPA1 KO rat will become a useful tool in further studies of TRPA1 as a drug target.
    DOI:  https://doi.org/10.1038/s41598-020-57936-5
  467. Br J Pharmacol. 2020 Jan 23.
    Pulmonary hypertension in chronic obstructive pulmonary disease.
    Gredic M, Blanco I, Kovacs G, Helyes Z, Ferdinandy P, Olschewski H, Barberà JA, Weissmann N.
      Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in chronic obstructive pulmonary disease (COPD) patients. However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long-term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Future research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to impact COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies.
    Keywords:  COPD; animal models; cigarette smoke; emphysema; pulmonary hypertension; small airway remodelling; vascular dysfunction
    DOI:  https://doi.org/10.1111/bph.14979
  468. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30106-6. [Epub ahead of print]
    Glucose-6-phosphate transporter mediates macrophage proliferation and functions by regulating glycolysis and mitochondrial respiration.
    Jeon EH, Park TS, Jang Y, Hwang E, Kim SJ, Song KD, Weinstein DA, Lee YM, Park BC, Jun HS.
      Glycogen storage disease type Ib (GSD-Ib), caused by a deficiency in glucose-6-phosphate transporter (G6PT), is characterized by disrupted glucose homeostasis, inflammatory bowel disease, neutropenia, and neutrophil dysfunction. The purpose of this study was to investigate the role of G6PT on macrophage functions and metabolism. Peritoneal macrophages of G6pt-/- mice were lower in number and their effector functions including migration, superoxide production, and phagocytosis were impaired. To investigate the underlying mechanisms of macrophage dysfunction, the G6PT gene was mutated in porcine alveolar macrophage 3D4/31 cells using the CRISPR/Cas9 technology. The G6PT-deficient macrophages exhibited significant decline in cell growth, bactericidal activity, and antiviral response. These phenotypes are associated with the impaired glycolysis and mitochondrial oxidative phosphorylation. We therefore propose that the G6PT-mediated metabolism is essential for effector functions of macrophage, the immune deficiencies observed in GSD-Ib extend beyond neutropenia and neutrophil dysfunction, and future therapeutic targets aimed both the neutrophils and macrophages may be necessary.
    Keywords:  Antiviral responses; Glucose-6-phosphate transporter; Macrophage; Metabolic reprogramming; Phagocytosis
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.043
  469. ACS Appl Mater Interfaces. 2020 Jan 21.
    Adjustable and Versatile 3D Tumor Spheroid Culture Platform with Interfacial Elastomeric Wells.
    An HJ, Kim HS, Kwon JA, Song J, Choi I.
      Three-dimensional (3D) cell culture platforms have recently received a great deal of attention, as these systems are able to recapitulate the in vivo microenvironment of tissues or tumors. Herein, we describe adjustable and versatile elastomeric well structures for spheroid formation and their use for in situ analyses as a tunable 3D cell culture platform. Elastomeric spherical wells are fabricated using a one-step interfacial reaction between aqueous droplets on immiscible liquid polydimethylsiloxane (PDMS) without any template or expensive equipment. Due to their differing surface tensions, spherical wells are spontaneously formed on the liquid PDMS with various sizes and curvatures that are easily controlled. Using arrays of these optimized wells, single tumor spheroids within each well were successfully formed at high efficiency (up to 97%) by co-culturing tumor cells and fibroblasts to reflect the complex microenvironment of cancer tissue. Moreover, the tumor spheroids formed within the interfacial wells were directly applied for observing drug responses and monitoring reactive oxygen species (ROS) to investigate tumor cell responses to drugs or their 3D microenvironment. We believe that our proposed platform provides a significant contribution to the multimodal analyses of anti-cancer therapeutics and the tumor microenvironment.
    DOI:  https://doi.org/10.1021/acsami.9b21471
  470. mBio. 2020 Jan 21. pii: e01019-19. [Epub ahead of print]11(1):
    A Zeaxanthin-Producing Bacterium Isolated from the Algal Phycosphere Protects Coral Endosymbionts from Environmental Stress.
    Motone K, Takagi T, Aburaya S, Miura N, Aoki W, Ueda M.
      Reef-building corals form a complex consortium with photosynthetic algae in the family Symbiodiniaceae and bacteria, collectively termed the coral holobiont. These bacteria are hypothesized to be involved in the stress resistance of the coral holobiont, but their functional roles remain largely elusive. Here, we show that cultured Symbiodiniaceae algae isolated from the reef-building coral Galaxea fascicularis are associated with novel bacteria affiliated with the family Flavobacteriaceae Antibiotic treatment eliminated the bacteria from cultured Symbiodiniaceae, resulting in a decreased maximum quantum yield of PSII (variable fluorescence divided by maximum fluorescence [Fv/Fm]) and an increased production of reactive oxygen species (ROS) under thermal and light stresses. We then isolated this bacterial strain, named GF1. GF1 inoculation in the antibiotic-treated Symbiodiniaceae cultures restored the Fv/Fm and reduced the ROS production. Furthermore, we found that GF1 produces the carotenoid zeaxanthin, which possesses potent antioxidant activity. Zeaxanthin supplementation to cultured Symbiodiniaceae ameliorated the Fv/Fm and ROS production, suggesting that GF1 mitigates thermal and light stresses in cultured Symbiodiniaceae via zeaxanthin production. These findings could advance our understanding of the roles of bacteria in Symbiodiniaceae and the coral holobiont, thereby contributing to the development of novel approaches toward coral protection through the use of symbiotic bacteria and their metabolites.IMPORTANCE Occupying less than 1% of the seas, coral reefs are estimated to harbor ∼25% of all marine species. However, the destruction of coral reefs has intensified in the face of global climate changes, such as rising seawater temperatures, which induce the overproduction of reactive oxygen species harmful to corals. Although reef-building corals form complex consortia with bacteria and photosynthetic endosymbiotic algae of the family Symbiodiniaceae, the functional roles of coral-associated bacteria remain largely elusive. By manipulating the Symbiodiniaceae bacterial community, we demonstrated that a bacterium that produces an antioxidant carotenoid could mitigate thermal and light stresses in cultured Symbiodiniaceae isolated from a reef-building coral. Therefore, this study illuminates the unexplored roles of coral-associated bacteria under stressful conditions.
    Keywords:  Symbiodiniaceae ; antioxidant; coral; microbiome; stress tolerance; zeaxanthin
    DOI:  https://doi.org/10.1128/mBio.01019-19
  471. J Clin Invest. 2020 Jan 21. pii: 133530. [Epub ahead of print]
    Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for transfusion.
    Francis RO, D'Alessandro A, Eisenberger A, Soffing M, Yeh R, Coronel E, Sheikh A, Rapido F, La Carpia F, Reisz JA, Gehrke S, Nemkov T, Thomas T, Schwartz J, Divgi C, Kessler DA, Shaz BH, Ginzburg Y, Zimring JC, Spitalnik SL, Hod EA.
      BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared to G6PD-normal RBCs.METHODS: Male volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated one RBC unit. After 42 days of refrigerated storage, autologous 51-Chromium 24-hour post-transfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed.
    RESULTS: The mean 24-hour PTR for G6PD-deficient subjects was 78.5 ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3 ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and three G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways.
    CONCLUSIONS: Based on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs.REGISTRATION. ClinicalTrials.gov NCT04081272.
    FUNDING: The Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation Grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation and the NHLBI grant R01HL14644 and R01HL148151.
    Keywords:  Hematology; Monogenic diseases
    DOI:  https://doi.org/10.1172/JCI133530
  472. J Anim Sci Biotechnol. 2020 ;11 8
    Early inoculation with caecal fermentation broth alters small intestine morphology, gene expression of tight junction proteins in the ileum, and the caecal metabolomic profiling of broilers.
    Gong Y, Xia W, Wen X, Lyu W, Xiao Y, Yang H, Zou X.
      Background: The establishment of stable microbiota in early life is beneficial to the individual. Changes in the intestinal environment during early life play a crucial role in modulating the gut microbiota. Therefore, early intervention to change the intestinal environment can be regarded as a new regulation strategy for the growth and health of poultry. However, the effects of intestinal environmental changes on host physiology and metabolism are rarely reported. This study was conducted to investigate the effects of early inoculation with caecal fermentation broth on small intestine morphology, gene expression of tight junction proteins in the ileum, and cecum microbial metabolism of broilers.Results: Our data showed that early inoculation with caecal fermentation broth could improve intestine morphology. The small intestine villus height was significantly increased (P < 0.05) in the intervened broilers compared to the control group, especially on day 28. A similar result was observed in the ratio of villus height to crypt depth (P < 0.05). Meanwhile, we found early inoculation significantly increased (P < 0.05) the expression levels of zonula occludens-1 (ZO1) on days 14 and 28, claudin-1 (CLDN1) on day 28, whereas the gene expression of claudin-2 (CLDN2) was significantly decreased (P < 0.05) on days 14 and 28. Gas chromatography time-of-flight/mass spectrometry (GC-TOF/MS) technology was further implemented to systematically evaluate the microbial metabolite profiles. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) displayed a distinct trend towards separation between the fermentation broth group (F group) and the control group (C group). The differentially expressed metabolites were identified, and they were mainly functionally enriched in beta-alanine metabolism and biosynthesis of unsaturated fatty acids. In addition, 1,3-diaminopropane was selected as a key biomarker that responded to early inoculation with caecal fermentation broth.
    Conclusions: These results provide insight into intestinal metabolomics and confirm that early inoculation with caecal fermentation broth can be used as a potential strategy to improve intestinal health of broilers.
    Keywords:  Broilers; Early inoculation; Gene expression; Intestine morphology; Metabolomics profiling
    DOI:  https://doi.org/10.1186/s40104-019-0410-1
  473. Clin Cancer Res. 2020 Jan 22. pii: clincanres.2158.2019. [Epub ahead of print]
    Circulating tumor cells are associated with recurrent disease in patients with early stage non-small cell lung cancer treated with stereotactic body radiation therapy.
    Frick MA, Feigenberg SJ, Jean-Baptiste SR, Aguarin LA, Mendes A, Chinniah C, Swisher-McClure S, Berman A, Levin W, Cengel K, Hahn SM, Dorsey JF, Simone CB, Kao GD.
      PURPOSE: Although stereotactic body radiation therapy (SBRT) is effective in early stage non-small cell lung cancer (NSCLC), ~10-15% of patients will fail regionally and 20-25% distantly. We evaluate a novel circulating tumor cell (CTC) assay as a prognostic marker for increased risk of recurrence following SBRT.EXPERIMENTAL DESIGN: 92 subjects (median age 71y) with T1a (64%), T1b (23%), or T2a (13%) stage I NSCLC treated with SBRT were prospectively enrolled. CTCs were enumerated by utilizing a GFP-expressing adenoviral probe that detects elevated telomerase activity in cancer cells. Samples were obtained before, during, and serially up to 24m after treatment. SBRT was delivered to a median dose of 50Gy (range, 40-60Gy), mostly commonly in 4-5 fractions (92%).
    RESULTS: 38 of 92 subjects (41%) had a positive CTC test prior to SBRT. A cutoff of ≥5 CTCs/mL before treatment defined favorable (n=78) and unfavorable (n=14) prognostic groups. Increased risk of nodal (p=0.04) and distant (p=0.03) failure was observed in the unfavorable group. Within 3m following SBRT, CTCs continued to be detected in 10 of 35 (29%) subjects. Persistent detection of CTCs was associated with increased risk of distant failure (p=0.04) and trended towards increased regional (p=0.08) and local failure (p=0.16).
    CONCLUSIONS: Higher pre-treatment CTCs and persistence of CTCs post-treatment is significantly associated with increased risk of recurrence outside the targeted treatment site. This suggests that CTC analysis may potentially identify patients at higher risk for regional or distant recurrences and who may benefit from either systemic therapy and/or timely locoregional salvage treatment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-2158
  474. Biomedicines. 2020 Jan 16. pii: E16. [Epub ahead of print]8(1):
    Comparative Evaluation of the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes and Platelet-Rich Plasma: An In Vitro Analysis.
    Moog P, Kirchhoff K, Bekeran S, Bauer AT, von Isenburg S, Dornseifer U, Machens HG, Schilling AF, Hadjipanayi E.
      Blood-derived factor preparations are being clinically employed as tools for promoting tissue repair and regeneration. Here we set out to characterize the in vitro angiogenic potential of two types of frequently used autologous blood-derived secretomes: platelet-rich plasma (PRP) and hypoxia preconditioned plasma (HPP)/serum (HPS). The concentration of key pro-angiogenic (VEGF) and anti-angiogenic (TSP-1, PF-4) protein factors in these secretomes was analyzed via ELISA, while their ability to induce microvessel formation and sprouting was examined in endothelial cell and aortic ring cultures, respectively. We found higher concentrations of VEGF in PRP and HPP/HPS compared to normal plasma and serum. This correlated with improved induction of microvessel formation by PRP and HPP/HPS. HPP had a significantly lower TSP-1 and PF-4 concentration than PRP and HPS. PRP and HPP/HPS appeared to induce similar levels of microvessel sprouting; however, the length of these sprouts was greater in HPP/HPS than in PRP cultures. A bell-shaped angiogenic response profile was observed with increasing HPP/HPS dilutions, with peak values significantly exceeding the PRP response. Our findings demonstrate that optimization of peripheral blood cell-derived angiogenic factor signalling through hypoxic preconditioning offers an improved alternative to simple platelet concentration and release of growth factors pre-stored in platelets.
    Keywords:  angiogenesis; blood-derived therapy; hypoxia; hypoxia preconditioned plasma; hypoxia preconditioned serum; peripheral blood cells; platelet rich plasma (PRP)
    DOI:  https://doi.org/10.3390/biomedicines8010016
  475. Reproduction. 2020 Jan 01. pii: REP-19-0311.R2. [Epub ahead of print]
    Modulatory effects of TGF-β1 and BMP6 on thecal angiogenesis and steroidogenesis in the bovine ovary.
    Mattar D, Samir M, Laird M, Knight PG.
      Angiogenesis plays an integral role in follicular and luteal development and is positively regulated by several intra-ovarian factors including vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 2 (FGF2). Various transforming growth factor-β (TGF-β) superfamily members function as intra-ovarian regulators of follicle and luteal function but their potential roles in modulating ovarian angiogenesis have received little attention. In this study, we used a bovine theca interna culture model (exhibiting characteristics of luteinization) to examine the effects of TGF-β1 and bone morphogenetic protein 6 (BMP6) on angiogenesis and steroidogenesis. VEGFA/FGF2 treatment promoted endothelial cell network formation but had little or no effect on progesterone and androstenedione secretion or expression of key steroidogenesis-related genes. TGF-β1 suppressed basal and VEGFA/FGF2-induced endothelial cell network formation and progesterone secretion, effects that were reversed by an activin receptor-like kinase 5 (ALK5) inhibitor (SB-431542). The ALK5 inhibitor alone raised androstenedione secretion and expression of several transcripts including CYP17A1. BMP6 also suppressed endothelial cell network formation under VEGFA/FGF2-stimulated conditions and inhibited progesterone secretion and expression of several steroidogenesis-related genes under basal and VEGFA/FGF2-stimulated conditions. These effects were reversed by an ALK1/2 inhibitor (K02288). Moreover, the ALK1/2 inhibitor alone augmented endothelial network formation, progesterone secretion, androstenedione secretion and expression of several steroidogenesis-related genes. The results indicate dual suppressive actions of both TGF-β1 and BMP6 on follicular angiogenesis and steroidogenesis. Further experiments are needed to unravel the complex interactions between TGF-β superfamily signalling and other regulatory factors controlling ovarian angiogenesis and steroidogenesis.
    DOI:  https://doi.org/10.1530/REP-19-0311
  476. J Cell Physiol. 2020 Jan 20.
    Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function.
    Van Der Steen N, Keller K, Dekker H, Porcelli L, Honeywell RJ, Van Meerloo J, Musters RJP, Kathmann I, Frampton AE, Liu DSK, Ruijtenbeek R, Rolfo C, Pauwels P, Giovannetti E, Peters GJ.
      In non-small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR-inhibitor erlotinib and the cMET-inhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and live-cell microscopy. We observed additive effects in EBC-1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFR-inhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, live-cell microscopy with a pH-sensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib-erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions.
    Keywords:  EGFR; cMET; crizotinib; erlotinib; lysosomes; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1002/jcp.29463
  477. Pflugers Arch. 2020 Jan 18.
    Exchange protein directly activated by cAMP (Epac) 1 plays an essential role in stress-induced exercise capacity by regulating PGC-1α and fatty acid metabolism in skeletal muscle.
    So WK, Kim HK, Chen Y, Jeong SH, Yeung PKK, Chow BCK, Han J, Chung SK.
      Exchange protein directly activated by cAMP (Epac) mediates cAMP-mediated cell signal independent of protein kinase A (PKA). Mice lacking Epac1 displayed metabolic defect suggesting possible functional involvement of skeletal muscle and exercise capacity. Epac1 was highly expressed, but not Epac 2, in the extensor digitorum longus (EDL) and soleus muscles. The exercise significantly increased protein expression of Epac 1 in EDL and soleus muscle of wild-type (WT) mice. A global proteomics and pathway analyses revealed that Epac 1 deficiency mainly affected "the energy production and utilization" process in the skeletal muscle. We have tested their forced treadmill exercise tolerance. Epac1-/- mice exhibited significantly reduced exercise capacity in the forced treadmill exercise and lower number of type 1 fibers than WT mice. The basal protein level of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was reduced in the Epac1-/- mice. Furthermore, increasing expression of PGC-1α by exercise was also significantly attenuated in the skeletal muscle of Epac1-/- mice. The expressions of downstream target genes of PGC-1α, which involved in uptake and oxidation of fatty acids, ERRα and PPARδ, and fatty acid content were lower in muscles of Epac1-/-, suggesting a role of Epac1 in forced treadmill exercise capacity by regulating PGC-1α pathway and lipid metabolism in skeletal muscle. Taken together, Epac1 plays an important role in exercise capacity by regulating PGC-1α and fatty acid metabolism in the skeletal muscle.
    Keywords:  Exchange protein directly activated by cAMP (Epac); Exercise capacity; Fatty acid metabolism; PGC-1α; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00424-019-02344-6
  478. Nutrients. 2020 Jan 19. pii: E254. [Epub ahead of print]12(1):
    Essential Amino Acid Supplement Lowers Intrahepatic Lipid despite Excess Alcohol Consumption.
    Coker MS, Ladd KR, Kim J, Murphy CJ, DeCort R, Newcomer BR, Wolfe RR, Coker RH.
      Excess alcohol consumption is a top risk factor for death and disability. Fatty liver will likely develop and the risk of liver disease increases. We have previously demonstrated that an essential amino acid supplement (EAAS) improved protein synthesis and reduced intrahepatic lipid in the elderly. The purpose of this exploratory pilot study was to initiate the evaluation of EAAS on intrahepatic lipid (IHL), body composition, and blood lipids in individuals with mild to moderate alcohol use disorder (AUD). Following consent, determination of eligibility, and medical screening, 25 participants (18 males at 38 ± 15 years/age and 7 females at 34 ± 18 years/age) were enrolled and randomly assigned to one of two dosages: a low dose (LD: 8 g of EAAS twice/day (BID)) or high dose (HD: 13 g of EAAS BID). Five of the twenty-five enrolled participants dropped out of the intervention. Both groups consumed the supplement BID for 4 weeks. Pre- and post-EAAS administration, IHL was determined using magnetic resonance imaging/spectroscopy, body composition was analyzed using dual-energy X-ray absorptiometry, and blood parameters were measured by LabCorp. T-tests were used for statistical analysis and considered significant at p < 0.05. While there was no significant change in IHL in the LD group, there was a significant 23% reduction in IHL in the HD group (p = 0.02). Fat mass, lean tissue mass, bone mineral content, and blood lipids were not altered. Post-EAAS phosphatidylethanol was elevated and remained unchanged in LD at 407 ± 141 ng/mL and HD at 429 ± 196 ng/mL, indicating chronic and excess alcohol consumption. The HD of the proprietary EAAS formulation consumed BID seemed to lower IHL in individuals with mild to moderate AUD. We suggest that further studies in a larger cohort be conducted to more completely address this important area of investigation.
    Keywords:  alcohol; amino acids; liver
    DOI:  https://doi.org/10.3390/nu12010254
  479. Lung Cancer. 2020 Jan 16. pii: S0169-5002(20)30003-9. [Epub ahead of print]
    Corrigendum to "Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis" [Lung Cancer 68 (1) (2010) 27-38].
    Zhuang H, Jiang W, Cheng W, Qian K, Dong W, Cao L, Huang Q, Li S, Dou F, Chiu JF, Fang XX, Lu M, Hua ZC.
      
    DOI:  https://doi.org/10.1016/j.lungcan.2020.01.003
  480. Molecules. 2020 Jan 16. pii: E372. [Epub ahead of print]25(2):
    Identification and Distribution of Novel Metabolites of Lolitrem B in Mice by High-Resolution Mass Spectrometry.
    Reddy P, Elkins A, Hemsworth J, Guthridge K, Vassiliadis S, Read E, Spangenberg G, Rochfort S.
      Lolitrem B is the most potent indole-diterpene mycotoxin produced by Epichloë festucae var. lolii (termed LpTG-1), with severe intoxication cases reported in livestock. To date, there are no in vivo metabolism studies conducted for the mycotoxin. A mouse model assay established for assessing toxicity of indole-diterpenes was used to investigate metabolic products of lolitrem B. Mice were administered lolitrem B at 0.5 and 2.0 mg/kg body weight (b.wt) intraperitoneally before body and brain tissues were collected at 6 h and 24 h post-treatment. Samples were cryoground and subjected to a biphasic or monophasic extraction. The aqueous and lipophilic phases were analysed using liquid chromatography high-resolution mass spectrometry (LC-HRMS); data analysis was performed with Compound Discoverer™ software. A total of 10 novel phase I metabolic products were identified in the lipophilic phase and their distribution in the liver, kidney and various brain regions are described. The biotransformation products of lolitrem B were found to be present in low levels in the brain. Based on structure-activity postulations, six of these may contribute towards the protracted tremors exhibited by lolitrem B-exposed animals.
    Keywords:  endophyte; lolitrem B; metabolism; mycotoxin
    DOI:  https://doi.org/10.3390/molecules25020372
  481. J Cell Physiol. 2020 Jan 24.
    Combination of melatonin and irisin ameliorates lipopolysaccharide-induced cardiac dysfunction through suppressing the Mst1-JNK pathways.
    Ouyang H, Li Q, Zhong J, Xia F, Zheng S, Lu J, Deng Y, Hu Y.
      Despite significant advances in therapies in past decades, the mortality rate of septic cardiomyopathy remains high. The aim of this study is to explore the therapeutic effects of combined treatment using melatonin and irisin in a mouse model of lipopolysaccharide (LPS)-mediated septic cardiomyopathy. Our data found that melatonin and irisin could further attenuate LPS-induced myocardial depression. Molecular investigation illustrated that melatonin and irisin cotreatment sustained cardiomyocyte viability and improved mitochondrial function under LPS stress. Pathway analysis demonstrated that macrophage-stimulating 1 (Mst1), which was significantly activated by LPS, was drastically inhibited by melatonin/irisin cotreatment. Mechanically, Mst1 activated c-Jun N-terminal kinase (JNK) pathway and the latter induced oxidative stress, adenosine triphosphate metabolism disorder, mitochondrial membrane potential reduction, and cardiomyocyte death activation. Melatonin and irisin cotreatment effectively inhibited the Mst1-JNK pathway and, thus, promoted cardiomyocyte survival and mitochondrial homeostasis. Interestingly, Mst1 overexpression abolished the beneficial effects of melatonin and irisin in vivo and in vitro. Altogether, our results confirmed that melatonin and irisin combination treatment could protect heart against sepsis-induced myocardial depression via modulating the Mst1-JNK pathways.
    Keywords:  ATP; LPS; cardiomyocyte; irisin; melatonin; mitochondria
    DOI:  https://doi.org/10.1002/jcp.29561
  482. ISME J. 2020 Jan 22.
    Evidence for auxiliary anaerobic metabolism in obligately aerobic Zetaproteobacteria.
    Jain A, Gralnick JA.
      Zetaproteobacteria are obligate chemolithoautotrophs that oxidize Fe(II) as an electron and energy source, and play significant roles in nutrient cycling and primary production in the marine biosphere. Zetaproteobacteria thrive under microoxic conditions near oxic-anoxic interfaces, where they catalyze Fe(II) oxidation faster than the abiotic reaction with oxygen. Neutrophilic Fe(II) oxidizing bacteria produce copious amounts of insoluble iron oxyhydroxides as a by-product of their metabolism. Oxygen consumption by aerobic respiration and formation of iron oxyhydroxides at oxic-anoxic interfaces can result in periods of oxygen limitation for bacterial cells. Under laboratory conditions, all Zetaproteobacteria isolates have been shown to strictly require oxygen as an electron acceptor for growth, and anaerobic metabolism has not been observed. However, genomic analyses indicate a range of potential anaerobic pathways present in Zetaproteobacteria. Heterologous expression of proteins from Mariprofundus ferrooxydans PV-1, including pyruvate formate lyase and acetate kinase, further support a capacity for anaerobic metabolism. Here we define auxiliary anaerobic metabolism as a mechanism to provide maintenance energy to cells and suggest that it provides a survival advantage to Zetaproteobacteria in environments with fluctuating oxygen availability.
    DOI:  https://doi.org/10.1038/s41396-020-0586-6
  483. SAGE Open Med Case Rep. 2020 ;8 2050313X19897707
    A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review.
    Politi A, Angelos D, Mauri D, Zarkavelis G, Pentheroudakis G.
      Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis-a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.
    Keywords:  Psoriasis; immune checkpoint inhibitors; lung cancer; nivolumab
    DOI:  https://doi.org/10.1177/2050313X19897707
  484. Adv Respir Med. 2019 ;87(6): 254-257
    Exogenous lipoid pneumonia induced by nasal instillation of paraffin oil.
    Bartosiewicz M, Zimna K, Lewandowska K, Sobiecka M, Dybowska M, Radwan-Rohrenschef P, Szturmowicz M, Tomkowski W.
      Lipoid pneumonia is a rare pulmonary disease, classified in terms of the source of lipid exposure into two variants: exogenous and endogenous. We present a patient with exogenous lipoid pneumonia, acquired after chronic exposure to paraffin oil-containing nasal drops. The diagnosis was established by demonstration of lipid-laden macrophages in bronchoalveolar lavage, chest computed tomography results and a history of lipid exposure.
    Keywords:  exogenous; foamy macrophages; lipoid pneumonia
    DOI:  https://doi.org/10.5603/ARM.2019.0063
  485. J Cell Biochem. 2020 Jan 21.
    Circular RNA circABCC4 regulates lung adenocarcinoma progression via miR-3186-3p/TNRC6B axis.
    Liu M, Wang P, Sui X, Ding F, Liu L, Gao Z, Cheng Z.
      Lung adenocarcinoma (LUAD), a general kind of bronchogenic malignancy globally, is depicted as one of the most critical factors affecting human health severely. Featured with loop structure, circular RNA (circRNA) has been described as an essential regulator of multiple human malignancies. Nevertheless, knowledge concerning the regulatory function of circRNA in LUAD progression remains limited. Identified as a novel circRNA, circABCC4 has not been studied in LUAD as yet. This is the first time to probe into the underlying role of circABCC4 in LUAD. In this study, a notably elevated expression of circABCC4 was found in LUAD tissues and cells. Besides, circABCC4 is verified to be characterized with a circular structure in LUAD. Functional assays elucidated that knockdown of circABCC4 significantly impaired LUAD cell proliferation, migration as well as accelerated cell apoptosis. Molecular mechanism experiments later revealed that circABCC4 could bind with miR-3186-3p and miR-3186-3p was a tumor suppressor in LUAD. Moreover, TNRC6B was validated to combine with miR-3186-3p, and its expression was respectively negatively and positively regulated by miR-3186-3p and circABCC4 in LUAD. Final rescue experiments further delineated that TNRC6B upregulation partially restored circABCC4 downregulation-mediated effect on LUAD progression. In sum, circABCC4 regulates LUAD progression via miR-3186-3p/TNRC6B axis.
    Keywords:  LUAD; TNRC6B; circABCC4; miR-3186-3p
    DOI:  https://doi.org/10.1002/jcb.29627
  486. J Chemother. 2020 Jan 21. 1-7
    Comparison of cisplatin-induced nephrotoxicity when using conventional versus short hydration in gastric cancer-a retrospective study.
    Aoyama T, Tsunoda T, Kato H, Hagino A, Furutani R, Ito K, Yoshioka H, Nakamura M, Hiraide M, Kawakami K, Kobayashi K, Suzuki K, Ichimura T, Yamaguchi K, Hama T.
      Although a short hydration protocol for cisplatin has been recently developed for use in lung cancer, this has yet to be established for gastric cancer. This study reviewed medical records of patients with gastric cancer who received XPT(capecitabine/cisplatin/trastuzumab) therapy containing cisplatin. Patients received either the conventional or short hydration regimen. Nephrotoxicity was compared between these two regimens by monitoring the serum creatinine. Out of the 26 total patients, 19 received the conventional regimen while 7 received the short hydration regimen. There was a higher nephrotoxicity was observed in the group receiving the conventional regimen (42.1%, 8/19) as compared to the short hydration regimen (0%, 0/7). There was a statistically significant difference in nephrotoxicity between the regimens (P = 0.039). Study results suggest that short hydration may be a feasible regimen for XPT therapy in gastric cancer patients.
    Keywords:  Cisplatin; gastric cancer; hydration; magnesium supplementation; nephrotoxicity; short hydration
    DOI:  https://doi.org/10.1080/1120009X.2020.1713507
  487. Oncol Lett. 2020 Feb;19(2): 1241-1246
    Expression levels of ARHI and Beclin1 in thyroid cancer and their relationship with clinical pathology and prognosis.
    Zhu H, Qu Y.
      Expression levels of autophagy-related genes ARHI and Beclin1 in thyroid cancer and their relationship with clinical pathology and prognosis were investigated. The expression levels of ARHI and Beclin1 proteins in 80 cases of thyroid cancer and adjacent tissues were detected by western blot analysis. According to the expression levels of ARHI and Beclin1, low- and high-expression groups were determined and the relationship of the expression levels with the pathological parameters and prognosis in thyroid cancer was compared between the two groups. The correlation between the ARHI and Beclin1 protein expression level was analyzed by Pearsons correlation analysis. The levels of ARHI and Beclin1 proteins in thyroid cancer tissues were significantly lower than those in adjacent tissues (P<0.05). There was a significant difference in the expression levels of ARHI and Beclin1 in terms of pathological stage and differentiation degree of cancer tissues (P<0.001); however, there was no significant difference in the expression levels of ARHI and Beclin1 for different types of cancer tissues (P>0 05). There was a positive correlation between the expression levels of Beclin1 and ARHI (r=0.5187, P<0.001). The 3-year survival rates of patients with low-expression level of ARHI and Beclin1 proteins were significantly lower than those of patients with high expression (P<0.05). In conclusion, the expression levels of Beclin1 and ARHI were low in thyroid cancer, and were significantly associated with the pathological stage, differentiation degree and prognosis in thyroid cancer. Beclin1 and ARHI can be used as predictors for the development and prognosis of thyroid cancer.
    Keywords:  ARHI; Beclin1; clinical pathology; prognosis; thyroid cancer
    DOI:  https://doi.org/10.3892/ol.2019.11223
  488. Sci Data. 2020 Jan 21. 7(1): 27
    High-throughput identification of protein functional similarities using a gene-expression-based siRNA screen.
    Neilsen BK, Kelly DL, Chakraborty B, Kim HS, White MA, Lewis RE, Fisher KW.
      A gene expression-based siRNA screen was used to evaluate functional similarity between genetic perturbations to identify functionally similar proteins. A siRNA library (siGenome library, Dharmacon) consisting of multiple siRNAs per gene that have been pooled in to one well per gene was arrayed in a 384-well format and used to individually target 14,335 proteins for depletion in HCT116 colon cancer cells. For each protein depletion, the gene expression of eight genes was quantified using the multiplexed Affymetrix Quantigene 2.0 assay in technical triplicate. As a proof of concept, six genes (BNIP3, NDRG1, ALDOC, LOXL2, ACSL5, BNIP3L) whose expression pattern reliably reflect the disruption of the molecular scaffold KSR1 were measured upon each protein depletion. The remaining two genes (PPIB and HPRT) are housekeeping genes used for normalization. The gene expression signatures from this screen can be used to estimate the functional similarity between any two proteins and successfully identified functional relationships for specific proteins such as KSR1 and more generalized processes, such as autophagy.
    DOI:  https://doi.org/10.1038/s41597-020-0365-2
  489. Spine Deform. 2018 Nov;6(6): 808-809
    Pre-Operative Lung Function in Children with EOS.
    Redding G, Bompadre V, Waldhausen J, Krengel W, White K.
      
    DOI:  https://doi.org/10.1016/j.jspd.2018.09.040
  490. Molecules. 2020 Jan 17. pii: E396. [Epub ahead of print]25(2):
    Metabolomics Analysis of the Peels of Different Colored Citrus Fruits (Citrus reticulata cv. 'Shatangju') During the Maturation Period Based on UHPLC-QQQ-MS.
    Wang F, Huang Y, Wu W, Zhu C, Zhang R, Chen J, Zeng J.
      Citrus is a globally consumed fruit with great popularity. Mandarin (Citrus reticulata cv. 'Shatangju') is a local variety, and its planting area and yield are the greatest regarding fruit tree planting in Guangdong Province, China. However, its resistance to Huanglongbing (HLB) is weak. After infection by HLB, the fruits cannot develop normally. In this study, four kinds of fruits were classified as HBG, XQG, ZQG, and DHG, according to the color of their peels. The metabolomes of the three abnormally colored groups (HBG, XQG, and ZQG) and the normally colored group (DHG) were compared using a UPLC-QQQ-MS-based metabolomics approach. In total, 913 metabolites were identified and classified into 23 different categories, including phenylpropanoids and flavonoids; among them, 215 (HBG, 177; XQG, 124; and ZQG, 62) metabolites showed differential accumulation in the three comparison groups (HBG/XQG/ZQG versus DHG). A total of 2 unique metabolites, O-caffeoyl maltotriose and myricetin were detected only in DHG samples. When comparing HBG with DHG, there were 109 decreased and 68 increased metabolites; comparing XQG with DHG, there were 88 decreased and 36 increased metabolites; comparing ZQG with DHG, 41 metabolites were decreased, and 21 metabolites were increased. Metabolic pathway enrichment analysis of these differential metabolites showed significant enrichment of the "phenylpropanoid biosynthesis" pathway in all comparison groups. The hierarchical cluster analysis of the differential metabolites of the four groups showed a clear grouping patterns. The relative contents of three phenylpropanoids, four flavonoids, two alkaloids, one anthocyanin, and two other metabolites were significantly different between each comparison group. This study might provide fundamental insight for the isolation and identification of functional compounds from the peels of citrus fruit infected with HLB and for in-depth research on the effect of HLB on the formation of fruits pigment and the development of HLB-resistant citrus varieties.
    Keywords:  Citrus reticulata cv. ‘Shatangju’; Huanglongbing (HLB); OPLS-DA; PCA; UHPLC-QQQ-MS; metabolomics
    DOI:  https://doi.org/10.3390/molecules25020396
  491. FEBS J. 2020 Jan 23.
    Hypoxia-inducible factors in metabolic reprogramming during sepsis.
    Vanderhaeghen T, Vandewalle J, Libert C.
      Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia-inducible factor-1a (HIF1α), and its family members, play an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the PHD-HIF system. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway.
    Keywords:  HIF; Sepsis; hypoxia; metabolism
    DOI:  https://doi.org/10.1111/febs.15222
  492. J Pharm Pharmacol. 2020 Jan 24.
    Regulation of breast cancer resistance protein and P-glycoprotein by ezrin, radixin and moesin in lung, intestinal and renal cancer cell lines.
    Yano K, Okabe C, Fujii K, Kato Y, Ogihara T.
      OBJECTIVES: Ezrin (Ezr), radixin (Rdx) and moesin (Msn) (ERM) proteins anchor other proteins to the cell membrane, serving to regulate their localization and function. Here, we examined whether ERM proteins functionally regulate breast cancer resistance protein (BCRP) and P-glycoprotein in cell lines derived from lung, intestinal and renal cancers.METHODS: ERM proteins were each silenced with appropriate siRNA. BCRP and P-gp functions were evaluated by means of efflux and uptake assays using 7-ethyl-10-hydroxycamptothecin (SN-38) and rhodamine123 (Rho123) as specific substrates, respectively, in non-small cell lung cancer HCC827 cells, intestinal cancer Caco-2 cells and renal cancer Caki-1 cells.
    KEY FINDINGS: In HCC827 cells, the efflux rates of SN-38 and Rho123 were significantly decreased by knockdown of Ezr or Msn, but not Rdx. However, BCRP function was unaffected by Ezr or Rdx knockdown in Caco-2 cells, which do not express Msn. In Caki-1 cells, Rdx knockdown increased the intracellular SN-38 concentration, while knockdown of Ezr or Msn had no effect.
    CONCLUSIONS: Our findings indicate that regulation of BCRP and P-gp functions by ERM proteins is organ-specific. Thus, if the appropriate ERM protein(s) are functionally suppressed, accumulation of BCRP or P-gp substrates in lung, intestine or kidney cancer tissue might be specifically increased.
    Keywords:  P-glycoprotein; breast cancer resistance protein; ezrin; intestinal cancer cell; non-small cell lung cancer cell; radixin and moesin (ERM) proteins
    DOI:  https://doi.org/10.1111/jphp.13225
  493. Phys Chem Chem Phys. 2020 Jan 23.
    The corrosion inhibition of stainless steel by ferrocene-polyoxometalate hybrid molecular materials - experimental and first principles studies.
    Sruthi G, Shakeela K, Shanmugam R, Ranga Rao G.
      The hybrid molecular materials [Fe(C5H5)2]3[PW12O40]·(H2O)4 and [Fe(C5H5)2]3[PMo12O40]·(H2O)6, denoted respectively as FcPW and FcPMo, are synthesized via a co-precipitation method under acidic conditions (pH: ∼2-3). The molecular properties of these compounds are investigated via various analytical methods. UV-vis diffuse reflectance and photoluminescence studies confirm that these compounds are charge-transfer salts. Stainless steel plates (SS, 316 grade) coated with these hybrid compounds and dipped in 0.5 M H2SO4 and Ringer's solutions show significantly inhibited corrosion. The corrosion inhibition properties of these materials are studied via weight loss, electrochemical impedance spectroscopy, and potentiodynamic polarization studies. The reproducibility of the corrosion inhibition results is ensured via repeat measurements, and error values are reported. The surfaces of the corroded steel plates are examined via scanning electron and atomic force microscopy techniques. It is found that the corrosion is of uniform type. The Tafel extrapolation method shows that the inhibition efficiency is 74% for SS@FcPMo and 65% for SS@FcPW. The corrosion inhibition mechanism is explained based on the redox nature of the hybrid materials. The experimental results are corroborated through computational studies carried out using a first principles approach with the optimized geometries and frontier molecular orbitals of the hybrid molecular materials.
    DOI:  https://doi.org/10.1039/c9cp06284j
  494. Nat Commun. 2020 Jan 24. 11(1): 507
    YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.
    Tanaka H, Homma H, Fujita K, Kondo K, Yamada S, Jin X, Waragai M, Ohtomo G, Iwata A, Tagawa K, Atsuta N, Katsuno M, Tomita N, Furukawa K, Saito Y, Saito T, Ichise A, Shibata S, Arai H, Saido T, Sudol M, Muramatsu SI, Okano H, Mufson EJ, Sobue G, Murayama S, Okazawa H.
      The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aβ) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aβ burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.
    DOI:  https://doi.org/10.1038/s41467-020-14353-6
  495. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19947. [Epub ahead of print]24(1): 461-468
    Effects of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury.
    Zhang NL, Wang HQ, Yang J, Yang P, Kang P, Zhao T.
      OBJECTIVE: To investigate the effect of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury.MATERIALS AND METHODS: Altogether 64 pure inbred male SD rats were divided into groups A, B, C, and D according to the principle of body weight similarity, with 24 rats in each group. Four groups of rats were respectively twisted on the left testis to establish unilateral testicular torsion rats. Group A was the control group, treated with normal saline, group B was the nalmefene hydrochloride high-dose group, treated with 20 μg/kg of nalmefene hydrochloride, group C was the nalmefene hydrochloride low-dose group, treated with 10 μg/kg of nalmefene hydrochloride, and group D was the sham operation group. Lung tissue was collected 60 h later. Western blotting was used to detect the expression levels of HMGB1, TLR4, CD14, and NF-κB protein, qPCR was used to detect the mRNA expression level, and enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of inflammatory factors IL-17, IL-6, and ICAM-1.
    RESULTS: The expression levels of HMGB1, TLR4, CD14, NF-κB protein, mRNA, IL-17, IL-6, and ICAM-1 in group A were significantly higher than those in groups B, C, and D (p<0.05), while were significantly lower in group D than in groups B and C (p<0.05), and were significantly lower in group B than in group C (p<0.05).
    CONCLUSIONS: Nalmefene hydrochloride can effectively inhibit the signal pathway of TLR4, and can effectively reduce the injury caused by lung ischemia-reperfusion. The large dose is closely related to the good effect, which is worthy of promotion.
    DOI:  https://doi.org/10.26355/eurrev_202001_19947
  496. Cell Chem Biol. 2020 Jan 21. pii: S2451-9456(20)30001-5. [Epub ahead of print]
    The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.
    Yoo E, Schulze CJ, Stokes BH, Onguka O, Yeo T, Mok S, Gnädig NF, Zhou Y, Kurita K, Foe IT, Terrell SM, Boucher MJ, Cieplak P, Kumpornsin K, Lee MCS, Linington RG, Long JZ, Uhlemann AC, Weerapana E, Fidock DA, Bogyo M.
      Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.
    Keywords:  Plasmodium falciparum; Salinipostin A; activity-based probes; chemical proteomics; lipid metabolism; malaria; natural products; serine hydrolases
    DOI:  https://doi.org/10.1016/j.chembiol.2020.01.001
  497. Int J Mol Sci. 2020 Jan 19. pii: E653. [Epub ahead of print]21(2):
    CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells.
    Wen L, Zhao C, Song J, Ma L, Ruan J, Xia X, Chen YE, Zhang J, Ma PX, Xu J.
      Mammalian telomere lengths are primarily regulated by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and an RNA subunit (TERC). TERC is constitutively expressed in all cells, whereas TERT expression is temporally and spatially regulated, such that in most adult somatic cells, TERT is inactivated and telomerase activity is undetectable. Most tumor cells activate TERT as a mechanism for preventing progressive telomere attrition to achieve proliferative immortality. Therefore, inactivating TERT has been considered to be a promising means of cancer therapy. Here we applied the CRISPR/Cas9 gene editing system to target the TERT gene in cancer cells. We report that disruption of TERT severely compromises cancer cell survival in vitro and in vivo. Haploinsufficiency of TERT in tumor cells is sufficient to result in telomere attrition and growth retardation in vitro. In vivo, TERT haploinsufficient tumor cells failed to form xenograft after transplantation to nude mice. Our work demonstrates that gene editing-mediated TERT knockout is a potential therapeutic option for treating cancer.
    Keywords:  CRISPR/Cas9; TERT; cancer therapy; gene editing; telomerase
    DOI:  https://doi.org/10.3390/ijms21020653
  498. Immunol Lett. 2020 Jan 16. pii: S0165-2478(19)30207-X. [Epub ahead of print]
    Effects of yolkin on the immune response of mice and its plausible mechanism of action.
    Obmińska-Mrukowicz B, Szczypka M, Lis M, Pawlak A, Suszko-Pawłowska A, Sysak A, Zambrowicz A, Burster T, Kocięba M, Artym J, Zaczyńska E, Kochanowska I, Zimecki M.
      Yolkin is a product of proteolytic degradation of vitellogenin, a protein contained in eggs' yolk, with already described procognitive properties. Here, we investigated effects of yolkin on the humoral and cellular immune response in mice, phenotype of cells from lymphoid organs and function of innate immunity cells. In vitro studies included effects of yolkin on mitogen-induced thymocyte proliferation, percentage of CD19 cells in bone marrow cells culture, expression of signaling molecules in Jurkat cells, interleukin 2 receptor (IL-2R) subunits in WEHI 231 cells and susceptibility of these cells to anti-Ig-induced cell death. The results showed that repeatable i.p. injections of yolkin stimulated the humoral immune response to sheep red blood cells (SRBC) irrespective of the time of the treatment. On the other hand, yolkin inhibited contact sensitivity to oxazolone. Treatment of mice with yolkin diminished the percentage of double positive cells and increasing the content of single positive CD4+ and CD8+ cells in the thymus. At the same time an increase of percentage of CD19 + B cells in the spleen and mesenteric lymph nodes was observed. In addition, the protein, given i.p., diminished ex vivo ability to synthesize nitric oxide by resident, peritoneal macrophages, stimulated with lipopolisaccharide (LPS). In vitro studies showed that yolkin increased CD19+ cell content in bone marrow cell population. The protein also enhanced proliferation of thymocytes to concanavalin A and stimulated expression of MAP kinases in Jurkat cells. In WEHI 231 B cell line yolkin caused a loss of IL-2R gamma chain expression, correlated with an increased resistance of these cells to proapoptotic action of anti-Ig antibodies. In conclusion, this is a first demonstration of immunotropic properties of yolkin in in vitro and in vivo tests. The results provide evidence for induction of maturation and stimulatory signals in immature T and B cells by the protein, suggesting its potential role in the development of an embryo's immune system.
    Keywords:  Contact sensitivity; Egg proteins; Humoral immune response; MAP kinases; T and B cells; Yolkin
    DOI:  https://doi.org/10.1016/j.imlet.2020.01.003
  499. Curr Pharm Des. 2020 Jan 22.
    Pharmacological strategies for insulin sensitivity: thiazolidinediones and metformin.
    Biondo LA, Teixeira AAS, de Oliveira Santos Ferreira KC, Neto JCR.
      BACKGROUND: Chronic diseases, such as obesity and cancer, have high prevalence rates. Both diseases have hyperinsulinemia, hyperglycemia, high levels of IGF-1 and inflammatory cytokines in common. Therefore, these can be considered triggers for cancer development and growth. In addition, low-grade inflammation that modulates activation of immune cells, cellular metabolism, and production of cytokines and chemokines are common in obesity, cancer, and insulin resistance. Pharmacological strategies are necessary when a change in lifestyle does not improve glycemic homeostasis. In this regard, thiazolidinediones (TZD) possess multiple molecular targets and regulates PPARγ in obesity and cancer related to insulin resistance, while metformin acts through the AMPK pathway.OBJECTIVE: The aim of this study was to review TZD and metformin as pharmacological treatments for insulin resistance associated with obesity and cancer.
    CONCLUSIONS: Thiazolidinediones restored adiponectin secretion and leptin sensitivity, reduced lipid droplets in hepatocytes and orexigen peptides in the hypothalamus. In cancer cells, TZD reduced proliferation, production of reactive oxygen species, and inflammation by acting through the mTOR and NFκB pathways. Metformin has similar effects, though these are AMPK-dependent. In addition, both drugs can be efficient against certain side effects caused by chemotherapy.
    Keywords:  cancer; chemotherapy; insulin resistance; metformin; obesity; thiazolidinediones
    DOI:  https://doi.org/10.2174/1381612826666200122124116
  500. Int J Mol Sci. 2020 Jan 22. pii: E722. [Epub ahead of print]21(3):
    Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib.
    Balmaña M, Diniz F, Feijão T, Barrias CC, Mereiter S, Reis CA.
      In the scenario of personalized medicine, targeted therapies are currently the focus of cancer drug development. These drugs can block the growth and spread of tumor cells by interfering with key molecules involved in malignancy, such as receptor tyrosine kinases (RTKs). MET and Recepteur d'Origine Nantais (RON), which are RTKs frequently overactivated in gastric cancer, are glycoprotein receptors whose activation have been shown to be modulated by the cellular glycosylation. In this work, we address the role of sialylation in gastric cancer therapy using an innovative 3D high-throughput cell culture methodology that mimics better the in vivo tumor features. We evaluate the response to targeted treatment of glycoengineered gastric cancer cell models overexpressing the sialyltransferases ST3GAL4 or ST3GAL6 by subjecting 3D spheroids to the tyrosine kinase inhibitor crizotinib. We show here that 3D spheroids of ST3GAL4 or ST3GAL6 overexpressing MKN45 gastric cancer cells are less affected by the inhibitor. In addition, we disclose a potential compensatory pathway via activation of the Insulin Receptor upon crizotinib treatment. Our results suggest that cell sialylation, in addition of being involved in tumor progression, could play a critical role in the response to tyrosine kinase inhibitors in gastric cancer.
    Keywords:  3D cell culture; MET; RON; crizotinib; gastric cancer; glycosylation; receptor tyrosine kinase; sialylation; spheroids; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.3390/ijms21030722
  501. J Exp Bot. 2020 Jan 20. pii: eraa028. [Epub ahead of print]
    Calcium channel CNGC19 mediates basal defense signaling to balance colonization of Piriformospora indica on Arabidopsis roots.
    Jogawat A, Meena MK, Kundu A, Varma M, Vadassery J.
      The activation of calcium signaling is a crucial event for perceiving environmental stress. Colonization by Piriformospora indica, a growth promoting root endosymbiont activates cytosolic Ca2+ in Arabidopsis roots. In this study, we analyze the role of calcium channels responsible for Ca2+ fluxes and its functional relevance. Expression profiling revealed that CNGC19 is a early activated gene, induced by unidentified components in P. indica cell wall extract. Functional analysis revealed that loss-of-function of CNGC19 results in growth inhibition by P.indica, due to increased colonization and loss of controlled P. indica growth. P. indica cell wall extract induced cytosolic Ca2+ elevation is reduced in cngc19 mutant indicating a role in generation of Ca2+cyt elevation. MAMP-trigerred immunity (MTI) is compromised in cngc19 lines as evident from unaltered callose deposition, reduced cis-OPDA, JA and JA-Ile levels and downregulation of jasmonate and other defense related genes which contributes to shift towards pathogenic response. Loss-of-function of CNGC19 results in inability to modulate indole glucosinolate content during P. indica-colonization. CNGC19 mediated basal immunity is AtPep receptor, PEPR dependent. CNGC19 is also crucial for P. indica mediated suppression of AtPep induced immunity. Thus, Arabidopsis CNGC19 is an important Ca2+ channel, maintaining a robust innate immunity and crucial for growth promotion signalling upon P. indica colonization.
    Keywords:   Piriformospora indica ; Serendipita indica ; CNGC19; callose; cell wall extract; cellotriose; indole glucosinolates; phytohormones
    DOI:  https://doi.org/10.1093/jxb/eraa028
  502. Lung Cancer. 2020 Jan 10. pii: S0169-5002(20)30019-2. [Epub ahead of print]141 64-71
    Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study.
    Niho S, Yoshida T, Akimoto T, Sakamaki K, Ono A, Seto T, Nishio M, Yamamoto N, Hida T, Okamoto H, Kurata T, Satouchi M, Goto K, Yamanaka T, Ohe Y.
      OBJECTIVES: SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study.MATERIALS AND METHODS: Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m2 on day 1 and S-1 80 mg/m2 on days 1-14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m2 + PEM 500 mg/m2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients.
    RESULTS: A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73-1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5-49.6)/32.1 % (95 %CI, 18.9-45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58-1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7-81.8)/66.4 % (95 %CI, 53.0-79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients).
    CONCLUSION: The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities.
    Keywords:  Chemoradiotherapy; Cisplatin; Locally advanced non-squamous non-small cell lung cancer; Pemetrexed; S-1
    DOI:  https://doi.org/10.1016/j.lungcan.2020.01.008
  503. J Cardiothorac Vasc Anesth. 2019 Dec 16. pii: S1053-0770(19)31266-2. [Epub ahead of print]
    High-Risk and Hepatitis C-Positive Organ Donors: Current Practice in Heart, Lung, and Liver Transplantation.
    Chacon MM, Adams AJ, Kassel CA, Markin NW.
      
    Keywords:  direct-acting antivirals; expanded criteria organ donor; heart transplantation; hepatitis C organ transplantation; high-risk organ donor; liver transplantation; lung transplantation
    DOI:  https://doi.org/10.1053/j.jvca.2019.12.012
  504. Adv Ther. 2020 Jan 18.
    Observational Study of Treatment Patterns in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer After First-Line EGFR-Tyrosine Kinase Inhibitors.
    Nadler E, Pavilack M, Espirito JL, Clark J, Fernandes A.
      INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are observed in approximately 15% of patients with non-small cell lung cancer (NSCLC) in the USA. Little is known about treatment patterns in EGFR mutation-positive NSCLC following progression on or after first-line (1L) treatment with first- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib, a third-generation EGFR-TKI, is a treatment option for patients with EGFR T790M-positive NSCLC following progression on 1L EGFR-TKIs. This study analyzed real-world treatment sequencing of EGFR-TKIs, EGFR T790M testing rates, and disposition of patients with EGFR mutations after 1L EGFR-TKI post-FDA approval of osimertinib in patients with EGFR mutation-positive NSCLC.METHODS: Adult patients with stage IV NSCLC and documented EGFR mutation-positive status were identified between December 1, 2015 and May 31, 2017 from the US Oncology Network iKnowMed™ electronic health record (EHR). Data were abstracted from the EHR database and supplemented by chart review.
    RESULTS: Of 308 patients, 302 (98%) received an EGFR-TKI overall, and 246 patients (80%) received a 1L EGFR-TKI. The most common 1L EGFR-TKI was erlotinib (66%); the remaining 1L regimens were predominantly combination chemotherapies with or without an EGFR-TKI. Only 80 patients (26%) received any 2L therapy. The most common EGFR-TKIs used as 2L monotherapy in patients who received 1L EGFR-TKI were afatinib and osimertinib (n = 7 for both). Among all patients treated with 1L EGFR-TKI (n = 246), 47 (19%) were tested for EGFR T790M [16 patients (34%) were positive], 48 (20%) remained on 1L EGFR-TKI, 29 (12%) received subsequent therapy, 38 (15%) had died on or after their 1L EGFR-TKI therapy, and 131 (53%) stopped their EGFR-TKI with no recorded evidence of having received subsequent therapy at follow-up end.
    CONCLUSION: Following 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.
    Keywords:  Advanced; EGFR; Epidermal growth factor receptor mutation; NSCLC; Non-small cell lung cancer; Osimertinib; Real-world study; Sequencing; Treatment patterns
    DOI:  https://doi.org/10.1007/s12325-020-01221-4
  505. Ann Thorac Surg. 2020 Jan 21. pii: S0003-4975(20)30038-2. [Epub ahead of print]
    Isolated diaphragmatic metastasis originating from early endometrial cancer.
    Okada S, Miyagawa-Hayashino A, Sonobe Y, Inoue M.
      Metastatic diaphragm tumors are rare. We herein describe an extremely rare case of isolated diaphragmatic metastasis from an endometrial cancer. A 47-year-old asymptomatic woman, who had previously undergone surgical resection for stage IA endometrial cancer with high uptake of fluorodeoxyglucose, presented with a diaphragmatic tumor. Resected diaphragmatic specimen revealed adenocarcinoma within the diaphragm, which was similar to the previous endometrial cancer. The tumor was eventually diagnosed as a diaphragmatic metastasis from endometrioid adenocarcinoma of uterus. Diaphragmatic metastasis should be considered in differential diagnosis in patients with previous malignancies that show high fluorodeoxyglucose uptake, even in early-stage primary tumors.
    Keywords:  Diaphragmatic metastasis; FDG-PET SUV(max); endometrial cancer
    DOI:  https://doi.org/10.1016/j.athoracsur.2019.11.049
  506. Nutrients. 2020 Jan 19. pii: E261. [Epub ahead of print]12(1):
    Regulation of Skeletal Muscle Function by Amino Acids.
    Kamei Y, Hatazawa Y, Uchitomi R, Yoshimura R, Miura S.
      Amino acids are components of proteins that also exist free-form in the body; their functions can be divided into (1) nutritional, (2) sensory, and (3) biological regulatory roles. The skeletal muscle, which is the largest organ in the human body, representing ~40% of the total body weight, plays important roles in exercise, energy expenditure, and glucose/amino acid usage-processes that are modulated by various amino acids and their metabolites. In this review, we address the metabolism and function of amino acids in the skeletal muscle. The expression of PGC1α, a transcriptional coactivator, is increased in the skeletal muscle during exercise. PGC1α activates branched-chain amino acid (BCAA) metabolism and is used for energy in the tricarboxylic acid (TCA) cycle. Leucine, a BCAA, and its metabolite, β-hydroxy-β-methylbutyrate (HMB), both activate mammalian target of rapamycin complex 1 (mTORC1) and increase protein synthesis, but the mechanisms of activation appear to be different. The metabolite of valine (another BCAA), β-aminoisobutyric acid (BAIBA), is increased by exercise, is secreted by the skeletal muscle, and acts on other tissues, such as white adipose tissue, to increase energy expenditure. In addition, several amino acid-related molecules reportedly activate skeletal muscle function. Oral 5-aminolevulinic acid (ALA) supplementation can protect against mild hyperglycemia and help prevent type 2 diabetes. β-alanine levels are decreased in the skeletal muscles of aged mice. β-alanine supplementation increased the physical performance and improved the executive function induced by endurance exercise in middle-aged individuals. Further studies focusing on the effects of amino acids and their metabolites on skeletal muscle function will provide data essential for the production of food supplements for older adults, athletes, and individuals with metabolic diseases.
    Keywords:  PGC1α; amino acid; branched-chain amino acid (BCAA); energy expenditure; exercise; leucine; metabolic diseases; skeletal muscle; β-aminoisobutyric acid (BAIBA); β-hydroxy-β-methylbutyrate (HMB)
    DOI:  https://doi.org/10.3390/nu12010261
  507. Toxicology. 2020 Jan 20. pii: S0300-483X(20)30017-2. [Epub ahead of print] 152378
    Effects of prenatal nicotine exposure on hepatic glucose and lipid metabolism in offspring rats and its hereditability.
    Hu W, Wang G, He B, Hu S, Luo H, Wen Y, Chen L, Wang H.
      Prenatal nicotine exposure (PNE) could induce an increased susceptibility to multiple chronic diseases in adult offspring, that mainly caused by intrauterine maternal glucocorticoid (GC) over-exposure. We investigated the changes and inheritability of hepatic glucose and lipid metabolism caused by PNE, to decipher the possible intrauterine programming mechanism. Pregnant Wistar rats were administered subcutaneously with 2 mg/kg·d nicotine from gestational day (GD) 9∼20, and second-generation (F2) were set according to the mating between control females and PNE males. The results showed that serum phenotypes and hepatic enzymes of glucose and lipid metabolism were lower in F1 fetal rats of PNE but higher in the F1 adult rats. Meanwhile, the activated states of hepatic glucocorticoid-activation system, including type 1 and type 2 11β-hydroxysteroid dehydrogenases (Hsd11b1/2), nuclear receptor subfamily 3, group C, member 1 (Nr3c1) and CCAAT enhancer binding protein α (Cebpa), were positively correlated with serum corticosterone levels but negatively correlated with the histone acetylation (H3K27ac) and expression levels of insulin-like growth factor 1 (Igf1) before and after birth. Furthermore, serum phenotypes and hepatic enzymes of glucose and lipid metabolism were lower in both F2 fetal and adult rats of PNE, which were consistent with the hepatic changes of GC-IGF1 axis and the glucocorticoid-activation system. In conclusion, PNE could lead to inheritable changes of hepatic glucose and lipid metabolism, which are related to the intrauterine programming of GC-IGF1 axis induced by the glucocorticoid-activation system.
    Keywords:  epigenetic modification; glucocorticoid; glucose and lipid metabolism; intrauterine programming of glucocorticoid-insulin-like growth factor 1 axis; prenatal nicotine exposure
    DOI:  https://doi.org/10.1016/j.tox.2020.152378
  508. Nutr Res. 2019 Dec 04. pii: S0271-5317(19)30553-6. [Epub ahead of print]75 32-43
    Time-restricted feeding improves markers of cardiometabolic health in physically active college-age men: a 4-week randomized pre-post pilot study.
    McAllister MJ, Pigg BL, Renteria LI, Waldman HS.
      Time-restricted feeding (TRF) has been shown to improve body composition, blood lipids, and reduce markers of inflammation and oxidative stress. However, most of these studies come from rodent models and small human samples, and it is not clear if the benefits are dependent upon a caloric deficit, or the time restriction nature of TRF. Based off of previous research, we hypothesized that humans following an ad libitum TRF protocol would reduce caloric intake and this caloric deficit would be associated with greater improvements in cardiometabolic health including blood pressure, body composition, blood lipids, and markers of inflammation and antioxidant status compared to an isocaloric TRF protocol. The purpose of this study was to: (1) examine the impact of TRF on markers of cardio-metabolic health and antioxidant status and (2) determine if the adaptations from TRF would differ under ad libitum compared to isocaloric conditions. Twenty-three healthy men were randomized to either an ad libitum or isocaloric 16:8 (fasting: feeding) TRF protocol. A total of 22 men completed the 28-day TRF protocol (mean ± SD; age: 22 ± 2.5 yrs.; height: 178.4 ± 6.9 cm; weight: 90.3 ± 24 kg; BMI: 28.5 ± 8.3 kg/m2). Fasting blood samples were analyzed for glucose, lipids, as well as adiponectin, human growth hormone, insulin, cortisol, C-reactive protein, superoxide dismutase, total nitrate/nitrite, and glutathione. Time-restricted feeding in both groups was associated with significant (P < .05) reductions in body fat, blood pressure, and significant increases in adiponectin and HDL-c. No changes in caloric intake were detected. In summary, the results from this pilot study in metabolically healthy, active young men, suggest that TRF can improve markers of cardiometabolic health.
    Keywords:  Antioxidants; Diet; Inflammation; Intermittent fasting; Oxidative stress; Weight loss
    DOI:  https://doi.org/10.1016/j.nutres.2019.12.001
  509. South Asian J Cancer. 2020 Jan-Mar;9(1):9(1): 50-52
    The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.
    Abbas W, Acharya RP, Pandit A, Gupta S, Rao RR.
      Background: PDL-1 inhibitors have emerged as the new standard of care for second line treatment of NSCLC.Methods: Eligible patients included, histologically proven NSCLC, ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1 or 2, age 18 years and above, availability of pre-treatment tumor specimen, adequate end organ function, at least one prior platinum-based therapy. Patients who received a minimum of 6 doses of nivolumab were eligible.
    Results: Eleven previously treated patients with chemotherapy, started on nivolumab from April of 2016 to December of 2018, were retrospectively studied and analysed. The median age of patients was 58 years. Eight (72.73%) of the eleven patients were male. Seven (63.64%) of the patients were current or former smokers. Majority of patients had non-squamous histology; seven (63.64%) adenocarcinoma and four (36.36%) squamous cell carcinoma. 5 (45.46%) of the patients received one prior therapy, three (27.27%) received two prior therapies, and three (27.27%) received three prior therapies. Four (36.36%) of the patients had brain metastasis. Two (18.18%) of the patients were more than 70 years of age. Median number of cycles of nivolumab administered were 10 (range, 6 to 21). At the time of analysis, the median PFS was 8 months (95% CI, 1.52-14.47) and median OS was 15 months (95% CI, 6.9-23.09). Treatment was well tolerated and generally side effects were grade 1 and grade 2, except two patients who develop grade 3/4 pneumonitis.
    Conclusions: This is a real-world study of eleven previously treated patients with chemotherapy, started on Nivolumab from April of 2016 to December of 2018. Although, our sample size was small, our data supports the use of nivolumab as a new treatment option for patients of stage 4 NSCLC.
    Keywords:  Immunotherapy in lung cancer; nivolumab in carcinoma lung; real-world data of nivolumab
    DOI:  https://doi.org/10.4103/sajc.sajc_111_19
  510. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19932. [Epub ahead of print]24(1): 345-351
    Relationship of asthma control test scores with pulmonary function tests, quality of life and adiposity in asthmatic children.
    Habib SS, Alsuhaim M, Alzahrani A, Alsaud A, Alzahrani K, Aldawsari S, Alhendas K, Al Saadi M, Bashir S.
      OBJECTIVE: This study aimed at assessing asthma control test (ACT score), quality of life (QOL), and pulmonary functions in asthmatic children, and to see the correlations between ACT score, QOL, and pulmonary functions.PATIENTS AND METHODS: This cross-sectional study was conducted at the departments of pediatrics and physiology, College of Medicine, King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia. A total of 109 (53 asthmatics and 56 controls) children (aged 6 to 13 years) of both genders were studied. All subjects underwent clinical evaluation, 36-Item Short Form Survey (SF-36) for QOL, Spirometry, and cognitive assessment through mini mental state examination (MMSE).
    RESULTS: QOL showed significantly lower scores in asthmatic compared to non-asthmatic children. The higher social functioning [SF] (p=0.0012) and less role limitation due to physical health [RLPH] (non-asthmatic patients had had higher physical functioning [PF] (p=0.0001), less energy/fatigue [EF] (p=0.0008=0.0068). On the opposite side, no significant difference was found regarding role limitations due to emotional problems [RLEP] (p=0.0644) and Emotional well-being [EW] (p=0.0758) between the two groups. A significant positive correlation was seen between QOL items and ACT score in PF (r=.535, p<0.01), less RLPH (r=.593, p<0.01), less FE (r=.379, p<0.01), higher EW (r=.310, p<0.05), and higher SF (r=.495, p<0.01). No significant correlation was found between body mass index (BMI) and lung functions in children with asthma. Interestingly, a positive correlation was found in asthmatic children between BMI and MMSE scores (r=.298, p=0.030).
    CONCLUSIONS: Our study concluded that QOL in asthmatic patients was significantly lower than healthy subjects in terms of patient's physical functioning and social life. However, the emotional aspects of QOL were not significantly affected in asthmatic children.
    DOI:  https://doi.org/10.26355/eurrev_202001_19932
  511. J Clin Oncol. 2020 Jan 21. JCO1901598
    Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors.
    Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, Stepan DE, Shumaker RC, Motzer RJ.
      PURPOSE: Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.METHODS: Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORRweek 24) at the recommended phase II dose.
    RESULTS: Overall, 137 patients were enrolled during phase Ib (n = 13) and the initial phase II expansion (n = 124). Two dose-limiting toxicities (DLTs; grade 3 arthralgia and grade 3 fatigue) were reported in the initial dose level (lenvatinib 24 mg/d plus pembrolizumab). No DLTs were observed in the subsequent dose-de-escalation cohort, establishing the MTD and recommended phase II dose at lenvatinib 20 mg/d plus pembrolizumab. ORRweek24 was as follows: RCC, 63% (19/30; 95% CI, 43.9% to 80.1%); endometrial cancer, 52% (12/23; 95% CI, 30.6% to 73.2%); melanoma, 48% (10/21; 95% CI, 25.7% to 70.2%); SCCHN, 36% (8/22; 95% CI, 17.2% to 59.3%); NSCLC, 33% (7/21; 95% CI, 14.6% to 57.0%); and urothelial cancer 25% (5/20; 95% CI, 8.7% to 49.1%). The most common treatment-related adverse events were fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%).
    CONCLUSION: Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.
    DOI:  https://doi.org/10.1200/JCO.19.01598
  512. Aging (Albany NY). 2020 Jan 20. 12
    Ubiquinol-10 delays postovulatory oocyte aging by improving mitochondrial renewal in pigs.
    Niu YJ, Zhou W, Nie ZW, Zhou D, Xu YN, Ock SA, Yan CG, Cui XS.
      Ubiquinol-10, the reduced form of coenzyme Q10, protects mammalian cells from oxidative damage and enhances mitochondrial activity. However, the protective effect of ubiquinol-10 on mammalian oocytes is not well understood. In this study, we investigated the effect of ubiquinol-10 on porcine oocytes during postovulatory aging. Metaphase II oocytes were selected as fresh oocytes and further cultured for 48 h with different concentrations of ubiquinol-10 (0-400 μM) in vitro as a postovulatory aging model. After choosing the optimal concentration of ubiquinol-10 (100 μM) that maintained oocyte morphology and developmental competence during the progression of aging, the oocytes were randomly divided into five groups: fresh, control-24 h, ubiquinol-24 h, control-48 h, and ubiquinol-48 h. The results revealed that ubiquinol-10 significantly prevented aging-induced oxidative stress, GSH reduction, cytoskeleton impairment, apoptosis, and autophagy. Mitochondrial biogenesis (SIRT1 and PGC-1α) and mitophagy (PINK1 and PARKIN)-related proteins were decreased during aging. Addition of ubiquinol-10 prevented the aging-induced reduction of these proteins. Consequently, although mitochondrial content was decreased, the number of active mitochondria and ATP level were significantly increased upon treatment with ubiquinol-10. Thus, ubiquinol-10 has beneficial effects on porcine postovulatory aging oocytes owing to its antioxidant properties and ability to promote mitochondrial renewal.
    Keywords:  mitochondria; oxidative stress; pig; postovulatory aging; ubiquinol-10
    DOI:  https://doi.org/10.18632/aging.102681
  513. J Ethnopharmacol. 2020 Jan 20. pii: S0378-8741(19)34218-7. [Epub ahead of print] 112604
    Metabolic disturbance in Korean red ginseng-induced "Shanghuo" (excessive heat).
    Zhao T, Yang Z, Mei X, Xu L, Fan Y.
      ETHNOPHARMACOLOGICAL RELEVANCE: Northeast China is one of the Korean Red Ginseng (KRG) producing areas. As a health care product, KRG is popular amongst Chinese people. However, few studies have reported the side effects of overusing KRG.AIM OF THE STUDY: The main purpose of this study is to explore the mechanism of Korean Red Ginseng (KRG)-induced "Shanghuo" (excessive heat).
    MATERIALS AND METHODS: After the baseline characteristics were evaluated, 30 healthy volunteers were administrated with 3g of KRG for 10-16 days and diagnosed with "Shanghuo". The volunteers prior to the administration of KRG were considered as the control group. The volunteers after being diagnosed with "Shanghuo" (excessive heat) were considered as "Shanghuo" group. The two groups were assessed by the tests of serum metabolic products, Succinate Dehydrogenase (SDH) activity, and mRNA expressions of adenosine monophosphate (AMP)-activated protein kinase (AMPK), PPARG Coactivator 1 Alpha (PGC-1α) and Nuclear Respiratory Factor 1 (NRF1).
    RESULTS: Most of the serum metabolites in the "Shanghuo" group were increased compared with the control group, from high to low including serine, valine, heptacosane, xylose, glycerol 1-monostearate, d-glucose, 3-pyridinol, glyceryl palmitate, urea, phosphoric acid, glycerol, stearic acid, palmitic acid, cyclohexaneacetic acid. Only cholesterol was significantly reduced, The SDH activity and the mRNA expressions of AMPK, PGC-1α and NRF1 were significantly increased in the "Shanghuo" group.
    CONCLUSIONS: Overconsumption of KRG could induce "Shanghuo", which has a close relationship with an accelerated TCA cycle and the increased AMPK activity.
    Keywords:  AMPK; Gas chromatography–mass spectrometry; Korean red ginseng; Metabolomics; “Shanghuo”
    DOI:  https://doi.org/10.1016/j.jep.2020.112604
  514. Toxicol Appl Pharmacol. 2020 Jan 21. pii: S0041-008X(20)30022-3. [Epub ahead of print] 114898
    Comparative analysis of lung and blood transcriptomes in mice exposed to multi-walled carbon nanotubes.
    Khaliullin TO, Yanamala N, Newman MS, Kisin ER, Fatkhutdinova LM, Shvedova AA.
      Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) causes inflammation, fibroproliferation, immunotoxicity, and systemic responses in rodents. However, the search for representative biomarkers of exposure is an ongoing endeavor. Whole blood gene expression profiling is a promising new approach for the identification of novel disease biomarkers. We asked if the whole blood transcriptome reflects pathology-specific changes in lung gene expression caused by MWCNT. To answer this question, we performed mRNA sequencing analysis of the whole blood and lung in mice administered MWCNT or vehicle solution via pharyngeal aspiration and sacrificed 56 days later. The pattern of lung mRNA expression as determined using Ingenuity Pathway Analysis (IPA) was indicative of continued inflammation, immune cell trafficking, phagocytosis, and adaptive immune responses. Simultaneously, innate immunity-related transcripts (Plunc, Bpifb1, Reg3g) and cancer-related pathways were downregulated. IPA analysis of the differentially expressed genes in the whole blood suggested increased hematopoiesis, predicted activation of cancer/tumor development pathways, and atopy. There were several common upregulated genes between whole blood and lungs, important for adaptive immune responses: Cxcr1, Cd72, Sharpin, and Slc11a1. Trim24, important for TH2 cell effector function, was downregulated in both datasets. Hla-dqa1 mRNA was upregulated in the lungs and downregulated in the blood, as was Lilrb4, which controls the reactivity of immune response. "Cancer" disease category had opposing activation status in the two datasets, while the only commonality was "hypersensitivity". Transcriptome changes occurring in the lungs did not produce a completely replicable pattern in whole blood; however, specific systemic responses may be shared between transcriptomic profiles.
    Keywords:  IPA Analysis; Lung Transcriptome; MWCNT; Whole Blood Transcriptome
    DOI:  https://doi.org/10.1016/j.taap.2020.114898
  515. J Ethnopharmacol. 2020 Jan 21. pii: S0378-8741(19)32690-X. [Epub ahead of print] 112583
    Mu-Xiang-You-Fang protects PC12 cells against OGD/R-induced autophagy via the AMPK/mTOR signaling pathway.
    Ma HX, Hou F, Chen AL, Li TT, Zhu YF, Zhao QP.
      ETHNOPHARMACOLOGICAL RELEVANCE: Mu-Xiang-You-Fang (MXYF) is a classic prescription of Hui medicine. It is composed of five herbs and has been used to treat ischemic stroke for many years. However, the potential pharmacological mechanisms of MXYF remain unclear. The present research is aimed to investigate the protective effect and possible mechanisms of MXYF treatment in an in vitro model of cerebral ischemia-reperfusion injury.MATERIALS AND METHODS: An oxygen-glucose deprivation and reperfusion (OGD/R) model of PC12 cells was established. The effect of MXYF on the cell viability after OGD/R injury was determined using a cell counting kit (CCK-8) assay. The colorimetric method was used to determine the lactate dehydrogenase (LDH) leakage rate. The calcium concentration was determined by the chemical fluorescence method, and mitochondrial membrane potential was determined using flow cytometry. Monodansylcadaverine (MDC) staining and electron microscopic analysis were then conducted to detect autophagy after oxygen-glucose deprivation and reperfusion in PC12 cells. Immunofluorescence and western blot analyses were used to detect the expression of proteins associated with autophagy.
    RESULTS: It was found that MXYF (1, 2, 4 μg/mL) could significantly increase cell viability and mitochondrial membrane potential and decrease the calcium concentration and LDH release rate in PC12 cells. After OGD/R injury in PC12 cells, the number of autophagosomes and autophagolysosome significantly increased. MXYF (4 μg/mL) inhibited the autophagy induced by OGD/R and inhibited the expression of LC3, beclin1, p-AMPK, and ULK1. In contrast, the expression of p-mTOR, p-p70s6k, and p62 was significantly enhanced.
    CONCLUSIONS: These findings suggest that MXYF inhibits autophagy after OGD/R-induced PC12 cell injury through the AMPK-mTOR pathway. Thus, MXYF might have therapeutic potential in treating ischemic stroke.
    Keywords:  AMPK/mTOR pathway; Autophagy; Ischemic stroke; Mu-Xiang-You-Fang; Oxygen-glucose deprivation and reperfusion; PC12 cells
    DOI:  https://doi.org/10.1016/j.jep.2020.112583
  516. Gene Ther. 2020 Jan 22.
    miR-19a/19b improves the therapeutic potential of mesenchymal stem cells in a mouse model of myocardial infarction.
    Chen C, Chen T, Li Y, Xu Y.
      Myocardial infarction (MI) is the cardiac emergency that may leads to myocardial necrosis. Mesenchymal stem cells (MSCs) could be used to induce myocardial differentiation. However, the efficiency remains low. The aim of this study is to explore whether miR-19a/19b could enhance the therapeutic potential of mesenchymal stem cells in MI. Myocardial infarction mouse model was established using coronary artery ligation. Cardiac functional recovery was detected by Masson's trichrome staining. Under hypoxic condition, miR-19a/19b expression levels decreased in bone marrow-derived MSCs (BM-MSCs). MiR-19a/19b suppressed the proliferation of MSCs under hypoxic condition. After cell engraftment, miR-19a/19b promoted survival of MSCs. Mechanically, miR-19a/19b inhibited inflammatory cells infiltration into myocardium cells. Moreover, MSCs-miR-19a/19b improves cardiac functional recovery in diabetic MI mice models. All the results indicated that miR-19a/19b improves the therapeutic potential of mesenchymal stem cells in a mouse model of myocardial infarction.
    DOI:  https://doi.org/10.1038/s41434-020-0122-3
  517. J Cell Physiol. 2020 Jan 22.
    Low-intensity pulsed ultrasound affects growth, differentiation, migration, and epithelial-to-mesenchymal transition of colorectal cancer cells.
    Lucchetti D, Perelli L, Colella F, Ricciardi-Tenore C, Scoarughi G, Barbato G, Boninsegna A, De Maria R, Sgambato A.
      Ultrasound (US) offers potentially important opportunities from a therapeutic point of view. Thus, the study of the biological effects of US on cancer cells is important to understand the consequences of these changes on the malignant phenotype. This study aimed to investigate the effects of low-intensity ultrasound (LIPUS) on the phenotype of colorectal cancer cell lines. Cell proliferation was evaluated by viability test and by evaluation of pERK expression, while cell motility using the scratch test. Cell differentiation was evaluated assessing alkaline phosphatase activity. Epithelial mesenchymal transition was assessed by analyzing the expression of Vimentin and E-Cadherin. Release and uptake of extracellular vesicles (EVs) were evaluated by flow cytometry. LIPUS effects on the organization of cytoskeleton were analyzed by confocal microscopy and by evaluation of Rho GTPase expression. No alterations in vitality and clonogenicity were observed when the intermediate (0.4 MPa) and the lowest (0.035 MPa) acoustic intensities were administered while the treatment with high intensity (1 MPa) induced a reduction of both cell viability and clonogenicity in both cell lines in a frequency-dependent manner. LIPUS promoted the differentiation of colon cancer cells, affected epithelial-to-mesenchymal transition, promoted the closure of a wound as well as increased the release of EVs compared with untreated cells. LIPUS-induced increase in cell motility was likely due to a Rho GTPase-dependent mechanism. Overall, the results obtained warrant further studies on the potential combined effect of LIPUS with differentiating agents and on their potential use in a clinical setting.
    Keywords:  EMT; LIPUS; colon cancer differentiation; extracellular vesicles; motility
    DOI:  https://doi.org/10.1002/jcp.29423
  518. Spectrochim Acta A Mol Biomol Spectrosc. 2020 Jan 16. pii: S1386-1425(20)30025-1. [Epub ahead of print]230 118048
    Potential of vibrational spectroscopy for rapid and accurate determination of the hydrogen peroxide treatment of plant leaves.
    Zhao Y, Chu B, Fang S, Zhao J, Zhang H, Yu K.
      Detection and characterization of interactions between crop plants and hydrogen peroxide (H2O2) is significant for the exploration of the mechanisms in plant pathology. The objective of this research is to estimate spectral characteristics of rapeseed leaves (Brassica napus L.) during treatment with different H2O2 concentrations (0, 0.5, 1.0, and 3.0 mmol/L) by using Raman spectroscopy (RS) (800-1800 cm-1) and hyperspectral imaging (HSI) (400-1000 nm). Cluster analysis of RS and HSI data between the control and treated samples was conducted using kernel principal component analysis (KPCA) and principal component analysis (PCA), respectively. Characteristic Raman shifts at 1012, 1163, and 1530 cm-1 and hyperspectral featured wavelengths at 452, 558, 655, and 703 nm were selected for discriminating control and treated samples. The one-way analysis of variance (ANOVA) was applied to demonstrate the significant difference in spectral signatures of samples, and results showed that 452 nm is promising to assess the control and treated samples at the p < 0.05 level. The featured Raman shifts and hyperspectral wavelengths were employed to establish least squares-support vector machine (LS-SVM) discriminative models. The approach of multiple-level data fusion of 1163 cm-1 combined with 452 nm produced the best recognize rate (RR) of 81.7% to detect the control and treated leaves than other models. Therefore, the results encouraged multiple sensor fusion to improve models for better model performance and to detect plant treatment situations with H2O2 solutions.
    Keywords:  H(2)O(2) treatment; Hyperspectral imaging; Raman spectroscopy; Rapeseed leaves
    DOI:  https://doi.org/10.1016/j.saa.2020.118048
  519. J Alzheimers Dis. 2020 Jan 13.
    Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer's Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study.
    Wong D, Atiya S, Fogarty J, Montero-Odasso M, Pasternak SH, Brymer C, Borrie MJ, Bartha R.
      Identification of biological changes underlying the early symptoms of Alzheimer's disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment.
    Keywords:  Alzheimer’s disease; diffusion tensor imaging; diffusion tractography; episodic memory; glutamate; hippocampus; magnetic resonance spectroscopy; magnetic resonance imaging; posterior cingulate cortex
    DOI:  https://doi.org/10.3233/JAD-190773
  520. Nat Commun. 2020 Jan 21. 11(1): 409
    Golgi organization is regulated by proteasomal degradation.
    Eisenberg-Lerner A, Benyair R, Hizkiahou N, Nudel N, Maor R, Kramer MP, Shmueli MD, Zigdon I, Cherniavsky Lev M, Ulman A, Sagiv JY, Dayan M, Dassa B, Rosenwald M, Shachar I, Li J, Wang Y, Dezorella N, Khan S, Porat Z, Shimoni E, Avinoam O, Merbl Y.
      The Golgi is a dynamic organelle whose correct assembly is crucial for cellular homeostasis. Perturbations in Golgi structure are associated with numerous disorders from neurodegeneration to cancer. However, whether and how dispersal of the Golgi apparatus is actively regulated under stress, and the consequences of Golgi dispersal, remain unknown. Here we demonstrate that 26S proteasomes are associated with the cytosolic surface of Golgi membranes to facilitate Golgi Apparatus-Related Degradation (GARD) and degradation of GM130 in response to Golgi stress. The degradation of GM130 is dependent on p97/VCP and 26S proteasomes, and required for Golgi dispersal. Finally, we show that perturbation of Golgi homeostasis induces cell death of multiple myeloma in vitro and in vivo, offering a therapeutic strategy for this malignancy. Taken together, this work reveals a mechanism of Golgi-localized proteasomal degradation, providing a functional link between proteostasis control and Golgi architecture, which may be critical in various secretion-related pathologies.
    DOI:  https://doi.org/10.1038/s41467-019-14038-9
  521. Mol Med Rep. 2020 Feb;21(2): 806-814
    Effect of SKF‑96365 on cardiomyocyte hypertrophy induced by angiotensin II.
    Cheng H, Li J, Wu Q, Zheng X, Gao Y, Yang Q, Sun N, He M, Zhou Y.
      Angiotensin II (Ang II) is an important bioactive peptide in the renin‑angiotensin system, and it can contribute to cell proliferation and cardiac hypertrophy. Dysfunctions in transient receptor potential canonical (TRPC) channels are involved in many types of cardiovascular diseases. The aim of the present study was to investigate the role of the TRPC channel inhibitor SKF‑96365 in cardiomyocyte hypertrophy induced by Ang II and the potential mechanisms of SKF‑96365. H9c2 cells were treated with different concentrations of Ang II. The expression levels of cardiomyocyte hypertrophy markers and TRPC channel‑related proteins were also determined. The morphology and surface area of the H9c2 cells, the expression of hypertrophic markers and TRPC channel‑related proteins and the [3H] leucine incorporation rate were detected in the Ang II‑treated H9c2 cells following treatment with the TRPC channel inhibitor SKF‑96365. The intracellular Ca2+ concentration was tested by flow cytometry. The present results suggested that the surface area of H9c2 cells treated with Ang II was significantly increased compared with untreated H9c2 cells. The fluorescence intensity of α‑actinin, the expression of hypertrophic markers and TRPC‑related proteins, the [3H] leucine incorporation rate and the intracellular Ca2+ concentration were all markedly increased in the Ang II‑treated H9c2 cells but decreased following SKF‑96365 treatment. The present results suggested that Ang II induced cardiomyocyte hypertrophy in H9c2 cells and that the TRPC pathway may be involved in this process. Therefore, SKF‑96365 can inhibit cardiomyocyte hypertrophy induced by Ang II by suppressing the TRPC pathway. The present results indicated that TRPC may be a therapeutic target for the development of novel drugs to treat cardiac hypertrophy.
    DOI:  https://doi.org/10.3892/mmr.2019.10877
  522. Rapid Commun Mass Spectrom. 2020 Jan 21.
    Quantification of glyphosate and AMPA from microbiome reactor fluids.
    Fritz-Wallace K, Engelmann B, Krause JL, Schäpe SS, Pöppe J, Herberth G, Rösler U, Jehmlich N, von Bergen M, Rolle-Kampczyk U.
      RATIONALE: Glyphosate is one of the most widely used herbicides and it is suspected to affect the intestinal microbiota through inhibition of aromatic amino acid synthesis via the shikimate pathway. In vitro microbiome bioreactors are increasingly used as model systems to investigate effects on the intestinal microbiota and consequently methods for the quantitation of glyphosate and its degradation product AMPA in microbiome model systems are required.METHODS: An optimized protocol enables the analysis of both glyphosate and AMPA by simple extraction with methanol:acetonitrile:water (2:3:1) without further enrichment steps. Glyphosate and AMPA are separated by liquid chromatography on an amide column and identified and quantified with a targeted MS/MS method on a QTRAP 5500 system (AB Sciex).
    RESULTS: Our method has a limit of detection (LOD) in extracted water samples of < 2 ng/mL for both glyphosate and AMPA. In complex intestinal medium the LOD is 2 ng/mL and 5 ng/mL for glyphosate and AMPA, respectively. These LODs allow for measurement at exposure-relevant concentrations. Glyphosate levels in a bioreactor model of porcine colon were determined and consequently it was verified whether AMPA was produced by porcine gut microbiota.
    CONCLUSIONS: The method presented here allows quantitation of glyphosate and AMPA in complex bioreactor fluids and thus enables studies on the impact of glyphosate and its metabolism on the intestinal microbiota. In addition, the extraction protocol is compatible with an untargeted metabolomics analysis, thus allowing other perturbations caused by glyphosate in the same sample to be looked for.
    DOI:  https://doi.org/10.1002/rcm.8668
  523. J Proteome Res. 2020 Jan 24.
    Quantitative Mitochondrial Proteomics Reveals ANXA7 as a Crucial Factor in Mitophagy.
    Meng K, Lu S, Yan X, Sun Y, Gao J, Wang Y, Yin X, Sun Z, He QY.
      Mitochondria are involved in many crucial cellular processes. Maintaining healthy mitochondria is essential for cellular homeostasis. Parkin-dependent mitophagy plays an important role in selectively eliminating damaged mitochondria in mammalian cells. However, mechanisms of Parkin-dependent mitophagy remain elusive. In this research, we performed data-independent acquisition (DIA)-based quantitative mitochondrial proteomics to study the proteomic alterations of carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced Parkin-mediated mitophagy. We identified 222 differentially expressed proteins, with 76 up-regulations and 146 down-regulations, which were potentially involved in mitophagy. We then demonstrated that annexin A7 (ANXA7), a calcium-dependent phospholipid-binding protein, can translocate to impaired mitochondria upon CCCP treatment, where it played a pivotal part in the process of Parkin-dependent mitophagy via interacting with BASP1. As a mitochondrial uncoupling agent, CCCP indirectly regulated ANXA7 and BASP1 to induce Parkin-dependent mitophagy. Keywords: mitochondrial proteomics, mitophagy, ANXA7.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00800
  524. J Recept Signal Transduct Res. 2020 Jan 21. 1-9
    Mief1 augments thyroid cell dysfunction and apoptosis through inhibiting AMPK-PTEN signaling pathway.
    Zhang Y, Zhang H, Shi W, Wang W.
      Objective: Inflammation-mediated thyroid cell dysfunction and apoptosis increases the like-hood of hypothyroidism.Aim: Our aim in the present study is to explore the role of mitochondrial elongation factor 1 (Mief1) in thyroid cell dysfunction induced by TNFα.Materials and methods: Different doses of TNFα were used to incubate with thyroid cells in vitro. The survival rate, apoptotic index and proliferation capacity of thyroid cells were measured. Cellular energy metabolism and endoplasmic reticulum function related to protein synthesis were detected.Results: In response to TNFα treatment, the levels of Mief1 were increased, coinciding with a drop in the viability of thyroid cells in vitro. Loss of Mief1 attenuates TNFα-induced cell death through reducing the ratio of cell apoptosis. Further, we found that Mief1 deletion reversed cell energy metabolism and this effect was attributable to mitochondrial protection. Mief1 knockdown sustained mitochondrial membrane potential and reduced mitochondrial ROS overproduction. In addition, Mief1 knockdown also reduced endoplasmic reticulum stress, as evidenced by decreased levels of Chop and Caspase-12. Finally, our data verified that TNFα treatment inhibited the activity of AMPK-PTEN pathway whereas Mief1 deletion reversed the activity of AMPK and thus promoted the upregulation of PTEN. However, inhibition of AMPK-PTEN pathways could abolish the beneficial effects exerted by Mief1 deletion on thyroid cells damage and dysfunction.Conclusions: Altogether, our data indicate that immune abnormality-mediated thyroid cell dysfunction and death are alleviated by Mief1 deletion possible driven through reversing the activity of AMPK-PTEN pathways.
    Keywords:  AMPK; Mief1; PTEN; Thyroid cell death
    DOI:  https://doi.org/10.1080/10799893.2020.1716799
  525. Mol Med Rep. 2020 Feb;21(2): 695-704
    Inhibition of the SIRT1 signaling pathway exacerbates endoplasmic reticulum stress induced by renal ischemia/reperfusion injury in type 1 diabetic rats.
    Zhang J, Wang L, Gong D, Yang Y, Liu X, Chen Z.
      The aim of the present study was to investigate whether the diabetic kidney is more susceptible to ischemia/reperfusion (I/R) injury, and identify the potential mechanisms involved. An animal model of type 1 diabetes was created by treating rats with streptozotocin (STZ). This model was then used, along with healthy controls, to investigate the effect of diabetes mellitus (DM) on renal I/R injury. After 45 min of ischemia and 24 h of reperfusion, kidney and serum samples were acquired and used to evaluate function and histopathological injury in the kidneys. Western blotting was also used to determine the expression levels of key proteins. Rats experiencing renal I/R exhibited significant characteristics of renal dysfunction, reduced levels of Sirtuin 1 (SIRT1) protein (a key signaling protein in the kidneys), increased endoplasmic reticulum stress (ERS) and pyroptosis. Furthermore, diabetic rats exhibited further reductions in the levels of SIRT1 in response to renal I/R injury and an increase in the levels of ERS. These effects were all alleviated by the administration of a SIRT1 agonist. The present analysis revealed that the SIRT1‑mediated activation of ER stress and pyroptosis played a pivotal role in diabetic rats subjected to renal I/R injury. Downregulation of the SIRT1 signaling pathway were exacerbated in response to renal I/R injury‑induced acute kidney injury (AKI). The present data indicated that DM enhanced ER stress and increased pyroptosis by downregulating the SIRT1 signaling pathway.
    DOI:  https://doi.org/10.3892/mmr.2019.10893
  526. J Control Release. 2020 Jan 16. pii: S0168-3659(20)30045-6. [Epub ahead of print]
    Ligand-installed anti-VEGF genomic nanocarriers for effective gene therapy of primary and metastatic tumors.
    Zhang H, Liu J, Chen Q, Mi P.
      The systemic dosage regimen exhibited low therapeutic efficacy and incurred severe adverse effect, thus, the development of tumor-targeted therapeutics is crucial important for tumor precision therapy. Herein, the active targeted modulation of tumor microenvironments was schemed by developing hyaluronic acid-installed genomic nanocarriers (HA-NPs) for effectively ablation of both primary and metastatic tumors through anti-vascular endothelial growth factor (anti-VEGF) approach. The anti-VEGF genomic payloads were strategically packaged into well-defined synthetic nanocarriers by layer-by-layer preparation strategy, exhibiting high colloidal stability and much lower cell viability than the cationic gene carriers. Besides, the HA-NPs could specifically and efficiently internalize with cancer cells for efficient intracellular gene delivery, leading to high gene transfection efficacy. Moreover, it further demonstrated efficient extravasation, high accumulation and deep penetration in tumors, which markedly facilitated tumor-targeted expression of anti-VEGF genomic payloads for inhabitation of neovasculature, consecutively contributing to potent ablation of solid tumors. In addition, the ligand-installed nanocarriers facilitated systemic treatment of melanoma lung metastasis by the expressed anti-VEGF proteins, which were extensively spread along blood circulation and metastatic niches to diminish the formation of neovasculature for tumorigenesis. Therefore, the proposed anti-VEGF genomic nanocarriers could shed intriguing implication in effectively treatment of primary tumors and metastasis.
    Keywords:  Anti-VEGF; Gene delivery; Layer-by-layer; Metastasis; Nanoparticles; Tumor
    DOI:  https://doi.org/10.1016/j.jconrel.2020.01.026
  527. Exp Mol Med. 2020 Jan 20.
    The USP21/YY1/SNHG16 axis contributes to tumor proliferation, migration, and invasion of non-small-cell lung cancer.
    Xu P, Xiao H, Yang Q, Hu R, Jiang L, Bi R, Jiang X, Wang L, Mei J, Ding F, Huang J.
      Deubiquitinases (DUBs) and noncoding RNAs have been the subjects of recent extensive studies regarding their roles in lung cancer, but the mechanisms involved are largely unknown. In our study, we used The Cancer Genome Atlas data set and bioinformatics analyses and identified USP21, a DUB, as a potential contributor to oncogenesis in non-small-cell lung cancer (NSCLC). We further demonstrated that USP21 was highly expressed in NSCLCs. We then conducted a series of in vitro and in vivo assays to explore the effect of USP21 on NSCLC progression and the underlying mechanism involved. USP21 promoted NSCLC cell proliferation, migration, and invasion and in vivo tumor growth by stabilizing a well-known oncogene, Yin Yang-1 (YY1), via mediating its deubiquitination. Furthermore, YY1 transcriptionally regulates the expression of SNHG16. Moreover, StarBase bioinformatics analyses predicted that miR-4500 targets SNHG16 and USP21. A series of in vitro experiments indicated that SNHG16 increased the expression of USP21 through miR-4500. In summary, the USP21/YY1/SNHG16 axis plays a role in promoting the progression of NSCLC. Therefore, the USP21/YY1/SNHG16/miR-4500 axis may be a potential therapeutic target in NSCLC treatment.
    DOI:  https://doi.org/10.1038/s12276-019-0356-6
  528. Methods Mol Biol. 2020 ;2117 229-234
    Derivation of LIF-Independent Embryonic Stem Cells Using Inducible OCT4 Expression.
    Kidder BL.
      Pluripotent mouse embryonic stem (ES) cells, which are derived from the inner cell mass (ICM) of preimplantation stage embryos, are capable of self-renewing indefinitely in the presence of the external signal leukemia inhibitory factor (LIF), activation of Wnt signaling through inhibition of GSK3, and inhibition of MAP kinase/ERK kinase signaling. The OCT4 transcription factor is expressed highly in pluripotent cells and is a central transcriptional regulator of the pluripotent state. Here, we describe a protocol to culture ES cells in LIF-independent and serum-free media using an inducible OCT4 (iOCT4) ES cell model system. This protocol is sufficient to sustain ES cell self-renewal in vitro in defined conditions in the absence of external signals. LIF-independent iOCT4 ES cells are fully capable of differentiating following deactivation of the inducible OCT4 transgene.
    Keywords:  Embryonic stem cells; LIF; OCT4; Pluripotent; Self-renewal
    DOI:  https://doi.org/10.1007/978-1-0716-0301-7_13
  529. J Mol Cell Cardiol. 2020 Jan 17. pii: S0022-2828(20)30008-0. [Epub ahead of print]
    Metabolic impairment in response to early induction of C/EBPβ leads to compromised cardiac function during pathological hypertrophy.
    Banerjee D, Chaudhuri RD, Niyogi S, Chowdhuri SR, Sarkar MP, Chatterjee R, Chakrabarti P, Sarkar S.
      Chronic pressure overload-induced left ventricular hypertrophy in heart is preceded by a metabolic perturbation that prefers glucose over lipid as substrate for energy requirement. Here, we establish C/EBPβ (CCAAT/enhancer-binding protein β) as an early marker of the metabolic derangement that triggers the imbalance in fatty acid (FA) oxidation and glucose uptake with increased lipid accumulation in cardiomyocytes during pathological hypertrophy, leading to contractile dysfunction and endoplasmic reticulum (ER) stress. This is the first study that shows that myocardium-targeted C/EBPβ knockdown prevents the impaired cardiac function during cardiac hypertrophy led by maladaptive metabolic response with persistent hypertrophic stimuli whereas its targeted overexpression in control increases lipid accumulation significantly compared to control hearts. A new observation from this study was the dual and opposite transcriptional regulation of the alpha and gamma isoforms of Peroxisomal proliferator activated receptors (PPARα and PPARγ) by C/EBPβ in hypertrophied cardiomyocytes. Before the functional and structural remodeling sets in the diseased myocardium, C/EBPβ aggravates lipid accumulation with the aid of the increased FA uptake involving induced PPARγ expression and decreased fatty acid oxidation (FAO) by suppressing PPARα expression. Glucose uptake into cardiomyocytes was greatly increased by C/EBPβ via PPARα suppression. The activation of mammalian target of rapamycin complex-1 (mTORC1) during increased workload in presence of glucose as the only substrate was prevented by C/EBPβ knockdown, thereby abating contractile dysfunction in cardiomyocytes. Our study thus suggests that C/EBPβ may be considered as a novel cellular marker for deranged metabolic milieu before the heart pathologically remodels itself during hypertrophy.
    Keywords:  C/EBPβ; Cardiomyocyte; Glucose uptake; Lipid accumulation; Metabolism; Pathological cardiac hypertrophy
    DOI:  https://doi.org/10.1016/j.yjmcc.2020.01.004
  530. Int Psychogeriatr. 2020 Jan 23. 1-8
    [18F]FDDNP PET binding predicts change in executive function in a pilot clinical trial of geriatric depression.
    Krause-Sorio B, Siddarth P, Laird KT, Ercoli L, Narr K, Barrio JR, Small G, Lavretsky H.
      OBJECTIVES: Geriatric depression often presents with memory and cognitive complaints that are associated with increased risk for Alzheimer's disease (AD). In a parent clinical trial of escitalopram combined with memantine or placebo for geriatric depression and subjective memory complaints, we found that memantine improved executive function and delayed recall performance at 12 months (NCT01902004). In this report, we used positron emission tomography (PET) to assess the relationship between in-vivo amyloid and tau brain biomarkers and clinical and cognitive treatment response.DESIGN: In a randomized double-blind placebo-controlled trial, we measured 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) binding at baseline and assessed mood and cognitive performance at baseline, posttreatment (6 months), and naturalistic follow-up (12 months).
    PARTICIPANTS: Twenty-two older adults with major depressive disorder and subjective memory complaints completed PET scans and were included in this report.
    RESULTS: Across both treatment groups, higher frontal lobe [18F]FDDNP binding at baseline was associated with improvement in executive function at 6 months (corrected p = .045). This effect was no longer significant at 12 months (corrected p = .12). There was no association of regional [18F]FDDNP binding with change in mood symptoms (corrected p = .2).
    CONCLUSIONS: [18F]FDDNP binding may predict cognitive response to antidepressant treatment. Larger trials are required to further test the value of [18F]FDDNP binding as a biomarker for cognitive improvement with antidepressant treatment in geriatric depression.
    Keywords:  Alzheimer’s disease; [18F]FDDNP positron emission tomography; amyloid and tau; clinical trial; cognitive impairment; escitalopram; executive function; geriatric depression; memantine; neuroimaging
    DOI:  https://doi.org/10.1017/S1041610219002047
  531. J Laryngol Otol. 2020 Jan 22. 1-5
    The effect of topical xylometazoline on Eustachian tube function.
    Joshi KS, Ho VWQ, Smith ME, Tysome JR.
      BACKGROUND: Topical nasal decongestants are frequently used as part of the medical management of symptoms related to Eustachian tube dysfunction.OBJECTIVE: This study aimed to assess the effect of topical xylometazoline hydrochloride sprayed in the anterior part of the nose on Eustachian tube active and passive opening in healthy ears.
    METHODS: Active and passive Eustachian tube function was assessed in healthy subjects before and after intranasal administration of xylometazoline spray, using tympanometry, video otoscopy, sonotubometry, tubo-tympano-aerodynamic-graphy and tubomanometry.
    RESULTS: Resting middle-ear pressures were not significantly different following decongestant application. Eustachian tube opening rate was not significantly different following the intervention, as measured by all function tests used. Sonotubometry data showed a significant increase in the duration of Eustachian tube opening following decongestant application.
    CONCLUSION: There remains little or no evidence that topical nasal decongestants improve Eustachian tube function. Sonotubometry findings do suggest that further investigation with an obstructive Eustachian tube dysfunction patient cohort is warranted.
    Keywords:  Barotrauma; Eustachian Tube; Middle Ear Ventilation; Nasal Sprays
    DOI:  https://doi.org/10.1017/S0022215120000158
  532. Mol Med Rep. 2020 Feb;21(2): 777-785
    Protein kinase C promotes choline transporter‑like protein 1 function via improved cell surface expression in immortalized human hepatic cells.
    Ishikawa T, Suwanai H, Shikuma J, Suzuki R, Yamanaka T, Odawara M, Inazu M.
      Choline is used to synthesize phospholipids and a lack of choline induces a number of liver‑related diseases, including non‑alcoholic steatohepatitis. The current study characterized the choline uptake system, at molecular and functional levels, in the immortalized human hepatic cell line, Fa2N‑4, to identify the specific choline transporter involved in choline uptake. The present study also assesed whether choline deficiency or the inhibited choline uptake affected cell viability and apoptosis. Reverse transcription‑quantitative polymerase chain reaction (PCR) revealed choline transporter‑like protein 1 (CTL1) and CTL2 mRNA and protein expression in Fa2N‑4 cells. [Methyl‑3H]choline studies revealed choline uptake was saturable and mediated by a single transport system that functioned in a Na+‑independent but pH‑dependent manner, which was similar to CTL1. Hemicholinium‑3 (HC‑3), which is a choline uptake inhibitor, and choline deficiency inhibited cell viability, increased caspase‑3 and ‑7 activities, and increased fluorescein isothiocyanate‑Annexin V immunofluorescent staining indicated apoptosis. Immunofluorescent staining also revealed CTL1 and CTL2 localized in plasma and mitochondrial membranes, respectively. [Methyl‑3H]choline uptake was enhanced by a protein kinase C (PKC) activator, phorbol‑12‑myristate 13‑acetate (PMA). Immunofluorescence staining and western blot analysis demonstrated increased CTL1 expression on the cell membrane following PMA treatment. The results of current study indicated that extracellular choline is primarily transported via CTL1, relying on a direct H+ gradient that functions as a driving force in Fa2N‑4 cells. Furthermore, it was hypothesized that CTL1 and the choline uptake system are strongly associated with cell survival, and that the choline uptake system is modulated by PKC signaling via increased CTL1 expression on the cell surface. These findings provide further insights into the pathogenesis of liver disease involving choline metabolism.
    DOI:  https://doi.org/10.3892/mmr.2019.10894
  533. Cells. 2020 Jan 18. pii: E244. [Epub ahead of print]9(1):
    Pathogenic Carboxyl Ester Lipase (CEL) Variants Interact with the Normal CEL Protein in Pancreatic Cells.
    Dalva M, Lavik IK, El Jellas K, Gravdal A, Lugea A, Pandol SJ, Njølstad PR, Waldron RT, Fjeld K, Johansson BB, Molven A.
      Mutations in the gene encoding the digestive enzyme carboxyl ester lipase (CEL) are linked to pancreatic disease. The CEL variant denoted CEL-HYB predisposes to chronic pancreatitis, whereas the CEL-MODY variant causes MODY8, an inherited disorder of endocrine and exocrine pancreatic dysfunction. Both pathogenic variants exhibit altered biochemical and cellular properties compared with the normal CEL protein (CEL-WT, wild type). We here aimed to investigate effects of CEL variants on pancreatic acinar and ductal cell lines. Following extracellular exposure, CEL-HYB, CEL-MODY, and CEL-WT were endocytosed. The two pathogenic CEL proteins significantly reduced cell viability compared with CEL-WT. We also found evidence of CEL uptake in primary human pancreatic acinar cells and in native ductal tissue. Moreover, coexpression of CEL-HYB or CEL-MODY with CEL-WT affected secretion of the latter, as CEL-WT was observed to accumulate intracellularly to a higher degree in the presence of either pathogenic variant. Notably, in coendocytosis experiments, both pathogenic variants displayed a modest effect on cell viability when CEL-WT was present, indicating that the normal protein might diminish toxic effects conferred by CEL-HYB and CEL-MODY. Taken together, our findings provide valuable insight into how the pathogenic CEL variants predispose to pancreatic disease and why these disorders develop slowly over time.
    Keywords:  BSDL; CEL; cell viability; coexpression; endocytosis; pancreatic cell models
    DOI:  https://doi.org/10.3390/cells9010244
  534. Pediatr Pulmonol. 2020 Jan 24.
    Lung ultrasound-a new diagnostic modality in persistent tachypnea of infancy.
    Urbankowska E, Urbankowski T, Drobczyński Ł, Griese M, Lange J, Brzewski M, Kulus M, Krenke K.
      Lung ultrasound (LUS) has been increasingly used in diagnosing and monitoring of various pulmonary diseases in children. The aim of the current study was to evaluate its usefulness in children with persistent tachypnea of infancy (PTI). This was a controlled, prospective, cross-sectional study that included children with PTI and healthy subjects. In patients with PTI, LUS was performed at baseline and then after 6 and 12 months of follow-up. Baseline results of LUS were compared to (a) baseline high-resolution computed tomography (HRCT) images, (b) LUS examinations in control group, and (c) follow-up LUS examinations. Twenty children with PTI were enrolled. B-lines were found in all children with PTI and in 11 (55%) control subjects (P < .001). The total number of B-lines, the maximal number of B lines in any intercostal space, the distance between B-lines, and pleural thickness were significantly increased in children with PTI compared to controls. An irregularity of the pleural line was found in all patients with PTI and in none of the healthy children. There were no significant changes in LUS findings in patients with PTI during the study period. The comparison of HRCT indices and LUS findings revealed significant correlations between the mean lung attenuation, skewness, kurtosis and fraction of interstitial pulmonary involvement, and the number of B-lines as well as the pleural line thickness. LUS seems to be a promising diagnostic tool in children with PTI. Its inclusion in the diagnostic work-up may enable to reduce the number of costly, hazardous, and ionizing radiation-based imaging procedures.
    Keywords:  computed tomography; imaging techniques; neuroendocrine cell hyperplasia of infancy; pediatrics
    DOI:  https://doi.org/10.1002/ppul.24654
  535. Eur J Nutr. 2020 Jan 21.
    Sarcopenia in relation to nutrition and lifestyle factors among middle-aged and older Korean adults with obesity.
    Yoo S, Kim DY, Lim H.
      PURPOSE: To examine the prevalence of sarcopenic obesity (SO) and its association with nutrition and lifestyle factors.METHODS: Data from the 2008-2011 Korea National Health and Nutrition Examination Survey for 3937 Korean individuals aged 40 years or older with obesity defined by the modified Asia-Pacific criteria (BMI ≥ 25 kg/m2) were used. Sarcopenia was defined as an appendicular skeletal muscle mass divided by weight (%) of < 1 SD below the sex-specific mean for young adults. Logistic regression models were used for the associations controlling covariates.
    RESULTS: The prevalence of SO was 52.5%. The SO group had insufficient energy intake, protein, and antioxidant micronutrients, a lower overall dietary quality, a lower physical activity, and higher rates of negative psychological factors than the non-sarcopenic obesity group (p < 0.05). After controlling for covariates, having high mean adequacy ratio scores which was calculated by averaging the sum of the nutrient adequacy ratios had a 94% lower prevalence of SO in the older individuals. Low participation in aerobic exercises had a 74% higher prevalence of SO in the older aged group, and high participation in flexibility exercises had a 11% lower prevalence of SO in the middle-aged group. Interestingly, negative psychological factors were found only in the middle-aged adults with SO (p < 0.05).
    CONCLUSION: Sarcopenia was present in over half of the middle-aged and older Korean adults with obesity. Having high dietary quality, increased physical activity, and positive psychological health were associated with a low prevalence of SO.
    Keywords:  Dietary qualities; Lifestyles; Nutrition; Sarcopenia; Sarcopenic obesity
    DOI:  https://doi.org/10.1007/s00394-020-02179-3
  536. Cancer. 2020 Jan 22.
    A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors.
    Santana VM, Sahr N, Tatevossian RG, Jia S, Campagne O, Sykes A, Stewart CF, Furman WL, McGregor LM.
      BACKGROUND: The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors.METHODS: In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients.
    RESULTS: Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline.
    CONCLUSIONS: The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors.
    Keywords:  bevacizumab; clinical oncology; everolimus; pediatrics
    DOI:  https://doi.org/10.1002/cncr.32722
  537. Int J Mol Sci. 2020 Jan 22. pii: E734. [Epub ahead of print]21(3):
    Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica.
    Hoch E, Levy M, Hershfinkel M, Sekler I.
      Cellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely zinc transporters (ZnTs; SLC30) that shuttle Zn2+ efflux, and ZRT-IRT-like proteins (ZIPs; SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3- or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3- failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis enteropathica, a rare condition of Zn2+ deficiency.
    Keywords:  SLC39A; ZIP structure function; ZRT-IRT-like proteins, ZIP; Zinc Transporters, ZnT; zinc transport
    DOI:  https://doi.org/10.3390/ijms21030734
  538. Ann Hum Biol. 2020 Jan 23. 1-7
    Micronuclei frequency in peripheral blood lymphocytes of healthy subjects living in turin (North-Italy): contribution of body mass index, age and sex.
    Santovito A, Gendusa C.
      Background: Increased micronuclei (MNi) frequencies in human lymphocytes are an indicator of chromosome instability and could be influenced by different exogenous and endogenous factors. The increased exposure to environmental pollutants has led to the awareness of the necessity for constant monitoring of urban human populations.Aim: We evaluated the MNi frequency in a sample belonging to the non-occupationally exposed population of Turin (North-Western Italy). A possible effect of body mass index, age and sex on the genomic damage levels was also investigated.Subjects and Methods: The study included 150 subjects. MNi, nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) were scored in 1,000 lymphocytes per subject.Results: The MNi, NPBs and NBUDs average frequencies (‰ ± S.D.) were 7.19 ± 2.51, 1.65 ± 1.54 and 2.07 ± 1.76, respectively. Turin shows one of the highest MNi frequencies with respect to other Italian cities and European regions. A significant correlation was found between MNi, NPBs, NBUDs frequencies, age and body mass index.Conclusion: Baseline MNi frequency was established in a sample of a city, like Turin, exposed to high levels of environmental pollutants. We hope that the results of this study can be used as a stimulus for future biomonitoring programmes in other Italian and globally distributed cities.
    Keywords:  Environmental pollution; Italian population; genomic damage; genotoxicology
    DOI:  https://doi.org/10.1080/03014460.2020.1714728
  539. Eur Respir J. 2020 Jan;pii: 1902255. [Epub ahead of print]55(1):
    Can a better understanding of frailty improve the quality of life of patients with fibrotic interstitial lung diseases?
    Aguilaniu B.
      
    DOI:  https://doi.org/10.1183/13993003.02255-2019
  540. ACS Chem Biol. 2020 Jan 22.
    A Multimodal Ca(II) Responsive Near IR-MR Contrast Agent Exhibiting High Cellular Uptake.
    Adams CJ, Krueger R, Meade TJ.
      Ca(II) ions are critical for the proper function of neurons by contributing to synaptic signaling and regulating neuronal plasticity. Dysregulation of Ca(II) is associated with a number of pathologies that cause neurodegeneration, therefore the ability to monitor Ca(II) intracellularly is an important target for molecular imaging. Contrast-enhanced MR imaging is a promising modality for imaging changes in Ca(II) concentrations; however, the majority of Ca(II) responsive MR agents are limited to the extracellular space or hindered by poor cellular uptake. Here, we describe a new class of multimodal, bioresponsive Ca(II) magnetic resonance agents that are coupled to the NIR probe IR-783. This new design is based on previous generations of our Ca(II) MR agents but overcomes two significant challenges: 1) the presence of the NIR probe dramatically increases cellular uptake of the agent and 2) provides histological validation of the MR signal using NIR fluorescence imaging. IR-783 targets organic anion transporter polypeptides, and we demonstrate that the agents are not toxic in HT-22 or U-87 MG cells up to 20 μM. The cellular uptake of complex 1 was measured to be greater than 16 femtomoles per cell (where ~1 femtomole/cell is detectable in acquired MR images). Complex 1 is simultaneously detectable by both MR and NIR fluorescence imaging in vitro and is activated (turned on) by intracellular Ca(II) at concentrations between 1-10 μM.
    DOI:  https://doi.org/10.1021/acschembio.9b00638
  541. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19938. [Epub ahead of print]24(1): 396-408
    Long non-coding RNA FTX alleviates hypoxia/reoxygenation-induced cardiomyocyte injury via miR-410-3p/Fmr1 axis.
    Li L, Li L, Zhang YZ, Yang HY, Wang YY.
      OBJECTIVE: Long non-coding RNAs (lncRNAs) are involved in the development of myocardial ischemia/reperfusion (I/R) injury. In this study, we aimed to investigate the roles and underlying mechanisms of five prime to Xist (FTX) in myocardial I/R injury using cardiomyocyte hypoxia/reoxygenation (H/R) model.MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to determine the expression of FTX, microRNA-410-3p (miR-410-3p) and fragile X mental retardation 1 (Fmr1) mRNA. Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis were employed to evaluate cell proliferation and apoptosis, respectively. Western blot assay was conducted to examine the protein levels of apoptosis-associated factors and Fmr1. Specific kits were used to detect the levels of oxidative stress-associated factors. Dual-luciferase reporter assay was performed to verify the association between miR-410-3p and FTX or Fmr1.
    RESULTS: FTX was reduced in myocardial I/R injury patients' serum and H/R-stimulated H9c2 cells. FTX overexpression relieved cell damage caused by H/R treatment through inducing cell proliferation and repressing cell apoptosis and oxidative stress in H9c2 cells. FTX was a sponge for miR-410-3p and the impact of FTX overexpression on H/R-induced cell injury was abolished by miR-410-3p elevation in H9c2 cells. Fmr1 was identified as a target of miR-410-3p and Fmr1 knockdown reversed the effect on H/R-induced cell damage mediated by miR-410-3p inhibition in H9c2 cells. Moreover, FTX positively regulated Fmr1 expression through sponging miR-410-3p in H9c2 cells.
    CONCLUSIONS: FTX regulated H/R-induced cardiomyocyte damage by upregulating Fmr1 via sponging miR-410-3p.
    DOI:  https://doi.org/10.26355/eurrev_202001_19938
  542. Cortex. 2019 Dec 30. pii: S0010-9452(19)30435-6. [Epub ahead of print]125 30-43
    Alterations to dual stream connectivity predicts response to aphasia therapy following stroke.
    Iyer KK, Angwin AJ, Van Hees S, McMahon KL, Breakspear M, Copland DA.
      BACKGROUND: Predicting aphasia recovery is difficult due to a high variability in treatment response. Detailed measures of treatment response are compounded by a dearth of information that examine brain connections that contribute to clinical improvement. In this study we measure alterations to cortical connectivity pathways during a therapy paradigm to detect whether key brain connections that contribute to language recovery can be detected prior to therapy.METHODS: We conducted a case-control trial with twenty-three adults including eight adults with chronic, post-stroke aphasia. Aphasia patients underwent 12 naming therapy sessions over 4 weeks, consisting of semantic and phonological treatment approaches. High-density electroencephalography (128 channel EEG) was measured prior to therapy and immediately following treatment in patients with aphasia. Analysis via a dynamic causal modelling (DCM) was used to assess which cortical connections significantly correlated with therapy response.
    RESULTS: Altered cortical responses in aphasia patients measured bilaterally in a dual stream DCM connectivity model were predictive of treatment-induced improvement in naming. Pre-treatment DCM coupling (i.e., strength of cortical connections) significant correlated with naming improvement for items treated with semantic therapy, as indicated by increased connection strengths between left inferior parietal lobule (LIPL) and inferior frontal gyrus (LIFG, r = .63, pFDR = .016). In particular, the mediating role of contralateral regions significantly influences overall treatment improvement in the latter stages of stroke recovery.
    CONCLUSIONS: Our findings identify a potential means to stratify larger cohorts of patients in neurorehabilitation settings into distinct treatments that are tailored to their individual language deficit.
    Keywords:  Dynamic causal modelling; High-density EEG; Naming treatment; Post-stroke aphasia; Stroke recovery
    DOI:  https://doi.org/10.1016/j.cortex.2019.12.017
  543. Prostate Int. 2019 Dec;7(4): 156-165
    The molecular targets of diclofenac differs from ibuprofen to induce apoptosis and epithelial mesenchymal transition due to alternation on oxidative stress management p53 independently in PC3 prostate cancer cells.
    Arisan ED, Akar RO, Rencuzogullari O, Obakan Yerlikaya P, Coker Gurkan A, Akın B, Dener E, Kayhan E, Palavan Unsal N.
      Background: Prostate cancer is the most common type of cancer among men. Studies showed that the regular use of nonsteroidal antiinflammatory drugs might reduce disease progression risk for prostate cancer patients with prostate cancer. We evaluated the effects of ectopic expression of p53 on the biological functions of ibuprofen and diclofenac.Materials and methods: For this purpose, We investigated cell death decision pathways related to survival and aggressive cellular phenotypes such as extrinsic/intrinsic apoptosis decision, Protein Kinase B/ Forkhead box O (AKT/FoxO) axis, mitogen-activated protein kinases (MAPKs), reactive oxygen species (ROS) generation, and EMT (epithelial mesenchymal transition) in wild type and p53 + PC3 prostate cancer cells.
    Results and Conclusions: Ibuprofen (1 mM) and diclofenac (250 μM) effectively induced cell cycle arrest and led to apoptosis via modulating both extrinsic and intrinsic pathways. However, diclofenac was the only drug to generate ROS intermediates. Diclofenac triggered a typical EMT process with downregulated E-cadherin and upregulated N-cadherin, vimentin, and Snail in PC3 cells, regardless of p53 expression. In conclusion, although both drugs are effective on cell death mechanism, only diclofenac caused EMT because of increased ROS generation independent of p53. On the other hand, ibuprofen could inhibit metastasis via upregulating E-cadherin. The biological targets of both nonsteroidal antiinflammatory drugs are different to highlight their role in cell survival and death axis.
    Keywords:  Apoptosis; Diclofenac; Epithelial mesenchymal transition; Ibuprofen; Nonsteroidal antiinflammatory drugs; Prostate cancer; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.prnil.2019.09.003
  544. J Appl Physiol (1985). 2020 Jan 23.
    Spinal AMP Kinase Activity Differentially Regulates Phrenic Motor Plasticity.
    Perim RR, Fields DP, Mitchell GS.
      Acute intermittent hypoxia (AIH) elicits phrenic motor plasticity via multiple, distinct cellular mechanisms. With moderate AIH, phrenic motor facilitation (pMF) requires Gq protein-coupled serotonin type 2 (5-HT2) receptor activation, ERK MAP kinase activity and new synthesis of brain derived neurotrophic factor. In contrast, severe AIH elicits pMF by an adenosine-dependent mechanism that requires EPAC, Akt and mammalian target of rapamycin (mTOR) activity, followed by new TrkB protein synthesis; this same pathway is also initiated by Gs protein-coupled serotonin 7 receptors (5-HT7). Since the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) inhibits mTOR-dependent protein synthesis, and mTOR signaling is necessary for 5-HT7 but not 5-HT2 receptor-induced pMF, we hypothesized that spinal AMPK activity differentially regulates pMF elicited by these distinct receptor subtypes. 5-HT2A (DOI hydrochloride) or 5HT7 (AS-19) receptor agonists were administered intrathecally at C4 (3 injections, 5-min intervals) while recording integrated phrenic nerve activity in anesthetized, vagotomized, paralyzed and ventilated rats. Consistent with our hypothesis, spinal AMPK activation with 2-deoxyglucose (2-DG) or metformin blocked 5-HT7, but not 5-HT2A receptor-induced pMF; in both cases, pMF inhibition was reversed by spinal administration of the AMPK inhibitor compound C. Thus, AMPK differentially regulates cellular mechanisms of serotonin-induced phrenic motor plasticity.
    Keywords:  AMPK; phrenic motor plasticity; serotonin receptors
    DOI:  https://doi.org/10.1152/japplphysiol.00546.2019
  545. Cancers (Basel). 2020 Jan 17. pii: E233. [Epub ahead of print]12(1):
    Elevated Expression of Lumican in Lung Cancer Cells Promotes Bone Metastasis through an Autocrine Regulatory Mechanism.
    Hsiao KC, Chu PY, Chang GC, Liu KJ.
      Background: The microarray analysis of whole-genome expression indicated that the gene encoding the protein lumican, which is associated with extracellular matrix (ECM) interaction, was highly expressed in osteotropic lung cancer cell lines with an enhanced capacity of bone metastasis. Methods: The expression of lumican in the osteotropic lung cancer cells was downregulated, and the in vitro migration, invasion, and adhesion of cancer cells to ECM components, and the in vivo bone metastasis capacity of these cells were examined. Exogenous lumican was provided to study the autocrine regulation mechanism of lumican in the bone metastasis of lung cancer cells. Results: Transfection with lumican-specific short hairpin RNA (shRNA) in the osteotropic lung cancer cells reduced the establishment of in vivo bone metastasis, but not lung metastasis. Reduction in the expression of lumican also decreased the attachment of lung osteotropic cancer cells to several components of the ECM and suppressed cell migration and invasion in vitro. Exogenous lumican restored these reduced capacities of lumican knockdown cells and promoted the seeding of lung cancer cells in the bone microenvironment. Conclusions: These results suggested that lumican promotes the metastasis of lung cancer cells to the bones via an autocrine regulatory mechanism, and blocking this interaction may provide a new therapeutic approach to reduce bone metastasis in cases of lung cancer.
    Keywords:  bone metastasis; lumican; lung cancer
    DOI:  https://doi.org/10.3390/cancers12010233
  546. Sci Rep. 2020 Jan 22. 10(1): 1003
    Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival.
    Granados-Soler JL, Bornemann-Kolatzki K, Beck J, Brenig B, Schütz E, Betz D, Junginger J, Hewicker-Trautwein M, Escobar HM, Nolte I.
      Feline mammary carcinomas (FMCs) are highly malignant. As the disease-free survival (DFS) and overall survival (OS) are short, prognostication is crucial. Copy-number variations (CNVs) analysis by next-generation sequencing serves to identify critical cancer-related genomic regions. Thirty-three female cats with FMCs were followed during two years after surgery. Tumours represented tubulopapillary and solid carcinomas encompassing six molecular subtypes. Regardless of the histopathological diagnosis, molecular subtypes showed important differences in survival. Luminal A tumours exhibited the highest DFS (p = 0.002) and cancer-specific OS (p = 0.001), and the lowest amount of CNVs (p = 0.0001). In contrast, basal-like triple-negative FMCs had the worst outcome (DFS, p < 0.0001; and OS, p < 0.00001) and were the most aberrant (p = 0.05). In the multivariate analysis, copy-number losses (CNLs) in chromosome B1 (1-23 Mb) harbouring several tumour-repressors (e.g. CSMD1, MTUS1, MSR1, DBC2, and TUSC3) negatively influenced DFS. Whereas, copy-number gains (CNGs) in B4 (1-29 Mb) and F2 (64-82.3 Mb) comprising epithelial to mesenchymal transition genes and metastasis-promoting transcription factors (e.g. GATA3, VIM, ZEB1, and MYC) negatively influenced DFS and cancer-specific OS. These data evidence an association between specific CNVs in chromosomes B1, B4 and F2, and poor prognosis in FMCs.
    DOI:  https://doi.org/10.1038/s41598-020-57942-7
  547. J Clin Invest. 2020 Jan 21. pii: 129635. [Epub ahead of print]
    Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.
    Ortiz-Munoz G, Yu MA, Lefrançais E, Mallavia B, Valet C, Tian JJ, Ranucci S, Wang KM, Liu Z, Kwaan N, Dawson D, Kleinhenz ME, Khasawneh FT, Haggie PM, Verkman AS, Looney MR.
      Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane regulator (CFTR) is mutated in CF and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets, and TRPC6, are what we believe to be novel therapeutic targets in the treatment of CF lung disease.
    Keywords:  Inflammation; Neutrophils; Platelets; Pulmonology
    DOI:  https://doi.org/10.1172/JCI129635
  548. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30034-6. [Epub ahead of print]
    The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension.
    Chowdhury B, Luu AZ, Luu VZ, Kabir MG, Pan Y, Teoh H, Quan A, Sabongui S, Al-Omran M, Bhatt DL, Mazer CD, Connelly KA, Verma S, Hess DA.
      Pulmonary arterial hypertension (PAH) is a rare, but progressive and devastating vascular disease with few treatment options to prevent the advancement to right ventricular dysfunction hypertrophy and failure. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, enhances urinary glucose excretion as well as reduces cardiovascular events and mortality in individuals with type 2 diabetes. While empagliflozin has been reported to lower systemic hypertension due to increased diuresis, the effect of empagliflozin on PAH is unknown. We used monocrotaline (MCT)-treated Sprague-Dawley rats to determine if empagliflozin alters PAH-associated outcomes. Compared to vehicle control, daily empagliflozin administration significantly improved survival in rats with severe MCT-induced PAH. Hemodynamic assessments showed that empagliflozin treatment significantly reduced mean pulmonary artery pressure, right ventricular systolic pressure, and increased pulmonary acceleration time. Empagliflozin treatment resulted in reduced right ventricular hypertrophy and fibrosis. Histological and molecular assessments of lung vasculature revealed significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles after empagliflozin treatment compared to vehicle-treated rats. In summary, SGLT2 inhibition with empagliflozin lowered mortality, reduced right ventricle systolic pressure, and attenuated maladaptive pulmonary remodeling in MCT-induced PAH. Clinical studies evaluating the efficacy of SGLT-2 inhibition should be considered for patients with PAH.
    Keywords:  Empagliflozin; Pulmonary arterial hypertension; Vascular remodeling
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.015
  549. Int J Cardiol. 2019 Dec 30. pii: S0167-5273(19)31854-6. [Epub ahead of print]
    Hyperglycemia-induced endothelial dysfunction is alleviated by thioredoxin mimetic peptides through the restoration of VEGFR-2-induced responses and improved cell survival.
    Hemling P, Zibrova D, Strutz J, Sohrabi Y, Desoye G, Schulten H, Findeisen H, Heller R, Godfrey R, Waltenberger J.
      BACKGROUND: Diabetes mellitus is an important cardiovascular risk factor characterized by elevated plasma glucose levels. High glucose (HG) negatively influences endothelial cell (EC) function, which is characterized by the inability of ECs to respond to vascular endothelial growth factor (VEGF-A) stimulation. We aimed to identify potential strategies to improve EC function in diabetes.METHODS AND RESULTS: Human umbilical cord endothelial cells (HUVECs) were subjected to hyperglycemic milieu by exposing cells to HG together with glucose metabolite, methylglyoxal (MG) in vitro. Hyperglycemic cells showed reduced chemotactic responses towards VEGF-A as revealed by Boyden chamber migration assays, indicating the development of "VEGF resistance" phenotype. Furthermore, HG/MG-exposed cells were defective in their general migratory and proliferative responses and were in a pro-apoptotic state. Mechanistically, the exposure to HG/MG resulted in reactive oxygen species (ROS) accumulation which is secondary to the impairment of thioredoxin (Trx) activity in these cells. Pharmacological and genetic targeting of Trx recapitulated VEGF resistance. Functional supplementation of Trx using thioredoxin mimetic peptides (TMP) reversed the HG/MG-induced ROS generation, improved the migration, proliferation, survival and restored VEGF-A-induced chemotaxis and sprouting angiogenesis of hyperglycemic ECs. Importantly, TMP treatment reduced ROS accumulation and improved VEGF-A responses of placental arterial endothelial cells isolated from gestational diabetes mellitus patients.
    CONCLUSIONS: Our findings suggest a putative role for Trx in modulating EC function and its functional impairment in HG conditions contribute to EC dysfunction. Supplementation of TMP could be used as a novel strategy to improve endothelial cell function in diabetes.
    Keywords:  Angiogenesis; Chemotaxis; Diabetes; Endothelial cells; Migration; Thioredoxin; VEGFR-2
    DOI:  https://doi.org/10.1016/j.ijcard.2019.12.065
  550. Mol Med Rep. 2020 Feb;21(2): 858-866
    ΜicroRNA‑421 participates in vitiligo development through regulating human melanocyte survival by targeting receptor‑interacting serine/threonine kinase 1.
    Sun X, Wang T, Huang B, Ruan G, Xu A.
      Vitiligo is a common localized or generalized skin pigmentation disorder. Endoplasmic reticulum (ER) stress may be implicated in the development of vitiligo. microRNA‑421 (miR‑421) has been reported to be dysregulated in various human tumors. However, there is no report to date on the role of miR‑421 in vitiligo development. The present study demonstrated that 3 µM tunicamycin (TM) increased the expression of the ER stress‑related proteins protein kinase RNA‑like endoplasmic reticulum kinase (PERK), α subunit of eukaryotic translation initiation factor 2 (eIF2α) and C/EBP homologous protein (CHOP) in human primary epidermal melanocytes. Moreover, TM suppressed melanocyte viability and induced apoptosis. Reverse transcription‑quantitative PCR analysis demonstrated that TM promoted miR‑421 expression in human melanocytes. Next, TargetScan and dual luciferase reporter gene assay indicated that receptor‑interacting serine/threonine kinase 1 (RIPK1) was a direct target of miR‑421. RIPK1 expression was significantly downregulated in TM‑induced human melanocytes. Subsequently, the effect of miR‑421 downregulation on the damage of human melanocytes induced by ER stress was investigated. Human melanocytes were transfected with inhibitor control, miR‑421 inhibitor, miR‑421 inhibitor + control‑short hairpin (sh)RNA, or miR‑421 inhibitor + RIPK1‑shRNA for 24 h and then treated with TM (3 µM) for 48 h. TM was found to upregulate PERK, eIF2α and CHOP protein expression in human melanocytes, which was reduced by an miR‑421 inhibitor. In addition, the miR‑421 inhibitor increased viability and reduced apoptosis in TM‑treated melanocytes. Furthermore, all these effects of the miR‑421 inhibitor on TM‑induced human melanocytes were reversed by RIPK1‑shRNA. Further analyses revealed that the miR‑421 inhibitor activated the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin signaling pathway in TM‑induced human melanocytes. These data collectively suggest that miR‑421 may serve as a new treatment target in vitiligo development.
    DOI:  https://doi.org/10.3892/mmr.2019.10878
  551. Magn Reson Imaging. 2020 Jan 21. pii: S0730-725X(19)30588-0. [Epub ahead of print]
    Repeatability of arterial input functions and kinetic parameters in muscle obtained by dynamic contrast enhanced MR imaging of the head and neck.
    Koopman T, Martens RM, Lavini C, Yaqub M, Castelijns JA, Boellaard R, Marcus JT.
      BACKGROUND: Quantification of pharmacokinetic parameters in dynamic contrast enhanced (DCE) MRI is heavily dependent on the arterial input function (AIF). In the present patient study on advanced stage head and neck squamous cell carcinoma (HNSCC) we have acquired DCE-MR images before and during chemo radiotherapy. We determined the repeatability of image-derived AIFs and of the obtained kinetic parameters in muscle and compared the repeatability of muscle kinetic parameters obtained with image-derived AIF's versus a population-based AIF.MATERIALS AND METHODS: We compared image-derived AIFs obtained from the internal carotid, external carotid and vertebral arteries. Pharmacokinetic parameters (ve, Ktrans, kep) in muscle-located outside the radiation area-were obtained using the Tofts model with the image-derived AIFs and a population averaged AIF. Parameter values and repeatability were compared. Repeatability was calculated with the pre- and post-treatment data with the assumption of no DCE-MRI measurable biological changes between the scans.
    RESULTS: Several parameters describing magnitude and shape of the image-derived AIFs from the different arteries in the head and neck were significantly different. Use of image-derived AIFs led to higher pharmacokinetic parameters compared to use of a population averaged AIF. Median muscle pharmacokinetic parameters values obtained with AIFs in external carotids, internal carotids, vertebral arteries and with a population averaged AIF were respectively: ve (0.65, 0.74, 0.58, 0.32), Ktrans (0.30, 0.21, 0.13, 0.06), kep (0.41, 0.32, 0.24, 0.18). Repeatability of pharmacokinetic parameters was highest when a population averaged AIF was used; however, this repeatability was not significantly different from image-derived AIFs.
    CONCLUSION: Image-derived AIFs in the neck region showed significant variations in the AIFs obtained from different arteries, and did not improve repeatability of the resulting pharmacokinetic parameters compared with the use of a population averaged AIF. Therefore, use of a population averaged AIF seems to be preferable for pharmacokinetic analysis using DCE-MRI in the head and neck area.
    Keywords:  Arterial input function; Dynamic contrast enhanced; Head and neck; Quantitative; Repeatability; Tracer kinetic modeling
    DOI:  https://doi.org/10.1016/j.mri.2020.01.010
  552. Curr Opin Chem Biol. 2020 Jan 21. pii: S1367-5931(19)30149-8. [Epub ahead of print]56 42-50
    Whole-genome mapping of small-molecule targets for cancer medicine.
    Solier S, Müller S, Rodriguez R.
      Cancers display intratumoral and intertumoral heterogeneity, which poses challenges to small-molecule intervention. Studying drug responses on a whole-genome and transcriptome level using next-generation sequencing has revolutionized our understanding of how small molecules intervene in cells, which helps us to study and potentially predict treatment outcomes. Some small molecules act directly at the genomic level by targeting DNA or chromatin proteins. Here, we review recent advances in establishing whole-genome and transcriptome maps of small-molecule targets, comprising chromatin components or downstream events. We also describe recent advances in studying drug responses using single-cell RNA and DNA sequencing. Furthermore, we discuss how this fundamental research can be taken forward to devise innovative personalized treatment modalities.
    Keywords:  Cancer; Chem-seq; ChiP-seq; NGS; RNA-seq; Sequencing; Small molecule
    DOI:  https://doi.org/10.1016/j.cbpa.2019.12.005
  553. Cell Death Dis. 2020 Jan 23. 11(1): 57
    Correction: Schwann cells support oncogenic potential of pancreatic cancer cells through TGFβ signaling.
    Roger E, Martel S, Bertrand-Chapel A, Depollier A, Chuvin N, Pommier RM, Yacoub K, Caligaris C, Cardot-Ruffino V, Chauvet V, Aires S, Mohkam K, Mabrut JY, Adham M, Fenouil T, Hervieu V, Broutier L, Castets M, Neuzillet C, Cassier PA, Tomasini R, Sentis S, Bartholin L.
      The original version of this article contained an error in the name of one of the co-authors (Kayvan Mohkam). This has been corrected in the PDF and HTML versions.
    DOI:  https://doi.org/10.1038/s41419-020-2262-1
  554. J Mol Cell Cardiol. 2020 Jan 20. pii: S0022-2828(20)30002-X. [Epub ahead of print]
    Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.
    Arsiwala T, Pahla J, van Tits LJ, Bisceglie L, Gaul DS, Costantino S, Miranda MX, Nussbaum K, Stivala S, Blyszczuk P, Weber J, Tailleux A, Stein S, Paneni F, Beer JH, Greter M, Becher B, Mostoslavsky R, Eriksson U, Staels B, Auwerx J, Hottiger MO, Lüscher TF, Matter CM.
      AIMS: Sirtuin 6 (Sirt6) is a NAD+-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model.METHODS AND RESULTS: Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe-/- mice fed a high-cholesterol diet for 12 weeks (n = 12-14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels.
    CONCLUSIONS: Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.
    Keywords:  Atherosclerosis; Foam cell; MSR1; SIRT6; oxLDL
    DOI:  https://doi.org/10.1016/j.yjmcc.2020.01.002
  555. ACS Appl Mater Interfaces. 2020 Jan 23.
    Engineering Shelf-Stable Coating for Microfluidic Organ-on-a-Chip using Bioinspired Catecholamine Polymers.
    Khetani S, Yong KW, Ozhukil Kollath V, Eastick E, Azarmanesh M, Karan K, Sen A, Sanati-Nezhad A.
      The conceptualization of body-on-a-chip in 2004 opened a new approach for studying human physiology in three-dimensional (3D) culture. Despite pioneering works, and the progress made in replicating human physiology on-a-chip, the stability, reliability, and preservation of cell-culture-treated microfluidic chips remains a challenge. The development of a reliable surface treatment technique to more efficiently and reproducibly modify microfluidic channels would significantly simplify the process of creating and implementing organ-on-a-chip (OOC)systems. In this work, a new flow-based coating technique using bio-inspired polymers was implemented to create reliable, reproducible, ready-to-use microfluidic cell culture chips for OOC studies. Single-channel polydimethylsiloxane (PDMS) microfluidic chips were coated with the bioinspired catecholamine polymers, polydopamine (PDA) and polynorepinephrine (PNE), using a flow-based coating technique. The functionality of resulting microfluidic chips was evaluated by extensive surface characterizations, at 130°C, in the presence of various cleaning and culture media in static and flow conditions regularly used in OOCs and tested for shelf life by storing the coated microfluidic chips for four months at room temperature. Microfluidic chips coated with polycatecholamine were then seeded with the mouse cancer cell line Cath.a.differentiated (CAD), and with the normal human cerebral microvascular endothelial cell line hCMEC/D3. Cell viability, cell phenotype, and cell functionality were assessed to evaluate the performance of both the coating and surface treatment technique. Both PDA- and PNE-coated microfluidic chips maintained high viability, phenotype, and functionality of CAD cells and hCMEC/D3 cells. In addition, CAD cells retained high viability when they were cultured in both the polymer-coated chips, which were stored at room temperature for up to 120 days. These results suggest that flow-based techniques to coat surfaces with polycatecholamines can be used to generate ready-to-use microfluidic OOC chips that offer long-term stability and reliability for the culture of cell types with application in pathophysiological studies and drug screening.
    DOI:  https://doi.org/10.1021/acsami.9b20826
  556. Biochem Pharmacol. 2020 Jan 16. pii: S0006-2952(20)30021-6. [Epub ahead of print] 113811
    OSU-A9 induced-reactive oxygen species cause cytotoxicity in duodenal and gastric cancer cells by decreasing phosphorylated nuclear pyruvate kinase M2 protein levels.
    Chiu CF, Weng JR, Lee SL, Wu CY, Chu PC, Shan YS, Yang HR, Bai LY.
      Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of pTyr105-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, pTyr105-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended in vivo, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear pTyr105-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer. Chemical compounds studies in this article: N-acetylcysteine (PubChem CID: 12035); Glutathione (PubChem CID: 124886); Dimethyl sulfoxide (PubChem CID: 679); Methylcellulose (PubChem CID: 44263857).
    Keywords:  OSU-A9; duodenal cancer; gastric cancer; glutathione; indole-3-carbinol; pyruvate kinase M2; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bcp.2020.113811
  557. Foods. 2020 Jan 22. pii: E117. [Epub ahead of print]9(2):
    Metabolic Profiling-Based Evaluation of the Fermentative Behavior of Aspergillus oryzae and Bacillus subtilis for Soybean Residues Treated at Different Temperatures.
    Hyeon H, Min CW, Moon K, Cha J, Gupta R, Park SU, Kim ST, Kim JK.
      Soybean processing, e.g., by soaking, heating, and fermentation, typically results in diverse metabolic changes. Herein, multivariate analysis-based metabolic profiling was employed to investigate the effects of fermentation by Aspergillus oryzae or Bacillus subtilis on soybean substrates extracted at 4, 25, or 55 °C. As metabolic changes for both A. oryzae and B. subtilis were most pronounced for substrates extracted at 55 °C, this temperature was selected to compare the two microbial fermentation strategies, which were shown to be markedly different. Specifically, fermentation by A. oryzae increased the levels of most organic acids, γ-aminobutyric acid, and glutamine, which were ascribed to carbohydrate metabolism and conversion of glutamic acid into GABA and glutamine. In contrast, fermentation by B. subtilis increased the levels of most amino acids and isoflavones, which indicated the high activity of proteases and β-glucosidase. Overall, the obtained results were concluded to be useful for the optimization of processing steps in terms of nutritional preferences.
    Keywords:  Aspergillus oryzae; Bacillus subtilis; extraction temperature; fermentation; metabolic profiling; multivariate analysis; soybean substrate
    DOI:  https://doi.org/10.3390/foods9020117
  558. Ann Thorac Surg. 2020 Jan 16. pii: S0003-4975(20)30011-4. [Epub ahead of print]
    Multiple Pulmonary Resections for Synchronous and Metachronous Lung Cancer at Two Chinese Centers (Commentary).
    Falcoz PE.
      
    DOI:  https://doi.org/10.1016/j.athoracsur.2019.11.032
  559. J Endocrinol. 2020 Jan 01. pii: JOE-19-0425.R1. [Epub ahead of print]
    miR-23b-3p acts as a counter-response against skeletal muscle atrophy.
    Okamura T, Hashimoto Y, Osaka T, Senmaru T, Fukuda T, Hamaguchi M, Fukui M.
      To investigate the role of microRNA in muscle atrophy, we performed microarray analysis of microRNA expression in skeletal muscles of Sham, orchiectomized (ORX) mice, and ORX mice treated with androgen and identified that the expression of miR-23b-3p in ORX mice was significantly higher than that in Sham mice (p = 0.007); however, miR-23b-3p expression in ORX mice treated with androgen was lower (p = 0.001). We also investigated the mechanism by which overexpression or knockdown of miR-23b-3p influences the expression of myosin heavy chain, muscle protein synthesis, ATP activity, and glucose uptake in C2C12 myotube cells. Moreover, we examined the serum miR-23b-3p levels among male subjects with type II diabetes and whether the serum miR-23b-3p levels could be a biomarker for muscle atrophy. The overexpression of miR-23b-3p in C2C12 myotube cells significantly upregulated the expression of myosin heavy chain, protein synthesis, ATP activity, and glucose uptake. Reporter assays raised a possible direct post-transcriptional regulation involving miR-23b-3p and the 3'-untranslated region of PTEN mRNA. Among subjects with type II diabetes, serum miR-23b-3p levels in the subjects with decreased muscle mass were significantly higher compared to the levels in the subjects without. Our results indicate that miR-23b-3p downregulates the expression of PTEN in myotube cells and induces the growth of myosin heavy chain. In addition, the serum level of miR-23b-3p can be used as a diagnostic marker for muscle atrophy.
    DOI:  https://doi.org/10.1530/JOE-19-0425
  560. BMC Gastroenterol. 2020 Jan 20. 20(1): 16
    The prognostic role of platelet-to-lymphocyte ratio on overall survival in gastric cancer: a systematic review and meta-analysis.
    Cao W, Yao X, Cen D, Zhi Y, Zhu N, Xu L.
      BACKGROUND: This study aimed to summarize the previously published literature on the role of platelet-to-lymphocyte ratio (PLR) on overall survival (OS) in patients with gastric cancer.METHODS: We systematically searched PubMed, EmBase, and the Cochrane library to identify eligible studies to review. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. Sensitivity and subgroup analyses were performed, and publication bias was assessed.
    RESULTS: A total of 28 studies comprising 15,617 patients with gastric cancer were included in this meta-analysis. The pooled results indicated that elevated PLR was associated with poor OS (HR: 1.37; 95% CI: 1.24-1.51; P < 0.001). A significant publication bias was observed (Egger test, P = 0.036; Begg test, P = 0.017). After adjusting for publication bias using the trim and fill method, an adjusted pooled HR of 1.19 (95% CI: 1.08-1.33; P = 0.001) was observed. Subgroup analyses indicated an elevated PLR in retrospective studies. Studies conducted in Turkey, the UK, the USA, and Costa Rica; studies with a sample size of < 1000, with < 70% male patients, and with patients treated with chemotherapy; studies with PLR cutoff value of ≥200; and studies with lower quality as determined by the Newcastle-Ottawa Scale all showed greater harmful effects on OS than their corresponding subsets (P < 0.05).
    CONCLUSIONS: An elevated PLR was associated with poor OS in patients with gastric cancer. These results might differ between studies due to differences in design, country of origin, sample size, sex proportion, treatment strategy, PLR cutoff value, and study quality.
    Keywords:  Blood platelets; Lymphocyte count; Meta-analysis; Prognosis; Stomach neoplasms
    DOI:  https://doi.org/10.1186/s12876-020-1167-x
  561. Biochem Pharmacol. 2020 Jan 21. pii: S0006-2952(20)30028-9. [Epub ahead of print] 113818
    Development of novel phosphodiesterase 5 inhibitors for the therapy of alzheimer's disease.
    Zuccarello E, Acquarone E, Calcagno E, Argyrousi EK, Deng SX, Landry DW, Arancio O, Fiorito J.
      Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer's disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acting on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target.
    Keywords:  Alzheimer's disease; Nitric oxide; Phosphodiesterase 5; Phosphodiesterase 5 Inhibitors; memory
    DOI:  https://doi.org/10.1016/j.bcp.2020.113818
  562. Free Radic Biol Med. 2020 Jan 20. pii: S0891-5849(19)31652-1. [Epub ahead of print]
    Increased mitochondrial content and function by resveratrol and select flavonoids protects against benzo[a]pyrene-induced bioenergetic dysfunction and ROS generation in a cell model of neoplastic transformation.
    Omidian K, Rafiei H, Bandy B.
      Dietary polyphenols act in cancer prevention and may inhibit carcinogenesis. A possible mitochondrial mechanism for carcinogen-induced neoplastic transformation and chemoprevention by polyphenols, however, is largely unexplored. Using the Bhas 42 cell model of carcinogen-induced neoplastic transformation, we investigated benzo[a]pyrene (B[a]P) along with different polyphenols for their effects on mitochondrial content and function, and on mitochondrial and intracellular ROS generation. Bhas 42 cells were either co-treated with 5 μM polyphenol starting 2 h before exposure to 4 μM B[a]P for 24 or 72 h, or pre-treated with polyphenol for 24 h and removed prior to B[a]P exposure. Exposure to B[a]P decreased mitochondrial content (by 46% after 24 h and 30% after 72 h), decreased mitochondrial membrane potential and cellular ATP, and increased generation of mitochondrial superoxide and intracellular ROS. Polyphenol co-treatments protected against the decreased mitochondrial content, with resveratrol being the most effective (increasing the mitochondrial content after 72 h by 75%). Measurements after 24 h of mRNA for mitochondria-related proteins and of SIRT1 enzyme activity suggested an involvement of increased mitochondrial biogenesis in the polyphenol effects. The polyphenol co-treatments also ameliorated B[a]P-induced deficits in mitochondrial function (most strongly resveratrol), and increases in generation of mitochondrial superoxide and intracellular ROS. Notably, 24 h pre-treatments with polyphenols strongly suppressed subsequent B[a]P-induced increases, after 24 and 72 h, in mitochondrial superoxide and intracellular ROS generation, with resveratrol being the most effective. In conclusion, the results support a mechanism for B[a]P carcinogenesis involving impaired mitochondrial function and increased mitochondria-derived ROS, that can be ameliorated by dietary polyphenols. The evidence supports an increase in mitochondrial biogenesis behind the strong chemoprevention by resveratrol, and a mitochondrial antioxidant effect in chemoprevention by quercetin.
    Keywords:  Benzo[a]pyrene carcinogenesis; Bioenergetic dysfunction; Cancer prevention; Dietary polyphenols; Mitochondrial and intracellular ROS generation; Mitochondrial biogenesis; Quercetin; Resveratrol
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.01.021
  563. J Thorac Cardiovasc Surg. 2019 Dec 21. pii: S0022-5223(19)39871-X. [Epub ahead of print]
    Commentary: Ex vivo lung perfusion plus solute adsorption: An exorcism of evil humors?
    Glenn IC, Raja S.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.12.009
  564. Mol Med Rep. 2020 Feb;21(2): 822-832
    High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma.
    Li H, Li X, Lin H, Gong J.
      Histone deacetylase 9 (HDAC9) is involved in a variety of malignant tumors, and leads to malignant tumor development and poor prognosis. However, the association between HDAC9 expression, and the prognosis and clinicopathological features of patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. The present study used reverse transcription‑quantitative PCR, western blotting and immunohistochemistry to detect the expression level of HDAC9 in PDAC tumors and cell lines. The Kaplan‑Meier method and Pearson's χ2 test were applied to evaluate the prognostic impact of HDAC9. The present study investigated the effect of HDAC9 on the biological function of PDAC cells. The present results indicated that HDAC9 was highly expressed in PDAC tissue and PDAC cell lines (P<0.05). HDAC9 expression level in tumor tissues was negatively associated with tumor size (P=0.026), T stage (P=0.014) and N stage (P=0.004). Kaplan‑Meier analysis suggested that patients with high HDAC9 had shorter recurrence‑free survival (RFS; P=0.017) and disease‑specific survival (DSS; P=0.022). Moreover, the present results suggested that T stage, N stage and HDAC9 expression level were independent predictive factors for RFS and DSS in patients with PDAC. In addition, silencing HDAC9 significantly inhibited the proliferation and migration of PDAC cells. The present results indicated that high expression levels of HDAC9 were associated with tumor progression and poor prognosis; thus, HDAC9 may serve as a prognostic predictor of PDAC.
    DOI:  https://doi.org/10.3892/mmr.2019.10869
  565. Mol Plant. 2020 Jan 18. pii: S1674-2052(20)30006-X. [Epub ahead of print]
    bHLH121 Functions as A Direct Link that Facilitates the Activation of FIT by bHLH IVc Transcription Factors for Maintaining Fe Homeostasis in Arabidopsis.
    Lei R, Li Y, Cai Y, Li C, Pu M, Lu C, Yang Y, Liang G.
      Iron (Fe) deficiency is prevalent in plants grown in neutral or alkaline soil. Plants have evolved sophisticated mechanisms that regulate Fe homeostasis, ensuring survival. In Arabidopsis FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) is a crucial regulator of Fe deficiency response. FIT is activated indirectly by bHLH IVc transcription factors (TFs) under Fe deficiency; however, it remains unclear which protein(s) act as a linker to mediate the activation of FIT by bHLH IVc TFs. In this study, we characterize the functions of bHLH121 and demonstrate that it directly associates with the FIT promoter. We found that loss-of-function mutations of bHLH121 cause severe Fe deficiency symptoms, reduced Fe accumulation, and disrupted expression of genes associated with Fe homeostasis. Genetic analysis showed that FIT is epistatic to bHLH121 and FIT overexpression partially rescues the bhlh121 mutant. Further investigation revealed, that bHLH IVc TFs interact with and promote nuclear accumulation of bHLH121. bHLH121 has DNA-binding function and can bind the promoters of FIT and bHLH Ib genes, but we did not find that it has either direct transcriptional activation or repression activity toward FIT and bHLH Ib genes. Meanwhile, we found that bHLH121 functions downstream of and is a direct target of bHLH IVc TFs, and its expression is induced by Fe deficiency in a bHLH IVc-dependent manner. Taken together, these results establish a direct link that bHLH121 functions together with bHLH IVc TFs to mediate the activation of FIT and thus plays a pivotal role in maintaining Fe homeostasis in Arabidopsis.
    Keywords:  Arabidopsis; FIT; bHLH IVc; bHLH Ib; bHLH121; iron uptake
    DOI:  https://doi.org/10.1016/j.molp.2020.01.006
  566. J Anxiety Disord. 2020 Jan 17. pii: S0887-6185(20)30006-2. [Epub ahead of print]70 102192
    Family accommodation of anxiety in a community sample of children on the autism spectrum.
    Adams D, Emerson LM.
      Anxiety is recognised as one of the most common co-occurring conditions for individuals with a diagnosis on the autism spectrum, with approximately 40 % of children on the spectrum receiving a clinical diagnosis of an anxiety disorder. To date, research has tended to focus upon understanding presentation and evaluating treatment, with little focus on assessing systemic factors, such as the way that family members accommodate the anxiety. This study aimed to investigate the relationship between parent and child anxiety levels and child autism characteristics on the four domains of family accommodation; Participation, Modification, Distress, and Consequence. A community sample (n = 132) of parents of children on the spectrum completed questionnaires on their child's autism characteristics and anxiety symptomatology as well as their own levels of anxiety and family accommodation behaviours. Regression models identified specific aspects of child anxiety as well as parent anxiety as predictive of family accommodation, with the child's difficulties with uncertainty being a consistent predictor of all four domains. Clinical and research implications of this study, including the importance of understanding similarities or differences in the nature and consequence of family accommodation in children on the autism spectrum, are discussed.
    Keywords:  Anxiety; Autism; Family accommodation; Intolerance of uncertainty; Mental health; Parenting
    DOI:  https://doi.org/10.1016/j.janxdis.2020.102192
  567. Mar Biotechnol (NY). 2020 Jan 21.
    Effects of Starvation on Antioxidant-Related Signaling Molecules, Oxidative Stress, and Autophagy in Juvenile Chinese Perch Skeletal Muscle.
    Wu P, Wang A, Cheng J, Chen L, Pan Y, Li H, Zhang Q, Zhang J, Chu W, Zhang J.
      The autophagic lysosomal protein degradation pathway is an evolutionarily conserved pathway, which utilizes lysosomes to degrade and to circulate cell components. Autophagy has been observed in many different types of cells, but its role in skeletal muscle protein degradation has not been thoroughly studied, especially in aquatic species. This study assessed the expression of antioxidant-related signaling genes and the effects of starvation on antioxidant capacity, reactive oxygen species (ROS) content, autophagy-related gene, and autophagosome formation in the skeletal muscle of juvenile Chinese perch after short-term starvation. The results indicated that after starvation for 2 days, the expression of antioxidant-related signaling genes, such as Nrf2 and S6K, was upregulated, while Keap1 was downregulated in the muscle of juvenile Chinese perch. The amounts of antioxidant enzymes ROS, MDA, AHRFR, and ASA and the activities of SOD, CAT, GPx, and GST were increased, and the mRNA levels of GPx, GSTA, GST4A, GSTT1, MnSOD, ZnSOD, and CAT were upregulated. Meanwhile, there was no significant change in the level of LC3-II protein. When starvation was prolonged to 5 days, Nrf2 and S6K1 continued to increase and mTOR and Keap1 significantly decreased; ROS and ASA content continued to be significantly increased, but the MDA and AHRFR content and the SOD, CAT GR, and GPx activities all decreased. The expression of MnSOD, ZnSOD, and GR decreased significantly, and GST4A, GSTT1, and CAT tended to decrease to levels consistent with normal feeding. The expression of all autophagy-related genes except Ulk1 significantly increased, the formation of autophagosomes and autolysosomes was enhanced in muscle, and LC3 protein levels in muscle increased significantly. Our data suggested that the autophagy that occurs in the skeletal muscle tissue of Chinese perch due to dietary deprivation is involved in a series of molecular and physiological responses, including changes in antioxidant signaling molecules, in antioxidant capacity and in autophagy and autophagy-related gene expression.
    Keywords:  Antioxidant capacity; Antioxidant signal molecules; Autophagy; Chinese perch skeletal muscle; ROS; Starvation
    DOI:  https://doi.org/10.1007/s10126-019-09933-7
  568. Clin Diabetes Endocrinol. 2020 ;6 2
    Achieving postprandial glucose control with lixisenatide improves glycemic control in patients with type 2 diabetes on basal insulin: a post-hoc analysis of pooled data.
    Davidson JA, Stager W, Paranjape S, Berria R, Leiter LA.
      Background: To examine the impact on glycemic control of achieving postprandial glucose (PPG) target with lixisenatide, a once-daily glucagon-like peptide-1 receptor agonist approved in the US, in patients with uncontrolled type 2 diabetes (T2D) on basal insulin, an agent that primarily targets fasting plasma glucose.Methods: A post hoc pooled analysis was conducted using clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L (NCT00715624), GetGoal-Duo 1 (NCT00975286) and GetGoal-L Asia trials (NCT00866658).
    Results: Data from 587 lixisenatide-treated patients and 484 placebo-treated patients were included. Patients on lixisenatide were more likely to achieve a PPG target of < 10 mmol/L (< 180 mg/dL) than placebo-treated patients (P < 0.001), regardless of baseline fasting plasma glucose (FPG) levels. More importantly, those who reached the PPG target experienced a significantly greater reduction in mean HbA1c, were more likely to achieve HbA1c target of < 53 mmol/mol (< 7.0%), and experienced weight loss. Those outcomes were achieved with no significant differences in the risk of symptomatic hypoglycemia compared with placebo.
    Conclusion: Compared with placebo, addition of lixisenatide to basal insulin improved HbA1c and reduced PPG, without increasing hypoglycemia risk. These findings highlight the importance of PPG control in the management of T2D, and provide evidence that adding an agent to basal insulin therapy that also impacts PPG has therapeutic value for patients who are not meeting glycemic targets.
    Trial registration: NCT00715624. Registered 15 July 2008, NCT00975286. Registered 11 September 2009, NCT00866658. Registered 20 March 2009.
    Keywords:  Glucagon-like peptide-1 receptor; Glycemic targets; Lixisenatide; Post-prandial glucose; Type 2 diabetes
    DOI:  https://doi.org/10.1186/s40842-019-0088-5
  569. J Hazard Mater. 2020 Jan 09. pii: S0304-3894(20)30047-9. [Epub ahead of print]388 122061
    Hydrogen sulfide (H2S) and nitric oxide (NO) alleviate cobalt toxicity in wheat (Triticum aestivum L.) by modulating photosynthesis, chloroplastic redox and antioxidant capacity.
    Ozfidan-Konakci C, Yildiztugay E, Elbasan F, Kucukoduk M, Turkan I.
      The role of hydrogen sulfide (H2S)/nitric oxide (NO) in mitigating stress-induced damages has gained interest in the past few years. However, the protective mechanism H2S and/or NO has towards the chloroplast system through the regulation of redox status and activation of antioxidant capacity in cobalt-treated wheat remain largely unanswered. Triticum aestivum L. cv. Ekiz was treated with alone/in combination of a H2S donor (sodium hydrosulfide (NaHS,600μM)), a NO donor (sodium nitroprusside (SNP,100μM)) and a NO scavenger (rutin hydrate (RTN,50μM)) to assess how the donors affect growth, water relations, redox and antioxidant capacity in chloroplasts, under cobalt (Co) concentrations of 150-300 μM. Stress decreased a number of parameters (growth, water content (RWC), osmotic potential (ΨΠ), carbon assimilation rate, stomatal conductance, intercellular CO2 concentrations, transpiration rate and the transcript levels of rubisco, which subsequently disrupt the photosynthetic capacity). However, SNP/NaHS counteracted the negative effects of stress on these aforementioned parameters and RTN application with stress/non-stress was reversed these effects. Hydrogen peroxide (H2O2) and TBARS were induced under stress in spite of activated ascorbate peroxidase (APX). SNP/NaHS under stress increased activation of superoxide dismutase (SOD), peroxidase (POX), APX, glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), ascorbate (tAsA) and glutathione (GSH). In conclusion, NaHS/SNP are involved in the regulation and modification of growth, water content, rubisco activity and up-regulation of ascorbate-glutathione cycle (AsA-GSH) in chloroplast under stress.
    Keywords:  Antioxidant enzyme; Chloroplast; Hydrogen sulfide; Nitric oxide; Triticum aestivum
    DOI:  https://doi.org/10.1016/j.jhazmat.2020.122061
  570. Curr Med Imaging Rev. 2019 ;15(2): 150-160
    Review on 2D and 3D MRI Image Segmentation Techniques.
    Shirly S, Ramesh K.
      BACKGROUND: Magnetic Resonance Imaging is most widely used for early diagnosis of abnormalities in human organs. Due to the technical advancement in digital image processing, automatic computer aided medical image segmentation has been widely used in medical diagnostics.DISCUSSION: Image segmentation is an image processing technique which is used for extracting image features, searching and mining the medical image records for better and accurate medical diagnostics. Commonly used segmentation techniques are threshold based image segmentation, clustering based image segmentation, edge based image segmentation, region based image segmentation, atlas based image segmentation, and artificial neural network based image segmentation.
    CONCLUSION: This survey aims at providing an insight about different 2-Dimensional and 3- Dimensional MRI image segmentation techniques and to facilitate better understanding to the people who are new in this field. This comparative study summarizes the benefits and limitations of various segmentation techniques.
    Keywords:  2-dimensional; 3- dimensional image segmentation; Magnetic resonance imaging; image processing; image segmentation
    DOI:  https://doi.org/10.2174/1573405613666171123160609
  571. Thorac Cancer. 2020 Jan 23.
    Treatment outcome and clinical characteristics of HER2 mutated advanced non-small cell lung cancer patients in China.
    Fei Xu , Yang G, Xu H, Yang L, Qiu W, Wang Y.
      BACKGROUND: HER2 mutation is found in 1%-2% of lung cancer patients. Studies comparing chemotherapy to HER2-TKIs are limited. This study aimed to investigate the molecular and clinical patterns of HER2 mutations in advanced non-small cell lung cancer (NSCLC), and compare the different outcomes between chemotherapy and HER2-TKIs.METHODS: Advanced or recurrent non-small cell lung cancer patients with de novo HER2 mutations (N = 75) were included in this study. Molecular information, clinical features, and treatment outcomes were retrospectively collected from a web-based patient registry and hospital chart review.
    RESULTS: Between October 2012 and December 2018, 65 patients with in-frame insertion mutations, eight with point mutations and two with gene amplification were found. The most common subtypes of insertion mutations were A775_G776insYVMA, G776delinsVC, and V777_G778insGSP. HER2 mutated patients were mostly young-aged, females, never or light smokers, with adenocarcinoma. Chemotherapy achieved better outcomes than HER2-TKIs (median PFS: 5.5 vs. 3.7 months in the first-line setting and 4.2 vs. 2.0 months in the second-line setting, P = 0.001 and 0.031, respectively). In particular for the most common subtype, YVMA insertions, PFS was significantly longer in chemotherapy than HER2-TKIs both in the first-line (6.0 vs. 2.6 months, P = 0.008) and the second-line (4.2 vs. 2.6 months P < 0.001).
    CONCLUSIONS: HER2 mutated lung cancer patients were younger, mostly females, never or light smokers, with histologically diagnosed adenocarcinomas. Compared with afatinib, chemotherapy might bring more benefit to HER2 mutated advanced lung cancer patients, especially the most common type of HER2 exon 20 insertions, A775_G776insYVMA subtype.
    KEY POINTS: Chemotherapy achieved better outcomes than afatinib for Chinese HER2 mutated advanced NSCLC patients, especially for the most common subtype, YVMA insertions.
    Keywords:  Chemotherapy; HER2/ERBB2 mutation; non-small cell lung cancer; targeted therapy
    DOI:  https://doi.org/10.1111/1759-7714.13317
  572. J Biosci. 2020 ;pii: 9. [Epub ahead of print]45
    Mining histone methyltransferases and demethylases from whole genome sequence.
    Gulati P, Kohli S, Narang A, Brahmachari V.
      Epigenetic regulation through post-translational modification of histones, especially methylation, is well conserved in evolution. Although there are several insect genomes sequenced, an analysis with a focus on their epigenetic repertoire is limited. We have utilized a novel work-flow to identify one or more domains as highpriority domain (HPD), if present in at least 50% of the genes of a given functional class in the reference genome, namely, that of Drosophila melanogaster. Based on this approach, we have mined histone methyltransferases and demethylases from the whole genome sequence of Aedes aegypti (Diptera), the pea aphid Acyrthosiphon pisum, the triatomid bug Rhodnius prolixus (Hemiptera), the honeybee Apis mellifera (Hymenoptera), the silkworm Bombyx mori (Lepidoptera) and the red flour beetle Tribolium castaneum (Coleoptera). We identified 38 clusters consisting of arginine methyltransferases, lysine methyltransferases and demethylases using OrthoFinder, and the presence of HPD was queried in these sequences using InterProScan. This approach led us to identify putative novel members and currently inaccurate ones. Other than the highpriority domains, these proteins contain shared and unique domains that can mediate protein-protein interaction. Phylogenetic analysis indicates that there is different extent of protein sequence similarity; average similarity between histone lysine methyltransferases varies from 41% (for active mark) to 48% (for repressive mark), arginine methyltransferases is 51%, and demethylases is 52%. The method utilized here facilitates reliable identification of desired functional class in newly sequenced genomes.
  573. Behav Anal Pract. 2019 Sep;12(3): 654-666
    Compassionate Care in Behavior Analytic Treatment: Can Outcomes be Enhanced by Attending to Relationships with Caregivers?
    Taylor BA, LeBlanc LA, Nosik MR.
      The practice of behavior analysis has become a booming industry with growth to over 30,000 Board Certified Behavior Analysts (BCBAs) who primarily work with children with autism and their families. Most of these BCBAs are relatively novice and have likely been trained in graduate programs that focus primarily on conceptual and technical skills. Successfully working with families of children with autism, however, requires critical interpersonal skills, as well as technical skills. As practitioners strive to respond efficiently and compassionately to distressed families of children with autism, technical skills must be balanced with fluency in relationship-building skills that strengthen the commitment to treatment. The current article provides an outline of important therapeutic relationship skills that should inform the repertoire of any practicing behavior analyst, strategies to cultivate and enhance those skills, and discussion of the potential effects of relationship variables on treatment outcomes.
    Keywords:  Autism; Collaboration; Compassion; Empathy; Family; Parents; Perspective taking; Therapeutic relationship
    DOI:  https://doi.org/10.1007/s40617-018-00289-3
  574. Comp Biochem Physiol C Toxicol Pharmacol. 2020 Jan 15. pii: S1532-0456(20)30009-0. [Epub ahead of print]230 108709
    Effects of low salinity on gill and liver glycogen metabolism of great blue-spotted mudskippers (Boleophthalmus pectinirostris).
    Guo T, Yang Y, Meng F, Wang S, Xia S, Qian Y, Li M, Wang R.
      This study investigated the effects of low salinity exposure on glycogen and its metabolism biomarkers, glycogen synthase (GS) and glycogen phosphorylase (GP), representing glycogen synthesis and catabolism, respectively, in the gills and liver of great blue-spotted mudskippers (Boleophthalmus pectinirostris). The fish were accumulated at 10‰ salinity seawater for 1 week, then 270 healthy great blue-spotted mudskippers with similar size were randomly transferred to 10‰ (control group) or 3‰ (low salinity group) seawater for 72-hour stress experiment. Fish significantly elevated their blood glucose levels 12 h after low salinity challenge. At the end of experiments, a decrease in liver glycogen contents was observed in both the control and low salinity groups, the latter showing a pronounced decrease, while the gill glycogen contents were not changed for either group. The mRNA abundance and enzyme activity of GS and GP were both elevated in gill tissues, showing a rising glycogen synthesis and catabolism, probably resulting in the unchanging gill glycogen content. While in liver tissues, the mRNA abundance and enzyme activity were decreased for GS and increased for GP, showing a net increase for breaking down glycogen in liver, probably for supplying a sufficient glucose level for gills and other tissues/organs involved in the response to salinity changes.
    Keywords:  Glycogen metabolism; Glycogen phosphorylase; Glycogen synthase; Great blue-spotted mudskippers; Low salinity stress
    DOI:  https://doi.org/10.1016/j.cbpc.2020.108709
  575. Hosp Pract (1995). 2020 Jan 24.
    The role of steroids in severe CAP.
    Nora D, Nedel W, Lisboa T, Salluh J, Póvoa P.
      Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality despite adequate antibiotic therapy. It is the single most common cause of infection-related mortality in the United States. An exaggerated host inflammatory response can potentially be harmful to both the lung and host, and has been associated with treatment failure and mortality. Modulation of inflammatory response may therefore be theoretically beneficial. The anti-inflammatory and immunosuppressive effects of steroids seem an attractive therapeutic option in severe CAP patients. Available data point to overall shorter time to clinical stability and decreased length-of-stay in CAP patients, with a potential mortality benefit in severe CAP. The level of evidence is, however, low to moderate regarding mortality due to high heterogeneity and insufficient power of data. Furthermore, steroids were deleterious in influenza pneumonia and in patients with pneumococcal pneumonia data suggest lack of efficacy and potential harm. Both European and American guidelines recommend not using corticosteroids in CAP. Patients who might benefit and those that can be harmed from steroids remain to be clearly identified, as does the ideal steroid for CAP patients, based on pharmacokinetic and pharmacodynamic properties. It is essential for future studies to avoid the same methodological bias present in the available data so that high-quality evidence on the true role of steroids in CAP can be provided.
    Keywords:  community-acquired pneumonia; mortality; outcomes; steroids
    DOI:  https://doi.org/10.1080/21548331.2020.1720215
  576. Sci Rep. 2020 Jan 21. 10(1): 799
    Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1.
    Ruggeberg KG, O'Sullivan P, Kovacs TJ, Dawson K, Capponi VJ, Chan PP, Golobish TD, Gruda MC.
      Mycotoxins, such as aflatoxin B1 (AFB1), pose a serious threat as biological weapons due to their high toxicity, environmental stability, easy accessibility and lack of effective therapeutics. This study investigated if blood purification therapy with CytoSorb (CS) porous polymer beads could improve survival after a lethal aflatoxin dose (LD90). The effective treatment window and potential therapeutic mechanisms were also investigated. Sprague Dawley rats received a lethal dose of AFB1 (0.5-1.0 mg/kg) intravenously and hemoperfusion with a CS or Control device was initiated immediately, or after 30, 90, or 240-minute delays and conducted for 4 hours. The CS device removes AFB1 from circulation and significantly improves survival when initiated within 90 minutes of toxin administration. Treated subjects exhibited improved liver morphology and health scores. Changes in the levels of cytokines, leukocytes and platelets indicate a moderately-severe inflammatory response to acute toxin exposure. Quantitative proteomic analysis showed significant changes in the level of a broad spectrum of plasma proteins including serine protease/endopeptidase inhibitors, coagulation factors, complement proteins, carbonic anhydrases, and redox enzymes that ostensibly contribute to the therapeutic effect. Together, these results suggest that hemoadsorption with CS could be a viable countermeasure against acute mycotoxin exposure.
    DOI:  https://doi.org/10.1038/s41598-020-57727-y
  577. Pathol Oncol Res. 2020 Jan 21.
    Correction to: Caveolin-1 Expression Together with VEGF can be a Predictor for Lung Metastasis and Poor Prognosis in Osteosarcoma.
    Mohamed FEA, Khalil EZI, Toni NDM.
      The original version of this article unfortunately contained an error. The Tables 1 and 2 were missing in the published paper.
    DOI:  https://doi.org/10.1007/s12253-019-00790-2
  578. Eur J Nucl Med Mol Imaging. 2020 Jan 20.
    Direct prospective comparison of 18F-FDG PET and arterial spin labelling MR using simultaneous PET/MR in patients referred for diagnosis of dementia.
    Ceccarini J, Bourgeois S, Van Weehaeghe D, Goffin K, Vandenberghe R, Vandenbulcke M, Sunaert S, Van Laere K.
      PURPOSE: 18F-FDG PET is routinely used as an imaging marker in the early and differential diagnosis of dementing disorders and has incremental value over the clinical neurological and neuropsychological evaluation. Perfusion MR imaging by means of arterial spin labelling (ASL) is an alternative modality to indirectly measure neuronal functioning and could be used as complement measurement in a single MR session in the workup of dementia. Using simultaneous PET-MR, we performed a direct head-to-head comparison between enhanced multiplane tagging ASL (eASL) and 18F-FDG PET in a true clinical context of subjects referred for suspicion of neurodegenerative dementia.METHODS: Twenty-seven patients underwent a 20-min 18F-FDG PET/MR and simultaneously acquired eASL on a GE Signa PET/MR. Data were compared with 30 screened age- and gender-matched healthy controls. Both integral eASL and 18F-FDG datasets were analysed visually by two readers unaware of the final clinical diagnosis, either in normal/abnormal classes, or full differential diagnosis (normal, Alzheimer type dementia [AD], dementia with Lewy Bodies [LBD], frontotemporal dementia [FTD] or other). Reader confidence was assessed with a rating scale (range 1-4). Data were also analysed semiquantitatively by VOI and voxel-based analyses.
    RESULTS: The ground truth diagnosis for the patient group resulted in 14 patients with a neurodegenerative cognitive disorder (AD, FTD, LBD) and 13 patients with no arguments for an underlying neurodegenerative cause. Visual analysis resulted in equal specificity (0.70) for differentiating normal and abnormal cases between the two modalities, but in a higher sensitivity (0.93), confidence rating (0.64) and interobserver agreement for 18F-FDG PET compared with eASL. The same was true for assigning a specific differential diagnosis (sensitivity: and 0.39 for 18F-FDG PET and eASL, respectively). Semiquantitative analyses revealed prototypical patterns for AD and FTD, with both higher volumes of abnormality and intensity differences on 18F-FDG PET.
    CONCLUSION: In a direct head-to-head comparison on a simultaneous GE Signa PET/MR, 18F-FDG PET performed better compared with ASL in terms of sensitivity and reader confidence, as well as volume and intensity of abnormalities. However, using pure semiquantitative analysis, similar diagnostic accuracy between the two modalities was obtained. Therefore, ASL may still serve as complement to neuroreceptor or protein deposition PET studies when a single simultaneous investigation is warranted.
    Keywords:  18F-FDG PET; Arterial spin labelling (ASL) MRI; Brain imaging; Clinical setting; Dementia; PET/MR
    DOI:  https://doi.org/10.1007/s00259-020-04694-1
  579. Phytomedicine. 2019 Dec 16. pii: S0944-7113(19)30466-0. [Epub ahead of print]67 153150
    Flavonoids from Houttuynia cordata attenuate H1N1-induced acute lung injury in mice via inhibition of influenza virus and Toll-like receptor signalling.
    Ling LJ, Lu Y, Zhang YY, Zhu HY, Tu P, Li H, Chen DF.
      BACKGROUND: Influenza virus is one of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. Houttuynia cordata is a traditionally used medicinal plant for the treatment of pneumonia. Flavonoids are one of the major bioactive constituents of Houttuynia cordata.PURPOSE: This study was designed to investigate the therapeutic effect and mechanism of flavonoid glycosides from H. cordata on influenza A virus (IAV)-induced acute lung injury (ALI) in mice.
    METHODS: Flavonoids from H. cordata (HCF) were extracted from H. cordata and identified by high-performance liquid chromatography. Mice were infected intranasally with influenza virus H1N1 (A/FM/1/47). HCF (50, 100, or 200 mg/kg) or Ribavirin (100 mg/kg, the positive control) were administered intragastrically. Survival rates, life spans, weight losses, lung indexes, histological changes, inflammatory infiltration, and inflammatory markers in the lungs were measured. Lung virus titers and neuraminidase (NA) activities were detected. The expression of Toll-like receptors (TLRs) and levels of NF-κB p65 phosphorylation (NF-κB p65(p)) in the lungs were analysed. The effects of HCF on viral replication and TLR signalling were further evaluated in cells.
    RESULTS: HCF contained 78.5% flavonoid glycosides. The contents of rutin, hyperin, isoquercitrin, and quercitrin in HCF were 8.8%, 26.7%, 9.9% and 31.7%. HCF (50, 100 and 200 mg/kg) increased the survival rate and life span of mice infected with the lethal H1N1 virus. In H1N1-induced ALI, mice treated with HCF (50, 100 and 200 mg/kg) showed lesser weight loss and lower lung index than the model group. The lungs of HCF-treated ALI mice presented more intact lung microstructural morphology, milder inflammatory infiltration, and lower levels of monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) than in the model group. Further investigation revealed that HCF exerted antiviral and TLR-inhibitory effects in vivo and in vitro. HCF (50, 100 and 200 mg/kg) reduced lung H1N1 virus titers and inhibited viral NA activity in mice. HCF (100 and 200 mg/kg) elevated the levels of interferon-β in lungs. HCF also decreased the expression of TLR3/4/7 and level of NF-κB p65(p) in lung tissues. In vitro experiments showed that HCF (50, 100 and 200 μg/ml) significantly inhibited viral proliferation and suppressed NA activity. In RAW 264.7 cells, TLR3, TLR4, and TLR7 agonist-stimulated cytokine secretion, NF-κB p65 phosphorylation, and nuclear translocation were constrained by HCF treatment. Furthermore, among the four major flavonoid glycosides in HCF, hyperin and quercitrin inhibited both viral replication and TLR signalling in cells.
    CONCLUSION: HCF significantly alleviated H1N1-induced ALI in mice, which were associated with its dual antiviral and anti-inflammatory effects via inhibiting influenzal NA activity and TLR signalling. among the four major flavonoid glycosides in HCF, hyperin and quercitrin played key roles in the therapeutic effect of HCF.
    Keywords:  Acute lung injury; Antiviral activity; Flavonoid glycosides; Houttuynia cordata; Influenza A virus; TLRs signalling
    DOI:  https://doi.org/10.1016/j.phymed.2019.153150
  580. Cancers (Basel). 2020 Jan 16. pii: E218. [Epub ahead of print]12(1):
    Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer.
    Sritangos P, Pena Alarcon E, James AD, Sultan A, Richardson DA, Bruce JIE.
      Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca2+ ([Ca2+]i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.
    Keywords:  apoptosis; cancer metabolism; cell migration; pancreatic ductal adenocarcinoma; plasma membrane Ca2+ ATPases 4 (PMCA4)
    DOI:  https://doi.org/10.3390/cancers12010218
  581. Antioxid Redox Signal. 2020 Jan 22.
    NADPH oxidase and neurodegenerative diseases: mechanisms and therapy.
    Hou L, Zhang L, Hong JS, Zhang D, Zhao J, Wang Q.
      SIGNIFICANCE: The growing incidence of neurodegenerative diseases significantly impacts the individuals who suffer from these disorders and is a major health concern globally. Although the specific mechanisms of neurodegenerative diseases are still far from being acknowledged, it is becoming clear that oxidative stress and neuroinflammation are critical contributing factors to the progression of neurodegeneration. Thus, it is conceivable that the inhibition of oxidative stress and neuroinflammation may represent promising therapeutic targets for the treatment of neurodegenerative diseases. Recent Advances: Recently, the strategy for neurodegenerative disease therapy has shifted from the use of antioxidants and conventional anti-inflammatory targets to upstream mediators due to the failure of most antioxidants and nonsteroidal anti-inflammatory drugs (NSAIDs) in clinical trials. NADPH oxidases (NOXs), a family of superoxide-producing enzyme complexes, have been identified as an upstream factor that controls both oxidative stress and neuroinflammation. Genetic inactivation or pharmacological inhibition of NOX enzymes displays potent neuroprotective effects in a broad spectrum of neurodegenerative disease models.CRITICAL ISSUES: The detailed mechanisms of how NOX enzymes regulate oxidative stress and neuroinflammation still remain unclear. Moreover, the currently available inhibitors of NOX enzymes exhibit nonspecificity, off-target effects, unsuitable pharmacokinetic properties and even high toxicity, markedly limiting their potential clinical applications.
    FUTURE DIRECTIONS: This review provides novel insights into the roles of NOXs in neurodegenerative pharmacology and indicates the types NOX enzyme inhibitors that should be identified and developed as candidates for future applications, which might reveal novel neurodegenerative disease therapies based on NOXs.
    DOI:  https://doi.org/10.1089/ars.2019.8014
  582. J Am Soc Mass Spectrom. 2020 Jan 22.
    A new energy setup strategy for intact N-glycopeptides characterization using higher-energy collisional dissociation.
    Wang Y, Tian Z.
      With the optional setting of multiple stepped collisional energies (NCEs), higher-energy collisional dissociation (HCD) as available on Orbitrap instruments is a widely adopted dissociation method for intact N-glycopeptide characterization, where peptide backbones and N-glycan moieties are selectively fragmented at high and low NCEs, respectively. Initially, a dependent setting of a central value plus minus a variation is available to the users to set up NCEs, and the combination of 30±10% to give the energies 20%/30%/40% has been mostly adopted in the literature. With the recent availability of independent NCE setup, we found that the combination of 20%/30%/30% is better than 20%/30%/40%; in the analysis of complex intact N-glycopeptides enriched from gastric cancer tissues, total IDs with spectrum-level FDR≤1%, site-specific IDs with site-determining fragment ions and structure-specific IDs with structure-diagnostic fragment ions were increased by 42% (4,7676,746), 57% (599942), and 97% (17713495), respectively. This finding will benefit all the coming N-glycoproteomics studies using HCD as the dissociation method.
  583. J Neurochem. 2020 Jan 24. e14971
    ASIC1a Channels Regulate Mitochondrial Ion Signaling and Energy Homeostasis in Neurons.
    Savic Azoulay I, Liu F, Qin H, Rozenfeld M, Ben Kasus Nissim T, Zhu MX, Sekler I, Xu TL.
      Acid sensing ion channel 1a (ASIC1a) is well-known to play a major pathophysiological role during brain ischemia linked to acute acidosis of ~ pH 6, while its function during physiological brain activity, linked to much milder pH changes, is still poorly understood. Here, by performing live cell imaging utilizing Na+ and Ca2+ sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na+ and Ca2+ signals elicited by a mild extracellular drop from pH 7.4 to 7.0 and how these affect mitochondrial Na+ and Ca2+ signaling or metabolic activity. We show that in mouse primary cortical neurons, this small extracellular pH change triggers cytosolic Na+ and Ca2+ waves that propagate to mitochondria. Inhibiting ASIC1a with Psalmotoxin 1 (PcTX1) or ASIC1a gene knockout blocked not only the cytosolic but also the mitochondrial Na+ and Ca2+ signals. Moreover, physiological activation of ASIC1a by this pH shift enhances mitochondrial respiration and evokes mitochondrial Na+ signaling even in digitonin - permeabilized neurons. Altogether our results indicate that ASIC1a is critical in linking physiological extracellular pH stimuli to mitochondrial ion signaling and metabolic activity and thus is an important metabolic sensor.
    Keywords:  ASIC1a; NCLX; cytosolic Ca2+ signaling; cytosolic Na+ signaling; mitochondrial Ca2+ signaling; mitochondrial Na+ signaling
    DOI:  https://doi.org/10.1111/jnc.14971
  584. Nutr Hosp. 2020 Jan 21.
    Determinants of vitamin D supplementation among older adults and its effect on 25(OH)D levels according to bone mineral density status.
    Orces CH, López Gavilánez E.
      BACKGROUND: although supplementation with vitamin D has been reported as a main determinant of 25-hydroxyvitamin D status [25(OH)D] levels, there are limited data in regard to the factors associated with vitamin D supplementation in older adults.AIMS: to examine the characteristics of participants associated with vitamin D supplement use and its effect on 25(OH)D concentrations according to bone mineral density (BMD).
    METHODS: the present analysis was based on data from participants aged 60 years and older in the National Health and Nutrition Examination Survey. Logistic regression models were created to examine the demographic, lifestyle, and health characteristics associated with vitamin D supplementation. Moreover, general linear models were assembled to assess the effect of vitamin D supplement doses on 25(OH)D concentrations according to BMD status.
    RESULTS: of 5,204 participants, 45.3% reported taking vitamin D supplements, at least 400 IU per day. Overall, women, non-Hispanic whites, college education, former smokers, physical activity, and > 2 comorbidities were variables significantly associated with increased odds of taking vitamin D supplements. Notably, among subjects with osteoporosis, those taking vitamin D supplements between 400 and 800 IU per day had on average 20.7 nmol/L higher 25(OH)D concentrations compared with their non-user counterparts.
    CONCLUSIONS: demographic and healthy lifestyle characteristics are the main determinants of vitamin D supplement use among older adults. Moreover, even among subjects with low bone mass, vitamin D supplements between 400 and 800 IU per day are adequate to reach sufficient 25(OH)D concentrations.
    DOI:  https://doi.org/10.20960/nh.02917
  585. CNS Neurol Disord Drug Targets. 2020 Jan 16.
    BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways are involved in mitochondria-mediated neuronal apoptosis in dorsal root ganglia after sciatic nerve transection.
    Wang X, Ma W, Wang T, Yang J, Wu Z, Liu K, Dai Y, Zang C, Liu W, Liu J, Liang Y, Guo J, Li L.
      BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear.OBJECTIVE: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and satellite glial cells (SGCs) in dorsal root ganglia (DRG) after sciatic nerve transection (SNT).
    METHODS: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect expression of glial fibrillary acidic protein (GFAP) and calcitonin gene-related peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways.
    RESULTS: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation.
    CONCLUSION: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGC loss following peripheral nerve injury.
    Keywords:  Dorsal root ganglia; Sciatic nerve transection; Sensory neurons; Sortilin; TrkB; p75NTR; proBDNF
    DOI:  https://doi.org/10.2174/1871527319666200117110056
  586. Biochem Biophys Res Commun. 2020 Jan 18. pii: S0006-291X(20)30072-3. [Epub ahead of print]
    Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions.
    Nishida S, Matsumura T, Senokuchi T, Murakami-Nishida S, Ishii N, Morita Y, Yagi Y, Motoshima H, Kondo T, Araki E.
      BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atherosclerotic mouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo.METHODS: Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1•day-1) or a vehicle (water) control.
    RESULTS: In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization.
    CONCLUSIONS: Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.
    Keywords:  Atherosclerosis; DPP-4 inhibitor; Macrophage; Polarization
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.027
  587. Cell. 2020 Jan 23. pii: S0092-8674(19)31385-6. [Epub ahead of print]180(2): 387-402.e16
    Quantitative Proteomics of the Cancer Cell Line Encyclopedia.
    Nusinow DP, Szpyt J, Ghandi M, Rose CM, McDonald ER, Kalocsay M, Jané-Valbuena J, Gelfand E, Schweppe DK, Jedrychowski M, Golji J, Porter DA, Rejtar T, Wang YK, Kryukov GV, Stegmeier F, Erickson BK, Garraway LA, Sellers WR, Gygi SP.
      Proteins are essential agents of biological processes. To date, large-scale profiling of cell line collections including the Cancer Cell Line Encyclopedia (CCLE) has focused primarily on genetic information whereas deep interrogation of the proteome has remained out of reach. Here, we expand the CCLE through quantitative profiling of thousands of proteins by mass spectrometry across 375 cell lines from diverse lineages to reveal information undiscovered by DNA and RNA methods. We observe unexpected correlations within and between pathways that are largely absent from RNA. An analysis of microsatellite instable (MSI) cell lines reveals the dysregulation of specific protein complexes associated with surveillance of mutation and translation. These and other protein complexes were associated with sensitivity to knockdown of several different genes. These data in conjunction with the wider CCLE are a broad resource to explore cellular behavior and facilitate cancer research.
    Keywords:  CCLE; MSI; RNA/Protein correlation; TMT; cancer cell lines; microsatellite instability; protein expression; quantitative proteomics; systems biology
    DOI:  https://doi.org/10.1016/j.cell.2019.12.023
  588. Respirol Case Rep. 2020 Mar;8(2): e00521
    Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma: a report of two cases.
    Uruga H, Fujii T, Nakamura N, Moriguchi S, Kishi K, Takaya H.
      Pathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment has been reported, but details of the transformation remain unclear. We report two cases with transformation to squamous cell carcinoma. The first case was a 61-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 19 insertion. He experienced squamous cell transformation after 28 months of erlotinib therapy. Next-generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS. The second case was a 72-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R. He experienced squamous cell transformation after nine months of erlotinib therapy. NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.
    Keywords:  Epidermal growth factor receptor‐tyrosine kinase inhibitor; PI3K/AKT/mTOR; PTEN; non‐small cell lung cancer; squamous cell transformation
    DOI:  https://doi.org/10.1002/rcr2.521
  589. Cancers (Basel). 2020 Jan 22. pii: E275. [Epub ahead of print]12(2):
    Pancreatic Enzyme Replacement Therapy in Pancreatic Cancer.
    Pezzilli R, Caccialanza R, Capurso G, Brunetti O, Milella M, Falconi M.
      Pancreatic cancer is an aggressive malignancy and the seventh leading cause of global cancer deaths in industrialised countries. More than 80% of patients suffer from significant weight loss at diagnosis and over time tend to develop severe cachexia. A major cause of weight loss is malnutrition. Patients may experience pancreatic exocrine insufficiency (PEI) before diagnosis, during nonsurgical treatment, and/or following surgery. PEI is difficult to diagnose because testing is cumbersome. Consequently, PEI is often detected clinically, especially in non-specialised centres, and treated empirically. In this position paper, we review the current literature on nutritional support and pancreatic enzyme replacement therapy (PERT) in patients with operable and non-operable pancreatic cancer. To increase awareness on the importance of PERT in pancreatic patients, we provide recommendations based on literature evidence, and when data were lacking, based on our own clinical experience.
    Keywords:  chemotherapy; nutritional support; pancreatic cancer; pancreatic enzyme replacement therapy; pancreatic exocrine insufficiency; pancreatic resection
    DOI:  https://doi.org/10.3390/cancers12020275
  590. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30095-7. [Epub ahead of print]49(1): 19-35
    Use of Diabetes Technology in Children: Role of Structured Education for Young People with Diabetes and Families.
    Desrochers HR, Schultz AT, Laffel LM.
      The current era has witnessed an explosion of advanced diabetes technologies. Young people with diabetes and their families require detailed, structured diabetes education in order to optimize use of such devices. There is need for youth and their families to participate in the selection of particular devices for personal use and comprehensive education regarding the safe and effective use of such technologies. The education process should ensure that youth and their families receive realistic expectations of what the advanced technologies can and cannot do to avoid disappointment and the premature discontinuation of such systems.
    Keywords:  Children; Closed-loop system; Continuous glucose monitoring; Continuous subcutaneous insulin infusion; Diabetes technology; Education; Youth
    DOI:  https://doi.org/10.1016/j.ecl.2019.11.001
  591. Purinergic Signal. 2020 Jan 18.
    Imatinib mesylate affects extracellular ATP catabolism and expression of NTPDases in a chronic myeloid leukemia cell line.
    Willig JB, Vianna DRB, Beckenkamp A, Beckenkamp LR, Sévigny J, Wink MR, Buffon A, Pilger DA.
      Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the occurrence of the t(9;22)(q34;q11) translocation. First-line therapy for CML consists of treatment with imatinib mesylate, which selectively inhibits the BCR-ABL protein by competing for its ATP-binding site. Adenine nucleotide signaling is modulated by the ectonucleotidases and this pathway is related to tumorigenic processes. Considering the relationship between ATP and cancer, we aimed to evaluate the influence of imatinib mesylate on the expressions and functions of the NTPDase and ecto-5'-nucleotidase (CD73) enzymes in imatinib-sensitive and -resistant K-562 cell lines. mRNA analysis showed that K-562 cells express all ENTPDs and NT5E. However, when treated with imatinib mesylate for 24 h, the expression of ENTPD1, -2, -3 and -5 increased, leading to a higher nucleotides hydrolysis rate. HPLC analysis identified increased ATP degradation in cells after 24 h of treatment, with consequent ADP and AMP formation, corroborating the increase in gene and protein expression of ectonucleotidases as observed in previous results. On the other hand, we observed that imatinib-resistant K-562 cells presented a decrease in nucleotide hydrolysis and expressions of ENTPD1 and -5. These results suggest an involvement of imatinib in modulating ectonucleotidases in CML that will need further investigation. Since these ectonucleotidases have important catalytic activities in the tumor microenvironment, their modulation in CML cells may represent an important therapeutic approach to regulate levels of extracellular adenine nucleotides.
    Keywords:  Chronic myeloid leukemia; Ectonucleotidases; Imatinib mesylate; Purinergic signaling; Resistance
    DOI:  https://doi.org/10.1007/s11302-019-09686-x
  592. Int J Mol Sci. 2020 Jan 18. pii: E641. [Epub ahead of print]21(2):
    Docosahexaenoic Acid Attenuates Mitochondrial Alterations and Oxidative Stress Leading to Cell Death Induced by Very Long-Chain Fatty Acids in a Mouse Oligodendrocyte Model.
    Nury T, Doria M, Lizard G, Vejux A.
      In the case of neurodegenerative pathologies, the therapeutic arsenal available is often directed towards the consequences of the disease. The purpose of this study is, therefore, to evaluate the ability of docosahexaenoic acid (DHA), a molecule present in certain foods and considered to have health benefits, to inhibit the cytotoxic effects of very long-chain fatty acids (C24:0, C26:0), which can contribute to the development of some neurodegenerative diseases. The effect of DHA (50 µM) on very long-chain fatty acid-induced toxicity was studied by several complementary methods: phase contrast microscopy to evaluate cell viability and morphology, the MTT test to monitor the impact on mitochondrial function, propidium iodide staining to study plasma membrane integrity, and DHE staining to measure oxidative stress. A Western blot assay was used to assess autophagy through modification of LC3 protein. The various experiments were carried out on the cellular model of 158N murine oligodendrocytes. In 158N cells, our data establish that DHA is able to inhibit all tested cytotoxic effects induced by very long-chain fatty acids.
    Keywords:  docosahexaenoic acid; lipotoxicity; oligodendrocytes; very long-chain fatty acid
    DOI:  https://doi.org/10.3390/ijms21020641
  593. BMC Med Imaging. 2020 Jan 22. 20(1): 7
    18F- FDG PET/CT-derived parameters predict clinical stage and prognosis of esophageal cancer.
    Mantziari S, Pomoni A, Prior JO, Winiker M, Allemann P, Demartines N, Schäfer M.
      BACKGROUND: Although 18F- FDG PET/CT is validated in baseline workup of esophageal cancer to detect distant metastases, it remains underused in assessing local staging and biology of the primary tumor. This study aimed to evaluate the association between 18F- FDG PET/CT-derived parameters of esophageal cancer, and its clinico-pathological features and prognosis.METHODS: All patients (n = 86) with esophageal adenocarcinoma or squamous cell cancer operated between 2005 and 2014 were analyzed. Linear regression was used to identify clinico-pathologic features of esophageal cancer associated with the tumor's maximal Standardized Uptake Value (SUVmax), Total Lesion Glycolysis (TLG) and Metabolic Tumor Volume (MTV). ROC curve analysis was performed to precise the optimal cutoff of each variable associated with a locally advanced (cT3/4) status, long-term survival and recurrence. Kaplan Meier curves and Cox regression were used for survival analyses.
    RESULTS: High baseline SUVmax was associated with cT3/4 status and middle-third tumor location, TLG with a cT3/4 and cN+ status, whereas MTV only with active smoking. A cT3/4 status was significantly predicted by a SUVmax > 8.25 g/mL (p < 0.001), TLG > 41.7 (p < 0.001) and MTV > 10.70 cm3 (p < 0.01) whereas a SUVmax > 12.7 g/mL was associated with an early tumor recurrence and a poor disease-free survival (median 13 versus 56 months, p = 0.030), particularly in squamous cell cancer.
    CONCLUSIONS: Baseline 18F- FDG PET/CT has a high predictive value of preoperative cT stage, as its parameters SUVmax, TLG and MTV can predict a locally advanced tumor with high accuracy. A SUVmax > 12.7 g/mL may herald early tumor recurrence and poor disease-free survival.
    Keywords:  18FDG PET/CT; Esophageal cancer; Metabolic imaging; Nuclear imaging; TNM stage
    DOI:  https://doi.org/10.1186/s12880-019-0401-x
  594. J Chem Phys. 2020 Jan 21. 152(3): 034302
    Measurement of electron affinity of iridium atom and photoelectron angular distributions of iridium anion.
    Lu Y, Zhao J, Tang R, Fu X, Ning C.
      The latest electron affinity value of an iridium atom is 1.564 36(15) eV, determined via a method based on the Wigner threshold law by Bilodeau and co-workers. However, they observed a significant deviation from the Wigner threshold law in the threshold photodetachment experiment. To address this dilemma, we conducted high-resolution photoelectron spectroscopy of Ir- via the slow-electron velocity-map imaging method in combination with an ion trap. The electron affinity of Ir was measured to be 12 614.97(9) cm-1 or 1.564 057(11) eV. We find that the Wigner threshold law is still valid for the threshold photodetachment of Ir- through a p-wave fitting of the photodetachment channel Ir-5d86s23F4→Ir5d86sb4F9/2. The photoelectron angular distributions of photodetachment channels Ir-5d86s23F4→Ir5d76s2a4F9/2 and Ir-5d86s23F4→Ir5d86sb4F9/2 were also investigated. The behavior of anisotropy parameter β indicates a strong interaction between the two channels. Moreover, the energy level 3P2 of Ir-, which was not observed in the previous works, was experimentally determined to be 4163.24(16) cm-1 above the ground state.
    DOI:  https://doi.org/10.1063/1.5134535
  595. Eur J Med Chem. 2020 Jan 11. pii: S0223-5234(20)30030-1. [Epub ahead of print]189 112063
    Natural heat shock protein 90 inhibitors in cancer and inflammation.
    Costa TEMM, Raghavendra NM, Penido C.
      Heat shock protein (HSP)90 is the most abundant HSPs, which are chaperone molecules whose major roles are cell protection and maintenance by means of aiding the folding, the stabilization and the remodeling of a wide range of proteins. A few hundreds of proteins depend on HSP90 chaperone activity, including kinases and transcriptional factors that play essential roles in cancer and inflammation, so that HSP90-targeted therapies have been considered as a potential strategy for the treatment of cancer and inflammatory-associated diseases. HSP90 inhibition by natural, semi-synthetic and synthetic compounds have yield promising results in pre-clinical studies and clinical trials for different types of cancers and inflammation. Natural products are a huge source of biologically active compounds widely used in drug development due to the great diversity of their metabolites which are capable to modulate several protein functions. HSP90 inhibitors have been isolated from bacteria, fungi and vegetal species. These natural compounds have a noteworthy ability to modulate HSP90 activity as well as serve as scaffolds for the development of novel synthetic or semi-synthetic inhibitors. Over a hundred clinical trials have evaluated the effect of HSP90 inhibitors as adjuvant treatment against different types of tumors and, currently, new studies are being developed to gain sight on novel promising and more effective approaches for cancer treatment. In this review, we present the naturally occurring HSP90 inhibitors and analogues, discussing their anti-cancer and anti-inflammatory effects.
    Keywords:  Cancer; HSP90; Inflammation; Natural products
    DOI:  https://doi.org/10.1016/j.ejmech.2020.112063
  596. Br J Pharmacol. 2020 Jan 24.
    Luteolin prevents irinotecan-induced intestinal mucositis in mice through antioxidant and anti-inflammatory properties.
    Boeing T, de Souza P, Speca S, Somensi LB, Mariano LNB, Cury BJ, Ferreira Dos Anjos M, Quintão NLM, Dubuqoy L, Desreumaux P, da Silva LM, de Andrade SF.
      BACKGROUND AND PURPOSE: Intestinal mucositis refers to mucosal damage caused by cancer treatment and irinotecan is one of the agents most associated with this condition. Focusing on the development of alternatives to prevent this important adverse effect, we evaluated the activity of the flavonoid luteolin, which has never been tested for this purpose despite its biological potential.EXPERIMENTAL APPROACH: The effects of luteolin were examined on irinotecan-induced intestinal mucositis in mice. Clinical signs were evaluated. Moreover, histological, oxidative and inflammatory parameters were analyzed, as well as the possible interference of luteolin in the antitumor activity of irinotecan.
    KEY RESULTS: Luteolin at 30 mg/kg (p.o. or i.p), prevents irinotecan-induced intestinal damage by reducing weight loss and diarrhea score and attenuating the shortening of the duodenum and colon. The histological analysis confirmed that luteolin (30 mg/kg, p.o.) prevented villous shortening, vacuolization, and apoptosis of cells and preserved mucin production in the duodenum and colon. Moreover, luteolin treatment mitigated irinotecan-induced oxidative stress (i.e. by reducing the levels of ROS and LOOH, and augmenting endogenous antioxidants) and inflammation (i.e. through the decrease of MPO enzyme activity, TNF, IL-1β, and IL-6 levels; and increasing IL-4 and IL-10). Besides, the disruption of the tight junctions ZO-1 and occludin were also prevented by luteolin treatment. Importantly, luteolin did not interfere with the antitumor activity of irinotecan.
    CONCLUSION AND IMPLICATIONS: Luteolin prevents intestinal mucositis induced by irinotecan and therefore could be a potential adjunct in antitumor therapy to control this adverse effect, increasing treatment adherence and consequently the chances of cancer remission.
    Keywords:  Flavonoid; chemotherapy; inflammation; oxidative stress; tight junctions
    DOI:  https://doi.org/10.1111/bph.14987
  597. Pathog Dis. 2020 Jan 23. pii: ftaa003. [Epub ahead of print]
    Anti-apoptotic activity of Chlamydia trachomatis Pgp3 protein involves activation of the ERK1/2 pathway mediated by up-regulation of DJ-1 protein.
    Luo F, Shu M, Gong S, Wen Y, He B, Su S, Li Z.
      Chlamydia trachomatis has evolved strategies to prevent host cell apoptosis to evade the host immune defense. However, the precise mechanisms of anti-apoptotic activity of C. trachomatis still need to be clarified. Pgp3, one of eight plasmid proteins of C. trachomatis, has been identified to be closely associated with chlamydial virulence. In this study, we attempted to explore the effects and the mechanisms of Pgp3 protein on apoptosis in HeLa cells, the results showed that Pgp3 increased Bcl-2/Bax ratio and prevented caspase-3 activation to suppress apoptosis induced by TNF-α and cycloheximide (CHX) through ERK1/2 pathway activation. Down-regulation of DJ-1 with siRNA-DJ-1(si-DJ-1) reduced ERK1/2 phosphorylation and elevated apoptotic rate significantly in Pgp3-HeLa cells. However, inhibition of ERK1/2 signal pathway with ERK inhibitor PD98059 had little effect on DJ-1 expression. These findings confirm that plasmid protein Pgp3 contributes to apoptosis resistance through ERK1/2 signal pathway mediated by up-regulation of DJ-1 expression. Therefore, the present study provided novel insights into the role of Pgp3 in apoptosis and suggested that manipulation of the host apoptosis response could be a new approach for the prevention and treatment of C. trachomatis infection.
    Keywords:   Chlamydia trachomatis ; Apoptosis; DJ-1 protein; ERK1/2 pathway; Pgp3 protein
    DOI:  https://doi.org/10.1093/femspd/ftaa003
  598. J Gastroenterol. 2020 Jan 20.
    Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis.
    Minaga K, Watanabe T, Arai Y, Shiokawa M, Hara A, Yoshikawa T, Kamata K, Yamashita K, Kudo M.
      BACKGROUND: Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified.METHODS: Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients.
    RESULTS: IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP.
    CONCLUSIONS: These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.
    Keywords:  Autoimmune pancreatitis; IRF7; Plasmacytoid dendritic cells
    DOI:  https://doi.org/10.1007/s00535-020-01662-2
  599. Water Res. 2020 Jan 07. pii: S0043-1354(20)30010-5. [Epub ahead of print]172 115474
    Evaluation of the integration of P recovery, polyhydroxyalkanoate production and short cut nitrogen removal in a mainstream wastewater treatment process.
    Larriba O, Rovira-Cal E, Juznic-Zonta Z, Guisasola A, Baeza JA.
      Wastewater treatment systems are nowadays evolving into systems where energy and resources are recovered from wastewater. This work presents the long term operation of a demo-scale pilot plant (7.8 m3) with a novel configuration named as mainstream SCEPPHAR (ShortCut Enhanced Phosphorus and polyhydroxyalkanoate (PHA) Recovery) and based on two sequencing batch reactors (R1-HET and R2-AUT). This is the first report of an implementation at demo scale and under relevant operational conditions of the simultaneous integration of shortcut nitrification, P recovery and production of sludge with a higher PHA content than conventional activated sludge. An operating period under full nitrification mode achieved successful removal efficiencies for total N, P and CODT (86 ± 12%, 93 ± 9% and 79 ± 6%). In the following period, nitrite shortcut (with undetectable activity of nitrite oxidising bacteria) was achieved by implementing automatic control of the aerobic phase length in R2-AUT using ammonium measurement and operating at a lower sludge retention time. Similar N, P and CODT removal efficiencies to the full nitrification period were obtained. P-recovery from the anaerobic supernatant of R1-HET was achieved in a separate precipitator by increasing pH and dosing MgCl2, recovering an average value of 45% of the P in the influent as struvite precipitate, with a peak up to 63%. These values are much higher than the typical values of sidestream P-recovery (12%). Regarding PHA, a percentage in the biomass in the range 6.9-9.2% (gPHA·g-1TSS) was obtained.
    Keywords:  EBPR; Polyhydroxyalkanoate (PHA); Recovery; Struvite; nitrite
    DOI:  https://doi.org/10.1016/j.watres.2020.115474
  600. Pain. 2020 Feb;161(2): 379-387
    Human induced pluripotent stem cell-derived GABAergic interneuron transplants attenuate neuropathic pain.
    Manion J, Khuong T, Harney D, Littleboy JB, Ruan T, Loo L, Costigan M, Larance M, Caron L, Neely GG.
      Neuropathic pain causes severe suffering, and most patients are resistant to current therapies. A core element of neuropathic pain is the loss of inhibitory tone in the spinal cord. Previous studies have shown that foetal GABAergic neuron precursors can provide relief from pain. However, the source of these precursor cells and their multipotent status make them unsuitable for therapeutic use. Here, we extend these findings by showing, for the first time, that spinally transplanted, terminally differentiated human induced pluripotent stem cell-derived GABAergic (iGABAergic) neurons provide significant, long-term, and safe relief from neuropathic pain induced by peripheral nerve injury in mice. Furthermore, iGABAergic neuron transplants survive long term in the injured spinal cord and show evidence of synaptic integration. Together, this provides the proof in principle for the first viable GABAergic transplants to treat human neuropathic pain patients.
    DOI:  https://doi.org/10.1097/j.pain.0000000000001733
  601. Clin Pharmacol Ther. 2020 Jan 19.
    Integration of omics data sources to inform mechanistic modelling of immune-oncology therapies: a tutorial for clinical pharmacologists.
    Lazarou G, Chelliah V, Small BG, Walker M, van der Graaf PH, Kierzek AM.
      Application of contemporary molecular biology techniques to clinical samples in oncology resulted in the accumulation of unprecedented experimental data. These "omics" data are mined for discovery of therapeutic target combinations and diagnostic biomarkers. It is less appreciated that omics resources could also revolutionise development of the mechanistic models informing clinical pharmacology quantitative decisions about dose amount, timing, and sequence. We discuss the integration of omics data to inform mechanistic models supporting drug development in immuno-oncology. To illustrate our arguments we present a minimal clinical model of the Cancer Immunity Cycle (CIC), calibrated for Non-Small Cell Lung Carcinoma using tumour microenvironment composition inferred from transcriptomics of clinical samples. We review omics data resources which can be integrated to parameterise mechanistic models of the CIC. We propose that virtual trial simulations with clinical Quantitative Systems Pharmacology platforms informed by omics data will be making increasing impact in the development of cancer immunotherapies.
    DOI:  https://doi.org/10.1002/cpt.1786
  602. Front Chem. 2019 ;7 873
    In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs.
    Gagic Z, Ruzic D, Djokovic N, Djikic T, Nikolic K.
      Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies.
    Keywords:  drug discovery; kinase inhibitors; molecular modeling; pharmacophore; rational drug design
    DOI:  https://doi.org/10.3389/fchem.2019.00873
  603. Water Res. 2020 Jan 11. pii: S0043-1354(20)30037-3. [Epub ahead of print]172 115501
    Mechanisms of nitrous oxide emission during photoelectrotrophic denitrification by self-photosensitized Thiobacillus denitrificans.
    Chen M, Zhou X, Chen X, Cai Q, Zeng RJ, Zhou S.
      Photoelectrotrophic denitrification (PEDeN) using bio-hybrids has the potential to remove nitrate (NO3-) from wastewater in an economical and sustainable way. As a gas of global concern, the mechanisms of nitrous oxide (N2O) emissions during this novel process remain unclear. Herein, a self-photosensitized bio-hybrid, i. e., Thiobacillus denitrificans-cadmium sulfide, was constructed and the factors affecting N2O emissions during PEDeN by the bio-hybrids were investigated. The system was sensitive to the input NO3--N and NO2--N, resulting in changes in the N2O/(N2+N2O) ratio from 1% to 95%. In addition to free nitrous acid (FNA), reactive oxidative species (ROS) were a unique factor affecting N2O emission during PEDeN. Importantly, the N2O reduction step exhibited greater susceptibility to the ROS than nitrate reduction step. The contributions of hydrogen peroxide (H2O2), superoxides (O2-•), hydroxyl radicals (•OH) and FNA to the inhibition of N2O reduction were >15.0%, >5.4%, 1.3%, and <70.2%, respectively for a reduction of 13.5 mg/L NO3--N. A significant down-regulation of the relative transcription of the gene nosZ demonstrated that the inhibition of N2O reductase occurred at the gene level. This finding has important implications not only for mitigating N2O emissions during the PEDeN process but also for encouraging a reexamination process of N2O emissions in nature, particularly in systems in which ROS are present during the denitrification process.
    Keywords:  FNA inhibition; Nitrate pollutant; Nitrous oxide emission; Photoelectrotrophic denitrification; Reactive oxidative species
    DOI:  https://doi.org/10.1016/j.watres.2020.115501
  604. Mar Pollut Bull. 2020 Jan 14. pii: S0025-326X(19)31031-8. [Epub ahead of print]152 110875
    Hypoxia in autumn of the East China Sea.
    Chen CC, Gong GC, Chou WC, Shiah FK.
      Hypoxia (O2 ≤ 2 mg L-1) can severely threaten the survival of marine life and alter the biogeochemical cycles of coastal ecosystems. Its impacts are dependent on its duration. In the present study, hypoxia was observed in autumn at the end of October 2011. It may be one of the latest recorded annual hypoxic events in the East China Sea (ECS). In the hypoxic regions, a large amount of nutrients and dissolved inorganic carbon were observed to regenerate. Also, acidification (low pH) was observed. On the other hand, hypoxic dissipation may be due to the destratification caused by the upwelling of the hypoxic regions in the ECS. These results suggest that hypoxia may occur for longer periods of time than expected and, accordingly, the effects of hypoxia on the ECS ecosystems should be reconsidered and further evaluated.
    Keywords:  Acidification; Changjiang River estuary; East China Sea; Fugacity of CO(2); Hypoxia; Nutrient regeneration
    DOI:  https://doi.org/10.1016/j.marpolbul.2019.110875
  605. J Chin Med Assoc. 2020 Jan 14.
    Longxuetongluo capsule alleviates LPS-induced neuro-inflammation by regulating multiple signaling pathways in BV2 microglia cells.
    Hong Q, Yang Y, Wang Z, Xu L, Yan Z.
      BACKGROUND: Longxuetongluo capsule (LTC), derived from the total phenolic compounds of Chinese dragon's blood, is now used to treatment of ischemic stroke in convalescence. The aim of this study is to explore the neuroprotective effect of LTC from the perspective of neuro-inflammation.METHODS: Cell viability and LDH release were measured by MTS and LDH assay kit. Pro-inflammatory mediators and cytokines production including NO, PGE2, IL-1β, IL-6 and TNF-α were detected by Elisa assay. Additionally, western blot was used to detect the expression of inflammatory proteins associated with the MAPKs, JAK/STAT, NF-κB and Nrf2/HO-1 signaling pathways. Moreover, immunofluorescence assay and EMSA were performed to determine the Nrf2 translocation and the binding-DNA activity of NF-κB, respectively.
    RESULTS: LTC at 0.5-2 μg/ml significantly increased cell viability and decreased LDH, NO, PGE2, IL-1β, IL-6 and TNF-α production in Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) and LPS-induced BV2 microglia cells. Meanwhile, LTC not only decreased the protein expressions of iNOS, COX-2, but also down-regulated phosphorylation of ERK1/2, p38, and up-regulated HO-1 expression via nuclear translocation of Nrf2. LTC can significantly inhibit the phosphorylation of JAK1/STAT3 and reduce the translocation of NF-κB from cytosol to nucleus as well as the binding-DNA activity. PC12 cell pretreated with LTC- condition medium (CM) significantly alleviated lipopolysaccharide (LPS)-induced neurotoxicity and increased PC12 cell viability in a dose-dependent manner.
    CONCLUSION: The present study showed that LTC exhibited a strong anti-neuroinflammatory activity and neuroprotective effects on LPS-stimulated BV2 microglia cells and PC12 cells.
    DOI:  https://doi.org/10.1097/JCMA.0000000000000258
  606. Molecules. 2020 Jan 19. pii: E415. [Epub ahead of print]25(2):
    Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase.
    Pierson E, Haufroid M, Gosain TP, Chopra P, Singh R, Wouters J.
      Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen's serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants ( K i ) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.
    Keywords:  2,7,9-trisubstituted harmine derivatives; M. tuberculosis; SerB2; phosphoserine phosphatase
    DOI:  https://doi.org/10.3390/molecules25020415
  607. Sci Rep. 2020 Jan 21. 10(1): 766
    Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation.
    Xie H, Gu Y, Wang W, Wang X, Ye X, Xin C, Lu M, Reddy BA, Shu P.
      The proteasome inhibitor bortezomib is the most successfully applied chemotherapeutic drug for treating multiple myeloma. However, its clinical efficacy reduced due to resistance development. The underlying molecular mechanisms of bortezomib resistance are poorly understood. In this study, by combining in silico analysis and sgRNA library based drug resistance screening assay, we identified SENP2 (Sentrin/SUMO-specific proteases-2) as a bortezomib sensitive gene and found its expression highly downregulated in bortezomib resistant multiple myeloma patient's samples. Furthermore, down regulation of SENP2 in multiple myeloma cell line RPMI8226 alleviated bortezomib induced cell proliferation inhibition and apoptosis, whereas, overexpression of SENP2 sensitized these cells to bortezomib treatment. We further demonstrate that knockdown of SENP2 in RPMI8226 cells increased SUMO2 conjugated IκBα that resulted in the activation of NF-κB. Taken together, we report that silencing of SENP2 and consequent activation of NF-κB through the modulation of IκBα sumoylation as a novel mechanism inducing bortezomib resistance in multiple myeloma.
    DOI:  https://doi.org/10.1038/s41598-020-57698-0
  608. Apoptosis. 2020 Jan 23.
    DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG.
    Shriwas O, Priyadarshini M, Samal SK, Rath R, Panda S, Das Majumdar SK, Muduly DK, Botlagunta M, Dash R.
      Platinum based drugs alone or in combination with 5FU and docetaxel are common regimen chemotherapeutics for the treatment of advanced OSCC. Chemoresistance is one of the major factors of treatment failure in OSCC. Human RNA helicase DDX3 plays an important role in cell proliferation, invasion, and metastasis in several neoplasms. The potential role of DDX3 in chemoresistance is yet to be explored. Enhanced cancer stem cells (CSCs) population significantly contributes to chemoresistance and recurrence. A recent study showed that m6A RNA regulates self-renewal and tumorigenesis property in cancer. In this study we found genetic (shRNA) or pharmacological (ketorolac salt) inhibition of DDX3 reduced CSC population by suppressing the expression of FOXM1 and NANOG. We also found that m6A demethylase ALKBH5 is directly regulated by DDX3 which leads to decreased m6A methylation in FOXM1 and NANOG nascent transcript that contribute to chemoresistance. Here, we found DDX3 expression was upregulated in both cisplatin-resistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. In a patient-derived cell xenograft model of chemoresistant OSCC, ketorolac salt restores cisplatin-mediated cell death and facilitates a significant reduction of tumor burdens. Our work uncovers a critical function of DDX3 and provides a new role in m6 demethylation of RNA. A combination regimen of ketorolac salt with cisplatin deserves further clinical investigation in advanced OSCC.
    Keywords:  ALKBH5; Chemoresistance; Ketorolac; PDX; m6A RNA methylation
    DOI:  https://doi.org/10.1007/s10495-020-01591-8
  609. Eur Heart J. 2020 Jan 23. pii: ehz915. [Epub ahead of print]
    Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.
    Ford TJ, Corcoran D, Padmanabhan S, Aman A, Rocchiccioli P, Good R, McEntegart M, Maguire JJ, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sattar N, Hsu LY, Arai AE, Oldroyd KG, Touyz RM, Davenport AP, Berry C.
      AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD).METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status.
    CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.
    TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294.
    Keywords:   Coronary microvascular dysfunction; Endothelin-1; Microvascular angina; Precision medicine; Single-nucleotide polymorphism; Stable angina pectoris
    DOI:  https://doi.org/10.1093/eurheartj/ehz915
  610. Brain Behav Immun. 2020 Jan 21. pii: S0889-1591(19)30662-2. [Epub ahead of print]
    The Relationship between Plasma Serotonin and Kynurenine Pathway Metabolite Levels and the Treatment Response to Escitalopram and Desvenlafaxine.
    Sun Y, Drevets W, Turecki G, Li QS.
      INTRODUCTION: The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels.METHODS: The levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤ 7.
    RESULTS: Response to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p= 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047).
    CONCLUSIONS: In MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.
    DOI:  https://doi.org/10.1016/j.bbi.2020.01.011
  611. J Assoc Physicians India. 2020 Jan;68(1): 47
    Prevalence of Vitamin B12 Defi ciency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes Mellitus Patients.
    Cherulil SJ, Chafekar ND, Babaliche P.
      
  612. Case Rep Med. 2019 ;2019 2740617
    Ranolazine Induced Bradycardia, Renal Failure, and Hyperkalemia: A BRASH Syndrome Variant.
    Zaidi SAA, Shaikh D, Saad M, Vittorio TJ.
      Ranolazine is a well-known antianginal drug, that was first licensed for use in the United States in 2006. It was objectively shown to improve exercise capacity and to lengthen the time to symptom onset in patients with coronary artery disease. The most commonly reported side effects of ranolazine include dizziness, headache, constipation, and nausea. Here, we describe a case of bradycardia, hyperkalemia, and acute renal injury in the setting of ranolazine use. Our patient is an 88-year-old female who presented with abdominal pain, nausea, and vomiting. Her medical comorbidities included hypertension, diabetes, CAD, heart failure with preserved ejection fraction, paroxysmal atrial fibrillation, hypothyroidism, and a history of cerebrovascular accident without any residual deficits. Her prescription regimen included amlodipine, furosemide, isosorbide mononitrate, levothyroxine, metformin, omeprazole, and ranolazine. Physical examination was remarkable for bradycardia and decreased breath sounds in the left lower lung field. Laboratory studies were significant for a serum potassium level of 6.8 mEq/L and a serum creatinine level of 1.6 mg/dL. She was given insulin with dextrose, sodium polystyrene, and calcium gluconate in addition to fluids. Her bradycardia and renal function worsened over the next 24 hours. Ranolazine was discontinued. Metabolic derangements were treated appropriately. After 48 hours from presentation, potassium and renal function returned to baseline and her heart rate improved to a range of 60-100 bpm. She was discharged with an outpatient cardiology follow-up. Ranolazine treatment was not continued upon discharge. In summary, our case illustrates an association between ranolazine and renal failure induced hyperkalemia, leading to conduction delays in the myocardium. Though further studies are warranted, we suspect that this is a variant of the recently described BRASH syndrome. We propose that in cases such as ours, along with treatment of the hyperkalemia, medication review and removal of any offending agent should be considered.
    DOI:  https://doi.org/10.1155/2019/2740617
  613. Nutrients. 2020 Jan 18. pii: E250. [Epub ahead of print]12(1):
    Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy.
    Preguiça I, Alves A, Nunes S, Gomes P, Fernandes R, Viana SD, Reis F.
      Unhealthy dietary habits are major modifiable risk factors for the development of type 2 diabetes mellitus, a metabolic disease with increasing prevalence and serious consequences. Microvascular complications of diabetes, namely diabetic peripheral neuropathy (DPN), retinopathy (DR), and nephropathy (DN), are associated with high morbidity rates and a heavy social and economic burden. Currently, available therapeutic options to counter the evolution of diabetic microvascular complications are clearly insufficient, which strongly recommends further research. Animal models are essential tools to dissect the molecular mechanisms underlying disease progression, to unravel new therapeutic targets, as well as to evaluate the efficacy of new drugs and/or novel therapeutic approaches. However, choosing the best animal model is challenging due to the large number of factors that need to be considered. This is particularly relevant for models induced by dietary modifications, which vary markedly in terms of macronutrient composition. In this article, we revisit the rodent models of diet-induced DPN, DR, and DN, critically comparing the main features of these microvascular complications in humans and the criteria for their diagnosis with the parameters that have been used in preclinical research using rodent models, considering the possible need for factors which can accelerate or aggravate these conditions.
    Keywords:  diabetic nephropathy; diabetic peripheral neuropathy; diabetic retinopathy; diet-induced; microvascular complications; rodent models; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/nu12010250
  614. J Clin Invest. 2020 Jan 21. pii: 134892. [Epub ahead of print]
    The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans.
    Finlin BS, Memetimin H, Zhu B, Confides AL, Vekaria HJ, El Khouli RH, Johnson ZR, Westgate PM, Chen J, Morris AJ, Sullivan PG, Dupont-Versteegden EE, Kern PA.
      BACKGROUND: Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3 adrenergic receptors (β3-AR), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle, and improve metabolic homeostasis.METHODS: Before and after β3AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemistry and gene expression profiling were performed from fat and muscle biopsies. PET CT scans quantified brown adipose tissue volume and activity and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.
    RESULTS: Clinical effects of mirabegron treatment included improved oral glucose tolerance (P<0.01), reduced hemoglobin A1c (P=0.01), and improved insulin sensitivity (P=0.03) and β-cell function (P=0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression and increased alternatively activated macrophages. Subjects with the most SC WAT beiging demonstrated the most improvement in β-cell function. In skeletal muscle, mirabegron reduced triglycerides, increased expression of PGC1A (P<0.05), and increased type I fibers (P<0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P<0.001).
    CONCLUSION: Mirabegron treatment significantly improves glucose tolerance in obese, insulin resistant humans. Since β-cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β-cell function.
    TRIAL REGISTRATION: Clinicaltrials.gov NCT02919176.
    FUNDING: NIH (DK112282, P30GM127211, DK 71349, and CTSA grant UL1TR001998).
    Keywords:  Adipose tissue; Clinical Trials; Glucose metabolism; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI134892
  615. Rapid Commun Mass Spectrom. 2020 Jan 22.
    The Effect of Processing Medium on The 2 H/1 H of Carbon-Bound Hydrogen in α-Cellulose Extracted from Higher Plants.
    Zhu Z, Yin X, Lu F, Wang B, Ma R, Zhao Y, Wang Y, Ma Y, Su J, Yan Q, Hocart CH, Zhou Y.
      RATIONALE: Although the 2 H/1 H ratio of the carbon-bound hydrogens (C-Hs) in α-cellulose extracted from higher plants has long been used successfully for climate, environmental and metabolic studies, the assumption that bleaching with acidified NaClO2 to remove lignin before pure α-cellulose can be obtained does not alter the 2 H/1 H ratio of α-cellulose C-Hs has nonetheless not been tested.METHODS: For reliable application of the 2 H/1 H ratio of α-cellulose C-H, we processed plant materials representing different phytochemistries and photosynthetic carbon assimilation modes in isotopically contrasting bleaching media (with an isotopic difference of 273 mUr). All the isotope ratios were measured by elemental analyzer/isotope ratio mass spectrometry (EA-IRMS).
    RESULTS: Our results show that H from the bleaching medium does appear in the final pure α-cellulose product, although the isotopic alteration to the C-H in α-cellulose due to the incorporation of processing H from the medium is small if isotopically "natural" water is used to prepare the processing medium. However, under prolonged bleaching such an isotope effect can be significant, implying that standardizing the bleaching process is necessary for reliable 2 H/1 H measurement.
    CONCLUSIONS: The currently adopted method for removing lignin for α-cellulose extraction from higher plant materials with acidified NaClO2 bleaching method is considered acceptable in terms of preserving the isotopic fidelity if isotopically "natural" water is used to prepare the bleaching solution.
    DOI:  https://doi.org/10.1002/rcm.8641
  616. Nat Commun. 2020 Jan 24. 11(1): 486
    The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing.
    Hu X, Harvey SE, Zheng R, Lyu J, Grzeskowiak CL, Powell E, Piwnica-Worms H, Scott KL, Cheng C.
      Alternative splicing has been shown to causally contribute to the epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein-protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.
    DOI:  https://doi.org/10.1038/s41467-020-14304-1
  617. BMB Rep. 2020 Jan 21. pii: 4684. [Epub ahead of print]
    15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism.
    Jang HY, Hong OY, Youn HJ, Kim MG, Kim CH, Jung SH, Kim JS.
      Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and over-expressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPARγ. In this study, we investigated the effects of induction of HO-1 by PPARγ on TPA-induced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-κB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPARγ ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP-9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPARγ/HO-1 signaling-pathway inhibition may be beneficial for prevention and treatment of breast cancer.
  618. J Pharm Biomed Anal. 2020 Jan 09. pii: S0731-7085(19)32459-8. [Epub ahead of print]181 113106
    Simultaneous determination of a promising anti-brain tumor agent CAT3 and its two major metabolites in mouse plasma and brain by a LC-MS/MS method.
    Zhao S, Wang RB, Bai J, Fan X, Hu M, Wang B, Hu J, Li Y.
      A rapid and reproducible method with high selectivity was developed for simultaneous determination of a promising anti-brain tumor agent CAT3 and its two metabolites PF403 and GLU-PF403 in mouse plasma and brain. An economic deproteinization with septuple acetonitrile (v/v) was applied to pretreat the samples in this study. All analytes were well retained and separated on a CAPCELL CORE PC (2.7 μm, 2.1 mm I.D. × 150 mm, SHISEIDO Technologies) column with an eluting solvent of acetonitrile /water containing 0.1 % formic acid (v/v) at the flow rate of 0.2 mL per minute. The detection was carried out on a Q Exactive high resolution mass spectrometer equipped with a HESI ion source in parallel reaction monitoring (PRM) mode. The corresponding transitions for quantitation were 434.23→ 70.07 for CAT3, 350.17→70.07 for PF403, 526.21→70.07 for GLU-PF403, 364.19→70.07 for IS-1 and 625.18→317.07 for IS-2, respectively. A well-linear fit curve was achieved among the range of 0.1∼50 ng/mL for CAT3, 0.2∼100 ng/mL for PF403 and 2.5∼600 ng/mL for GLU-PF403 both in mouse plasma and brain homogenate. The intra-/inter-day accuracies of three analytes were within ±14.5 % and precisions were below to 13.44 %. The mean values of recovery of three compounds in mouse plasma and brain homogenate were among 98.06 ∼ 118.63 % and 81.04∼108.69 %. The analytes in NaF-treated ice cold blood of mouse was stable within tested 30 min. Plasma and brain homogenate samples had no obvious changes during all storage, sample treatment and analytic process of mouse plasma sample. The reproducible and reliable method was well employed to the research of CAT3 pharmacokinetic characteristics in mouse plasma and brain after a single intragastric administration at dose of 10 mg/kg.
    Keywords:  Anti-brain tumor agent; CAT3; LC–MS/MS; Pharmacokinetic
    DOI:  https://doi.org/10.1016/j.jpba.2020.113106
  619. Curr Biol. 2020 Jan 20. pii: S0960-9822(19)31703-8. [Epub ahead of print]
    Highly Reduced Genomes of Protist Endosymbionts Show Evolutionary Convergence.
    George EE, Husnik F, Tashyreva D, Prokopchuk G, Horák A, Kwong WK, Lukeš J, Keeling PJ.
      Genome evolution in bacterial endosymbionts is notoriously extreme: the combined effects of strong genetic drift and unique selective pressures result in highly reduced genomes with distinctive adaptations to hosts [1-4]. These processes are mostly known from animal endosymbionts, where nutritional endosymbioses represent the best-studied systems. However, eukaryotic microbes, or protists, also harbor diverse bacterial endosymbionts, but their genome reduction and functional relationships with their hosts are largely unexplored [5-7]. We sequenced the genomes of four bacterial endosymbionts from three species of diplonemids, poorly studied but abundant and diverse heterotrophic protists [8-12]. The endosymbionts come from two bacterial families, Rickettsiaceae and Holosporaceae, that have invaded two families of diplonemids, and their genomes have converged on an extremely small size (605-632 kilobase pairs [kbp]), similar gene content (e.g., metabolite transporters and secretion systems), and reduced metabolic potential (e.g., loss of energy metabolism). These characteristics are generally found in both families, but the diplonemid endosymbionts have evolved greater extremes in parallel. They possess modified type VI secretion systems that could function in manipulating host metabolism or other intracellular interactions. Finally, modified cellular machinery like the ATP synthase without oxidative phosphorylation, and the reduced flagellar apparatus present in some diplonemid endosymbionts and nutritional animal endosymbionts, indicates that intracellular mechanisms have converged in bacterial endosymbionts with various functions and from different eukaryotic hosts across the tree of life.
    Keywords:  Holosporaceae; Muller’s ratchet; Rickettsiaceae; T6SS; convergent evolution; diplonemid; endosymbiosis; genome reduction; protist; secretion systems
    DOI:  https://doi.org/10.1016/j.cub.2019.12.070
  620. Spine Deform. 2019 Nov;7(6): 1029
    Lung Function before and after Spine fusion in Children with EOS Treated Previously with Distraction-based Devices.
    Redding G, Kawakami N, Matsumoto H, Bompadre V, Krengel W, White K.
      
    DOI:  https://doi.org/10.1016/j.jspd.2019.09.027
  621. Pharmacol Biochem Behav. 2020 Jan 17. pii: S0091-3057(19)30643-4. [Epub ahead of print] 172856
    Electrophysiological biomarkers of antidepressant response to ketamine in treatment-resistant depression: Gamma power and long-term potentiation.
    Gilbert JR, Zarate CA.
      Over the last two decades, the discovery of ketamine's antidepressant properties has galvanized research into the neurobiology of treatment-resistant depression. Nevertheless, the mechanism of action underlying antidepressant response to ketamine remains unclear. This study reviews electrophysiological studies of ketamine's effects in individuals with depression as well as healthy controls, with a focus on two putative markers of synaptic potentiation: gamma oscillations and long-term potentiation. The review focuses on: 1) measures of gamma oscillations and power and their relationship to both acute, psychotomimetic drug effects as well as delayed antidepressant response in mood disorders; 2) changes in long-term potentiation as a promising measure of synaptic potentiation following ketamine administration; and 3) recent efforts to model antidepressant response to ketamine using novel computational modeling techniques, in particular the application of dynamic causal modeling to electrophysiological data. The latter promises to better characterize the mechanisms underlying ketamine's antidepressant effects.
    Keywords:  Dynamic causal modeling; Electrophysiology; Gamma; Ketamine; Long-term potentiation
    DOI:  https://doi.org/10.1016/j.pbb.2020.172856
  622. Oncol Lett. 2020 Feb;19(2): 1145-1150
    Downregulation of long non-coding RNA NR2F2-AS1 inhibits proliferation and induces apoptosis of nasopharyngeal carcinoma cells by upregulating the expression of PTEN.
    Qin H, Qin C.
      The novel long non-coding RNA NR2F2-AS1 has been characterized as an oncogene in lung cancer. The present study aimed to investigate the role of NR2F2-AS1 in nasopharyngeal carcinoma (NPC). The results demonstrated that expression of NR2F2-AS1 and phosphatase and tensin homolog (PTEN) were negatively associated with each other in NPC tissues. Furthermore, upregulated NR2F2-AS1 expression levels and downregulated PTEN expression levels in NPC tissues predicted less favorable survival outcomes in patients with NPC. Transfection of NPC cells with NR2F2-AS1 small interfering RNA resulted in increased expression of PTEN. In addition, NR2F2-AS1 silencing and PTEN overexpression resulted in decreased proliferation and an increase in the apoptotic rate of NPC cells. In conclusion, NR2F2-AS1 downregulation decreased proliferation and increased apoptosis of NPC cells via upregulation of PTEN.
    Keywords:  long non-coding RNA NR2F2-AS1; nasopharyngeal carcinoma; phosphatase and tensin homolog; prognosis
    DOI:  https://doi.org/10.3892/ol.2019.11211
  623. Commun Biol. 2020 Jan 22. 3(1): 39
    Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis.
    Wang Z, Bian L, Mo C, Shen H, Zhao LJ, Su KJ, Kukula M, Lee JT, Armstrong DW, Recker R, Lappe J, Bonewald LF, Deng HW, Brotto M.
      Osteoporosis is a highly prevalent chronic aging-related disease that frequently is only detected after fracture. We hypothesized that aminobutyric acids could serve as biomarkers for osteoporosis. We developed a quick, accurate, and sensitive screening method for aminobutyric acid isomers and enantiomers yielding correlations with bone mineral density (BMD) and osteoporotic fracture. In serum, γ-aminobutyric acid (GABA) and (R)-3-aminoisobutyric acid (D-BAIBA) have positive associations with physical activity in young lean women. D-BAIBA positively associated with hip BMD in older individuals without osteoporosis/osteopenia. Lower levels of GABA were observed in 60-80 year old women with osteoporotic fractures. Single nucleotide polymorphisms in seven genes related to these metabolites associated with BMD and osteoporosis. In peripheral blood monocytes, dihydropyrimidine dehydrogenase, an enzyme essential to D-BAIBA generation, exhibited positive association with physical activity and hip BMD. Along with their signaling roles, BAIBA and GABA might serve as biomarkers for diagnosis and treatments of osteoporosis.
    DOI:  https://doi.org/10.1038/s42003-020-0766-y
  624. Sci Rep. 2020 Jan 20. 10(1): 655
    DNA epigenetic marks are linked to embryo aberrations in amphipods.
    Gorokhova E, Martella G, Motwani NH, Tretyakova NY, Sundelin B, Motwani HV.
      Linking exposure to environmental stress factors with diseases is crucial for proposing preventive and regulatory actions. Upon exposure to anthropogenic chemicals, covalent modifications on the genome can drive developmental and reproductive disorders in wild populations, with subsequent effects on the population persistence. Hence, screening of chemical modifications on DNA can be used to provide information on the probability of such disorders in populations of concern. Using a high-resolution mass spectrometry methodology, we identified DNA nucleoside adducts in gravid females of the Baltic amphipods Monoporeia affinis, and linked the adduct profiles to the frequency of embryo malformations in the broods. Twenty-three putative nucleoside adducts were detected in the females and their embryos, and eight modifications were structurally identified using high-resolution accurate mass data. To identify which adducts were significantly associated with embryo malformations, partial least squares regression (PLSR) modelling was applied. The PLSR model yielded three adducts as the key predictors: methylation at two different positions of the DNA (5-methyl-2'-deoxycytidine and N6-methyl-2'-deoxyadenosine) representing epigenetic marks, and a structurally unidentified nucleoside adduct. These adducts predicted the elevated frequency of the malformations with a high classification accuracy (84%). To the best of our knowledge, this is the first application of DNA adductomics for identification of contaminant-induced malformations in field-collected animals. The method can be adapted for a broad range of species and evolve as a new omics tool in environmental health assessment.
    DOI:  https://doi.org/10.1038/s41598-020-57465-1
  625. J Neurooncol. 2020 Jan 24.
    Rate of change in maximum 18F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.
    Oughourlian TC, Yao J, Schlossman J, Raymond C, Ji M, Tatekawa H, Salamon N, Pope WB, Czernin J, Nghiemphu PL, Lai A, Cloughesy TF, Ellingson BM.
      PURPOSE: To examine whether the rate of change in maximum 18F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial 18F-FDOPA PET and MRI scans.METHODS: 27 LGG patients with ≥ 2 18F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized 18F-FDOPA specific uptake value (nSUVmax/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS.
    RESULTS: A GLM using patient age, treatment, the rate of change in FLAIR and 18F-FDOPA nSUVmax could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS.
    CONCLUSIONS: The change in maximum normalized 18F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.
    Keywords:  18F-FDOPA PET; Biomarker; Low grade glioma; MRI
    DOI:  https://doi.org/10.1007/s11060-020-03407-w
  626. Clin Nucl Med. 2020 Jan 17.
    "Hot Lung" Sign in Pulmonary Intravascular Large B-Cell Lymphoma on 18F-FDG PET/CT.
    Şahin Ö, Kaya B, Serdengeçti M, Çizmecioğlu HA, Şen AE.
      Intravascular large B-cell lymphoma is a rare type of non-Hodgkin lymphoma characterized by intravascular proliferation of clonal lymphocytes within the lumen of small vessels, which is often fatal. Diffuse FDG uptake in the lung without clear/evident CT findings, "hot lung," is quasi-pathognomonic for lung intravascular large B-cell lymphoma. In this report, we present the case of a 43-year-old man who was diagnosed as having intravascular lymphoma thanks to this rare finding.
    DOI:  https://doi.org/10.1097/RLU.0000000000002939
  627. Cell Death Dis. 2020 Jan 20. 11(1): 40
    Transmissible gastroenteritis virus targets Paneth cells to inhibit the self-renewal and differentiation of Lgr5 intestinal stem cells via Notch signaling.
    Wu A, Yu B, Zhang K, Xu Z, Wu , He J, Luo J, Luo Y, Yu J, Zheng P, Che L, Mao X, Huang Z, Wang L, Zhao J, Chen D.
      Infection with transmissible gastroenteritis virus (TGEV) has been associated with villous atrophy within 48 h, which seriously disrupts intestinal homeostasis. However, the underlying mechanisms remain elusive. In this study, we found that TGEV infection severely disrupted intestinal homeostasis via inhibition of self-renewal and differentiation in Lgr5 intestinal stem cells (ISCs). Profoundly, TGEV-encoded NSP10/NSP16 protein complex-mediated the inactivation of Notch signaling provided a mechanistic explanation for this phenomenon. Initial invasions by TGEV-targeted Paneth cells through aminopeptidase N (APN) receptor, then inducing mitochondrial damage and ROS generation in them, ultimately causing Paneth cell decrease and loss of Notch factors (DII4 and Hes5), which are essential for Lgr5 ISCs self-renewal and differentiation. Interestingly, loss of Notch signaling induced goblet cells differentiation at the cost of absorptive enterocytes and promoted mucins secretion, which accelerated TGEV replication. Therefore, the more differentiation of goblet cells, the greater TGEV infection in jejunum. These results provide a detailed mechanistic pathway by which villous atrophy sharply occurs in TGEV-infected jejunum within 48 h. Thus, the pathogenesis of TGEV can be described as a "bottom up scenario", which is contrary to the traditional "top down" hypothesis. Together, our findings provide a potential link between diarrheal virus infection and crypt cells response that regulates Paneth cells function and Lgr5 ISCs fate and could be exploited for therapeutic application.
    DOI:  https://doi.org/10.1038/s41419-020-2233-6
  628. Angew Chem Int Ed Engl. 2020 Jan 25.
    Calixarene-Based Supramolecular AIE Dots with Highly Inhibited Nonradiative Decay and Intersystem Crossing for Ultrasensitive Fluorescence Image-Guided Cancer Surgery.
    Chen C, Ni X, Tian HW, Liu Q, Guo DS, Ding D.
      Molecular motion-associated organic molecules such as aggregation-induced emission luminogens (AIEgens) for disease phototheranostics are attracting increasing attention; however, how to optimally harvest absorbed excitation energy for advanced fluorescence imaging/diagnosis and concurrently avoid unnecessary phototoxicity during bioimaging process is still challenging. To address this issue, herein, we report that the host-guest complexation between calix[5]arene and AIEgen can significantly turn off both the energy dissipation pathways of intersystem crossing and thermal deactivation, enabling the absorbed excitation energy mostly focusing on fluorescence emission. The co-assembly of calix[5]arene amphiphiles and AIEgens affords highly emissive supramolecular AIE nanodots thanks to their interaction extremely restricting the intramolecular motion of AIEgens, which also show negligible cytotoxic reactive oxygen species generation. In vivo studies with a peritoneal carcinomatosis-bearing mouse model indicate that such supramolecular AIE dots have rather low in vivo side toxicity and can serve as a superior fluorescent bioprobe for ultrasensitive fluorescence image-guided cancer surgery.
    Keywords:  aggregation-induced emission; calixarene; fluorescence image-guided cancer surgery; photophysical property; supramolecular nanoparticle
    DOI:  https://doi.org/10.1002/anie.201916430
  629. Pol J Radiol. 2019 ;84 e424-e429
    Familial pneumothoraces - Birt-Hogg-Dubé syndrome. Differentiation with other cystic lung diseases.
    Opoka L, Wakulinski J, Winek J, Bestry I, Błasinska K, Radzikowska E.
      Birt-Hogg-Dubé syndrome (BHDS) is a rare, genetic, autosomal dominant disease caused by mutation in a folliculin gene. This syndrome is characterised by three main symptoms: benign lesions originating from hair follicles, variously shaped cysts in the lungs, and various types of benign and malignant kidney neoplasms. In our article we are going to present cases of two sisters with BHDS. In the case of the first sister skin lesions were accompanied by lung abnormalities. The second sister, however, presented with recurrent pneumothoraces associated with variously shaped lung cysts located mainly below the tracheal carina. In both instance diagnosis was confirmed by genetic test.
    Keywords:  Birt-Hogg-Dubé syndrome; cystic lung diseases; pneumothorax; recurrent pneumothoraces
    DOI:  https://doi.org/10.5114/pjr.2019.89964
  630. Mol Med Rep. 2020 Feb;21(2): 685-694
    Identification of hub genes and key pathways of dietary advanced glycation end products‑induced non‑alcoholic fatty liver disease by bioinformatics analysis and animal experiments.
    Wang J, Liu H, Xie G, Cai W, Xu J.
      Non‑alcoholic fatty liver disease (NAFLD) is a common chronic liver disease. Advanced glycation end products (AGEs) negatively affect the liver and accelerate NAFLD progression; however, the underlying mechanisms remain unclear. The present study aimed to examine the effect and mechanism of dietary AGEs on the mouse liver using bioinformatics and in vivo experimental approaches. Gene expression datasets associated with NAFLD were obtained from the Gene Expression Omnibus and differentially expressed genes (DEGs) were identified using GEO2R. Functional enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery and a protein‑protein interaction network for the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes database. MCODE, a Cytoscape plugin, was subsequently used to identify the most significant module. The key genes involved were verified in a dietary AGE‑induced non‑alcoholic steatohepatitis (NASH) mouse model using reverse transcription‑quantitative PCR (RT‑qPCR). The 462 DEGs associated with NAFLD in the two datasets, of which 34 overlapping genes were found in two microarray datasets. Functional analysis demonstrated that the 34 DEGs were enriched in the 'PPAR signaling pathway', 'central carbon metabolism in cancer', and 'cell adhesion molecules (CAMs)'. Moreover, four hub genes (cell death‑inducing DFFA‑like effector a, cell death‑inducing DFFA‑like effector c, fatty acid‑binding protein 4 and perilipin 4) were identified from a protein‑protein interaction network and were verified using RT‑qPCR in a mouse model of NASH. The results suggested that AGEs and their receptor axis may be involved in NAFLD onset and/or progression. This integrative analysis identified candidate genes and pathways in NAFLD, as well as DEGs and hub genes related to NAFLD progression in silico and in vivo.
    DOI:  https://doi.org/10.3892/mmr.2019.10872
  631. Bone. 2020 Jan 21. pii: S8756-3282(20)30032-6. [Epub ahead of print] 115252
    Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells.
    Ali D, Chen L, Kowal JM, Okla M, Manikandan M, AlShehri M, AlMana Y, AlObaidan R, AlOtaibi N, Hamam R, Alajez NM, Aldahmash A, Kassem M, Alfayez M.
      Bone marrow adipose tissue (BMAT) is a unique adipose depot originating from bone marrow stromal stem cells (BMSCs) and regulates bone homeostasis and energy metabolism. An increased BMAT volume is observed in several conditions e.g. obesity, type 2 diabetes, osteoporosis and is known to be associated with bone fragility and increased risk for fracture. Therapeutic approaches to decrease the accumulation of BMAT are clinically relevant. In a screening experiment of natural compounds, we identified Resveratrol (RSV), a plant-derived antioxidant mediating biological effects via sirtuin- related mechanisms, to exert significant effects of BMAT formation. Thus, we examined in details the effects RSV on adipocytic and osteoblastic differentiation of tolermerized human BMSCs (hBMSC-TERT). RSV (1.0 μM) enhanced osteoblastic differentiation and inhibited adipocytic differentiation of hBMSC-TERT when compared with control and Sirtinol (Sirtuin inhibitor). Global gene expression profiling and western blot analysis revealed activation of a number of signaling pathways including focal adhesion kinase (FAK). Pharmacological inhibition of FAK using PF-573228 (5 μM), diminished RSV-induced osteoblast differentiation. In addition, RSV reduced the levels of senescence-associated secretory phenotype (SASP), gene markers associated with senescence (P53, P16, and P21), intracellular ROS levels and increased gene expression of enzymes protecting cells from oxidative damage (HMOX1 and SOD3). In vitro treatment of primary hBMSCs characterized with high adipocytic and low osteoblastic differentiation ability with RSV, significantly enhanced osteoblast and decreased adipocyte formation. RSV targets hBMSCs and inhibits adipogenic differentiation and senescence-associated phenotype and thus a potential agent for treating conditions of increased BMAT formation.
    Keywords:  Adipogenesis; Antioxidant; Bone marrow adiposity; Bone marrow skeletal stromal cells; Cellular senescence; Osteogenesis
    DOI:  https://doi.org/10.1016/j.bone.2020.115252
  632. ACS Nano. 2020 Jan 23.
    High-Fidelity Single Molecule Quantification in a Flow Cytometer Using Multiparametric Optical Analysis.
    Smith LD, Liu Y, Zahid MU, Canady TD, Wang L, Kohli M, Cunningham BT, Smith AM.
      Microfluidic techniques are widely used for high-throughput quantification and discrete analysis of micron-scale objects like cells, but are difficult to apply to molecular-scale targets. Instead, single-molecule methods primarily rely on low-throughput imaging of immobilized molecules using high-resolution microscopy. Here we report that commercial-grade flow cytometers can detect single nucleic acid targets following enzymatic extension and dense labeling with multiple distinct fluorophores. We focus on microRNAs, short nucleic acids that can be extended by rolling circle amplification and labeled with multicolor fluorophores to generate repetitive nucleic acid products with sub-micron sizes and tunable multispectral profiles. By cross-correlating the multiparametric optical features, signal-to-background ratios were amplified 1600-fold to allow single-molecule detection across 4 orders of magnitude of concentration. The limit of detection was measured to be 47 femtomolar, which is 100-fold better than gold-standard methods based on polymerase chain reaction. Furthermore, multiparametric analysis allowed discrimination of different microRNA sequences in the same solution using distinguishable optical barcodes. Barcodes can apply both ratiometric and colorimetric signatures, which could facilitate high-dimensional multiplexing. Due to the wide availability of flow cytometers, we anticipate that this technology can provide immediate access to high-throughput multiparametric single-molecule measurements, and can further be adapted to the diverse range of molecular amplification methods that are continually emerging.
    DOI:  https://doi.org/10.1021/acsnano.9b09498
  633. Exp Cell Res. 2020 Jan 20. pii: S0014-4827(20)30054-9. [Epub ahead of print] 111860
    A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.
    Madigan JP, Robey RW, Poprawski JE, Huang H, Clarke CJ, Gottesman MM, Cabot MC, Rosenberg DW.
      There is growing evidence to support a role for the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in resistance to a variety of chemotherapeutic agents. Whether GCS contributes to oxaliplatin resistance in colorectal cancer (CRC) has not yet been determined. We have addressed this potentially important clinical issue by examining GCS function in two panels of oxaliplatin-resistant, isogenic CRC cell lines. Compared to parental cell lines, oxaliplatin-resistant cells have increased expression of GCS protein associated with increased levels of the pro-survival ceramide metabolite, glucosylceramide (GlcCer). Inhibition of GCS expression by RNAi-mediated gene knockdown resulted in a reduction in cellular GlcCer levels, with restored sensitivity to oxaliplatin. Furthermore, oxaliplatin-resistant CRC cells displayed lower ceramide levels both basally and after treatment with oxaliplatin, compared to parental cells. GlcCer, formed by GCS-mediated ceramide glycosylation, is the precursor to a complex array of glycosphingolipids. Differences in cellular levels and species of gangliosides, a family of glycosphingolipids, were also seen between parental and oxaliplatin-resistant CRC cells. Increased Akt activation was also observed in oxaliplatin-resistant CRC cell lines, together with increased expression of the anti-apoptotic protein survivin. Finally, this study shows that GCS protein levels are greatly increased in human CRC specimens, compared to matched, normal colonic mucosa, and that high levels of UGCG gene expression are significantly associated with decreased disease-free survival in colorectal cancer patients. These findings uncover an important cellular role for GCS in oxaliplatin chemosensitivity and may provide a novel cellular target for augmenting chemotherapeutic drug effectiveness in CRC.
    Keywords:  Chemoresistance; Colorectal cancer; Glucosylceramide; Glucosylceramide synthase; Oxaliplatin
    DOI:  https://doi.org/10.1016/j.yexcr.2020.111860
  634. ACS Omega. 2020 Jan 14. 5(1): 179-188
    Lipophilic Metabolic Efficiency (LipMetE) and Drug Efficiency Indices to Explore the Metabolic Properties of the Substrates of Selected Cytochrome P450 Isoforms.
    Kiani YS, Jabeen I.
      Cytochrome P450 (CYP450) enzymes belong to a superfamily of heme-containing proteins that are involved in the metabolism of structurally diverse endogenous and exogenous compounds. Various proof-of-concept studies indicate that metabolic stability and intrinsic clearance of CYP450 substrates are linked with the respective lipophilicity (log P or log D). This necessitates the normalization of lipophilicity (log P or log D) of a given CYP450 substrate with respect to its metabolic stability (LipMetE) and intrinsic clearance (log10CLint,u). Therefore, in this article, the LipMetE values of already known substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, including some marketed drugs, have been calculated to elucidate the relationship between lipophilicity (log D 7.4) and in vitro clearance. Moreover, various drug efficiency metrics including lipophilic efficiency (LipE) and ligand efficiency (LE) have been evaluated, and the thresholds of these parameters have been defined for the CYP450 substrates exhibiting normalized LipMetE. Our results indicate that for a given range of LipMetE, greater the log D value of the substrate the more avidly it binds to a given CYP450 enzyme and shows more intrinsic clearance (log10CLint,u). Overall, the majority of the model substrates of CYP450 isoforms and already marketed drugs in our datasets exhibit log D 7.4 values of ∼2.5 with LipMetE values in the range of 0-2.5 and LipE values of ≤3. Overall, consideration of these parameters in ADME profiling could aid in reducing the drug failure rate in the later stages of clinical investigations.
    DOI:  https://doi.org/10.1021/acsomega.9b02344
  635. J Hepatol. 2020 Jan 15. pii: S0168-8278(20)30009-X. [Epub ahead of print]
    Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming.
    Kowalik MA, Puliga E, Cabras L, Sulas P, Petrelli A, Perra A, Ledda-Columbano GM, Morandi A, Merlin S, Orrù C, Sanchez-Martin C, Fornari F, Gramantieri L, Parri M, Rasola A, Bellomo SE, Sebastian C, Follenzi A, Giordano S, Columbano A.
      BACKGROUND & AIMS: The limited therapeutic options available for hepatocellular carcinoma (HCC) make mandatory to find alternative effective treatments for this tumor. Based on the recent finding that systemic or local hypothyroidism is associated with HCC development in humans and rodents, we investigated whether the thyroid hormone triiodothyronine (T3) could inhibit the progression of hepatocellular carcinomas (HCCs).METHODS: Different rat and mouse models of hepatocarcinogenesis were investigated. The effect of T3 on tumorigenesis and metabolism/differentiation was evaluated by transcriptomic analysis, quantitative-PCR, immunohistochemistry, and enzymatic assay.
    RESULTS: A short treatment with T3 caused a shift of global expression profile of the most aggressive preneoplastic nodules towards that of normal liver. This genomic reprogramming preceded the disappearance of nodules and involved reprogramming of metabolic genes as well as pro-differentiating transcription factors, including Kruppel-like factor 9 (Klf9), a target of the thyroid hormone receptor β (TRβ). Treatment of HCCs-bearing rats with T3 strongly reduced the number and burden of HCCs. Reactivation of a local T3/TRβ axis, switch from Warburg to oxidative metabolism and loss of markers of poorly differentiated hepatocytes accompanied HCC reduction. This effect persisted one month after T3 withdrawal suggesting a long-lasting effect of the hormone. The antitumorigenic effect of T3 was further supported by its inhibitory activity on cell growth and tumorigenic ability of human HCC cell lines.
    CONCLUSIONS: Collectively, these findings suggest that re-activation of the T3/TRβ axis induces differentiation of neoplastic cells towards a more benign phenotype and that T3 or its analogues, particularly agonists of the TRβ, can represent useful tools in HCC therapy.
    Keywords:  HCC; KLF9; OXPHOS; PPP; T3; Thyroid hormone receptors; differentiation; metabolic reprogramming; rats
    DOI:  https://doi.org/10.1016/j.jhep.2019.12.018
  636. Chem Commun (Camb). 2020 Jan 23.
    Nucleoside-modified AdoMet analogues for differential methyltransferase targeting.
    Cornelissen NV, Michailidou F, Muttach F, Rau K, Rentmeister A.
      Methyltransferases (MTases) modify a wide range of biomolecules using S-adenosyl-l-methionine (AdoMet) as the cosubstrate. Synthetic AdoMet analogues are powerful tools to site-specifically introduce a variety of functional groups and exhibit potential to be converted only by distinct MTases. Extending the size of the substituent at the sulfur/selenium atom provides selectivity among MTases but is insufficient to discriminate between promiscuous MTases. We present a panel of AdoMet analogues differing in the nucleoside moiety (NM-AdoMets). These NM-AdoMets were efficiently produced by a previously uncharacterized methionine adenosyltransferase (MAT) from methionine and ATP analogues, such as ITP and N6-propargyl-ATP. The N6-modification changed the relative activity of three representative MTases up to 13-fold resulting in discrimination of substrates for the methyl transfer and could also be combined with transfer of allyl and propargyl groups.
    DOI:  https://doi.org/10.1039/c9cc07807j
  637. J Assoc Physicians India. 2020 Jan;68(1): 82
    ABPA - Presenting as Total Lung Collapse.
    Singh N, Maskey D.
      
  638. Int J Food Sci Nutr. 2020 Jan 21. 1-10
    Whole grain consumption and human health: an umbrella review of observational studies.
    Tieri M, Ghelfi F, Vitale M, Vetrani C, Marventano S, Lafranconi A, Godos J, Titta L, Gambera A, Alonzo E, Sciacca S, Riccardi G, Buscemi S, Del Rio D, Ray S, Galvano F, Beck E, Grosso G.
      Whole grains have been associated with a number of health benefits. We systematically reviewed existing meta-analyses of observational studies and evaluated the level of evidence for their putative effects based on pre-selected criteria. Of the 23 included studies, we found convincing evidence of an inverse association between whole grain consumption and risk of type-2 diabetes and colorectal cancer; possible evidence of decreased risk of colon cancer and cardiovascular mortality with increased whole grain intake, as well as increased risk of prostate cancer. Limited or insufficient evidence was available for all other outcomes investigated. Overall findings are encouraging for a positive effect of whole grain consumption on certain diseases, especially highly prevalent metabolic diseases, however, uncertainty of some negative associations deserves further attention.
    Keywords:  Whole grain; cohort; evidence; fibre; meta-analysis; umbrella review
    DOI:  https://doi.org/10.1080/09637486.2020.1715354
  639. J Evol Biol. 2020 Jan 21.
    Dietary polyunsaturated fatty acids affect volume and metabolism of Drosophila melanogaster sperm.
    Guo R, Reinhardt K.
      Dietary fatty acids can accumulate in sperm and affect their function in vertebrates. As Drosophila melanogaster shares several pathways of lipid metabolism and shows similar lipid-dependent phenotypes but lacks some hormones that in vertebrates regulate lipid metabolism, there is currently no clear prediction as to how dietary fatty acids affect the sperm of D. melanogaster. We manipulated the amount and identity of dietary polyunsaturated fatty acids (PUFA) in the food of D. melanogaster males (a treatment known to affect membrane fluidity) and measured changes in sperm parameters. We found that i) males reared on food containing PUFA-rich, plant-derived lipids showed a slower increase in sperm volume over male age compared to males reared on yeast-derived lipid food which is richer in saturated fatty acids. ii) The resistance of sperm membrane integrity to osmotic stress was not altered by dietary lipid treatment but iii) food containing yeast-derived lipids induced a 46% higher in-situ rate of production of reactive oxygen species in sperm cells. These findings show that dietary lipids have similar effects on sperm parameters in Drosophila as in vertebrates, affect some, but not all, sperm parameters, and modulate male reproductive ageing. In concert with recent findings of sex-specific seasonal variation of diet choice in the wild, our results suggest a substantial dietary impact on the dynamics of male reproduction in the wild.
    Keywords:  ROS production; dietary lipids; fluorescence lifetime; sperm membrane
    DOI:  https://doi.org/10.1111/jeb.13591
  640. J Assoc Physicians India. 2020 Jan;68(1): 78
    Wegner Granulomatosis -Great Masquiderer of Lung Malignancy.
    Prakash G, Rai M.
      
  641. Genes (Basel). 2020 Jan 23. pii: E124. [Epub ahead of print]11(2):
    Selection of the Reference Gene for Expression Normalization in Papaver somniferum L. under Abiotic Stress and Hormone Treatment.
    Zhang Z, Li C, Zhang J, Chen F, Gong Y, Li Y, Su Y, Wei Y, Zhao Y.
      Papaver somniferum L. is an important medical plant that produces analgesic drugs used for the pain caused by cancers and surgeries. Recent studies have focused on the expression genes involved in analgesic drugs biosynthesis, and the real-time quantitative polymerase chain reaction (RT-qPCR) technique is the main strategy. However, no reference genes have been reported for gene expression normalization in P. somniferum. Herein, nine reference genes (actin (ACT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cyclophilin 2 (CYP2), elongation factor 1-alpha (EF-1α), glyceraldehyde-3-phosphate dehydrogenase 2, cytosolic (GAPC2), nuclear cap-binding protein subunit 2 (NCBP2), protein phosphatase 2A (PP2A), TIP41-like protein (TIP41), and tubulin beta chain (TUB)) of P. somniferum were selected and analyzed under five different treatments (cold, drought, salt, heavy metal, and hormone stress). Then, BestKeeper, NormFinder, geNorm, and RefFinder were employed to analyze their gene expression stability. The results reveal that NCBP2 is the most stable reference gene under various experimental conditions. The work described here is the first report regarding on reference gene selection in P. somniferum, which could be used for the accurate normalization of the gene expression involved in analgesic drug biosynthesis.
    Keywords:  NormFinder; P. somniferum L.; RT-qPCR; RefFinder; geNorm; reference gene
    DOI:  https://doi.org/10.3390/genes11020124
  642. Med Phys. 2020 Jan 18.
    Experimental measurement of ionization chamber angular response and associated magnetic field correction factors in MR-linac.
    Iakovenko V, Keller B, Sahgal A, Sarfehnia A.
      PURPOSE: To measure ionization chamber dose response as a function of angle between magnetic field direction and ionization chamber orientation in magnetic resonance-guided radiation therapy (MRgRT) system, and to evaluate angular dependence of magnetic field correction factor for reference dosimetry.METHODS: Measurements were performed on an Elekta MR-linac that integrates a 1.5 T Philips MRI and a 7 MV FFF photon beam accelerator. The response of four reference class chambers (Exradin-A19, A1SL, IBA FC65-G and CC13, paired with a PTW UE electrometer) were studied. An in-house built MR-compatible water tank and an accompanying cylindrical insert that allowed chamber rotation around the cylinder's axis was used. The EPID onboard imaging was used to centre chamber at the MR-linac isocentre (143.5 cm, SAD), as well as to verify position at each datapoint.
    RESULTS: A clear angular dependence of dose response for all chambers has been measured. The most significant effect of magnetic field on relative chamber response in the presence of magnetic field was observed in the orientation when chamber axis is perpendicular to the direction of magnetic field with the tip pointing in the same direction as Lorentz force. This effect is more pronounced for larger volume chambers; the maximum relative variation in the chamber response (between the setup described above and the one where chamber and magnetic field are parallel) is a 5.3% and 4.6% increase for A19 and FC65-G respectively, and only 2.0% and 1.9% for smaller volume A1SL and CC13 chamber, respectively. We measured the absolute magnitude of the magnetic field correction factor k Q m a g for the Exradin-A19, A1SL, IBA FC65-G and CC13 to be 0.938 ± 1.13%, 0.968 ± 0.99%, 0.950 ± 1.13% and 0.975 ± 1.13%, respectively. The values are for perpendicular orientation of the chamber relative to magnetic field and parallel to the Lorentz force.
    CONCLUSIONS: Experimental measurements carried out in this study have verified the optimal orientation of ionization chamber in terms of minimizing effect of magnetic field on the chamber dose response. This study provides a detailed high resolution measurement of absolute k Q m a g values for 4 reference class chambers as a function of the angle between ionization chamber's central axis and the direction of strong magnetic field over a full 360-degree rotation. The experimental results of this study can further be used for optimization of the actual sensitive volume of the chamber (and analysis of dead volume) in future Monte Carlo chamber simulations in the presence of strong magnetic fields. In addition, it will provide some necessary data for future reference dosimetry protocols for MR-linac.
    Keywords:  MR-linac; MRgRT; dosimetry; ionization chamber; magnetic field correction factor; magnetic fields
    DOI:  https://doi.org/10.1002/mp.14025
  643. Commun Biol. 2020 Jan 23. 3(1): 42
    A normalized drug response metric improves accuracy and consistency of anticancer drug sensitivity quantification in cell-based screening.
    Gupta A, Gautam P, Wennerberg K, Aittokallio T.
      Accurate quantification of drug effects is crucial for identifying pharmaceutically actionable cancer vulnerabilities. Current cell viability-based measurements often lead to biased response estimates due to varying growth rates and experimental artifacts that explain part of the inconsistency in high-throughput screening results. We developed an improved drug scoring model, normalized drug response (NDR), which makes use of both positive and negative control conditions to account for differences in cell growth rates, and experimental noise to better characterize drug-induced effects. We demonstrate an improved consistency and accuracy of NDR compared to existing metrics in assessing drug responses of cancer cells in various culture models and experimental setups. Notably, NDR reliably captures both toxicity and viability responses, and differentiates a wider spectrum of drug behavior, including lethal, growth-inhibitory and growth-stimulatory modes, based on a single viability readout. The method will therefore substantially reduce the time and resources required in cell-based drug sensitivity screening.
    DOI:  https://doi.org/10.1038/s42003-020-0765-z
  644. Eur J Appl Physiol. 2020 Jan 23.
    Alterations in energy system contribution following upper body sprint interval training.
    La Monica MB, Fukuda DH, Starling-Smith TM, Clark NW, Panissa VLG.
      PURPOSE: The primary purpose of this study was to examine the influence of different work-to-rest ratios on relative energy system utilization during short-term upper-body sprint interval training (SIT) protocols.METHODS: Forty-two recreationally trained men were randomized into one of three training groups [10 s work bouts with 2 min of rest (10:2, n = 11) or 4 min of rest (10:4, n = 11), or 30 s work bouts with 4 min of rest (30:4, n = 10)] or a control group (CON, n = 10). Participants underwent six training sessions over 2 weeks with 4-6 'all-out' sprints. Participants completed an upper body Wingate test (30 s 'all-out' using 0.05 kg kg-1 of the participant's body mass) pre- and post-intervention from which oxygen consumption and blood lactate were used to estimate oxidative, glycolytic, and adenosine triphosphate-phosphocreatine (ATP-PCr) energy system provisions. An analysis of covariance was performed on all testing measurements collected at post with the associated pre-values used as covariates.
    RESULTS: Relative energy contribution (p = 0.026) and energy expenditure (p = 0.019) of the ATP-PCr energy system were greater in 10:4 (49.9%; 62.1 kJ) compared to CON (43.1%; 47.2 kJ) post training. No significant differences were found between groups in glycolytic or oxidative energy contribution over a 30 s upper body Wingate test.
    CONCLUSION: SIT protocols with smaller work-to-rest ratios may enhance ATP-PCr utilization in a 30 s upper body Wingate over a 2-week intervention.
    Keywords:  ATP-PCr; Energy expenditure; High-intensity interval training; Performance; Upper body training; Wingate test
    DOI:  https://doi.org/10.1007/s00421-020-04304-w
  645. Biochem Biophys Res Commun. 2020 Jan 18. pii: S0006-291X(20)30135-2. [Epub ahead of print]
    AIFM2 blocks ferroptosis independent of ubiquinol metabolism.
    Dai E, Zhang W, Cong D, Kang R, Wang J, Tang D.
      Ferroptosis is a multi-step regulated cell death that is characterized by excessive iron accumulation and lipid peroxidation. Cancer cells can acquire resistance to ferroptosis by the upregulation of anti-ferroptotic proteins or by the downregulation of pro-ferroptotic proteins. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1 or PRG3) has been recently demonstrated as an endogenous ferroptosis suppressor, but its mechanism remains obscure. Here, we show that AIFM2 blocks erastin-, sorafenib-, and RSL3-induced ferroptotic cancer cell death through a mechanism independent of ubiquinol, the reduced and active antioxidant form of coenzyme Q10. In contrast, AIFM2-dependent endosomal sorting complexes required for transport (ESCRT)-III recruitment in the plasma membrane is responsible for ferroptosis resistance through the activation of a membrane repair mechanism that regulates membrane budding and fission. Importantly, the genetic inhibition of the AIFM2-dependent ESCRT-III pathway increases the anticancer activity of sorafenib in a xenograft tumor mouse model. These findings shed new light on the mechanism involved in ferroptosis resistance during tumor therapy.
    Keywords:  AIFM2; CoQ10; ESCRT; Ferroptosis; Lipid peroxidation; Ubiquinol
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.066
  646. Adv Respir Med. 2019 ;87(6): 244-253
    Atypical manifestations of granulomatosis with polyangiitis: the diagnostic challenge for pulmonologists.
    Szymanowska-Narloch A, Gawryluk D, Błasińska-Przerwa K, Siemińska A.
      This is a review considering atypical manifestations of granulomatosis with polyangiitis (GPA). Virtually any organ can be affected, and in some patients, GPA can manifest unusually. Since thoracic involvement of GPA often predominates, the first who might be expected to establish a diagnosis are pulmonary specialists. We would like to familiarize pulmonary specialists with several extra-ELK (E: ear-nose-throat; L: lung; K: kidney) involvements of the disease. We describe sites rarely affected by GPA like the breast, skeletal system, orbit and eye, heart and vessels, central nervous system, urogenital system as well as endocrine and gastrointestinal tract involvement.
    Keywords:  atypical manifestations; breast; diagnosis; granulomatosis with polyangiitis; skeletal system; therapy; vasculitis
    DOI:  https://doi.org/10.5603/ARM.2019.0062
  647. Neurobiol Dis. 2020 Jan 21. pii: S0969-9961(20)30033-4. [Epub ahead of print] 104758
    Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease.
    Sah M, Shore AN, Petri S, Kanber A, Yang M, Weston MC, Frankel WN.
      Mutations in the X-linked gene IQSEC2 are associated with multiple cases of epilepsy, epileptic encephalopathy, intellectual disability and autism spectrum disorder, the mechanistic understanding and successful treatment of which remain a significant challenge in IQSEC2 and related neurodevelopmental genetic diseases. To investigate disease etiology, we studied behaviors and synaptic function in IQSEC2 deficient mice. Hemizygous Iqsec2 null males exhibit growth deficits, hyperambulation and hyperanxiety phenotypes. Adult hemizygotes experience lethal spontaneous seizures, but paradoxically have a significantly increased threshold to electrically induced limbic seizures and relative resistance to chemically induced seizures. Although there are no gross defects in brain morphology, hemizygotes exhibit stark hippocampal reactive astrogliosis. Electrophysiological recordings of hippocampal neurons reveal increased excitatory drive specifically onto interneurons, and significant alterations in intrinsic electrical properties specific to the interneuron population. As they age, hemizygotes also develop an increased abundance of parvalbumin-positive interneurons in the hippocampus, neurons in which IQSEC2 is expressed in addition to the excitatory neurons. These findings point to a novel role of IQSEC2 in hippocampal interneuron synaptic function and development with implications for a class of intractable neurodevelopmental diseases.
    Keywords:  Behavior; Epileptic encephalopathy; IQSEC2; Interneurons; Knockout mouse model; Seizure; Synaptic signaling
    DOI:  https://doi.org/10.1016/j.nbd.2020.104758
  648. Clin Biochem. 2020 Jan 20. pii: S0009-9120(19)30917-8. [Epub ahead of print]
    Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis.
    Paquette M, Gauthier D, Chamberland A, Prat A, De Lucia Rolfe E, Rasmussen JJ, Kaduka L, Seidah NG, Bernard S, Christensen DL, Baass A.
      BACKGROUND: In parallel to the increasing prevalence of metabolic syndrome, the prevalence of hepatic steatosis has also increased dramatically worldwide. Hepatic steatosis is a major risk factor of hepatic cirrhosis, cardiovascular disease and type 2 diabetes. Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been positively associated with the metabolic syndrome. However, the association between PCSK9 and the liver function is still controversial.OBJECTIVE: The objective of this study is to investigate the association between circulating PCSK9 levels and the presence of hepatic steatosis, as well as with liver biomarkers in a cohort of healthy individuals.
    METHODS: Total PCSK9 levels were measured by an in-house ELISA using a polyclonal antibody. Plasma albumin, alkaline phosphatase, ALT, AST, total bilirubin and GGT were measured in 698 individuals using the COBAS system. The presence of hepatic steatosis was assessed using ultrasound liver scans.
    RESULTS: In a multiple regression model adjusted for age, sex, insulin resistance, body mass index and alcohol use, circulating PCSK9 level was positively associated with albumin (β=0.102, P=0.008), alkaline phosphatase (β=0.201, P<0.0001), ALT (β=0.238, P<0.0001), AST (β=0.120, P=0.003) and GGT (β=0.103, P=0.007) and negatively associated with total bilirubin (β= -0.150, P<0.0001). Tertile of circulating PCSK9 was also associated with hepatic steatosis (OR 1.48, 95% CI 1.05-2.08, P=0.02).
    CONCLUSION: Our data suggest a strong association between PCSK9 and liver biomarkers as well as hepatic steatosis. Further studies are needed to explore the role of PCSK9 on hepatic function.
    Keywords:  Liver; PCSK9; hepatic steatosis; insulin resistance; metabolic syndrome
    DOI:  https://doi.org/10.1016/j.clinbiochem.2020.01.003
  649. BMB Rep. 2020 Jan 21. pii: 4775. [Epub ahead of print]
    Characterization of human cardiac mesenchymal stromal cells and their extracellular vesicles comparing with human bone marrow derived mesenchymal stem cells.
    Kang IS, Suh J, Lee MN, Lee C, Jin J, Lee C, Yang YI, Jang Y, Oh GT.
      Cardiac regeneration with adult stem-cell (ASC) therapy is a promising field to address advanced cardiovascular diseases. In addition, extracellular vesicles (EVs) from ASCs have been implicated in acting as paracrine factors to improve cardiac functions in ASC therapy. In our work, we isolated human cardiac mesenchymal stromal cells (h-CMSCs) by means of three-dimensional organ culture (3D culture) during ex vivo expansion of cardiac tissue, to compare the functional efficacy with human bone-marrow derived mesenchymal stem cells (h-BM-MSCs), one of the actively studied ASCs. We characterized the h-CMSCs as CD90low, c-kitnegative, CD105positive phenotype and these cells express NANOG, SOX2, and GATA4. To identify the more effective type of EVs for angiogenesis among the different sources of ASCs, we isolated EVs which were derived from CMSCs with either normoxic or hypoxic condition and BM-MSCs. Our in vitro tube-formation results demonstrated that the angiogenic effects of EVs from hypoxia-treated CMSCs (CMSC-Hpx EVs) were greater than the well-known effects of EVs from BM-MSCs (BM-MSC EVs), and these were even comparable to human vascular endothelial growth factor (hVEGF), a potent angiogenic factor. Therefore, we present here that CD90lowc-kitnegativeCD105positive CMSCs under hypoxic conditions secrete functionally superior EVs for in vitro angiogenesis. Our findings will allow more insights on understanding myocardial repair.
  650. iScience. 2020 Jan 24. pii: S2589-0042(19)30553-X. [Epub ahead of print]23(1): 100807
    Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity.
    Li G, Ding H, Yu X, Meng Y, Li J, Guo Q, Zhou H, Shen N.
      Dendritic cells (DCs) function is intimately linked to microenvironment and metabolism. Type I interferons (IFNs) condition dendritic cells to respond to weak self-signals, leading to autoimmunity. However, the metabolic adaption in the process is unclear. Here, we identified spermidine as a critical metabolite impacting the metabolic fitness of DC. First, dynamic metabolome screening indicated that spermidine decreased during IFN priming and following TLR7 ligand stimulation, accompanied by metabolic change from oxidative phosphorylation to glycolysis. Second, spermidine supplement restrained the glycolysis and prevented the overactivation of IFN-α primed DC both in vivo and in vitro. Third, mechanism study uncovered that the activity of FOXO3 adapted to the metabolic change, mediating the anti-inflammatory effect of spermidine. More importantly, addition of spermidine in vivo greatly alleviated the development of psoriasis-like symptom in mice. Thus, our studies revealed metabolic changes boosting DC responses and identified spermidine as a potential therapeutic agent for autoimmune diseases.
    Keywords:  Biological Sciences; Cell Biology; Immunology; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2019.100807
  651. J Biomol Struct Dyn. 2020 Jan 20. 1-15
    The performance of the single-walled carbon nanotube covalently modified with polyethylene glycol to delivery of Gemcitabine anticancer drug in the aqueous environment.
    Moradnia H, Raissi H, Shahabi M.
      A computational investigation of Gemcitabine drug adsorption on the single-walled carbon nanotube covalently modified with polyethylene glycol in a series of the configurations is studied using density functional theory calculations. It is observed that O…H hydrogen bonds are the dominating intermolecular interactions during the complex formation between anti-cancer drug and the nanotube. The studied hydrogen bonded complexes are treated theoretically to elucidate the nature of the intermolecular hydrogen bonds, geometrical structures, the binding energy and electron density topological analysis. The existence of the bond critical points between hydrogen and the electronegative atoms and their concomitant bond paths which connect the bond critical points to the two interacting atoms confirm by Quantum Theory of Atoms in Molecules method. In addition, considering the charge transfer for all of the adsorbed configurations reveals the capability of the drug molecule to accept precisely the electron from the functionalized carbon nanotube during the drug adsorption on external surface of the carbon nanotube. Also, the effect of weight percent of polyethylene glycol on the drug adsorption strength is investigated by molecular dynamics simulations.
    Keywords:  Density functional theory; Gemcitabine drug delivery; Molecular dynamics simulation; Non-covalent interaction; Polymer-functionalized carbon nanotube
    DOI:  https://doi.org/10.1080/07391102.2020.1719204
  652. Int J Obes (Lond). 2020 Jan 21.
    Physical activity attenuates metabolic risk of adolescents with overweight or obesity: the ICAD multi-country study.
    Werneck AO, Silva DR, Oyeyemi AL, Fernandes RA, Steene-Johannesen J, Andersen LB, Northstone K, Sardinha LB, .
      BACKGROUND: Although the benefits of physical activity (PA) at an early age are well established, there is no robust evidence of the role of PA as well as its intensities in attenuating the association between weight status and metabolic risk among adolescents. In this investigation, we analyzed the association between weight status, intensities of PA, and metabolic risk among adolescents.METHODS: Data from six cross-sectional studies in the International Children's Accelerometry Database were used (N = 5216 adolescents; boys 14.6 ± 2.1 years and girls 14.7 ± 2.0 years). Weight status was assessed and classified according to body mass index. Fasting glucose, triglycerides, inverse high-density lipoprotein cholesterol, and blood pressure composed the metabolic risk indicator (z-score). PA was measured by accelerometers. The estimated age of peak height velocity was used as a covariate for somatic maturation.
    RESULTS: We observed that increase in weight status showed a strong positive relationship with metabolic risk. However, adolescents with overweight or obesity in the highest tertile of PA (moderate-to-vigorous and vigorous intensity) showed a similar metabolic risk score as the normal weight groups. Moderate intensity PA seemed related to metabolic risk even within some categories of vigorous PA.
    CONCLUSIONS: We conclude that PA attenuates the metabolic risk of adolescents with overweight or obesity. Although this attenuation is largely explained by vigorous PA, moderate intensity seems also important for better metabolic profile.
    DOI:  https://doi.org/10.1038/s41366-020-0521-y
  653. Am J Nucl Med Mol Imaging. 2019 ;9(6): 296-308
    [89Zr]Zr-rituximab PET/CT activity in patients with therapy refractory interstitial pneumonitis: a feasibility study.
    Adams H, van de Garde EM, van Moorsel CH, Vugts DJ, van Dongen GA, Grutters JC, Keijsers RG.
      Recent studies on immune-mediated inflammatory lung diseases show encouraging treatment results with rituximab, a monoclonal antibody (mAb) against CD20-expressing B lymphocytes. The present pilot study aimed to explore the possibility to image CD20-expression in the lungs as future early predictor of treatment response. We describe a series of 10 patients with therapy refractory interstitial pneumonitis who were treated with rituximab (1000 mg at day 0 and day 14) and underwent PET/CT after the administration of [89Zr]Zr-N-suc-DFO-rituximab abbreviated as [89Zr]Zr-rituximab. [89Zr]-rituximab PET/CT of the chest was performed on day 3 and 6. [89Zr]Zr-rituximab PET/CT showed visual and quantifiable increased pulmonary activity in four patients. Other patients demonstrated no increased activity in the lungs. One patient developed a severe allergic reaction during infusion of the first 10% unlabeled rituximab after which rituximab infusion was ceased. Subsequent administration of [89Zr]Zr-rituximab, however, did not result in any adverse reaction. This patient demonstrated the highest uptake of [89Zr]Zr-rituximab in mediastinal lymph nodes and lung parenchyma compared to the other 9 patients who did receive the full dose rituximab before [89Zr]Zr-rituximab. This pilot study demonstrates that [89Zr]Zr-rituximab PET/CT imaging in patients with therapy refractory interstitial pneumonitis is feasible and shows lung-specific uptake in some patients. Further research with larger sample size should establish if the [89Zr]Zr-rituximab uptake correlates with treatment response to rituximab. The higher uptake in the absence of a full 1000 mg rituximab preload may suggest that future studies should consider [89Zr]Zr-rituximab imaging at low mAb dose before treatment with rituximab.
    Keywords:  Rituximab; [89Zr]Zr-rituximab PET/CT; immuno-PET; interstitial pneumonitis; pulmonary activity; zirconium
  654. Mol Cancer Ther. 2020 Jan 23. pii: molcanther.0947.2019. [Epub ahead of print]
    Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression.
    Joshi S, Liu KX, Zulcic M, Singh AR, Skola D, Glass CK, Sanders PD, Sharabi AB, Pham TV, Tamayo P, Shiang D, Dinh HQ, Hedrick CC, Morales GA, Garlich JR, Durden DL.
      Macrophages (MΦ) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for Transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow derived macrophages (BMDMs) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the "first in class" dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-19-0947
  655. Sci Total Environ. 2020 Jan 07. pii: S0048-9697(19)36477-0. [Epub ahead of print]713 136481
    Metal bioaccessibility, particle size distribution and polydispersity of playground dust in synthetic lysosomal fluids.
    Meza-Figueroa D, Barboza-Flores M, Romero FM, Acosta-Elias M, Hernández-Mendiola E, Maldonado-Escalante F, Pérez-Segura E, González-Grijalva B, Meza-Montenegro M, García-Rico L, Navarro-Espinoza S, Santacruz-Gómez K, Gallego-Hernández A, Pedroza-Montero M.
      Inhalation of playground dust-derived fine particles in schoolyards poses a risk from exposure to metal(oids) and minerals. In this work, we obtained the total concentration and bioaccessibility of metal(oids) with Gamble Solution (GS) and Artificial Lysosomal Fluid (ALF) synthetic solutions, simulating the extracellular neutral pH environment of the lung and the intracellular conditions of the macrophage, respectively. Scanning Electron Microscope (SEM), and Dynamic Light Scattering analysis (DLS) techniques were used to characterize particles with a size smaller than 2.5 μm, which can be assimilated by macrophages in the deep part of the lung. Arsenic (As), lead (Pb), copper (Cu), manganese (Mn), zinc (Zn), and iron (Fe) showed concentrations of 39.9, 147.9, 286, 1369, 2313, 112,457 mg·kg-1, respectively. The results indicated that all studied elements were enriched when compared to (i) local geochemical background and (ii) findings reported in other cities around the world. Bioaccessibility of metal(oids) in GS was low-moderate for most studied elements. However, in ALF assays, bioaccessibility was high among the samples: for lead (Pb = 34-100%), arsenic (As = 14.7-100%), copper (Cu = 17.9-100%), and zinc (Zn = 35-52%) possibly related to hydrophobic minerals in dust. SEM and DLS image analysis showed that playground dust particles smaller than 2.5 μm are dominant, particularly particles with a size range of 500-600 nm. The polydispersity detected in these particle sizes showed that most of them might be crystalline compounds (elongated shapes) forming agglomerates instead of combustion particles (spheres). Moreover, the circularity detected varies from 0.57 to 0.79 (low roundness), which corroborates this finding. The presence of agglomerates of ultrafine/nanoparticles containing highly bioaccessible metals in playground sites may have severe implications in children's health. Therefore, further studies are required to characterize the size distribution, structure, shape and composition of such minerals which are essential factors related to the toxicology of inhaled dust particles.
    Keywords:  Agglomerates; Lung bioaccessibility; Metal(oids); Particle size; Playground dust
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.136481
  656. Semin Roentgenol. 2020 Jan;pii: S0037-198X(19)30082-3. [Epub ahead of print]55(1): 60-69
    Surveillance Imaging After Curative Intent Therapy for Lung Cancer.
    Omballi M, Fernandez-Bussy S, Patel PP, Jantz MA, Becnel D, Patel NM, Mehta HJ.
      
    DOI:  https://doi.org/10.1053/j.ro.2019.10.008
  657. Metabolomics. 2020 Jan 23. 16(2): 18
    LC-MS untargeted approach showed that methyl jasmonate application on Vitis labrusca L. grapes increases phenolics at subtropical Brazilian regions.
    Moro L, Da Ros A, da Mota RV, Purgatto E, Mattivi F, Arapitsas P.
      INTRODUCTION: Vitis labrusca L. grapes are largely cultivated in Brazil, but the tropical climate negatively affects the phenols content, especially anthocyanin. According to the projections of the incoming climatic changes, the climate of several viticulture zone might change to tropical. Therefore, researches are focusing on increasing grape phenols content; with methyl jasmonate application (MeJa) is considered a good alternative.OBJECTIVES: The aim was to investigate with an untargeted approach the metabolic changes caused by the MeJa pre-harvest application on two Vitis labrusca L. cultivars grapes, both of them grown in two Brazilian regions.
    METHODS: Isabel Precoce and Concord grapes cultivated under subtropical climate, in the south and southeast of Brazil, received MeJa pre-harvest treatment. Grape metabolome was extracted and analyzed with a MS based metabolomics protocol by UPLC-HRMS-QTOF.
    RESULTS: Unsupervised data analysis revealed a clear separation between the two regions and the two cultivars, while supervised data analysis revealed biomarkers between the MeJa treatment group and the control group. Among the metabolites positively affected by MeJa were (a) flavonoids with a high degree of methylation at the B-ring (malvidin and peonidin derivatives and isorhamentin) for Isabel Precoce grapes; (b) glucosides of hydroxycinnamates, gallocatechin, epigallocatechin and cis-piceid for Concord grapes; and (c) hydroxycinnamates esters with tartaric acid, and procyanidins for the Southeast region grapes.
    CONCLUSION: These results suggest that MeJa can be used as elicitor to secondary metabolism in grapes grown even under subtropical climate, affecting phenolic biosynthesis.
    Keywords:  LC–MS; Methyl jasmonate; Phenols; Pigments; Stilbenoids; Vitis labrusca
    DOI:  https://doi.org/10.1007/s11306-020-1641-z
  658. Arch Pediatr. 2020 Jan 16. pii: S0929-693X(19)30230-1. [Epub ahead of print]
    Metabolic disturbances and cardiovascular risk factors in obese children with vitamin D deficiency.
    Colak R, Anil M, Yasar F, Rahmi Bakiler A, Pirgon O, Helvaci M, Dündar B.
      OBJECTIVES: The prevalence of obesity among children and adolescents has been rapidly increasing in recent years. Obese individuals are at risk of vitamin D deficiency. The aim of this study was to investigate the relationship between vitamin D deficiency and anthropometric measurements, cardiovascular risk factors, and glucose homeostasis in obese children.METHODS: Between June 2011 and January 2012, 40 obese and 30 non-obese children (between 7 and 14 years of age) were evaluated at Tepecik Training and Research Hospital. The following characteristics were recorded: height; weight; body mass index (BMI); total body fat content; fasting glucose, insulin, and lipid levels; basic biochemical parameters; complete blood count; bilateral carotid intima media thickness; liver ultrasound results; and left ventricular wall thickness were recorded. 25-hydroxy (OH) vitamin D levels were measured from serum.
    RESULTS: The serum 25(OH) vitamin D level was low in 45 children (64.3%). The 24-h ambulatory blood pressure measurements, carotid intima-media thickness, and the prevalence of 25(OH) vitamin D deficiency were different between obese and non-obese children (P<0.05). The incidence of dyslipidemia was not statistically different between obese and non-obese children (P>0.05). Plasma 25(OH) vitamin D concentrations were negatively correlated with age, BMI, total body fat content, 24-h ambulatory blood pressure, and carotid intima-media thickness (P<0.05). Plasma 25(OH) vitamin D levels were not correlated with fasting plasma glucose, HOMA-IR, triglycerides, total cholesterol, low-density cholesterol, and high-density cholesterol (P>0.05).
    CONCLUSION: Vitamin D deficiency is more prevalent in obese children. Serum 25(OH)vitamin D was significantly associated with several cardiometabolic risk factors. There was no relationship between abnormal glucose homeostasis and dyslipidemia with vitamin D deficiency in obese children.
    Keywords:  Cardiovascular risk factors; Children; Insulin resistance; Obesity; Vitamin D deficiency
    DOI:  https://doi.org/10.1016/j.arcped.2019.12.005
  659. Rev Esp Enferm Dig. 2020 Jan 21. 112
    An atypical bronchogenic cyst with yeast over-infection.
    Viso Vidal D, Villanueva Pavón R, Hernando Martín M.
      Bronchogenic cysts (BC) are rare congenital anomalies that result from abnormal budding of the tracheobronchial tree during fetal development. BC are usually located in the lung and the mediastinum, an abdominal location is unusual.
    DOI:  https://doi.org/10.17235/reed.2020.6560/2019
  660. Nanomaterials (Basel). 2020 Jan 21. pii: E183. [Epub ahead of print]10(2):
    Multifunctional Nanocarriers for Lung Drug Delivery.
    Pontes JF, Grenha A.
      Nanocarriers have been increasingly proposed for lung drug delivery applications. The strategy of combining the intrinsic and more general advantages of the nanostructures with specificities that improve the therapeutic outcomes of particular clinical situations is frequent. These include the surface engineering of the carriers by means of altering the material structure (i.e., chemical modifications), the addition of specific ligands so that predefined targets are reached, or even the tuning of the carrier properties to respond to specific stimuli. The devised strategies are mainly directed at three distinct areas of lung drug delivery, encompassing the delivery of proteins and protein-based materials, either for local or systemic application, the delivery of antibiotics, and the delivery of anticancer drugs-the latter two comprising local delivery approaches. This review addresses the applications of nanocarriers aimed at lung drug delivery of active biological and pharmaceutical ingredients, focusing with particular interest on nanocarriers that exhibit multifunctional properties. A final section addresses the expectations regarding the future use of nanocarriers in the area.
    Keywords:  antibiotics; cancer; drug delivery; lung delivery; nanocarriers; nanopharmaceuticals; proteins
    DOI:  https://doi.org/10.3390/nano10020183
  661. Lab Chip. 2020 Jan 23.
    A self-calibrating and multiplexed electrochemical lab-on-a-chip for cell culture analysis and high-resolution imaging.
    Giménez-Gómez P, Rodríguez-Rodríguez R, Ríos JM, Pérez-Montero M, González E, Gutiérrez-Capitán M, Plaza JA, Muñoz-Berbel X, Jiménez-Jorquera C.
      In vitro analysis requires cell proliferation in conditions close to physiological ones. Lab-on-a-chip (LoC) devices simplify, miniaturize and automate traditional protocols, with the advantages of being less expensive and faster due to their shorter diffusion distances. The main limitation of current LoCs is still the control of the culture conditions. Most LoCs employ off-chip equipment to determine cell culture activity, which confers limited monitoring capacity. The few systems integrating transducers on-chip present important functional problems mostly associated with the attachment of biomolecules to the transducer surface (i.e., biofouling) and the impossibility of re-calibrating the sensors during cell culturing. This limitation is addressed in the present LoC containing a network of micro-channels and micro-chambers, which allows (i) cell seeding and cultivation, avoiding biofouling risk, (ii) multiplexed analysis of cell culture, reactivation and recalibration of the (bio)sensors without compromising cell viability, (iii) cell imaging and (iv) reference electrode compartmentalization to guarantee stability. The activity of the culture is monitored with four independent electrochemical micro-electrodes for glucose, hydrogen peroxide, conductivity and oxidation reduction potential. Electrochemical analysis is complemented with high-resolution confocal microscopy analysis. This paper demonstrates the suitability of the current configuration for cell culture monitoring and future applications in drug screening or organ-on-a-chip development.
    DOI:  https://doi.org/10.1039/c9lc01051c
  662. J Clin Invest. 2020 Jan 21. pii: 97040. [Epub ahead of print]
    GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
    Cheng J, Klei LR, Hubel NE, Zhang M, Schairer R, Maurer LM, Klei HB, Kang H, Concel VJ, Delekta PC, Dang EV, Mintz MA, Baens M, Cyster JG, Parameswaran N, Thome M, Lucas PC, McAllister-Lucas LM.
      Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery, and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.
    Keywords:  Immunology; Lymphomas; NF-kappaB; Oncology; Signal transduction
    DOI:  https://doi.org/10.1172/JCI97040
  663. Int J Mol Sci. 2020 Jan 22. pii: E724. [Epub ahead of print]21(3):
    Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network.
    Kang Q, Hu M, Jia J, Bai X, Liu C, Wu Z, Chen W, Li M.
      The glucagon receptor (GCGR) is a G-protein-coupled receptor (GPCR) that mediates the activity of glucagon. Disruption of GCGR results in many metabolic alterations, including increased glucose tolerance, decreased adiposity, hypoglycemia, and pancreatic α-cell hyperplasia. To better understand the global transcriptomic changes resulting from GCGR deficiency, we performed whole-organism RNA sequencing analysis in wild type and gcgr-deficient zebrafish. We found that the expression of 1645 genes changes more than two-fold among mutants. Most of these genes are related to metabolism of carbohydrates, lipids, and amino acids. Genes related to fatty acid β-oxidation, amino acid catabolism, and ureagenesis are often downregulated. Among gcrgr-deficient zebrafish, we experimentally confirmed increases in lipid accumulation in the liver and whole-body glucose uptake, as well as a modest decrease in total amino acid content. These results provide new information about the global metabolic network that GCGR signaling regulates in addition to a better understanding of the receptor's physiological functions.
    Keywords:  RNA sequencing; diabetes; glucagon receptor; metabolic network; zebrafish
    DOI:  https://doi.org/10.3390/ijms21030724
  664. World J Clin Cases. 2020 Jan 06. 8(1): 1-10
    Role of oxysterol-binding protein-related proteins in malignant human tumours.
    Liu H, Huang S.
      The oxysterol-binding protein-related protein (ORP) family is a group of proteins that mediate oxysterol metabolism and bioactivity in cells. ORPs constitute a large family of lipid transfer proteins. Much of the current evidence indicates that certain members of the family of oxysterol-binding proteins (OSBPs) can lead to cancer. Many studies have revealed the putative roles of OSBPs in various cancer types. However, the exact effects and mechanisms of action of members of the OSBP/ORP family in cancer initiation and progression are currently unclear. This review focuses on ORP family members that can accelerate human tumour cell proliferation, migration, and invasion. The mechanisms and functions of various ORPs are introduced in detail. We also attempt to identify the roles of these proteins in malignant tumours with the ultimate aim of determining the exact role of the OSBP/ORP family in human tumour cells.
    Keywords:  Human tumour; Malignant tumour; Oxysterol-binding protein family; Oxysterol-binding protein-related protein; Role; Tumour proliferation, migration, and invasion
    DOI:  https://doi.org/10.12998/wjcc.v8.i1.1
  665. Molecules. 2020 Jan 16. pii: E367. [Epub ahead of print]25(2):
    Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes.
    Rundgren IM, Ryningen A, Anderson Tvedt TH, Bruserud Ø, Ersvær E.
      Immunomodulatory drugs (IMiDs) are used in the treatment of hematological malignancies, especially multiple myeloma. IMiDs have direct anticancer effects but also indirect effects via cancer-supporting stromal cells. Monocytes are a stromal cell subset whose metabolism is modulated by the microenvironment, and they communicate with neighboring cells through extracellular release of soluble mediators. Toll-like receptor 4 (TLR4) is then a common regulator of monocyte metabolism and mediator release. Our aim was to investigate IMiD effects on these two monocyte functions. We compared effects of thalidomide, lenalidomide, and pomalidomide on in vitro cultured normal monocytes. Cells were cultured in medium alone or activated by lipopolysaccharide (LPS), a TLR4 agonist. Metabolism was analyzed by the Seahorse XF 96 cell analyzer. Mediator release was measured as culture supernatant levels. TLR4 was a regulator of both monocyte metabolism and mediator release. All three IMiDs altered monocyte metabolism especially when cells were cultured with LPS; this effect was strongest for lenalidomide that increased glycolysis. Monocytes showed a broad soluble mediator release profile. IMiDs decreased TLR4-induced mediator release; this effect was stronger for pomalidomide than for lenalidomide and especially thalidomide. To conclude, IMiDs can alter the metabolism and cell-cell communication of normal monocytes, and despite their common molecular target these effects differ among various IMiDs.
    Keywords:  cell metabolism; cytokines; immunomodulatory drugs; monocytes
    DOI:  https://doi.org/10.3390/molecules25020367
  666. Ann Oncol. 2020 Feb;pii: S0923-7534(19)39095-7. [Epub ahead of print]31(2): 167-168
    Using personalized immune-humanized xenograft mouse models to predict immune checkpoint responses in malignant melanoma: potential and hurdles.
    Helleday T.
      
    DOI:  https://doi.org/10.1016/j.annonc.2019.11.007
  667. J Mol Biol. 2020 Jan 18. pii: S0022-2836(20)30069-3. [Epub ahead of print]
    Autophagy as a cellular stress response mechanism in the nervous system.
    Peker N, Gozuacik D.
      Cells of an organism face with various types of insults during their lifetime. Exposure to toxins, metabolic problems, ischemia/reperfusion, physical trauma, genetic diseases, neurodegenerative diseases are among the conditions that trigger cellular stress responses. In this context, autophagy is one of the mechanisms that supports cell survival under stressful conditions. Autophagic vesicle engulf the cargo and transport it to lysosome for degradation and turnover. As such, autophagy eliminates abnormal proteins, clears damaged organelles, limits oxidative stress and helps to improve metabolic balance. Nervous system cells and particularly post-mitotic neurons are highly sensitive to a spectrum of insults, and autophagy emerges as one of the key stress response mechanism, ensuring health and survival of these vulnerable cell types. In this review, we will overview mechanisms through which cells cope with stress, and how these stress responses regulate autophagy, with a special focus on the nervous system.
    Keywords:  autophagy; cellular stress; nervous system; neurodegenerative disease; neuron
    DOI:  https://doi.org/10.1016/j.jmb.2020.01.017
  668. Bioorg Chem. 2020 Jan 15. pii: S0045-2068(19)31311-2. [Epub ahead of print]96 103581
    Dihydropyridines as potential α-amylase and α-glucosidase inhibitors: Synthesis, in vitro and in silico studies.
    Yousuf H, Shamim S, Khan KM, Chigurupati S, Kanwal , Hameed S, Khan MN, Taha M, Arfeen M.
      Dihydropyridine derivatives 1-31 were synthesized via one-pot solvent free condition and screened for in vitro against α-amylase and α-glucosidase enzyme. The synthetic derivatives 1-31 showed good α-amylase inhibition in the range of IC50 = 2.21 ± 0.06-9.97 ± 0.08 µM, as compared to the standard drug acarbose (IC50 = 2.01 ± 0.1 µM) and α-glucosidase inhibition in the range of IC50 = 2.31 ± 0.09-9.9 ± 0.1 µM as compared to standard acarbose (IC50 = 2.07 ± 0.1 µM), respectively. To determine the mode of binding interactions of synthetic molecules with active sites of enzyme, molecular docking studies were also performed. Different spectroscopic techniques such as 1H, 13C NMR, EI-MS, and HREI-MS were used to characterize all the synthetic compounds.
    Keywords:  Dihydropyridine; In silico studies; In vitro; Structure-activity relationship (SAR); Synthesis; α-amylase; α-glucosidase
    DOI:  https://doi.org/10.1016/j.bioorg.2020.103581
  669. J Integr Plant Biol. 2020 Jan 21.
    Phototropin- and photosynthesis-dependent mitochondrial positioning in Arabidopsis thaliana mesophyll cells.
    Islam MS, Van Nguyen T, Sakamoto W, Takagi S.
      Mitochondria are frequently observed in the vicinity of chloroplasts in photosynthesizing cells, and this association is considered necessary for their metabolic interactions. We previously reported that, in leaf palisade cells of Arabidopsis thaliana, mitochondria exhibit blue-light-dependent redistribution together with chloroplasts, which conduct accumulation and avoidance responses under the control of blue-light receptor phototropins. In this study, precise motility analyses by fluorescent microscopy revealed that the individual mitochondria in palisade cells, labeled with green fluorescent protein, exhibit typical stop-and-go movement. When exposed to blue light, the velocity of moving mitochondria increased in 30 min, whereas after 4 h, the frequency of stoppage of mitochondrial movement markedly increased. Using different mutant plants, we concluded that the presence of both phototropin1 and phototropin2 is necessary for the early acceleration of mitochondrial movement. On the contrary, the late enhancement of stoppage of mitochondrial movement occurs only in the presence of phototropin2 and only when intact photosynthesis takes place. A plasma-membrane ghost assay suggested that the stopped mitochondria are firmly adhered to chloroplasts. These results indicate that the physical interaction between mitochondria and chloroplasts is cooperatively mediated by phototropin2- and photosynthesis-dependent signals. The present study might add novel regulatory mechanism for light-dependent plant organelle interactions. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/jipb.12910
  670. Endocr Connect. 2020 Jan 01. pii: EC-19-0478.R1. [Epub ahead of print]
    Studies of mice deleted for Sox3 and uc482: relevance to X-linked hypoparathyroidism.
    Gaynor KU, Grigorieva IV, Mirczuk SM, Piret S, Kooblall KG, Stevenson M, Rizzoti K, Bowl MR, Nesbit MA, Christie PT, Fraser WD, Hough T, Whyte MP, Lovell-Badge R, Thakker R.
      Hypoparathyroidism is genetically heterogeneous and characterized by low plasma calcium and parathyroid hormone (PTH) concentrations. X-linked hypoparathyroidism (XLHPT) in two American families, is associated with interstitial deletion-insertions involving deletions of chromosome Xq27.1 downstream of SOX3 and insertions of predominantly non-coding DNA from chromosome 2p25.3. These could result in loss, gain, or movement of regulatory elements, which include ultraconserved element uc482, that could alter SOX3 expression,. To investigate this, we analysed SOX3 expression in EBV-transformed lymphoblastoid cells from 3 affected males, 3 unaffected males, and 4 carrier females from one XLHPT family. SOX3 expression was similar in all individuals, indicating that the spatiotemporal effect of the interstitial deletion-insertion on SOX3 expression postulated to occur in developing parathyroids did not manifest in lymphoblastoids. Expression of SNTG2, which is duplicated and inserted into the X chromosome, and ATP11C, which is moved telomerically, were also similarly expressed in all individuals. Investigation of male hemizygous (Sox3-/Y and uc482-/Y) and female heterozygous (Sox3+/- and uc482+/-) knock-out mice, together with wild-type littermates (male Sox3+/Y and uc482+/Y, and female Sox3+/+ and uc482+/+), revealed Sox3-/Y, Sox3+/-, uc482-/Y, and uc482+/- mice to have normal plasma biochemistry, compared to their respective wild-type littermates. When challenged with a low calcium diet, all mice had hypocalcaemia, and elevated plasma PTH concentrations and alkaline phosphatase activities, and Sox3-/Y, Sox3+/-, uc482-/Y, and uc482+/- mice had similar plasma biochemistry, compared to wild-type littermates. Thus, these results indicate that absence of Sox3 or uc482 does not cause hypoparathyroidism, and that XLHPT likely reflects a more complex mechanism.
    DOI:  https://doi.org/10.1530/EC-19-0478
  671. J Mater Chem B. 2020 Jan 24.
    A new strategy to improve the water solubility of an organic fluorescent probe using silicon nanodots and fabricate two-photon SiND-ANPA-N3 for visualizing hydrogen sulfide in living cells and onion tissues.
    Fu YJ, Shen SS, Guo XF, Wang H.
      A small-molecule fluorescent probe offers unique advantages for the detection of hydrogen sulfide (H2S) and other reactive small molecules including high sensitivity, cell permeability and high spatiotemporal resolution. Generally, in order to obtain good cell permeability, fluorescent probes are liposoluble, which in turn leads to poor water solubility. Thus, it is regrettable that most of these fluorescent probes cannot be used in fully aqueous systems and hence, organic solvents are used, which may cause negative effects on living cells. Silicon nanodots (SiNDs) have been widely used in many fields due to good water solubility, benign nature, biocompatibility and low toxicity. Herein, we proposed a two-photon SiND-ANPA-N3 fluorescent probe with good water solubility, excellent biocompatibility and low toxicity; it is suitable to detect H2S in totally aqueous media and living cells. This strategy may provide a technically simple and facile approach for designing fluorescent probes with excellent solubility, benign nature, and biocompatibility for use in fully aqueous systems and in vivo.
    DOI:  https://doi.org/10.1039/c9tb02237f
  672. Neuroimage. 2020 Jan 20. pii: S1053-8119(20)30031-8. [Epub ahead of print] 116544
    Striatal iron content is linked to reduced fronto-striatal brain function under working memory load.
    Rodrigue KM, Daugherty AM, Foster CM, Kennedy KM.
      Non-heme iron accumulation contributes to age-related decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. N = 166 healthy adults (age 20-94) underwent cognitive testing and an imaging session including n-back (0-, 2-, 3-, and 4-back fMRI), R2*-weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an age × iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middle-aged and younger adults with greater iron content. Further, iron-related decreases in modulation were associated with poorer executive function in an age-dependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.
    Keywords:  Aging; Iron; Striatal; Working memory; fMRI
    DOI:  https://doi.org/10.1016/j.neuroimage.2020.116544
  673. Curr Top Dev Biol. 2020 ;pii: S0070-2153(19)30099-7. [Epub ahead of print]136 429-454
    Guts and gastrulation: Emergence and convergence of endoderm in the mouse embryo.
    Nowotschin S, Hadjantonakis AK.
      Gastrulation is a central process in mammalian development in which a spatiotemporally coordinated series of events driven by cross-talk between adjacent embryonic and extra-embryonic tissues results in stereotypical morphogenetic cell behaviors, massive cell proliferation and the acquisition of distinct cell identities. Gastrulation provides the blueprint of the body plan of the embryo, as well as generating extra-embryonic cell types of the embryo to make a connection with its mother. Gastrulation involves the specification of mesoderm and definitive endoderm from pluripotent epiblast, concomitant with a highly ordered elongation of tissue along the anterior-posterior (AP) axis. Interestingly, cells with an endoderm identity arise twice during mouse development. Cells with a primitive endoderm identity are specified in the preimplantation blastocyst, and which at gastrulation intercalate with the emergent definitive endoderm to form a mosaic tissue, referred to as the gut endoderm. The gut endoderm gives rise to the gut tube, which will subsequently become patterned along its AP axis into domains possessing unique visceral organ identities, such as thyroid, lung, liver and pancreas. In this way, proper endoderm development is essential for vital organismal functions, including the absorption of nutrients, gas exchange, detoxification and glucose homeostasis.
    Keywords:  Definitive endoderm; EMT; Gastrulation; Gut endoderm; Gut tube; Intercalation; MET; Mesoderm; Mouse development; Preimplantation; Primitive endoderm; Visceral endoderm
    DOI:  https://doi.org/10.1016/bs.ctdb.2019.11.012
  674. Chirurg. 2020 Jan 21.
    [Neoadjuvant treatment of primarily resectable and borderline resectable pancreatic cancer].
    Scheufele F, Friess H.
      Due to the increasing prevalence pancreatic cancer represents a severe tumor burden to the population and will be ranked second for cancer-related mortality by the year 2030. If a curative approach is pursued a radical R0 resection of the tumor with sufficient cancer-free resection margins (≥1 mm) should be performed. This has been shown to be associated with a clear benefit for survival. For treatment planning of pancreatic cancer the tumor stage plays a pivotal role. In cases of distant metastases a palliative concept is normally initiated. If no distant metastases are detected neoadjuvant treatment can be performed in cases of borderline resectability or locally advanced stages in order to downsize these tumors. In this situation a neoadjuvant treatment has been shown to significantly increase resectability rates and to improve the tumor stage (downstaging). The most recent randomized trials were able to show a significant survival advantage of neoadjuvant treatment for borderline resectable pancreatic cancer. In cases of primarily resectable pancreatic cancer the current standard of care is an upfront resection followed by adjuvant chemotherapy. Initial data are also available indicating a survival benefit even for resectable pancreatic cancer after neoadjuvant treatment; however, reliable randomized controlled trials showing a survival advantage of neoadjuvant treatment compared to the current standard treatment of adjuvant chemotherapy following resection are missing. Numerous randomized controlled trials investigating the efficacy of neoadjuvant chemotherapy for resectable pancreatic cancer are currently underway.
    Keywords:  Chemoradiotherapy; Chemotherapy; Ductal adenocarcinoma of the pancreas; Prognosis; Resection status
    DOI:  https://doi.org/10.1007/s00104-019-01093-7
  675. Cancers (Basel). 2020 Jan 22. pii: E268. [Epub ahead of print]12(2):
    Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin.
    Nguyen YT, Moon JY, Ediriweera MK, Cho SK.
      Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan-Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, including β-catenin, CD44+, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.
    Keywords:  cancer stem cells; metadherin; phenethyl isothiocyanate; reactive oxygen species; resistance
    DOI:  https://doi.org/10.3390/cancers12020268
  676. ACS Omega. 2020 Jan 14. 5(1): 822-831
    Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.
    Huggins DJ, Hardwick BS, Sharma P, Emery A, Laraia L, Zhang F, Narvaez AJ, Roberts-Thomson M, Crooks AT, Boyle RG, Boyce R, Walker DW, Mateu N, McKenzie GJ, Spring DR, Venkitaraman AR.
      Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a recognized drug target for cancer therapy. Inhibiting the polo-box domain of PLK1 offers potential advantages of increased selectivity and subsequently reduced toxicity compared with targeting the kinase domain. However, many if not all existing polo-box domain inhibitors have been shown to be unsuitable for further development. In this paper, we describe a novel compound series, which inhibits the protein-protein interactions of PLK1 via the polo-box domain. We combine high throughput screening with molecular modeling and computer-aided design, synthetic chemistry, and cell biology to address some of the common problems with protein-protein interaction inhibitors, such as solubility and potency. We use molecular modeling to improve the solubility of a hit series with initially poor physicochemical properties, enabling biophysical and biochemical characterization. We isolate and characterize enantiomers to improve potency and demonstrate on-target activity in both cell-free and cell-based assays, entirely consistent with the proposed binding model. The resulting compound series represents a promising starting point for further progression along the drug discovery pipeline and a new tool compound to study kinase-independent PLK functions.
    DOI:  https://doi.org/10.1021/acsomega.9b03626
  677. FEMS Microbiol Lett. 2020 Jan 22. pii: fnaa015. [Epub ahead of print]
    Functions of reactive oxygen species in apoptosis and ganoderic acid biosynthesis in Ganoderma lucidum.
    Zhu J, Wu F, Yue S, Chen C, Song S, Wang H, Zhao M.
      Ganoderma lucidum is a medicinal fungus that is widely used in traditional medicine. Fungal PacC is recognized as an important transcription factor that functions during adaptation to environmental pH, fungal development and secondary metabolism. Previous studies have revealed that GlPacC plays important roles in mycelial growth, fruiting body development and ganoderic acid (GA) biosynthesis. In this study, using a TUNEL assay, we found that the apoptosis level was increased when PacC was silenced. The transcript and activity levels of caspase-like proteins were significantly increased in the PacC-silenced (PacCi) strains compared with the control strains. Silencing PacC also resulted in an increased ROS levels (approximately 2-fold) and decreased activity levels of enzymes involved in the antioxidant system. Further, we found that the intracellular ROS levels contributed to apoptosis and GA biosynthesis. Adding N-acetyl-cysteine and vitamin C decreased intracellular ROS and resulted in the inhibition of apoptosis in the PacCi strains. Additionally, the GA biosynthesis was different between the control strains and the PacCi strains after intracellular ROS was eliminated. Taken together, the findings showed that silencing PacC can result in an intracellular ROS burst, which increases cell apoptosis and GA biosynthesis levels. Our study provides novel insight into the functions of PacC in filamentous fungi.
    Keywords:  PacC; apoptosis; ganoderic acid biosynthesis; reactive oxygen species
    DOI:  https://doi.org/10.1093/femsle/fnaa015
  678. J Phys Chem Lett. 2020 Jan 24.
    Ambient Condition Mg2+-Doping Producing Highly Luminescent Green and Violet Emitting Perovskite Nanocrystals with Reduced Toxicity and Enhanced Stability.
    Das S, De A, Samanta A.
      Lack of long-term stability, presence of toxic lead and low photoluminescence (PL) efficiency are the major obstacles to commercialization of the lead halide perovskites-based optoelectronic and photovoltaic devices. Herein, we report a facile ambient condition doping protocol, which addresses all three issues of the CsPbX3 perovskite nanocrystals (NCs) to a substantial extent. We show that room-temperature treatment of these NCs with MgX2 results in partial (18-23%) replacement of toxic lead, enhances PL quantum yield (QY) of green-emitting CsPbBr3 (to ~100% from ~51%) and violet-emitting CsPbCl3 NCs (to ~79% from ~1%) and improves the stability under ambient condition, and in presence of light and polar solvent. Ultrafast pump-probe and temperature dependent PL studies reveal that curing of intrinsic structural disorder, introduction of some shallow energy levels close to the conduction band edge and effective passivation of the halide deficiency contribute to the improved properties of the doped system.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03831
  679. ACS Chem Neurosci. 2020 Jan 21.
    Synthesis and Preclinical Evaluation of an 18F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [18F]SynVesT-2.
    Cai Z, Li S, Zhang W, Pracitto R, Wu X, Baum E, Finnema SJ, Holden D, Toyonaga T, Lin SF, Lindemann M, Shirali A, Labaree DC, Ropchan J, Nabulsi N, Carson RE, Huang Y.
      Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass trans-membrane glycoprotein ubiquitously expressed in presynaptic vesicles. In vivo imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g., Alzheimer's disease, Parkin-son's disease, schizophrenia, multiple sclerosis, autism, epi-lepsy, stroke, traumatic brain injury, post-traumatic stress disorder, depression, etc. Herein, we report the synthesis and evaluation of a new 18F-labeled SV2A PET imaging probe, [18F]SynVesT-2, which possesses fast in vivo binding kinetics and high specific binding signals in nonhuman primate brain.
    DOI:  https://doi.org/10.1021/acschemneuro.9b00618
  680. Angew Chem Int Ed Engl. 2020 Jan 20.
    Single-Atom-Enzyme as Efficient Multiple Reactive Oxygen and Nitrogen Species Scavenger for Sepsis Management.
    Ren J, Cao F, Zhang L, You Y, Zheng L, Qu X.
      Sepsis, characterized by immoderate production of multiple reactive oxygen and nitrogen species (RONS), continues to cause high morbidity and mortality worldwide. Despite the progress made with nanozymes, the efficient antioxidant therapy that could fast eliminate all of these RONS remains challenging, owing largely to the specificity and low activity of exploited nanozymes. Herein, we report a novel single-atom-enzyme, Co/PMCS, featuring with atomically dispersed coordinatively unsaturated active Co-porphyrin centers, can fast obliterate multiple RONS to alleviate sepsis. Co/PMCS can eliminate O2•- and H2O2 by mimicking superoxide dismutase, catalase and glutathione peroxidase, while remove •OH via the oxidative-reduction cycle, exhibiting markedly higher activity than nanozymes. Notably, it can also scavenge •NO through the formation of nitrosyl-metal complex, hardly accomplished by the current nanozymes. Eventually, it can reduce proinflammatory cytokine level, protect organs from damage and confer a distinct survival advantage to the infected sepsis mice, demonstrating a promising agent for antioxidative therapy.
    Keywords:  single-atom nanozymes * antioxidant * sepsis * reactive oxygen and nitrogen species
    DOI:  https://doi.org/10.1002/anie.201912182
  681. J Steroid Biochem Mol Biol. 2020 Jan 19. pii: S0960-0760(19)30493-5. [Epub ahead of print] 105594
    Expression of estrogen receptor α variants and c-Fos in rat mammary gland and tumors.
    Gutiérrez A, Sambuco L, Álvarez L, Núñez M, Bergoc R, Zotta E, Martín G, Randi A.
      Breast cancer is currently the leading cause of cancer death among women worldwide. AP-1 (c-Fos/c-Jun) is associated with proliferation and survival, while cytoplasmic c-Fos activates phospholipid synthesis in cells induced to differentiate or grow. Estrogen receptor α 46 (ERα46) is a splice variant of full-length ERα66 and it is known that it has an inhibitory role in cancer cell growth. We investigated c-Fos localization, its relationship to AP-1, the non genomic pathway of phospho-Tyr537-ERα66, as well as ERα46 and ERα66 isoforms in rat mammary gland development and carcinogenic transformation, and in mammary tumors. Female rats were injected: a) saline solution (Control mammary gland, CMG) or b) N-Nitroso-N-methyl urea (NMU), and samples were taken at 60, 90, 120 and 150 days of life. In addition, we analyzed hormone-dependent (HD) and independent (HI) tumors in ovariectomized rats, and intact tumors (IT) in non-ovariectomized ones. Our results show that, in CMG, nuclear c-Fos and proliferation decreased with age, AP-1 content was low, and nuclear ERα46/ERα66 ratio was higher than 1. In NMU, nuclear c-Fos and proliferation increased with carcinogenic transformation, AP-1 content was high, and nuclear ERα46/ERα66 was below 1. As tumor grade increased, proliferation, nuclear c-Fos and AP-1 expression were negatively associated to nuclear ERα46/ERα66 in IT. In HD, nuclear ERα46/ERα66, nuclear c-Fos expression, AP-1 levels and proliferation were lower than in HI, whose growth is estrogen-independent. Phospho-Tyr537-ERα66 content and ERK1/2 activation were associated with AP-1 levels and cell proliferation. Collectively, our findings support the notion that variant detection and ERα46/ERα66 ratio could shed light on the role of ERα isoforms in mammary gland transformation and the behavior of ERα positive mammary tumors.
    Keywords:  breast cancer; c-Fos protein; estrogen receptor α variants; mammary gland
    DOI:  https://doi.org/10.1016/j.jsbmb.2020.105594
  682. Chemosphere. 2020 Jan 02. pii: S0045-6535(19)33048-6. [Epub ahead of print]247 125807
    Degradation of antibiotic ciprofloxacin by different AOP systems using electrochemically generated hydrogen peroxide.
    Lima VB, Goulart LA, Rocha RS, Steter JR, Lanza MRV.
      The present work reports the degradation of the antibiotic ciprofloxacin (CIP) by different advanced oxidative process systems (UV; Anodic Oxidation; H2O2; H2O2/UV; H2O2/Fe2+ and H2O2/UV/Fe2+) in an electrochemical cell using gas diffusion electrode (GDE) for the synthesis of hydrogen peroxide. CIP degradation and mineralization were evaluated by high efficiency liquid chromatography (HPLC) and total organic carbon (TOC) techniques. Of all the systems investigated, the photoelectro-Fenton system presented the best degradation efficiency; this system promoted highly significant mineralization percentages of 54.8% and 84.6% in 90 and 360 min, and relatively lower energy consumption rates of 4110.0 and 9808.2 kWh kg-1 TOC, respectively. In 6 h period of experiment, the main degradation products of ciprofloxacin were identified, and the aliphatic acids obtained helped confirm the rupture of the aromatic ring. The application of the photoelectro-Fenton process with in situ eletroctrogeneration of H2O2 using GDE has proved to be suitably promising for the treatment of organic pollutants.
    Keywords:  Ciprofloxacin; Fenton processes; Gas diffusion electrode; Hydrogen peroxide
    DOI:  https://doi.org/10.1016/j.chemosphere.2019.125807
  683. J Assoc Physicians India. 2020 Jan;68(1): 47
    Study of Lipoprotein (A) and Lipid Profi le in Type 2 Diabetes Mellitus and their Relationship with Glycemic Control.
    K M, Ac N.
      
  684. Plant Cell Environ. 2020 Jan 18.
    Mechanical stimulation in Brachypodium distachyon: implications for fitness, productivity and cell wall properties.
    Gladala-Kostarz A, Doonan JH, Bosch M.
      Mechanical stimulation, including exposure to wind, is a common environmental variable for plants. However, knowledge about the morphogenetic response of the grasses (Poaceae) to mechanical stimulation and impact on relevant agronomic traits is very limited. Two natural accessions of Brachypodium distachyon were exposed to wind- and mechanical- treatments. We surveyed a wide range of stem related traits to determine the effect of the two treatments on plant growth, development and stem biomass properties. Both treatments induced significant quantitative changes across multiple scales, from the whole plant down to cellular level. The two treatments resulted in shorter stems, reduced biomass, increased tissue rigidity, delayed flowering and reduced seed yield in both accessions. Amongst changes in cell wall-related features, a substantial increase in lignin content and pectin methylesterase activity were most notable. Mechanical stimulation also reduced the enzymatic sugar release from the cell wall, thus increasing biomass recalcitrance. Notably, treatments had a distinct and opposite effect on vascular bundle area in the two accessions, suggesting genetic variation in modulating these responses to mechanical stimulation. Our findings highlight that exposure of grasses to mechanical stimulation is a relevant environmental factor affecting multiple traits important for their utilisation in food, feed and bioenergy applications. This article is protected by copyright. All rights reserved.
    Keywords:  Biomass; Brachypodium distachyon; cell wall; fitness; grasses; growth and development; mechanical stress; plant morphology; thigmomorphogenesis; wind
    DOI:  https://doi.org/10.1111/pce.13724
  685. Cureus. 2019 Dec 20. 11(12): e6432
    Inflammatory Myofibroblastic Tumor of the Lung: An Extremely Rare Condition in Adults.
    Al-Obaidi A, Buess C, Mogire J, Reddy PS.
      Inflammatory myofibroblastic tumors (IMTs) of the lung were first reported in 1939. The most common site of predilection is the lungs of the pediatric population. They are extremely rare in adults, constituting less than 1% of adult lung tumors. They are mesenchymal neoplasms that may arise in the soft tissues of almost every organ. IMTs often arise from excessive inflammatory response, and as the name implies, they are composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils.
    Keywords:  inflammatory myofibroblastic tumor; inflammatory pseudotumor; lung tumors; pseudotumor
    DOI:  https://doi.org/10.7759/cureus.6432
  686. Anat Rec (Hoboken). 2020 Jan 21.
    Resibufogenin (RB) Inhibited Colorectal Cancer Cell Growth and Tumorigenesis through Triggering Ferroptosis and ROS Production Mediated by GPX4 Inactivation.
    Shen LD, Qi WH, Bai JJ, Zuo CY, Bai DL, Gao WD, Zong XL, Hao TT, Ma Y, Cao GC.
      AIM: Resibufogenin (RB) has been used for cancer treatment, but the underlying mechanisms are still unclear. This study aimed to investigate the effects of RB treatment on colorectal cancer (CRC) cells, and to determine the underlying mechanisms.METHODS: The cell counting kit-8 (CCK-8) assay was used to determine cell viability. Cell morphology was observed under light microscopy, and Terminal Deoxynucleotidyl Transferase (TdT)-mediated dUTP Nick-End Labeling (TUNEL) assay was employed to detect cell apoptosis. Intracellular ferrous iron (Fe2+ ), Malondialdehyde (MDA), Glutathione (GSH), and reactive oxygen species (ROS) levels were detected by using commercial iron assay kit, MDA assay kit, GSH assay kit, and 2, 7-Dichlorodihydrofluorescein diacetate (DCFH-DA) probes, respectively. The protein expressions were determined by Western Blot and Immunohistochemistry (IHC).
    RESULTS: RB inhibited cell viability in the CRC cell lines (HT29 and SW480) in a dose- and time-dependent manner, and caused cytotoxicity to the normal colonic epithelial cell line (NCM460) at high dose. Similarly, RB induced morphological changes in CRC cells from normal to round shape, and promoted cell death. Of note, RB triggered oxidative stress and ferroptotic cell death in CRC cells, and only ferroptosis inhibitors (DFO and Ferrostatin-1), instead of inhibitors for other types of cell death (apoptosis, autophagy and necroptosis), reversed the inhibitory effects of RB on CRC cell proliferation. Furthermore, glutathione peroxidase 4 (GPX4) was inactivated by RB treatment, and overexpression of GPX4 alleviated RB-induced oxidative cell death in CRC cells. Consistently, the in vivo experiments validated that RB also triggered oxidative stress, and inhibited CRC cells growth and tumorigenicity in mice models.
    CONCLUSION: RB can inhibit CRC cells growth and tumorigensis by triggering ferroptotic cell death in a GPX4 inactivation dependent manner. This article is protected by copyright. All rights reserved.
    Keywords:  Colorectal Cancer; Ferroptosis; GPX4; Oxidative Stress; Resibufogenin
    DOI:  https://doi.org/10.1002/ar.24378
  687. Nat Commun. 2020 Jan 22. 11(1): 423
    Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.
    Wang JX, Irvine MW, Burnell ES, Sapkota K, Thatcher RJ, Li M, Simorowski N, Volianskis A, Collingridge GL, Monaghan DT, Jane DE, Furukawa H.
      N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.
    DOI:  https://doi.org/10.1038/s41467-020-14321-0
  688. Sci Rep. 2020 Jan 24. 10(1): 1152
    Transcriptome analysis of potato shoots, roots and stolons under nitrogen stress.
    Tiwari JK, Buckseth T, Zinta R, Saraswati A, Singh RK, Rawat S, Dua VK, Chakrabarti SK.
      Potato crop requires high dose of nitrogen (N) to produce high tuber yield. Excessive application of N causes environmental pollution and increases cost of production. Hence, knowledge about genes and regulatory elements is essential to strengthen research on N metabolism in this crop. In this study, we analysed transcriptomes (RNA-seq) in potato tissues (shoot, root and stolon) collected from plants grown in aeroponic culture under controlled conditions with varied N supplies i.e. low N (0.2 milli molar N) and high N (4 milli molar N). High quality data ranging between 3.25 to 4.93 Gb per sample were generated using Illumina NextSeq500 that resulted in 83.60-86.50% mapping of the reads to the reference potato genome. Differentially expressed genes (DEGs) were observed in the tissues based on statistically significance (p ≤ 0.05) and up-regulation with ≥ 2 log2 fold change (FC) and down-regulation with ≤ -2 log2 FC values. In shoots, of total 19730 DEGs, 761 up-regulated and 280 down-regulated significant DEGs were identified. Of total 20736 DEGs in roots, 572 (up-regulated) and 292 (down-regulated) were significant DEGs. In stolons, of total 21494 DEG, 688 and 230 DEGs were significantly up-regulated and down-regulated, respectively. Venn diagram analysis showed tissue specific and common genes. The DEGs were functionally assigned with the GO terms, in which molecular function domain was predominant in all the tissues. Further, DEGs were classified into 24 KEGG pathways, in which 5385, 5572 and 5594 DEGs were annotated in shoots, roots and stolons, respectively. The RT-qPCR analysis validated gene expression of RNA-seq data for selected genes. We identified a few potential DEGs responsive to N deficiency in potato such as glutaredoxin, Myb-like DNA-binding protein, WRKY transcription factor 16 and FLOWERING LOCUS T in shoots; high-affinity nitrate transporter, protein phosphatase-2c, glutaredoxin family protein, malate synthase, CLE7, 2-oxoglutarate-dependent dioxygenase and transcription factor in roots; and glucose-6-phosphate/phosphate translocator 2, BTB/POZ domain-containing protein, F-box family protein and aquaporin TIP1;3 in stolons, and many genes of unknown function. Our study highlights that these potential genes play very crucial roles in N stress tolerance, which could be useful in augmenting research on N metabolism in potato.
    DOI:  https://doi.org/10.1038/s41598-020-58167-4
  689. Sci Total Environ. 2020 Feb 25. pii: S0048-9697(19)35874-7. [Epub ahead of print]705 135879
    Benzene exposure induces gut microbiota dysbiosis and metabolic disorder in mice.
    Sun R, Xu K, Ji S, Pu Y, Man Z, Ji J, Chen M, Yin L, Zhang J, Pu Y.
      The gut microbiota comprises a multispecies microbial community and is essential for maintaining health. Benzene is a widespread environmental and occupational pollutant that mainly causes blood and bone marrow abnormalities. However, the effects of benzene on gut microbiota and metabolism have not yet been investigated. In this study, C57BL/6 mice were exposed to 0, 6, 30 and 150 mg/kg benzene by subcutaneous injection for 30 days. We observed that white blood cell levels significantly decreased in the three benzene exposure groups, while red blood cell and hemoglobin levels were only changed remarkably in 30 and 150 mg/kg benzene-treated mice. The results of 16S rRNA sequencing showed that benzene exposure altered the overall structure of the gut microbial communities. In addition, significant enrichments of Actinobacteria (p < .05) at the phylum level and Helicobacter at the genus level were observed in the cecal contents and feces of mice exposed to 150 mg/kg benzene. Moreover, there was a significant negative correlation between Actinobacteria abundance and basic blood indicators, including white blood cell, red blood cell, and hemoglobin levels. Furthermore, according to LC-MS analysis, a total of 42 cecal metabolites were significantly altered by 150 mg/kg benzene. Several metabolic pathways were significantly influenced by benzene exposure, including cysteine and methionine metabolism, porphyrin and chlorophyll metabolism, steroid biosynthesis, aminoacyl-tRNA biosynthesis, and arginine and proline metabolism. In summary, this study demonstrated that benzene exposure causes dysbiosis of the gut microbiota and metabolic disorder in mice.
    Keywords:  Benzene exposure; Gut microbiota; Hematotoxicity; Metabonomics
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.135879
  690. J Inorg Biochem. 2020 Jan 08. pii: S0162-0134(19)30559-8. [Epub ahead of print]205 110983
    Dual functions of iridium(III) 2-phenylpyridine complexes: Metastasis inhibition and lysosomal damage.
    Liu X, Chen S, Ge X, Zhang Y, Xie Y, Hao Y, Wu D, Zhao J, Yuan XA, Tian L, Liu Z.
      Six N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) 2-phenylpyridine complexes ([(η5-Cp*)Ir(C^N)Cl]) were prepared and characterized. Compared with cisplatin, these complexes exhibited potential antitumor activity against A549 and HeLa tumor cells, with IC50 values (half-maximum inhibitory concentration) that changed from 2.8 ± 0.8 μM to 39.5 ± 2.7 μM, and could block the migration of tumor cells. These complexes also effectively bound to protein (binding constant: ~104 M-1) and were transported through serum proteins, catalyzed the oxidation of coenzyme nicotinamide-adenine dinucleotide. Additionally, laser confocal microscopy and flow cytometry confirmed that these complexes possessed a non-energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (Pearson colocalization coefficient: ~0.74), damaged the integrity of acidic lysosomes, led to a change in the mitochondrial membrane potential, disrupted the cell cycle (G0/G1 phase), and eventually induced apoptosis. Above all, these complexes are potential antitumor agents with dual functions: metastasis inhibition and lysosomal damage.
    Keywords:  Antitumor; Iridium(III) complexes; Lysosomal damage; Metastasis inhibition
    DOI:  https://doi.org/10.1016/j.jinorgbio.2019.110983
  691. Biochimie. 2020 Jan 16. pii: S0300-9084(20)30009-2. [Epub ahead of print]
    Metabolic memory and diabetic nephropathy: beneficial effects of natural epigenetic modifiers.
    Kushwaha K, Sharma S, Gupta J.
      Nephropathy is one of the most frequent complications of chronic diabetes. The main reason for nephropathy despite being hyperglycemia, but it progresses even after good glycemic control has been achieved in diabetic patients. The effects of prior exposure to high blood glucose conditions depend upon the severity and duration of this exposure, indicating a "metabolic memory' phenomenon. Hyperglycemia not only increases oxidative stress but is also alleged to start several biochemical anomalies and alter gene expression associated with metabolic homeostasis. High glucose levels induce epigenetic modifications that alter gene expression without changing DNA sequences. These epigenetic modifications have shown to be reversible and have the potential to cease adverse effects if good glycemic control is achieved from initiation of diabetes. However, if good glycemic control is not achieved for months, these modifications stand firm to reversals. Therapies and drugs have been in use to prevent epigenetic modifications and oxidative stress, which also helped in ameliorating diabetic nephropathy. But these synthetic drugs are loaded with side effects like increased body weight, kidney dysfunction etc. So phytochemicals are emerging as alternatives and many of them have already been used to treat nephropathy. But still, there is rigorous need to evaluate phytochemicals which can regulate epigenetic events and have the potential to decelerate the further progression of these life-threatening diseases. In this review article we discuss the potential epigenetic modifiers from plants that can erase metabolic memory and can thus be protective against diabetic nephropathy.
    Keywords:  Diabetes; Diabetic nephropathy; Epigenetics; Metabolic memory; Oxidative stress; Phytochemical
    DOI:  https://doi.org/10.1016/j.biochi.2020.01.007
  692. Mol Med Rep. 2020 Feb;21(2): 623-630
    Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors.
    Shi Y, Qian J, Zhang F, Jia B, Liu X, Hu Y, Zhang Q, Yang Y, Sun D, Jiang L.
      Placental structural abnormalities and dysfunction in those with gestational diabetes mellitus (GDM) can lead to increased placental permeability, which is in turn related to a poorer maternal and fetal prognosis. The present study sought to assess whether increased placental permeability in rats with GDM was accompanied by alterations in tight junction (TJ) factors and to evaluate the impact of low molecular weight heparin (LMWH) on these factors. The present study was conducted using pregnant female rats that were randomized into control, GDM and GDM + LMWH groups. Diabetes was induced via intraperitoneal administration of streptozotocin to rats in the GDM and GDM + LMWH groups, whereas rats in the GDM + LMWH group received daily subcutaneous LMWH starting on day 5 of pregnancy. On gestational day 16, all rats were sacrificed and Evans Blue (EB) assay was used to gauge vascular permeability based on EB dye leakage. Transmission electron microscopy was further used to assess TJ structures, and the TJ proteins zonular occludens‑1 (ZO‑1) and occludin (OCLN) were assessed using immunohistochemistry and western blotting. Blood samples were obtained from the abdominal aorta for ELISA measurements of advanced glycation end products (AGEs) concentrations, and placental receptor for AGEs (RAGE) and vascular endothelial growth factor (VEGF) expression was assessed using reverse transcription‑quantitative PCR. In addition, western blotting was used to measure placental NF‑κB. Compared with in the control group, EB leakage was markedly increased in GDM group rats; this was associated with reduced ZO‑1 and OCLN expression. Conversely, LMWH attenuated this increase in placental permeability in rats with GDM and also mediated a partial recovery of ZO‑1 and OCLN expression. Blood glucose and serum AGEs concentrations did not differ between the GDM and GDM + LMWH groups. Furthermore, LMWH treatment resulted in decreases in RAGE and VEGF mRNA expression levels, which were upregulated in the GDM group, whereas it had the opposite effect on the expression of NF‑κB. In conclusion, GDM was associated with increased placental permeability and this may be linked with changes in TJs. LMWH intervention mediated protection against this GDM‑associated shift in placental permeability via the RAGE/NF‑κB pathway.
    DOI:  https://doi.org/10.3892/mmr.2019.10868
  693. Drug Alcohol Depend. 2019 Dec 23. pii: S0376-8716(19)30592-7. [Epub ahead of print]208 107815
    History of withdrawal modulates drug- and food-cue reactivity in cocaine dependent participants.
    Denomme WJ, Shane MS.
      While the centrality of withdrawal in the diagnosis of addiction has been decreasing with each successive edition of the Diagnostic and Statistical Manual of Mental Disorders, psychometric and neurobiological evidence provides withdrawal a central role in the development and maintenance of addiction. The current study offers insight into these conflicting positions by using secondary analyses to assess how a history of DSM-assessed withdrawal influences the magnitude of bias in neural reactivity to drug- and/or food-related reward cues. To this end, we separated an existing sample of cocaine-dependent participants (Denomme et al., 2018) into those with (WD) and without (N-WD) a history of withdrawal, and compared food- and drug-cue reactivity between these groups, and to a non-dependent control group (ND). Analyses indicated that biases in neural reactivity towards drug- versus food-related cues only occurred among the WD participants (within: left dorsomedial prefrontal cortex, left anterior cingulate cortex, left orbitofrontal cortex, left caudate nucleus, and right ventrolateral prefrontal cortex). Thus, withdrawal status may be an important factor to consider when interpreting dependence-related biases in neural reactivity following reward-related cues. Interestingly, while N-WD participants did not show these broad biases in neural reactivity, the magnitude of their bias correlated positively with years of lifetime substance use history, particularly when psychopathic traits were low. It may be that for individuals who's addiction has not yet reached a compulsive state (see Wise and Koob, 2014), the magnitude of their drug > food bias could serve as a valuable biomarker of addiction severity.
    Keywords:  Addiction; Cue-reactivity; Psychopathy; Withdrawal; fMRI
    DOI:  https://doi.org/10.1016/j.drugalcdep.2019.107815
  694. Cell Death Dis. 2020 Jan 20. 11(1): 42
    P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head.
    Zhang F, Peng W, Zhang J, Dong W, Wu J, Wang T, Xie Z.
      Survival and stemness of bone marrow mesenchymal stem cells (BMSCs) in osteonecrotic areas are especially important in the treatment of early steroid-induced osteonecrosis of the femoral head (ONFH). We had previously used BMSCs to repair early steroid-induced ONFH, but the transplanted BMSCs underwent a great deal of stress-induced apoptosis and aging in the oxidative-stress (OS) microenvironment of the femoral-head necrotic area, which limited their efficacy. Our subsequent studies have shown that under OS, massive accumulation of damaged mitochondria in cells is an important factor leading to stress-induced apoptosis and senescence of BMSCs. The main reason for this accumulation is that OS leads to upregulation of protein 53 (P53), which inhibits mitochondrial translocation of Parkin and activation of Parkin's E3 ubiquitin ligase, which decreases the level of mitophagy and leads to failure of cells to effectively remove damaged mitochondria. However, P53 downregulation can effectively reverse this process. Therefore, we upregulated Parkin and downregulated P53 in BMSCs. We found that this significantly enhanced mitophagy in BMSCs, decreased the accumulation of damaged mitochondria in cells, effectively resisted stress-induced BMSCs apoptosis and senescence, and improved the effect of BMSCs transplantation on early steroid-induced ONFH.
    DOI:  https://doi.org/10.1038/s41419-020-2238-1
  695. Anal Chem. 2020 Jan 22.
    Enzyme-assist-interference-free Strategy for Raman Selective Determination of Sialic Acid.
    Teng X, Chen F, Gao Y, Meng R, Wu Y, Wang F, Ying Y, Liu X, Guo X, Sun Y, Lin P, Wen Y, Yang HF.
      Abnormal physiological levels of sialic acid (SA) could be used to diagnosis cancer progression stage. In this work, we describe an enzyme-assist-interference-free strategy for Raman selective determination of SA in serum. First, we assemble gold nanoparticles (Au NPs) onto the indium tin oxide glass (ITO) to construct ITO/Au two-dimension substrate. Through modification of 4-mercaptoboric acid (4-MPBA) onto the surface of ITO/Au, the SA sensing plate is prepared based on the reversible esterification. In this strategy, a sandwich structure is rationally designed as ITO/Au/4-MPBA/SA/4-MPBA/Au to enhance the Raman scattering. The Raman detection linear concentration of SA ranging from 2.5x10-7 to 1.5x10-6 M and limit of detection about 1.2x10-7 M could be achieved. Considering the presence of glucose (Glu) in physiological fluid, we introduce glucose oxidase to remove the interference from Glu and realize the accurate determination of SA. The proposed novel Raman rapid method provide ultrasensitive and interference-free protocol for early diagnosis of cancer.
    DOI:  https://doi.org/10.1021/acs.analchem.9b05264
  696. Nat Commun. 2020 Jan 20. 11(1): 384
    Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer.
    Tiwari R, Manzar N, Bhatia V, Yadav A, Nengroo MA, Datta D, Carskadon S, Gupta N, Sigouros M, Khani F, Poutanen M, Zoubeidi A, Beltran H, Palanisamy N, Ateeq B.
      Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.
    DOI:  https://doi.org/10.1038/s41467-019-14184-0
  697. Nat Commun. 2020 Jan 24. 11(1): 494
    Redox-coupled proton pumping drives carbon concentration in the photosynthetic complex I.
    Schuller JM, Saura P, Thiemann J, Schuller SK, Gamiz-Hernandez AP, Kurisu G, Nowaczyk MM, Kaila VRI.
      Photosynthetic organisms capture light energy to drive their energy metabolism, and employ the chemical reducing power to convert carbon dioxide (CO2) into organic molecules. Photorespiration, however, significantly reduces the photosynthetic yields. To survive under low CO2 concentrations, cyanobacteria evolved unique carbon-concentration mechanisms that enhance the efficiency of photosynthetic CO2 fixation, for which the molecular principles have remained unknown. We show here how modular adaptations enabled the cyanobacterial photosynthetic complex I to concentrate CO2 using a redox-driven proton-pumping machinery. Our cryo-electron microscopy structure at 3.2 Å resolution shows a catalytic carbonic anhydrase module that harbours a Zn2+ active site, with connectivity to proton-pumping subunits that are activated by electron transfer from photosystem I. Our findings illustrate molecular principles in the photosynthetic complex I machinery that enabled cyanobacteria to survive in drastically changing CO2 conditions.
    DOI:  https://doi.org/10.1038/s41467-020-14347-4
  698. Int J Biol Macromol. 2020 Jan 18. pii: S0141-8130(19)39041-5. [Epub ahead of print]
    Genome-wide analysis and expression profiles of the StR2R3-MYB transcription factor superfamily in potato (Solanum tuberosum L.).
    Li Y, Lin-Wang K, Liu Z, Allan AC, Qin S, Liu Y, Zhang J.
      MYB transcription factors comprise one of the largest families in plant kingdom, which play a variety of functions in plant developmental processes and defence responses, the R2R3-MYB members are the predominant form found in higher plants. In the present study, a total of 111 StR2R3-MYB transcription factors were identified and further phylogenetically classified into 31 subfamilies, as supported by highly conserved gene structures and motifs. Collinearity analysis showed that the segmental duplication events played a crucial role in the expansion of StR2R3-MYB gene family. Synteny analysis indicated that 37 and 13 StR2R3-MYB genes were orthologous to Arabidopsis and wheat, respectively, and these gene pairs have evolved under strong purifying selection. RNA-seq data from different tissues and abiotic stresses revealed tissue-preferential and abiotic stress-responsive StR2R3-MYB genes. We further analyzed StR2R3-MYB genes might be involved in anthocyanin biosynthesis and drought stress by using RNA-seq data of pigmented tetraploid potato cultivars and drought-sensitive and -tolerant tetraploid potato cultivars under drought stress, respectively. Moreover, EAR motifs were found in 21 StR2R3-MYB proteins and 446 pairs of proteins were predicted to interact with 21 EAR motif-containing StR2R3-MYB proteins by constructing the interaction network with medium confidence (0.4). Additionally, Gene Ontology (GO) analysis of the 21 EAR motif-containing StR2R3-MYB proteins was performed to further investigate their functions. This work will facilitate future biologically functional studies of potato StR2R3-MYB transcription factors and enrich the knowledge of MYB superfamily genes in plant species.
    Keywords:  Anthocyanin biosynthesis; Drought stress; EAR; Expression profiles; MYB transcription factor; Potato
    DOI:  https://doi.org/10.1016/j.ijbiomac.2020.01.167
  699. Endocr Metab Immune Disord Drug Targets. 2020 Jan 22.
    Mechanisms of Nickel-Induced Cell Damage in Allergic Contact Dermatitis and Nutritional Intervention Strategies.
    Filatova D, Cherpak C.
      BACKGROUND: Hypersensitivity to nickel is a very common cause of allergic contact dermatitis since this metal is largely present in industrial and consumer products as well as in some commonly consumed foods, air, soil, and water. In nickel-sensitized individuals, a cell-mediated delayed hypersensitivity response results in contact dermatitis due to mucous membrane coming in long-term contact with nickel-containing objects. This process involves the generation of reactive oxidative species and lipid peroxidation-induced oxidative damage. Immunologically, the involvement of T helper (h)-1 and Th-2 cells, as well as the reduced function of T regulatory cells, are of importance. The toxicity, mutagenicity, and carcinogenicity of nickel are attributed to the generation of reactive oxygen species and induction of oxidative damage via lipid peroxidation, which results in DNA damage.OBJECTIVE: The aim of this research review is to identify nutritionally actionable interventions that can intercept nickel-induced cell damage due to their antioxidant capacities.
    CONCLUSION: Nutritional interventions, may be used to modulate immune dysregulation, thereby, intercepting nickel-induced cellular damage. Among these are a low-nickel diet and an antioxidant-rich diet that is sufficient in iron needed to minimize nickel absorption. These dietary approaches not only reduce the likelihood of nickel toxicity by minimizing nickel exposure, but also help prevent oxidative damage by supplying the body with antioxidants that neutralize free radicals.
    Keywords:  Antioxidant therapy; Free radicals; Nickel-induced cell damage; Nickel-induced contact dermatitis; Nickel-induced contact dermatitis therapy; Nickel-induced pathogenic mechanisms
    DOI:  https://doi.org/10.2174/1871530320666200122155804
  700. Sci Rep. 2020 Jan 20. 10(1): 723
    Automated Flow Synthesis of Tumor Neoantigen Peptides for Personalized Immunotherapy.
    Truex NL, Holden RL, Wang BY, Chen PG, Hanna S, Hu Z, Shetty K, Olive O, Neuberg D, Hacohen N, Keskin DB, Ott PA, Wu CJ, Pentelute BL.
      High-throughput genome sequencing and computation have enabled rapid identification of targets for personalized medicine, including cancer vaccines. Synthetic peptides are an established mode of cancer vaccine delivery, but generating the peptides for each patient in a rapid and affordable fashion remains difficult. High-throughput peptide synthesis technology is therefore urgently needed for patient-specific cancer vaccines to succeed in the clinic. Previously, we developed automated flow peptide synthesis technology that greatly accelerates the production of synthetic peptides. Herein, we show that this technology permits the synthesis of high-quality peptides for personalized medicine. Automated flow synthesis produces 30-mer peptides in less than 35 minutes and 15- to 16-mer peptides in less than 20 minutes. The purity of these peptides is comparable with or higher than the purity of peptides produced by other methods. This work illustrates how automated flow synthesis technology can enable customized peptide therapies by accelerating synthesis and increasing purity. We envision that implementing this technology in clinical settings will greatly increase capacity to generate clinical-grade peptides on demand, which is a key step in reaching the full potential of personalized vaccines for the treatment of cancer and other diseases.
    DOI:  https://doi.org/10.1038/s41598-019-56943-5
  701. Cytotherapy. 2020 Jan 21. pii: S1465-3249(19)30923-5. [Epub ahead of print]
    Glycogen synthase kinase 3β inhibitor- CHIR 99021 augments the differentiation potential of mesenchymal stem cells.
    Govarthanan K, Vidyasekar P, Gupta PK, Lenka N, Verma RS.
      AIM: Mesenchymal stem cells (MSCs) are immunomodulatory, non-teratogenic and multipotent alternatives to embryonic or induced pluripotent stem cells (ESCs or iPSCs). However, the potency of MSCs is not equivalent to the pluripotency of ESCs or iPSCs. We used CHIR 99021 to improve current protocols and methods of differentiation for the enhanced transdifferentiation potency of MSCs.MAIN METHODS: We used Flurescence activated cell sorter (FACS) for MSC immunophenotyping and biochemical assay for demonstrating the trilineage potential of MSCs. We used real-time polymerase chain reaction, immunocytochemistry and Western blotting assay for analyzing the expression of lineage-specific markers.
    KEY FINDINGS: CHIR 99021 treatment of MSCs resulted in enhanced transdifferentiation into neurological, hepatogenic and cardiomyocyte lineages with standardized protocols of differentiation. CHIR 99021-treated MSCs showed increased nuclear localization of β-catenin. These MSCs showed a significantly increased deposition of active histone marks (H3K4Me3, H3K36Me3), whereas no change was observed in repressive marks (H3K9Me3, H3K27Me3). Differential methylation profiling showed demethylation of the transcription factor OCT4 promoter region with subsequent analysis revealing increased gene expression and protein content. The HLA-DR antigen was absent in CHIR 99021-treated MSCs and their differentiated cell types, indicating their immune-privileged status. Karyotyping analysis showed that CHIR 99021-treated MSCs were genomically stable. Teratoma analysis of nude mice injected with CHIR 99021-treated MSCs showed the increased presence of cell types of mesodermal origin at the site of injection.
    SIGNIFICANCE: MSCs pretreated with CHIR 99021 can be potent, abundant alternative sources of stem cells with enhanced differentiation capabilities that are well suited to cell-based regenerative therapy.
    Keywords:  CHIR 99021; differentiation; mesenchymal stem cells; multipotency; regenerative therapy
    DOI:  https://doi.org/10.1016/j.jcyt.2019.12.007
  702. FEMS Microbiol Ecol. 2020 Jan 21. pii: fiaa011. [Epub ahead of print]
    Differential visible spectral influence on carbon metabolism in heterotrophic marine flavobacteria.
    Hameed A, Lai WA, Shahina M, Stothard P, Young LS, Lin SY, Sridhar KR, Young CC.
      The visible spectrum of solar radiation is known to stimulate photoheterotrophic bacterial carbon metabolism. However, its impact on 'strictly' heterotrophic bacteria remains less explored. Here, we show that heterotrophic flavobacteria exhibit enhanced uptake and mineralization of dissolved organic carbon with increasing wavelengths of visible light, without employing any 'known' light-harvesting mechanisms. RNA sequencing identified blue light as a major constraint in the extracellular enzymatic hydrolysis of polymeric carbohydrates and acquisition of sugars, despite acting as a stimulus for inorganic carbon sequestration. In contrast, green-red and continuous full-spectrum lights activated diverse hydrolytic enzymes and sugar transporters, but obstructed inorganic carbon fixation. This 'metabolic switching' was apparent through limited nutrient uptake, suppressed light-sensitivity, oxidative stress response and promotion of inorganic carbon sequestration pathways under blue light. The visible light impact on metabolism may be of significant ecological relevance as it appears to promote cell-mediated mineralization of organic carbon in 'green-colored' chlorophyll-rich copiotrophic coastal seawater and inorganic carbon sequestration in 'blue-colored' oligotrophic open ocean. Thus, a novel regulatory role played by light on heterotrophic metabolism and a hidden potential of flavobacteria to sense and respond differentially to monochromatic lights influencing marine carbon cycling were unraveled.
    Keywords:   Siansivirga zeaxanthinifaciens ; blue light; carbon sequestration; hydrolases; microbial carbon pump; mineralization; rhodopsin photosystem
    DOI:  https://doi.org/10.1093/femsec/fiaa011
  703. Hum Gene Ther. 2020 Jan 23.
    Human papillomavirus Oncogene Manipulation Using Clustered Regularly Interspersed Short Palindromic Repeats/Cas9 Delivered by pH-Sensitive Cationic Liposomes.
    Zhen S, Liu Y, Lu J, Tuo X, Yang X, Chen H, Chen W, Li X.
      CRISPR/Cas9 technology enables targeted gene editing, but cancer gene therapy with this approach requires improvements to enable safe and efficient delivery of CRISPR/Cas9 to tumors. We developed and evaluated a self-assembled liposome to selectively deliver CRISPR/Cas9 to cancer tissues. Our CRISPR/Cas9 system effectively inhibited proliferation of Human papillomavirus 16-positive cervical cancer cells and induced apoptosis by inactivating the HR-HPV16E6/E7 oncogene. Based on this system, we prepared a long-circulating pH-sensitive cationic nano- liposome complex with a high cell targeting and gene knockout rate. Intratumoral injection of cationic liposomes targeted to splicing HPV16 E6/E7 in nude mice significantly inhibited tumor growth without significant toxicity in vivo. Liposomes that targeted HPV16 E6/E7 splicing were established as a basis for treatment of HPV16-positive cervical cancer drug candidates. Our study demonstrates that this liposome offers an efficient delivery system for nonviral gene editing, adding to the armamentarium of gene editing tools to advance safe and effective precision medicine-based cancer therapeutics.
    DOI:  https://doi.org/10.1089/hum.2019.312
  704. Molecules. 2020 Jan 23. pii: E484. [Epub ahead of print]25(3):
    Small Peptide-Doxorubicin Co-Assembly for Synergistic Cancer Therapy.
    Li S, Chen X, Chen H, Peng J, Yang X.
      Design of elaborated nanomaterials to improve the therapeutic efficacy and mitigate the side effects of chemotherapeutic anticancer drugs, such as Doxorubicin (Dox), is significant for cancer treatment. Here, we describe a co-assembled strategy, where amphiphile short peptides are co-assembled with Doxorubicin to form nanoscale particles for enhanced delivery of Dox. Two kinds of short peptides, Fmoc-FK (FK) and Fmoc-FKK (FKK), are synthesized. Through adjusting the component ratio of peptide and Dox, we obtain two kinds of co-assembled nanoparticles with homogeneous size distributions. These nanoparticles show several distinct characteristics. First, they are pH-responsive as they are stable in alkaline and neutral conditions, however, de-assembly at acidic pH enables selective Dox release in malignant cancer cells. Second, the nanoparticles show an average size of 50-100 nm with positive charges, making them effective for uptake by tumor cells. Moreover, the side effects of Dox on healthy cells are mitigated due to decreased exposure of free-Dox to normal cells. To conclude, the co-assembled peptide-Dox nanoparticles exhibit increased cellular uptake compared to free-Dox, therefore causing significant cancer cell death. Further apoptosis and cell cycle analysis indicates that there is a synergistic effect between the peptide and Doxorubicin.
    Keywords:  Doxorubicin; cancer therapy; co-assembly; delivery; peptide
    DOI:  https://doi.org/10.3390/molecules25030484
  705. J Cell Mol Med. 2020 Jan 19.
    FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.
    Chen R, Li D, Zheng M, Chen B, Wei T, Wang Y, Li M, Huang W, Tong Q, Wang Q, Zhu Y, Fang W, Guo L, Fang S.
      Fibroblast growth factor receptor-like 1 (FGFRL1), a member of the FGFR family, has been demonstrated to play important roles in various cancers. However, the role of FGFRL1 in small-cell lung cancer (SCLC) remains unclear. Our study aimed to investigate the role of FGFRL1 in chemoresistance of SCLC and elucidate the possible molecular mechanism. We found that FGFRL1 levels are significantly up-regulated in multidrug-resistant SCLC cells (H69AR and H446DDP) compared with the sensitive parental cells (H69 and H446). In addition, clinical samples showed that FGFRL1 was overexpressed in SCLC tissues, and high FGFRL1 expression was associated with the clinical stage, chemotherapy response and survival time of SCLC patients. Knockdown of FGFRL1 in chemoresistant SCLC cells increased chemosensitivity by increasing cell apoptosis and cell cycle arrest, whereas overexpression of FGFRL1 in chemosensitive SCLC cells produced the opposite results. Mechanistic investigations showed that FGFRL1 interacts with ENO1, and FGFRL1 was found to regulate the expression of ENO1 and its downstream signalling pathway (the PI3K/Akt pathway) in SCLC cells. In brief, our study demonstrated that FGFRL1 modulates chemoresistance of SCLC by regulating the ENO1-PI3K/Akt pathway. FGFRL1 may be a predictor and a potential therapeutic target for chemoresistance in SCLC.
    Keywords:  ENO1; FGFRL1; PI3K/Akt pathway; chemoresistance; small-cell lung cancer
    DOI:  https://doi.org/10.1111/jcmm.14763
  706. J Mater Chem B. 2020 Jan 21.
    Development of functional liposomes by modification of stimuli-responsive materials and their biomedical applications.
    Yuba E.
      Liposomes are a promising nanocarrier for drug delivery because of their biocompatibility and the encapsulation capacity of drugs. Liposomes can be functionalized easily by introduction of functional materials such as stimulus-responsive materials. Temperature-responsive liposomes and pH-responsive liposomes are representative stimulus-responsive liposomes that can deliver drugs to locally heated target tissues and intracellular organelles. Here, temperature-responsive liposomes for the selective release of cargo and pH-responsive liposomes for the induction of antigen-specific immunity are overviewed. Temperature-responsive polymer-modified liposomes immediately released drugs in response to heating, which achieved selective drug release at a tumour after topical heating of tumour-bearing mice. Introduction of MR-detectable molecules enabled the tracing of liposome accumulation into target sites to optimize the heating timing. These liposomes can also be combined with magnetic nanoparticles or carbon nanomaterials to attain magnetic field-responsive, electric field-responsive and light-responsive properties to support on-demand drug release or control of biological reactions using these external stimuli. pH-Responsive liposomes were produced by modification of poly(carboxylic acid) derivatives or by pH-responsive amphiphiles. These liposomes delivered antigenic proteins into the cytosol of antigen presenting cells, which induced cross-presentation and antigen-specific cellular immunity. Adjuvant molecules or bioactive polysaccharide-based pH-responsive polymers improved their immunity-inducing effect further, leading to tumour regression in tumour-bearing mice. Precise design and control of the structures of stimulus-responsive materials and combination with functional materials are expected to create novel methodologies to control biological functions and to produce highly potent liposomal drugs that can achieve selective release of bioactive molecules.
    DOI:  https://doi.org/10.1039/c9tb02470k
  707. Appl Clin Inform. 2020 Jan;11(1): 70-78
    Self-Management Behaviors of Patients with Type 1 Diabetes: Comparing Two Sources of Patient-Generated Data.
    Karway G, Grando MA, Grimm K, Groat D, Cook C, Thompson B.
      OBJECTIVES:  This article aims to evaluate adult type 1 diabetes mellitus (T1DM) self-management behaviors (SMBs) related to exercise and alcohol on a survey versus a smartphone app to compare self-reported and self-tracked SMBs, and examine inter- and intrapatient variability.METHODS:  Adults with T1DM on insulin pump therapy were surveyed about their alcohol, meal, and exercise SMBs. For 4 weeks, participants self-tracked their alcohol, meal, and exercise events, and their SMBs corresponding with these events via an investigator-developed app. Descriptive statistics and generalized linear mixed-effect models were used to analyze the data RESULTS:  Thirty-five participants self-tracked over 5,000 interactions using the app. Variability in how participants perceived the effects of exercise and alcohol on their blood glucose was observed. The congruity between SMBs self-reported on the survey and those self-tracked with the app was measured as mean (SD). The lowest congruity was for alcohol and exercise with 61.9% (22.7) and 66.4% (20.2), respectively. Congruity was higher for meals with 80.9% (21.0). There was significant daily intra- and interpatient variability in SMBs related to preprandial bolusing: recommended bolus, p < 0.05; own bolus choice, p < 0.01; and recommended basal adjustment, p < 0.01.
    CONCLUSION:  This study highlights the variability in intra- and interpatient SMBs obtained through the use of a survey and app. The outcomes of this study indicate that clinicians could use both one-time and every-day assessment tools to assess SMBs related to meals. For alcohol and exercise, further research is needed to understand the best assessment method for SMBs. Given this degree of patient variability, there is a need for an educational intervention that goes beyond the traditional "one-size-fits-all" approach of diabetes management to target individualized treatment barriers.
    DOI:  https://doi.org/10.1055/s-0039-1701002
  708. Sci Rep. 2020 Jan 22. 10(1): 983
    Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects.
    Kawakubo M, Tanaka M, Ochi K, Watanabe A, Saka-Tanaka M, Kanamori Y, Yoshioka N, Yamashita S, Goto M, Itoh M, Shirakawa I, Kanai S, Suzuki H, Sawada M, Ito A, Ishigami M, Fujishiro M, Arima H, Ogawa Y, Suganami T.
      Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism-independent effects of anagliptin on NASH and HCC development.
    DOI:  https://doi.org/10.1038/s41598-020-57935-6
  709. Cell Death Differ. 2020 Jan 20.
    Prolyl hydroxylase 3 controls the intestine goblet cell generation through stabilizing ATOH1.
    Xu YM, Gao Q, Zhang JZ, Lu YT, Xing DM, Qin YQ, Fang J.
      Intestinal epithelia self-renew constantly and generate differentiated cells such as secretary goblet cells. The intestine goblet cells secrete gel-forming mucins that form mucus to create a barrier of defense. We reported previously that loss of prolyl hydroxylase (PHD) 3 led to disruption of the intestinal epithelial barrier function. However, the underlying mechanism remains elusive. Here, we demonstrate that PHD3 controls the generation of intestine goblet cell. We found that genetic ablation of Phd3 in mice intestine epithelial cells reduced the amount of goblet cells. Mechanistically, PHD3 bounds the E3 ubiquitin ligase HUWE1 and prevented HUWE1 from mediating ubiquitination and degradation of ATOH1, an essential driver for goblet cell differentiation. The prolyl hydroxylase activity-deficient variant PHD3(H196A) also prevented ATOH1 destruction. A genetic intestine epithelial PHD3(H196A)-knockin had no effect on ATOH1 expression or goblet cell amount in mice, suggesting that the PHD3 prolyl hydroxylase activity is dispensable for its ability to control ATOH1 expression and goblet cell generation. In dextran sulfate sodium (DSS)-induced experimental colitis, PHD3-knockout rather than PHD3(H196A)-knockin sensitized the mice to DSS treatment. Our results reveal an additional critical mechanism underlying the regulation of ATOH1 expression and goblet cell generation and highlight that PHD3 plays a role in controlling intestine goblet cell generation in a hydroxylase-independent manner.
    DOI:  https://doi.org/10.1038/s41418-020-0490-7
  710. ACS Nano. 2020 Jan 24.
    Graphene Oxide-Grafted Magnetic Nanorings Mediated Magnetothermodynamic Therapy Favoring Reactive Oxygen Species-Related Immune Response for Enhanced Antitumor Efficacy.
    Liu X, Yan B, Li Y, Ma X, Jiao W, Shi K, Zhang T, Chen S, He Y, Liang XJ, Fan H.
      In this study, a magnetothermodynamic (MTD) therapy is introduced as an efficient systemic cancer treatment, by combining the magnetothermal effect and the reactive oxygen species (ROS)-related immunologic effect, in order to overcome the obstacle of limited therapeutic efficacy in current magnetothermal therapy (MTT). This approach was achieved by the development of an elaborate ferrimagnetic vortex-domain iron oxide nanoring and graphene oxide (FVIOs-GO) hybrid nanoparticle as the efficient MTD agent. Such a FVIOs-GO nanoplatform was shown to have high thermal conversion efficiency, and it was further proved to generate a significantly amplified ROS level under an alternating magnetic field (AMF). Both in vitro and in vivo results revealed that amplified ROS generation was the dominant factor in provoking a strong immune response at a physiological tolerable temperature below 40 °C in a hypoxic tumor microenvironment. This was supported by the exposure of calreticulin (CRT) on 83% of the 4T1 breast cancer cell surface, direct promotion of macrophage polarization to pro-inflammatory M1 phenotypes, and further elevation of tumor-infiltrating T lymphocytes. As a result of the dual action of magnetothermal effect and ROS-related immunologic effect, impressive in vivo systemic therapeutic efficacy was attained at a low dosage of 3 mg Fe/kg with two AMF treatments, as compared to that of MTT (high dosage of 6-18 mg/kg under four to eight AMF treatments). The MTD therapy reported here has highlighted the inadequacy of conventional MTT that solely relies on the heating effect of the MNPs. Thus, by employing a ROS-mediated immunologic effect, future cancer magnetotherapies can be designed with greatly improved antitumor capabilities.
    Keywords:  FVIOs-GO nanomaterials; ROS; immunological effect; magnetothermodynamic therapy; systemic delivery
    DOI:  https://doi.org/10.1021/acsnano.9b08320
  711. Am J Respir Crit Care Med. 2020 Jan 24.
    In the Wrong Place at the Wrong Time: Microbial Misplacement and ARDS.
    Cookson WOCM, Moffatt MF.
      
    DOI:  https://doi.org/10.1164/rccm.202001-0004ED
  712. Med Sci Sports Exerc. 2020 Jan 17.
    High-Intensity Training and Saffron: Effects on Breast Cancer-related Gene Expression.
    Nezamdoost Z, Saghebjoo M, Hoshyar R, Hedayati M, Keska A.
      PURPOSE: Exercise training and some herbal components have an anti-cancer function and can suppress tumor growth. However, the role of these protective factors in altering breast cancer- related gene expression is still unknown. Thus, this study aimed to assess the effect of 4 weeks of high-intensity interval training (HIIT) and saffron (Crocus Sativus L.) aqueous extract (SAE) on Sirtuin-1 (SIRT1), hTERT, and p53 gene expression in female mice breast tumor tissue induced by 4T1 cell line.METHODS: This study was performed on female BALB/c mice. The 4T1 breast cancer cells were subcutaneously implanted and mice were randomly sorted into the following groups: control, HIIT, SAE, HIIT+ SAE (n=10 mice/group) and sham (n=4 mice/group). Mice were sacrificed at the end of the intervention period and the expression of SIRT-1, hTERT, and p53 was determined by real-time PCR.
    RESULTS: The mRNA level of SIRT1 was increased in the HIIT+SAE group compared to HIIT and control groups (P = 0.007 and P = 0.03; respectively). Moreover, the amount of mRNA of p53 was increased following 4-weeks HIIT compared to control and HIIT+SAE groups in tumor tissue (P = 0.03 and P = 0.02; respectively). No change was found in the mRNA expression of hTERT between groups (P = 0.92).
    CONCLUSIONS: These findings suggest that HIIT may reduce tumor burden through the up-regulation of p53 associated with tumor suppression pathway. In contrast, the combination of HIIT and SAE did not alter p53 and SIRT1 expression levels and may suppress tumor growth by other mechanisms.
    DOI:  https://doi.org/10.1249/MSS.0000000000002274
  713. Cancer Discov. 2020 Jan 24.
    VEGFC-Mediated Lymphatic Drainage Increases Brain Tumor Immunogenicity.
      A VEGFC-expressing mRNA construct improved immunotherapy response in mouse models of glioblastoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-014
  714. Curr Biol. 2020 Jan 20. pii: S0960-9822(19)31530-1. [Epub ahead of print]30(2): R83-R86
    Cell Biology: Tight Junctions as Biomolecular Condensates.
    Citi S.
      Two recent studies report that ZO proteins, the main scaffolding proteins of tight junctions, undergo liquid phase separation. This new concept provides understanding at the mechanistic level of how tight junctions are formed and how they participate in mechanochemical signaling in early development.
    DOI:  https://doi.org/10.1016/j.cub.2019.11.060
  715. J Biosci. 2020 ;pii: 7. [Epub ahead of print]45
    Metabolic choreography of gene expression: nutrient transactions with the epigenome.
    Maniyadath B, Sandra US, Kolthur-Seetharam U.
      Eukaryotic complexity and thus their ability to respond to diverse cues are largely driven by varying expression of gene products, qualitatively and quantitatively. Protein adducts in the form of post-translational modifications, most of which are derived from metabolic intermediates, allow fine tuning of gene expression at multiple levels. With the advent of high-throughput and high-resolution mapping technologies there has been an explosion in terms of the kind of modifications on chromatin and other factors that govern gene expression. Moreover, even the classical notion of acetylation and methylation dependent regulation of transcription is now known to be intrinsically coupled to biochemical pathways, which were otherwise regarded as 'mundane'. Here we have not only reviewed some of the recent literature but also have highlighted the dependence of gene regulatory mechanisms on metabolic inputs, both direct and indirect. We have also tried to bring forth some of the open questions, and how our understanding of gene expression has changed dramatically over the last few years, which has largely become metabolism centric. Finally, metabolic regulation of epigenome and gene expression has gained much traction due to the increased incidence of lifestyle and age-related diseases.
  716. Spine Deform. 2019 Nov;7(6): 945-949
    Comparative Sacral Morphology in Spondylolisthesis Patients.
    Hresko MT, Deckey DG, Hinchcliff E, Kalish LA.
      STUDY DESIGN: Retrospective comparative case series.OBJECTIVES: Evaluation of sacral morphology in spondylolisthesis patients compared with asymptomatic controls. Patients with spondylolisthesis are known to differ from asymptomatic controls in sagittal plane anatomy, but few studies examine the coronal and axial plane differences in these cohorts.
    METHODS: This is a retrospective evaluation of magnetic resonance imaging of the lumbosacral spine in 29 spondylolisthesis patients and an asymptomatic cohort (n = 154). Measurements of the linear distance and angular position of L5 and sacrum were performed in the sagittal, coronal, and axial planes. Receiver operating characteristic (ROC) curve analysis quantified these associations. High- and low-grade spondylolisthesis patients were compared with two-sample t-tests. All p-values are two-sided and considered significant when p < .05.
    RESULTS: Axial measurements showed the distance of the right to left anterior ala and the L5 body width did not differ between the cohorts. Sacroiliac (SI) joint angles in the spondylolisthesis cohort were closer to the true sagittal plane than in the controls 109° versus 121° (p < .001). In the sagittal plane, the linear measurement of the ratio of the midpoint anteroposterior width L5 to the sacral end plate was larger in the high-grade patients than the low-grade patients and controls. In addition, the kyphosis between S1-S2 and S2-S3 was larger in the spondylolisthesis cohort.
    CONCLUSIONS: The SI joints in patients with spondylolisthesis were orientated closer to the sagittal plane than in the controls. An awareness of this positioning may be important in surgical implant insertion as well as rehabilitation of hip extensor weakness. The main anatomical differences found in this study were in the sagittal plane. Sacral end plate abnormalities were well visualized and consistent with radiographic findings in the literature.
    LEVEL OF EVIDENCE: Level III, diagnostic.
    Keywords:  Pelvis; Sacral morphology; Sacrum; Spondylolisthesis
    DOI:  https://doi.org/10.1016/j.jspd.2019.03.008
  717. Exp Clin Endocrinol Diabetes. 2020 Jan 22.
    Placental Accumulation of Triacylglycerols in Gestational Diabetes Mellitus and Its Association with Altered Fetal Growth are Related to the Differential Expressions of Proteins of Lipid Metabolism.
    Balachandiran M, Bobby Z, Dorairajan G, Jacob SE, Gladwin V, Vinayagam V, Packirisamy RM.
      INTRODUCTION: Gestational diabetes mellitus (GDM) exhibit altered placental lipid metabolism. The molecular basis of this altered metabolism is not clear. Altered placental expression of proteins of lipogenesis and fatty acid oxidation may be involved in the placental accumulation of triacylglycerols (TG). The present study was aimed at investigating the differential expressions of placental proteins related to lipid metabolism among GDM women in comparison with control pregnant women (CPW) and to correlate them with maternal and fetal lipid parameters as well as altered fetal growth.MATERIALS AND METHODS: Maternal blood, cord blood, and placental samples were collected from GDM and CPW. The biochemical parameters, glucose, lipid profile and free fatty acids (FFA) were measured. The placental TG content was measured. Differential placental expressions of proteins; phosphatidylinositol-3-kinase (PI3K) p85α, PI3K p110α,liver X receptor alpha (LXRα), sterol regulatory element binding protein1(SREBP1), fatty acid synthase (FAS), stearyl CoA desaturase1 (SCD1), lipoprotein lipase (LPL),Peroxisome proliferator-activated receptor (PPAR)α and PPARγ were analysed by western blotting and immunohistochemistry.
    RESULTS: Placental protein expressions of PI3K p110α, LXRα, FAS, SCD1, and LPL were found to be significantly higher, whereas PPARα and PPARγ were lower in GDM women compared with CPW. The placental TG content and cord plasma FFA were increased in GDM women compared with CPW. The placental TG content positively correlated with Ponderal index of GDM new-borns.
    CONCLUSION: Differential expressions of placental proteins related to lipid metabolism in GDM might have led to placental TG accumulation. This might have contributed to the fetal overgrowth in GDM.
    DOI:  https://doi.org/10.1055/a-1017-3182
  718. Reprod Biomed Online. 2019 Dec 24. pii: S1472-6483(19)30798-9. [Epub ahead of print]
    Association between vascular endothelial growth factor gene polymorphisms and PCOS risk: A meta-analysis.
    Li Y, Fang L, Yu Y, Shi H, Wang S, Li Y, Ma Y, Yan Y, Sun YP.
      Vascular endothelial growth factor (VEGF) plays important roles in the pathogenesis of polycystic ovary syndrome (PCOS). Several single nucleotide polymorphisms (SNP) of the VEGF gene have been identified and are associated with the aberrant secretion of VEGF protein. This meta-analysis aimed to evaluate the impact of the VEGF +405G>C (rs2010963), -460C>T (rs833061) and -2578A>C (rs699947) polymorphisms on PCOS susceptibility. A systematic search of the Embase, PubMed, Web of Science and Wanfang databases was carried out to identify relevant studies published before 19 July 2019. Seven eligible studies were included in this meta-analysis involving 1100 patients with PCOS and 1141 control individuals. The pooled analysis revealed no significant association between PCOS risk and the +405G>C (rs2010963), -460C>T (rs833061) or -2578A>C (rs699947) polymorphisms in women. Subgroup analysis by ethnicity indicated that Asian women carrying the VEGF +405C allele had a lower risk of PCOS (C versus G: odds ratio [OR] 0.731, 95% confidence interval [CI] 0.544-0.982, P < 0.05, I2 = 46.4%; CG versus GG: OR 0.667, 95% CI 0.469-0.948, P < 0.05, I2 = 18.4%; CC versus GG: OR 0.611, 95% CI 0.390-0.958, P < 0.05, I2 = 24.3%). The study demonstrates that for all women regardless of ethnicity, no significant associations between VEGF SNP and PCOS were observed; however, +405G>C (rs2010963) may protect Asian women from PCOS.
    Keywords:  Meta-analysis; Polycystic ovary syndrome; Polymorphisms; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1016/j.rbmo.2019.10.018
  719. Phytomedicine. 2020 Jan 11. pii: S0944-7113(20)30003-9. [Epub ahead of print] 153170
    The roles of strawberry and honey phytochemicals on human health: A possible clue on the molecular mechanisms involved in the prevention of oxidative stress and inflammation.
    Battino M, Giampieri F, Cianciosi D, Ansary J, Chen X, Zhang D, Gil E, Forbes-Hernández T.
      BACKGROUND: Oxidative stress and inflammation contribute to the etiopathogenesis of several human chronic diseases, such as cancer, diabetes, cardiovascular diseases and metabolic syndrome. Besides classic stimuli, such as reactive oxidant species, endotoxins (i.e., bacteria lipopolysaccharide), cytokines or carcinogens, oxidative stress and inflammation can be triggered by a poor diet and an excess of body fat and energy intake. Strawberry and honey are common rich sources of nutrients and bioactive compounds, widely studied for their roles exerted in health maintenance and disease prevention.PURPOSE: This review aims to summarize and update the effects of strawberry and honey against oxidative stress and inflammation, with emphasis on metabolism and on the main molecular mechanisms involved in these effects.
    METHODS: A wide range of literature, published in the last 10 years, elucidating the effects of strawberry and honey in preventing oxidative stress and inflammation both in vitro (whole matrix and digested fractions) and in vivo was collected from online electronic databases (PubMed, Scopus and Web of Science) and reviewed.
    RESULTS: Strawberry and honey polyphenols may potentially prevent the chronic diseases related to oxidative stress and inflammation. Several in vitro and in vivo studies reported the effects of these foods in suppressing the oxidative stress, by decreasing ROS production and oxidative biomarkers, restoring the antioxidant enzyme activities, ameliorating the mitochondrial antioxidant status and functionality, among others, and the inflammatory process, by modulating the mediators of acute and chronic inflammation essential for the onset of several human diseases. These beneficial properties are mediated in part through their ability to target multiple signaling pathways, such as p38 MAPK, AMPK, PI3K/Akt, NF-κB and Nrf2.
    CONCLUSIONS: Available scientific literature show that strawberry and honey may be effective in preventing oxidative stress and inflammation. The deep evaluation of the factors that affect their metabolism as well as the assessment of the main molecular mechanisms involved are of extreme importance for the possible therapeutic and preventive benefit against the most common human diseases. However, published literature is still scarce so that deeper studies should be performed in order to evaluate the bioavailability of these food matrices and their effects after digestion.
    Keywords:  Bioavailability; Honey; Inflammation; Oxidative stress; Polyphenols; Strawberry
    DOI:  https://doi.org/10.1016/j.phymed.2020.153170
  720. Spine Deform. 2019 Jan;7(1): 47-52
    Incidence of Intraspinal and Extraspinal MRI Abnormalities in Patients With Adolescent Idiopathic Scoliosis.
    Swarup I, Silberman J, Blanco J, Widmann R.
      STUDY DESIGN: Retrospective study with follow-up.OBJECTIVES: The purpose of this study was to determine the incidence of intraspinal and extraspinal MRI abnormalities in a consecutive series of patients with adolescent idiopathic scoliosis (AIS) and to describe the evaluation and management of these abnormalities. Indications for preoperative magnetic resonance imaging (MRI) in patients with AIS remain controversial. Previous studies have reported a wide range of abnormality rates; however, the majority of these studies focus on a nonconsecutive series of patients, and none of these studies report the incidence of extraspinal abnormalities.
    METHODS: We studied a consecutive series of patients with AIS managed with spinal deformity surgery. All patients underwent a routine neural axis MRI prior to surgery. MRI reports were reviewed, and intraspinal and extraspinal abnormalities were recorded. Additional chart review and follow-up was performed to determine the rates of evaluation and management for these abnormalities. Descriptive statistics were used to describe the incidence and types of abnormalities, as well as the rates of evaluation and management.
    RESULTS: This study included a consecutive series of 259 patients with AIS. MRI abnormalities were noted in 115 patients (44%). After excluding patients with degenerative changes, MRI abnormalities were noted in 64 patients (25%). The incidence of Chiari malformation was 4.2% and syringomyelia was 5%. Extraspinal abnormalities were noted in 10% of patients, and these findings ranged from benign cysts to malignant soft tissue tumor. Approximately 10% of patients needed additional evaluation because of their preoperative MRI findings, and 0.7% of patients required surgical management prior to spinal deformity surgery.
    CONCLUSIONS: Significant MRI abnormalities were noted in patients with AIS, and some patients required further evaluation prior to surgery. Additional study including cost-effectiveness analysis is needed to better define the role of preoperative MRI in patients with AIS.
    LEVEL OF EVIDENCE: Level II.
    Keywords:  Adolescent idiopathic scoliosis; Extraspinal abnormalities; Intraspinal abnormalities; Magnetic resonance imaging
    DOI:  https://doi.org/10.1016/j.jspd.2018.06.006
  721. BMC Palliat Care. 2020 Jan 23. 19(1): 11
    Correction to: Health-related quality of life and its socio-economic and cultural predictors among advanced cancer patients: evidence from the APPROACH cross-sectional survey in Hyderabad-India.
    Jacob J, Palat G, Verghese N, Kumari P, Rapelli V, Kumari S, Malhotra C, Teo I, Finkelstein E, Ozdemir S.
      Following publication of the original article [1], the corresponding author reported an error on the name of the fourth author.
    DOI:  https://doi.org/10.1186/s12904-020-0519-1
  722. Ann Oncol. 2020 Feb;pii: S0923-7534(19)39096-9. [Epub ahead of print]31(2): 163-164
    Metabolic response assessment and PET-guided treatment of esophageal cancer.
    Lordick F, Herrmann K.
      
    DOI:  https://doi.org/10.1016/j.annonc.2019.11.008
  723. J Aging Phys Act. 2020 Jan 22. pii: japa.2019-0100. [Epub ahead of print] 1-8
    An Intense, But Ecologically Valid, Resistance Exercise Session Does Not Alter Growth Factors Associated With Cognitive Health.
    Marston KJ, Brown BM, Rainey-Smith SR, Bird S, Wijaya LK, Teo SYM, Martins RN, Peiffer JJ.
      The purpose of this investigation was to assess the acute changes in growth factors associated with cognitive health following two ecologically valid, intense resistance exercise sessions. Twenty-nine late-middle-aged adults performed one session of either (a) moderate-load resistance exercise or (b) high-load resistance exercise. Venous blood was collected prior to warm-up, immediately following exercise and 30 min following exercise. Serum was analyzed for brain-derived neurotrophic factor, insulin-like growth factor 1, and vascular endothelial growth factor. Session intensity was determined by blood lactate concentration and session rating of perceived exertion. Postexercise blood lactate was greater following moderate-load when compared with high-load resistance exercise. Subjective session intensity was rated higher by the session rating of perceived exertion following moderate-load when compared with high-load resistance exercise. No differences were observed in serum growth factor levels between groups. Ecologically valid and intense moderate-load or high-load exercise methods do not alter serum growth factor levels in late-middle-aged adults.
    Keywords:  cognitive decline; healthy aging; neurotrophic factors; strength training
    DOI:  https://doi.org/10.1123/japa.2019-0100
  724. Nat Commun. 2020 Jan 24. 11(1): 485
    Interrogation of enhancer function by enhancer-targeting CRISPR epigenetic editing.
    Li K, Liu Y, Cao H, Zhang Y, Gu Z, Liu X, Yu A, Kaphle P, Dickerson KE, Ni M, Xu J.
      Tissue-specific gene expression requires coordinated control of gene-proximal and -distal cis-regulatory elements (CREs), yet functional analysis of gene-distal CREs such as enhancers remains challenging. Here we describe CRISPR/dCas9-based enhancer-targeting epigenetic editing systems, enCRISPRa and enCRISPRi, for efficient analysis of enhancer function in situ and in vivo. Using dual effectors capable of re-writing enhancer-associated chromatin modifications, we show that enCRISPRa and enCRISPRi modulate gene transcription by remodeling local epigenetic landscapes at sgRNA-targeted enhancers and associated genes. Comparing with existing methods, the improved systems display more robust perturbations of enhancer activity and gene transcription with minimal off-targets. Allele-specific targeting of enCRISPRa to oncogenic TAL1 super-enhancer modulates TAL1 expression and cancer progression in xenotransplants. Single or multi-loci perturbations of lineage-specific enhancers using an enCRISPRi knock-in mouse establish in vivo evidence for lineage-restricted essentiality of developmental enhancers during hematopoiesis. Hence, enhancer-targeting CRISPR epigenetic editing provides opportunities for interrogating enhancer function in native biological contexts.
    DOI:  https://doi.org/10.1038/s41467-020-14362-5
  725. PLoS Genet. 2020 Jan 21. 16(1): e1008582
    Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality.
    Lagree K, Woolford CA, Huang MY, May G, McManus CJ, Solis NV, Filler SG, Mitchell AP.
      Metabolic adaptation is linked to the ability of the opportunistic pathogen Candida albicans to colonize and cause infection in diverse host tissues. One way that C. albicans controls its metabolism is through the glucose repression pathway, where expression of alternative carbon source utilization genes is repressed in the presence of its preferred carbon source, glucose. Here we carry out genetic and gene expression studies that identify transcription factors Mig1 and Mig2 as mediators of glucose repression in C. albicans. The well-studied Mig1/2 orthologs ScMig1/2 mediate glucose repression in the yeast Saccharomyces cerevisiae; our data argue that C. albicans Mig1/2 function similarly as repressors of alternative carbon source utilization genes. However, Mig1/2 functions have several distinctive features in C. albicans. First, Mig1 and Mig2 have more co-equal roles in gene regulation than their S. cerevisiae orthologs. Second, Mig1 is regulated at the level of protein accumulation, more akin to ScMig2 than ScMig1. Third, Mig1 and Mig2 are together required for a unique aspect of C. albicans biology, the expression of several pathogenicity traits. Such Mig1/2-dependent traits include the abilities to form hyphae and biofilm, tolerance of cell wall inhibitors, and ability to damage macrophage-like cells and human endothelial cells. Finally, Mig1 is required for a puzzling feature of C. albicans biology that is not shared with S. cerevisiae: the essentiality of the Snf1 protein kinase, a central eukaryotic carbon metabolism regulator. Our results integrate Mig1 and Mig2 into the C. albicans glucose repression pathway and illuminate connections among carbon control, pathogenicity, and Snf1 essentiality.
    DOI:  https://doi.org/10.1371/journal.pgen.1008582
  726. Lancet. 2020 Jan 20. pii: S0140-6736(19)33153-8. [Epub ahead of print]
    Population-level impact of human papillomavirus vaccination.
    Brotons M, Bruni L.
      
    DOI:  https://doi.org/10.1016/S0140-6736(19)33153-8
  727. BJU Int. 2020 Jan 24.
    Modifiable Lifestyle Behaviours Impact the Health-Related Quality of Life of Bladder Cancer Survivors.
    Chung J, Maganti M, Kulkarni GS, Morash R, Matthew A, Papadakos J, Breau RH, Guttman D, Bender J, Jones JM.
      OBJECTIVE: To examine health behaviours including physical activity (PA), body mass index, diet quality, smoking and alcohol consumption, and explore their relationship with HRQoL.SUBJECTS/PATIENTS AND METHODS: Cross-sectional questionnaire packages were distributed to bladder cancer survivors (muscle-invasive (MIBC) and non-muscle invasive (NMIBC)) over the age of 18, and proficient in English. Lifestyle behaviours were measured using established measures/questions, and reported using descriptive statistics. HRQoL was assessed using the validated Bladder Utility Symptom Scale, and its association with lifestyle behaviours was evaluated using Analysis of Covariance (ANCOVA) and multivariate regression analyses.
    RESULTS: A total of 586 participants completed the questionnaire (52% response rate). The mean age was 67.3±10.2, and 68% were male. Twenty percent (n=117) met PA guidelines, and 22.7% (n=133) met dietary guidelines. 60.9% (n=357) were overweight/obese, and majority met alcohol recommendations (n=521, 92.5%) and were current non-smokers (n=535, 91.0%). Health behaviours did not differ between MIBC and NMIBC and cancer treatment stages. Sufficient PA, healthy diet, and non-smoking were significantly associated with HRQoL, and the number of health behaviours participants engaged in was positively associated with HRQoL (p<0.001).
    CONCLUSION: Bladder cancer survivors are not meeting guidelines for important lifestyle behaviours that may improve their overall HRQoL. Future research should investigate the impact of behavioural and educational interventions for health behaviours on HRQoL in this population.
    DOI:  https://doi.org/10.1111/bju.15007
  728. Ambio. 2020 Jan 18.
    Developing a circumpolar programme for the monitoring of Arctic terrestrial biodiversity.
    Christensen T, Barry T, Taylor JJ, Doyle M, Aronsson M, Braa J, Burns C, Coon C, Coulson S, Cuyler C, Falk K, Heiðmarsson S, Kulmala P, Lawler J, MacNearney D, Ravolainen V, Smith PA, Soloviev M, Schmidt NM.
      The Arctic is undergoing biological and environmental changes, and a coordinated effort to monitor is critical to detect these changes. The Circumpolar Biodiversity Monitoring Programme (CBMP) of the Arctic Council biodiversity working group, Conservation of Arctic Flora and Fauna (CAFF), has developed pan-Arctic biodiversity monitoring plans that aims to improve the ability to detect and report on long-term changes. Whilst introducing this special issue, this paper also presents the making of the terrestrial monitoring plan and discusses how the plan follows the steps required for an adaptive and ecosystem-based monitoring programme. In this article, we discuss how data on key findings can be used to inform circumpolar and global assessments, including the State of the Arctic Terrestrial Biodiversity Report, which will be the first terrestrial assessment made by the CBMP. Key findings, advice for future monitoring and lessons learned will be used in planning next steps of pan-Arctic coordinated monitoring.
    Keywords:  Adaptive monitoring; Arctic; CAFF; CBMP; State of the Arctic Biodiversity Report; Terrestrial biodiversity monitoring
    DOI:  https://doi.org/10.1007/s13280-019-01311-w
  729. Nucleic Acids Res. 2020 Jan 23. pii: gkaa011. [Epub ahead of print]
    Lysine acetylation of the housekeeping sigma factor enhances the activity of the RNA polymerase holoenzyme.
    Kim JE, Choi JS, Kim JS, Cho YH, Roe JH.
      Protein lysine acetylation, one of the most abundant post-translational modifications in eukaryotes, occurs in prokaryotes as well. Despite the evidence of lysine acetylation in bacterial RNA polymerases (RNAPs), its function remains unknown. We found that the housekeeping sigma factor (HrdB) was acetylated throughout the growth of an actinobacterium, Streptomyces venezuelae, and the acetylated HrdB was enriched in the RNAP holoenzyme complex. The lysine (K259) located between 1.2 and 2 regions of the sigma factor, was determined to be the acetylated residue of HrdB in vivo by LC-MS/MS analyses. Specifically, the label-free quantitative analysis revealed that the K259 residues of all the HrdB subunits were acetylated in the RNAP holoenzyme. Using mutations that mimic or block acetylation (K259Q and K259R), we found that K259 acetylation enhances the interaction of HrdB with the RNAP core enzyme as well as the binding activity of the RNAP holoenzyme to target promoters in vivo. Taken together, these findings provide a novel insight into an additional layer of modulation of bacterial RNAP activity.
    DOI:  https://doi.org/10.1093/nar/gkaa011
  730. Cancer Discov. 2020 Jan 23.
    Avapritinib Approved for GIST Subgroup.
      The FDA approved avapritinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors with mutations in exon 18 of PDGFRA-genetic alterations that render tumors insensitive to all previously approved therapies for this rare sarcoma of the digestive tract.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2020-003
  731. Sci Rep. 2020 Jan 21. 10(1): 809
    Genomic, metabolic and phenotypic variability shapes ecological differentiation and intraspecies interactions of Alteromonas macleodii.
    Koch H, Germscheid N, Freese HM, Noriega-Ortega B, Lücking D, Berger M, Qiu G, Marzinelli EM, Campbell AH, Steinberg PD, Overmann J, Dittmar T, Simon M, Wietz M.
      Ecological differentiation between strains of bacterial species is shaped by genomic and metabolic variability. However, connecting genotypes to ecological niches remains a major challenge. Here, we linked bacterial geno- and phenotypes by contextualizing pangenomic, exometabolomic and physiological evidence in twelve strains of the marine bacterium Alteromonas macleodii, illuminating adaptive strategies of carbon metabolism, microbial interactions, cellular communication and iron acquisition. In A. macleodii strain MIT1002, secretion of amino acids and the unique capacity for phenol degradation may promote associations with Prochlorococcus cyanobacteria. Strain 83-1 and three novel Pacific isolates, featuring clonal genomes despite originating from distant locations, have profound abilities for algal polysaccharide utilization but without detrimental implications for Ecklonia macroalgae. Degradation of toluene and xylene, mediated via a plasmid syntenic to terrestrial Pseudomonas, was unique to strain EZ55. Benzoate degradation by strain EC673 related to a chromosomal gene cluster shared with the plasmid of A. mediterranea EC615, underlining that mobile genetic elements drive adaptations. Furthermore, we revealed strain-specific production of siderophores and homoserine lactones, with implications for nutrient acquisition and cellular communication. Phenotypic variability corresponded to different competitiveness in co-culture and geographic distribution, indicating linkages between intraspecific diversity, microbial interactions and biogeography. The finding of "ecological microdiversity" helps understanding the widespread occurrence of A. macleodii and contributes to the interpretation of bacterial niche specialization, population ecology and biogeochemical roles.
    DOI:  https://doi.org/10.1038/s41598-020-57526-5
  732. Comb Chem High Throughput Screen. 2020 Jan 21.
    Systematic Understanding of the Mechanisms of Flos Chrysanthemi Indici-mediated Eeffects on Hypertension via Computational Target Fishing.
    Chen YH, Lei SS, Li B, Luo R, He X, Wang YZ, Zhou FC, Lv GY, Chen SH.
      AIM AND OBJECTIVE: Hypertension-induced stroke and coronary artery disease are significant causes of global morbidity and mortality. Metabolic hypertension has recently become the main cause of hypertension. Flos Chrysanthemi indici (CIF) has a long history as a treatment of hypertension as part of traditional Chinese medicine. However, its mechanisms of activity remain largely unknown. This study was aimed to uncover the potential anti-hypertensive mechanisms of CIF based on network pharmacology.MATERIALS AND METHODS: In this research, a systems pharmacology approach integrating the measurement of active compounds, target fishing, gene screening, Gene Ontology (GO) pathway analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) database analysis, and compound-target network construction were performed to explore the anti-hypertensive mechanisms of CIF.
    RESULTS: These studies revealed that 12 bioactive compounds in CIF had good druggability, 5 of which were flavonoids. After screening, 8 of those 12 bioactive compounds interacted with 118 hypertension-related target genes, which were mapped to 218 signal pathways. Network analysis showed that these targets were associated with improving insulin resistance, improving vascular function, inhibiting rennin-angiotensin-aldosterone system (RAAS), inhibiting the sympathetic nervous system (SNS) and regulating other physiological processes.
    CONCLUSION: In summary, CIF is predicted to target multiple proteins and pathways to form a network that exerts systematic pharmacological effects in order to regulate blood pressure and metabolic disorder.
    Keywords:  Flos Chrysanthemi Indici; Hypertension; Metabolic hypertension; Systematic pharmacology
    DOI:  https://doi.org/10.2174/1386207323666200122105410
  733. Clin Diabetes. 2020 Jan;38(1): 112-116
    Sodium-Glucose Cotransporter 2 Inhibitor-Associated Prolonged Euglycemic Diabetic Ketoacidosis in Type 2 Diabetes: A Case Report and Literature Review.
    Yehya A, Sadhu A.
      
    DOI:  https://doi.org/10.2337/cd19-0035
  734. FASEB J. 2020 Jan 21.
    Advances in histone demethylase KDM4 as cancer therapeutic targets.
    Lee DH, Kim GW, Jeon YH, Yoo J, Lee SW, Kwon SH.
      The KDM4 subfamily H3K9 histone demethylases are epigenetic regulators that control chromatin structure and gene expression by demethylating histone H3K9, H3K36, and H1.4K26. The KDM4 subfamily mainly consists of four proteins (KDM4A-D), all harboring the Jumonji C domain (JmjC) but with differential substrate specificities. KDM4A-C proteins also possess the double PHD and Tudor domains, whereas KDM4D lacks these domains. KDM4 proteins are overexpressed or deregulated in multiple cancers, cardiovascular diseases, and mental retardation and are thus potential therapeutic targets. Despite extensive efforts, however, there are very few KDM4-selective inhibitors. Defining the exact physiological and oncogenic functions of KDM4 demethylase will provide the foundation for the discovery of novel potent inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM4s and the interplay between KDM4-mediated epigenetic and metabolic pathways in cancer. We also review currently available KDM4 inhibitors and discuss their potential as therapeutic agents for cancer treatment.
    Keywords:  KDM4; KDM4 inhibitor; anticancer agent; epigenetic agent; histone H3K9 demethylase
    DOI:  https://doi.org/10.1096/fj.201902584R
  735. Aging (Albany NY). 2020 Jan 21. 12
    Identification of key genes by integrating DNA methylation and next-generation transcriptome sequencing for esophageal squamous cell carcinoma.
    Chen Y, Liao LD, Wu ZY, Yang Q, Guo JC, He JZ, Wang SH, Xu XE, Wu JY, Pan F, Lin DC, Xu LY, Li EM.
      Aberrant DNA methylation leads to abnormal gene expression, making it a significant regulator in the progression of cancer and leading to the requirement for integration of gene expression with DNA methylation. Here, we identified 120 genes demonstrating an inverse correlation between DNA methylation and mRNA expression in esophageal squamous cell carcinoma (ESCC). Sixteen key genes, such as SIX4, CRABP2, and EHD3, were obtained by filtering 10 datasets and verified in paired ESCC samples by qRT-PCR. 5-Aza-dC as a DNA methyltransferase (DNMT) inhibitor could recover their expression and inhibit clonal growth of cancer cells in seven ESCC cell lines. Furthermore, 11 of the 16 genes were correlated with OS (overall survival) and DFS (disease-free survival) in 125 ESCC patients. ChIP-Seq data and WGBS data showed that DNA methylation and H3K27ac histone modification of these key genes displayed inverse trends, suggesting that there was collaboration between DNA methylation and histone modification in ESCC. Our findings illustrate that the integrated multi-omics data (transcriptome and epigenomics) can accurately obtain potential prognostic biomarkers, which may provide important insight for the effective treatment of cancers.
    Keywords:  DNA methylation; esophageal squamous cell carcinoma; histone modification; next-generation sequencing; survival analysis
    DOI:  https://doi.org/10.18632/aging.102686
  736. J Assoc Physicians India. 2020 Jan;68(1): 50
    Study of Serum Magnesium Level in Type 2 Diabetes Mellitus Patients with Special Emphasis on Microvascular Macrovascular Complications.
    Jain S.
      
  737. Endocr Pract. 2020 Jan 22.
    IMPACT OF STRUCTURED INSULIN ORDER SETS ON INPATIENT HYPOGLYCEMIA AND GLYCEMIC CONTROL.
    Kravchenko MI, Tate JM, Clerc PG, Forbes WL, Gettle MC, Wardian JL, Colburn JA.
      OBJECTIVE: In hospitalized patients, glycemic excursions outside recommended glycemic targets have been associated with increased morbidity and mortality. Despite recommendations to avoid use of correctional insulin alone for managing hyperglycemia, this approach remains common. We performed a quality improvement project aimed at both reducing hypoglycemic events and promoting increased use of basal insulin by updating our insulin order sets to reflect clinical practice guideline recommendations.METHODS: Brooke Army Medical Center correctional insulin order sets were modified to reflect higher treatment thresholds and targets, and a basal insulin order was added with a recommended weight-based starting dose. Pre- and post- intervention analysis was performed. Patients were included if they were prescribed subcutaneous insulin during their hospital stay. The following outcomes were measured: 1) Glucose levels 2) Prescriptions for basal insulin.
    RESULTS: A significant reduction in hypoglycemia events was noted following the intervention (glucose <70mg/dL: 9.2% pre-intervention vs 8.8% post-intervention; glucose <55mg/dL: 4.2% pre-intervention vs 2.2% post-intervention). When excluding patients that were ordered correctional insulin alone but did not receive a dose, an increase in basal insulin use was seen (50% pre-intervention vs 61% post-intervention). Rates and severity of hyperglycemia (glucose >180 mg/dL) remained unchanged.
    CONCLUSION: The alteration in insulin order set parameters resulted in significant reduction in hypoglycemia without significant increases in hyperglycemia. Although basal insulin use increased, optimal dosing recommendations were not often utilized. Further interventions are necessary to reduce hyperglycemia.
    DOI:  https://doi.org/10.4158/EP-2019-0341
  738. Int J Hypertens. 2020 ;2020 1347165
    Association of Lactate Dehydrogenase with In-Hospital Mortality in Patients with Acute Aortic Dissection: A Retrospective Observational Study.
    He H, Chai X, Zhou Y, Pan X, Yang G.
      Background: Evidence regarding the relationship between serum lactate dehydrogenase (LDH) levels and in-hospital mortality in acute aortic dissection (AAD) patients is extremely limited. We aimed to investigate the relationship between LDH and in-hospital mortality in AAD patients.Methods: The present study was a retrospective observational study. A total of 1526 participants with acute aortic dissection were involved in a hospital in China from January 2014 to December 2018. The target-independent variable was LDH measured at baseline, and the dependent was all-cause mortality during hospitalization. Covariates involved in this study included age, gender, body mass index (BMI), hypertension, diabetes, smoking, stroke, atherosclerosis, systolic blood pressure (SBP), diastolic blood pressure (DBP), white blood cell (WBC), hemoglobin (Hb), alanine transaminase (ALT), aspartate aminotransferase (AST), albumin (ALB), creatinine (Cr), symptom, type of AAD (Stanford), and management.
    Results: The average age of 1526 selected participants was 52.72 ± 11.94 years old, and about 80.41% of them were male. The result of the fully adjusted model showed LDH was positively associated with in-hospital mortality in AAD patients after adjusting confounders (OR = 1.09, 95% CI 1.05 to 1.13). A nonlinear relationship was detected between LDH and in-hospital mortality in AAD patients after adjusting for potential confounders (age, gender, BMI, hypertension, diabetes, stroke, atherosclerosis, smoking, symptom, SBP, DBP, WBC, Hb, ALT, AST, ALB, Cr, type of AAD (Stanford), and management), whose point was 557. The effect sizes and the confidence intervals of the left and right sides of the inflection point were 0.90 (0.74-1.10) and 1.12 (1.06-1.19), respectively. Subgroup analysis in participants showed that the relationship between LDH and in-hospital mortality was stable, and all of the P value for the interaction in different subgroup were more than 0.05.
    Conclusions: The relationship between LDH and in-hospital mortality in AAD patients is nonlinear. LDH was positively related with in-hospital mortality when LDH is more than 557.
    DOI:  https://doi.org/10.1155/2020/1347165
  739. Cell Stress Chaperones. 2020 Jan 21.
    Cell-free synthesis of functionally active HSPB5.
    Kojima R, Uchiya K, Manshio H, Masuda K.
      Human αB-crystallin (HSPB5) is frequently modified post-translationally by UV radiation, oxidation, and age-associated processes, which complicates functional analyses of the protein using natural sources. Thus, determining the biological function of HSPB5 at the molecular structure level requires unmodified protein. Here, we employed an Escherichia coli cell-free protein synthesis system to prepare unmodified, functionally active human HSPB5. An S30 extract prepared from E. coli strain BL21 (DE3) was used for HSPB5 synthesis. The efficacy of protein synthesis was assessed by monitoring influencing factors, such as the concentrations of Mg2+ and other reaction mixture constituents, and by evaluating batch and/or dialysis synthesis systems. Chaperone-like activity of synthesized HSPB5 was assayed using alcohol dehydrogenase (ADH) under thermal stress. The amount of HSPB5 synthesized using the cell-free system depended significantly on the concentration of Mg2+ in the reaction mixture. Use of condensed S30 extract and increased levels of amino acids promoted HSPB5 production. Compared with the batch system, HSPB5 synthesis was markedly increased using the dialysis system. The construction vector played a critical role in regulating the efficacy of protein synthesis. HSPB5 synthesized using the cell-free system had a native molecular mass, as determined by mass spectrometry analysis. The co-presence of synthesized HSPB5 suppressed heat-associated denaturation of ADH. Human HSPB5 synthesized using the cell-free system thus retains functional activity as a molecular chaperone.
    Keywords:  Cell-free protein synthesis; Chaperoning activity; E. coli S30 extract; Human αB-crystallin (HSPB5)
    DOI:  https://doi.org/10.1007/s12192-020-01073-5
  740. Vaccines (Basel). 2020 Jan 19. pii: E32. [Epub ahead of print]8(1):
    Vaccination with Ectoparasite Proteins Involved in Midgut Function and Blood Digestion Reduces Salmon Louse Infestations.
    Contreras M, Karlsen M, Villar M, Olsen RH, Leknes LM, Furevik A, Yttredal KL, Tartor H, Grove S, Alberdi P, Brudeseth B, de la Fuente J.
      Infestation with the salmon louse Lepeophtheirus salmonis (Copepoda, Caligidae) affects Atlantic salmon (Salmo salar L.) production in European aquaculture. Furthermore, high levels of salmon lice in farms significantly increase challenge pressure against wild salmon populations. Currently, available control methods for salmon louse have limitations, and vaccination appears as an attractive, environmentally sound strategy. In this study, we addressed one of the main limitations for vaccine development, the identification of candidate protective antigens. Based on recent advances in tick vaccine research, herein, we targeted the salmon louse midgut function and blood digestion for the identification of candidate target proteins for the control of ectoparasite infestations. The results of this translational approach resulted in the identification and subsequent evaluation of the new candidate protective antigens, putative Toll-like receptor 6 (P30), and potassium chloride, and amino acid transporter (P33). Vaccination with these antigens provided protection in Atlantic salmon by reducing adult female (P33) or chalimus II (P30) sea lice infestations. These results support the development of vaccines for the control of sea lice infestations.
    Keywords:  aquaculture; copepod; immunology; salmon louse; vaccinology
    DOI:  https://doi.org/10.3390/vaccines8010032
  741. Int J Environ Res Public Health. 2020 Jan 17. pii: E603. [Epub ahead of print]17(2):
    Study Protocol for the Evaluation of "SuperFIT", a Multicomponent Nutrition and Physical Activity Intervention Approach for Preschools and Families.
    van de Kolk I, Gerards SMPL, Harms LSE, Kremers SPJ, van Dinther-Erkens AMHS, Snellings M, Gubbels JS.
      The promotion of healthy energy balance-related behaviours (EBRB) is already important for children at a young age. Different settings, for example childcare and home, play an important role in the EBRB of young children. Further, factors in different types of environment (e.g., physical, sociocultural and political) influence their behaviours. SuperFIT (Systems of Underprivileged Preschoolers in their home and preschool EnviRonment: Family Intervention Trial) is a comprehensive, integrated intervention approach for 2-4 year old children. This paper describes the development and design of the evaluation of SuperFIT. The SuperFIT intervention approach consists of preschool-based, family-based, and community-based components. Intervention activities aimed at changing the physical, sociocultural and political environments in each setting and establishing an increased alignment between the settings. A quasi-experimental design was adopted with twelve intervention and nine control preschools to evaluate effectiveness. The primary outcomes were Body Mass Index (BMI) z-scores (objectively assessed height and weight), dietary intake (24 h recall), and physical activity (accelerometer) of the children. Further, the effects on the nutrition- and physical activity-related practices of preschool teachers and parents were evaluated (questionnaires). Intervention effectiveness was evaluated using linear mixed models. Process evaluation was performed using mixed methods; both quantitative (questionnaires) and qualitative (observations and in-depth interviews) measures were used. The comprehensive, integrated approach of SuperFIT is expected to support healthy EBRB in young children.
    Keywords:  BMI z-score; childcare; environment; family; integrated intervention; nutrition; overweight prevention; physical activity; sedentary behaviour; toddlers
    DOI:  https://doi.org/10.3390/ijerph17020603
  742. J Am Geriatr Soc. 2020 Jan 22.
    Geriatric Conditions Predict Discontinuation of Anticoagulation in Long-Term Care Residents With Atrial Fibrillation.
    Kapoor A, Foley G, Zhang N, Zhou Y, Crawford S, McManus D, Gurwitz J.
      BACKGROUND: Anticoagulation (AC) for stroke prevention in long-term care (LTC) residents with atrial fibrillation (AF) involves a challenging risk-benefit evaluation. We measured the association of geriatric conditions with discontinuation of AC.DESIGN: Retrospective cohort analysis.
    SETTING: LTC facilities across the United States.
    PARTICIPANTS: A total of 48 545 individuals residing in LTC facilities in 2015 with AF and sufficient information to establish their status as someone who stopped AC vs someone who continued AC.
    MEASUREMENTS: We measured the association of six geriatric conditions-recent fall, severe activity of daily living (ADL) dependency (21-28 on a 28-point scale), mobility impairment, cognitive impairment, body mass index (BMI) less than 18.5 kg/m2 , and weight loss (≥5% in 1 month or ≥10% in 6 months)-with discontinuation of AC. To identify cases of discontinuation, we required a pattern of being on AC over two consecutive recordings of the Minimum Data Set, the nursing home quality control data set recorded every 90 days, followed by two assessments being off AC-pattern of "on-on-off-off." By contrast, we required a pattern of "on-on-on-on" for continuers. We then constructed six logistic regression models to measure the independent association between each geriatric condition and discontinuation of AC, adjusted for CHA2 DS2 -VASc stroke risk score, recent bleeding hospitalization, and other confounders.
    RESULTS: There were 4172 discontinuers and 44 373 continuers. Recent fall predicted a 1.9-fold increase in the odds of discontinuation (odds ratio = 1.91; 95% confidence interval = 1.66-2.20), whereas mobility and cognitive impairment only increased the odds by 14% to 17%. Severe ADL dependency, BMI less than 18.5 kg/m2 , and weight loss of 10% each increased odds of discontinuation by 55% to 68%. CHA2 DS2 -VASc score did not predict discontinuation.
    CONCLUSION: Several geriatric conditions predicted discontinuation of AC, whereas CHA2 DS2 -VASc score did not. Future research should examine the association of geriatric conditions and discontinuation of warfarin discrete from newer anticoagulants and association of geriatric conditions with development of stroke and bleeding.
    Keywords:  anticoagulation; atrial fibrillation; geriatric conditions; long-term care
    DOI:  https://doi.org/10.1111/jgs.16335
  743. BMC Genet. 2020 Jan 23. 21(1): 8
    Distribution of allele frequencies for genes associated with physical activity and/or physical capacity in a homogenous Norwegian cohort- a cross-sectional study.
    Goleva-Fjellet S, Bjurholt AM, Kure EH, Larsen IK, Støren Ø, Sæbø M.
      BACKGROUND: There are large individual differences in physical activity (PA) behavior as well as trainability of physical capacity. Heritability studies have shown that genes may have as much impact on exercise participation behavior as environmental factors. Genes that favor both trainability and participation may increase the levels of PA. The present study aimed to assess the allele frequencies in genes associated with PA and/or physical capacity, and to see if there is any association between these polymorphisms and self-reported PA levels in a cohort of middle-aged Norwegians of Scandinavian descent (n = 831; mean age mean age (± SD) 55.5 ± 3.8 years).RESULTS: The genotype distributions of the ACTN3 R577X, ACE I/D and MAOA uVNTR polymorphisms were similar to other populations of European descent. When comparing the genotype distribution between the low/medium level PA group (LMPA) and high level PA groups (HPA), a significant difference in ACTN3 577X allele distribution was found. The X allele frequency was 10% lower in the HPA level group (P = 0.006). There were no differences in the genotype distribution of the ACE I/D or MAOA uVNTR polymorphism. Education and previous participation in sports or outdoor activities was positively associated with the self-reported PA levels (P ≤ 0.001).
    CONCLUSIONS: To the best of our knowledge, this is the first study to report association between ACTN3 R577X genotype and PA level in middle-aged Scandinavians. Nevertheless, the contribution of a single polymorphism to a complex trait, like PA level, is likely small. Socioeconomic variables, as education and previous participation in sports or outdoor activities, are positively associated with the self-reported PA levels.
    Keywords:  ACTN3; Genes; Physical activity; Polymorphism
    DOI:  https://doi.org/10.1186/s12863-020-0813-1
  744. J Clin Invest. 2020 Jan 21. pii: 133264. [Epub ahead of print]
    Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer.
    Xie Y, Zhao Y, Shi L, Li W, Chen K, Li M, Chen X, Zhang H, Li T, Yu MI, Yao X, Shao D, Ke Z, Li J, Chen Y, Zhang X, Cui J, Cui S, Leng Q, Cadwell K, Li X, Wei H, Zhang H, Li H, Xiao H.
      While the Western-diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1-mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered by the Western-diet or Tsc1-ablation led to epithelium necroptosis, barrier disruption, and predisposition to DSS (dextran sulfate sodium)-induced colitis and inflammation-associated colon cancer. Mechanistically, our results uncovered a critical role for TSC1-mTOR in restraining the expression and activation of RIPK3 in the gut epithelium through Trim11-mediated ubiquitination and autophagy-dependent degradation. Notably, microbiota-depletion by antibiotics or gnotobiotics attenuated RIPK3 expression and activation, thereby alleviating epithelial necroptosis and colitis driven by mTOR hyperactivation. mTOR primarily impinged on RIPK3 to potentiate TNF- and microbial PAMP-induced necroptosis, and hyperactive mTOR and aberrant necroptosis were intertwined in human IBDs. Together, our data reveal a previously unsuspected link between the Western-diet, microbiota and necroptosis, and identify the mTOR-RIPK3-necroptosis axis as a driving force for intestinal inflammation and cancer.
    Keywords:  Apoptosis survival pathways; Cell Biology; Inflammation; Inflammatory bowel disease; Innate immunity
    DOI:  https://doi.org/10.1172/JCI133264
  745. Curr Med Imaging Rev. 2019 ;15(1): 81-83
    Pulmonary Sarcoidosis Presenting with Miliary Opacities.
    Arar O, Boni F, Meschi T, Tana C.
      BACKGROUND: Lung lesions often appear in patients with sarcoidosis; however, miliary opacities are rare. We present the case of a 55-year-old Indian man who presented with dyspnea and low-grade fever.DISCUSSION: Miliary Tuberculosis (TB) was initially suspected, despite the direct microscopic examination from bronchoalveolar lavage was negative for acid-fast bacilli because imaging showed miliary opacities, and transbronchial lung biopsy revealed the presence of typical caseating granulomas. Antitubercular treatment with the classic four-drug regimen was initiated. However, the patient did not improve and cultures were negative for Mycobacterium growth. The diagnosis of sarcoidosis was made only after a negative culture and clinical and histopathological re-evaluation of the case.
    CONCLUSION: Although miliary sarcoidosis is rare, physicians should consider sarcoidosis in the differential diagnosis with conditions like tuberculosis, malignancy, and pneumoconiosis when patients present with miliary opacities who do not respond to the traditional treatment.
    Keywords:  Mycobacterium; Pulmonary sarcoidosis; granuloma; lung lesions; miliary; tuberculosis
    DOI:  https://doi.org/10.2174/1573405614666180806141415
  746. Clin J Oncol Nurs. 2020 Feb 01. 24(1): 19-21
    Liquid Biopsy: A Tool for the Diagnostic and Prognostic Evaluation of Cancers.
    Stanciu J, Tariman JD.
      Liquid biopsy is defined as the process of obtaining material for pathologic examination and analysis from body fluids. Liquid biopsy has been intensively researched for its clinical application in patients with solid malignancies, including melanoma and colon, breast, and lung cancers. This will become a standard and routine tool for the diagnostic and prognostic evaluation of all cancer types. This article provides an overview of liquid biopsy, its uses in cancer management, and its implications for nursing practice.
    Keywords:  genetic biomarkers; genomic data; liquid biopsy; precision medicine
    DOI:  https://doi.org/10.1188/20.CJON.19-21
  747. J Pak Med Assoc. 2020 Jan;70(1): 183-185
    Diabeto-theranostics.
    Kalra S, Gupta Y.
      This communication is an interesting and off-beat take on the concept of theranostics, as applied to diabetes care. It proposes the use of the term diabeto-theranostics, to define the combined use of diagnostic and therapeutic modalities, so as to create individualized or personalized treatment strategies in persons with diabetes. Historical examples such as the chlorpropamide challenge test and modern innovations such as genotyping are described. The rubrics of gluco-phenotype, endo-phenotype, metabolic phenotype, glucagon: insulin ratio, and adenosine monophosphate activated protein kinase (AMPK) status in planning glucose lowering therapy are explained. Novel concepts such as psycho-theranostics and electro-theranostics in diabetes are discussed.
    Keywords:  Diabetes, LADA, MODY, person centered care, type 2 diabetes.
  748. Sci Rep. 2020 Jan 20. 10(1): 697
    Targeted metabolomics of pellicle and saliva in children with different caries activity.
    Schulz A, Lang R, Behr J, Hertel S, Reich M, Kümmerer K, Hannig M, Hannig C, Hofmann T.
      Pellicle is the initial proteinaceous layer that is formed almost instantaneously on all solid surfaces in the oral cavity. It is of essential relevance for any interactions and metabolism on the tooth surface. Up to now, there is no information on the metabolome of this structure. Accordingly, the present study aims to characterise the metabolomic profile of in-situ pellicle in children with different caries activity for the first time in comparison to saliva. Small molecules such as carbohydrates, amino acids, organic acids, and fatty acids, putatively involved in the formation of caries were quantified using mass spectrometry (MS)-based techniques, such as (stable isotope dilution analysis)-ultra-performance liquid chromatography-tandem MS and gas chromatography/electron ionisation-MS. Pellicle and corresponding saliva samples were collected from caries-active, caries-free and caries-rehabilitated 4- to 6-year-old children. The most abundant analytes in pellicle were acetic acid (1.2-10.5 nmol/cm2), propionic acid (0.1-8.5 nmol/cm2), glycine (0.7-3.5 nmol/cm2), serine (0.08-2.3 nmol/cm2), galactose (galactose + mannose; 0.035-0.078 nmol/cm2), lactose (0.002-0.086 nmol/cm2), glucose (0.018-0.953 nmol/cm2), palmitic acid (0.26-2.03 nmol/cm2), and stearic acid (0.34-1.81 nmol/cm2). Significant differences depending on caries activity were detected neither in saliva nor in the corresponding pellicle samples.
    DOI:  https://doi.org/10.1038/s41598-020-57531-8
  749. Curr Opin Immunol. 2020 Jan 16. pii: S0952-7915(19)30103-7. [Epub ahead of print]62 91-98
    Evolutionary perspective on the hematopoietic system through a colonial chordate: allogeneic immunity and hematopoiesis.
    Rosental B, Raveh T, Voskoboynik A, Weissman IL.
      Evolution and selection have shaped diverse immune systems throughout phylogeny, the vast majority of which remain unexplored. Botryllus schlosseri is a colonial tunicate, a sister group to vertebrates, that develops as a chordate, then metamorphoses to an asexually reproductive invertebrate that every week makes the same body plan from budded stem cells. Genetically distinct B. schlosseri colonies can fuse to form a chimera, or reject each other based on allogeneic recognition. In chimeras, circulating germline and somatic stem cells participate in development; stem cells compete in all individuals in the fused colonies, with rejection preventing germline parasitism. Here we review the isolation and characterization of B. schlosseri hematopoietic stem cells (HSC) and their niches, and the role of the immune effector cells in allorecognition.
    DOI:  https://doi.org/10.1016/j.coi.2019.12.006
  750. Allergy. 2020 Jan 23.
    TSLP and IL-33 reciprocally promote each other's lung protein expression and ILC2 receptor expression to enhance innate type-2 airway inflammation.
    Toki S, Goleniewska K, Zhang J, Zhou W, Newcomb DC, Zhou B, Kita H, Boyd KL, Peebles RS.
      BACKGROUND: The epithelial cell-derived danger signal mediators thymic stromal lymphopoietin (TSLP) and IL-33 are consistently associated with adaptive Th2 immune responses in asthma. In addition, TSLP and IL-33 synergistically promoted group 2 innate lymphoid cell (ILC2) activation to induce innate allergic inflammation. However, the mechanism of this synergistic ILC2 activation is unknown.METHODS: BALB/c WT and TSLP receptor deficient (TSLPR-/- ) mice were challenged intranasally with Alternaria extract (Alt-Ext) or PBS for 4 consecutive days to evaluate innate airway allergic inflammation. WT mice pre-administered with rTSLP or vehicle, TSLPR-/- mice, and IL-33 receptor deficient (ST2-/- ) mice were challenged intranasally with Alt-Ext or vehicle once or twice to evaluate IL-33 release and TSLP expression in the lung. TSLPR and ST2 expression on lung ILC2 were measured by flow cytometry after treatment of rTSLP, rIL-33, rTSLP+rIL-33 or vehicle.
    RESULTS: TSLPR-/- mice had significantly decreased the number of lung ILC2 expressing IL-5 and IL-13 following Alt-Ext-challenge compared to WT mice. Further, eosinophilia, protein level of lung IL-4, IL-5, and IL-13, and airway mucus score were also significantly decreased in TSLPR-/- mice compared to WT mice. Endogenous and exogenous TSLP increased Alt-Ext-induced IL-33 release into BALF, and ST2 deficiency decreased Alt-Ext-induced TSLP expression in the lung. Further, rTSLP and rIL-33 treatment reciprocally increased each other's receptor expression on lung ILC2 in vivo and in vitro.
    CONCLUSION: TSLP and IL-33 signaling reciprocally enhanced each other's protein release and expression in the lung following Alt-Ext-challenge, and each other's receptor expression on lung ILC2 to enhance ILC2 activation.
    Keywords:  Alternaria-extract (Alt-Ext); Group 2 innate lymphoid cells (ILC2); IL-33; TSLP
    DOI:  https://doi.org/10.1111/all.14196
  751. Biochim Biophys Acta Proteins Proteom. 2020 Jan 17. pii: S1570-9639(20)30006-6. [Epub ahead of print] 140365
    Standard Gibbs energy of metabolic reactions: V. enolase reaction.
    Greinert T, Vogel K, Seifert AI, Siewert R, Andreeva IV, Verevkin SP, Maskow T, Sadowski G, Held C.
      The glycolytic pathway is one of the most important pathways for living organisms, due to its role in energy production and as supplier of precursors for biosynthesis in living cells. This work focuses on determination of the standard Gibbs energy of reaction ΔRg'0 of the enolase reaction, the ninth reaction in the glycolysis pathway. Exact ΔRg'0 values are required to predict the thermodynamic feasibility of single metabolic reactions or even of metabolic reaction sequences under cytosolic conditions. So-called "apparent" standard data from literature are only valid at specific conditions. Nevertheless, such data are often used in pathway analyses, which might lead to misinterpretation of the results. In this work, equilibrium measurements were combined with activity coefficients in order to obtain new standard values ΔRg'0 for the enolase reaction that are independent of the cytosolic conditions. Reaction equilibria were measured at different initial substrate concentrations and temperatures of 298.15, 305.15 and 310.15 K at pH 7. The activity coefficients were predicted using the equation of state electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC-SAFT). The ePC-SAFT parameters were taken from literature or fitted to new experimentally determined osmotic coefficients and densities. At 298.15 K and pH 7, a ΔRg'0(298.15 K, pH 7) value of -2.8 ± 0.2 kJ mol-1 was obtained. This value differs by up to 5 kJ mol-1 from literature data. Reasons are the poorly defined "standard" conditions and partly undefined reaction conditions of literature works. Finally, using temperature-dependent equilibrium constants and the van 't Hoff equation, the standard enthalpy of reaction of ΔRh0(298.15 K, pH 7) = 27 ± 10 kJ mol-1 was determined, and a similar value was found by quantum-chemistry calculations.
    DOI:  https://doi.org/10.1016/j.bbapap.2020.140365
  752. Biomolecules. 2020 Jan 16. pii: E147. [Epub ahead of print]10(1):
    Combined Kinetin and Spermidine Treatments Ameliorate Growth and Photosynthetic Inhibition in Vigna angularis by Up-Regulating Antioxidant and Nitrogen Metabolism under Cadmium Stress.
    Ahanger MA, Aziz U, Sahli AA, Alyemeni MN, Ahmad P.
      Pot experiments were conducted to investigate the probable beneficial role of the individual as well as combined application of kinetin (50 μM Kn) and spermidine (200 μM Spd) on Vigna angularis under cadmium (Cd) stress. Cd treatment reduced growth by declining the content of chlorophylls and carotenoids, photosynthesis, and gas exchange parameters. Exogenously, Kn and Spd application enhanced the photosynthetic parameters and up-regulated the antioxidant system by improving the activities of antioxidant enzymes and the content of non-enzymatic components. In addition, the application of Kn and Spd resulted in significant improvement in the content of sugars, proline, and glycine betaine, ameliorating the decline in relative water content. Oxidative stress parameters including hydrogen peroxide, superoxide, lipid peroxidation, lipoxygenase activity, and electrolyte leakage increased due to Cd stress; however, the application of Kn and Spd imparted a significant decline in all these parameters. Further, reduced Cd uptake was also observed due to Kn and Spd application. Total phenols and flavonoids also increased due to Kn and Spd treatments under normal as well as Cd stress conditions, which may have further helped with the elimination of reactive oxygen species. Reduction in the activity of nitrate reductase and the content of nitrogen was ameliorated due to the exogenous application of Kn and Spd. Therefore, the exogenous application of Kn and Spd benefited Vigna angularis counteracting the damaging effects of Cd stress by up-regulating the tolerance mechanisms, including antioxidant and osmolyte metabolism.
    Keywords:  Vigna angularis; antioxidants; cadmium; osmolytes; oxidative damage; secondary metabolites
    DOI:  https://doi.org/10.3390/biom10010147
  753. Int Immunopharmacol. 2020 Jan 21. pii: S1567-5769(19)32748-1. [Epub ahead of print]80 106148
    Hypofractionated radiation therapy with versus without immune checkpoint inhibitors in patients with brain metastases: A meta-analysis.
    Yang L, Liu L, Wu X, Guo X, Yang Y, Wang T.
      INTRODUCTION: The efficacy and safety of hypofractionated radiation therapy (HFRT) combined with immune checkpoint inhibitors (ICIs) in patients with brain metastases (BM) remain controversial. This meta-analysis was performed to compare the efficacy and safety of HFRT with and without ICIs in BM patients.MATERIALS AND METHODS: PubMed, Embase, and Cochrane Library were searched up to 25 December 2018 for studies that compared the efficacy and safety of HFRT with and without ICIs in BM patients.
    RESULTS: Twenty-four studies involving 2,365 patients were included in this analysis. Compared with those of HFRT without ICIs, the 6-month locoregional recurrence-free survival (LRFS) rate (P = 0.002), 6-month overall survival (OS) rate (P = 0.001), 1-year OS rate (P = 0.001), 2-year OS rate (P = 0.007), and median OS (mOS) (P < 0.001) were significantly improved in combined HFRT and ICI treatment. A trend toward improved 1-year LRFS rate (P = 0.392) and 3-year OS rate (P = 0.266) for the ICI arm was observed compared with the non-ICI arm, although there was no statistically significant difference between the two arms. No significant difference in toxicity was found between the two arms (radionecrosis: P = 0.361; BM hemorrhage: P = 0.738).
    CONCLUSIONS: Compared with HFRT without ICIs, the combination of these two therapies improved efficacy but did not increase toxicity in patients with BM.
    Keywords:  Brain metastases; Hypofractionated radiation therapy; Immune checkpoint inhibitors; Meta-analysis
    DOI:  https://doi.org/10.1016/j.intimp.2019.106148
  754. Front Endocrinol (Lausanne). 2019 ;10 896
    Melatonin Inhibits Formation of Mitochondrial Permeability Transition Pores and Improves Oxidative Phosphorylation of Frozen-Thawed Ram Sperm.
    Fang Y, Zhao C, Xiang H, Zhao X, Zhong R.
      Structural and functional damages to mitochondria of frozen-thawed sperm are a typical cryoinjury, with mitochondrial permeability transition pore (MPTP) formation being the hallmark change. Mitochondria are both a primary synthesis site and principle target for melatonin; this compound can directly inhibit MPTP formation and therefore confer protection at a mitochondrial level. The objective was to determine effects of melatonin on MPTP opening, viability, motility, and oxidative phosphorylation (OXPHOS) of frozen-thawed ram sperm. Ram semen was diluted in glucose-egg yolk buffer with 0 or 10-7 M melatonin (frozen and frozen + melatonin groups, respectively) and slow frozen, with fresh semen as Control. In frozen-thawed sperm, melatonin inhibited MPTP opening and lactate concentrations and improved sperm viability, motility, acetyl-CoA concentration and adenosine triphosphate (ATP) production. With regard to the underlying physiological mechanism, melatonin suppressed movement of citrate synthase, isocitrate dehydrogenase, oxoglutarate dehydrogenase complex, and F0F1-ATP synthase permeability from mitochondrial to cytosolic fractions induced by MPTP opening; furthermore, it increased mRNA expressions of respiratory chain complex components and activities of complexes I, II, III, and IV and thereby improved oxygen consumption capacity in frozen-thawed sperm. In conclusion, melatonin improved OXPHOS of frozen-thawed ram sperm, attributed to inhibition of cryopreservation-induced MPTP opening.
    Keywords:  cryopreservation; melatonin; mitochondrial permeability transition pore; oxidative phosphorylation; ram; sperm
    DOI:  https://doi.org/10.3389/fendo.2019.00896
  755. Int J Sports Med. 2020 Jan 22.
    Injury Occurrence in Male Handball Players and its Impact on Physical Constitution.
    Salzer S, Heansel R, Rey J, Maltry L, Holzgreve F, Lampe J, Wanke EM, Groneberg DA, Ohlendorf D.
      In male handball, limited knowledge exists about the body posture and postural control in correlation to their injury occurrence and their impact on physical constitution. 91 male handball players participated and were asked about playing position and years, NSAIDs intake, sustained injuries and therapy duration. A three-dimensional back scanner and a pressure measuring plate were used. Shoulder injuries cause a differing scapular height and increase the vertebrae rotation in correlation to playing years. Lower limb injuries lead to a decrease on the Centre of Pressure (CoP) with growing game experience. Wing players show the lowest injury risk. Lower limb and shoulder girdle are mostly affected regarding the incidence of injuries. Pivot players suffer most injuries in the lower limb area (59%), whereas wing players mostly have shoulder injuries (19%). Being injured, 21% of the players continue playing, 79% pause for a minimum of six months (25%). No correlation can be determined between level of profession, use of NSAIDs and body posture or postural control. Playing position, employment situation or NSAIDs have no influence on type of injury, body posture or postural control. While shoulder injuries can be recognized in the vertebrae area, lower limb injuries can affect the CoP.
    DOI:  https://doi.org/10.1055/a-1028-7630
  756. Chem Phys Lipids. 2020 Jan 21. pii: S0009-3084(20)30005-0. [Epub ahead of print] 104874
    Squeezing lipids: NMR characterization of lipoprotein particles under pressure.
    Starich MR, Tang J, Remaley AT, Tjandra N.
      Determining the particle size and number of lipoprotein components found in blood plasma (HDL, LDL and VLDL) has become an important clinical tool in diagnosing risk of cardiovascular disease. Proton (1H) NMR spectroscopy methods to quantify lipoprotein particle subclasses have been advancing since NMR lineshape analysis of plasma samples was first proposed in the 1990's. NMR methods, including a more recent DOSY-based diffusion spectroscopy test, provide the foundation for the advanced lipoprotein tests, including Lipoprotein® and Liposcale® analyses available for clinical use to determine particle size and number. At the time of this submission, no NMR studies exist which explore physical parameters of individual lipoprotein fractions when they are deformed by pressure. This study reports 1H NMR frequency shifts and T2* measurements for the broad methyl peak attributed to terminal methyls (cholesteryl positions 26, 27 and terminal acyl methyl groups) in three primary lipoprotein fractions as a function of hydraulic pressure. This terminal CH3 resonance shifted linearly upfield as a function of pressure for HDL and VLDL (observed slopes of -0.014 Hz/bar). The LDL terminal CH3 resonance shows segmented behavior, with a shallow slope between 0-900 bar (-0.008 hz/bar) and a slope similar to HDL and VDL across the range from 1000 to 2400 bar (slope -0.016 Hz/bar). 1H T2* values measured for VLDL and HDL dropped linearly with increasing pressure. 1H T2* values for LDL demonstrated segmented behavior as a function of pressure. The unique behavior observed for LDL terminal CH3 frequency and 1H T2* trends suggests an approximate pressure at which phase transition occurs.
    Keywords:  Cardiovascular; Cholesterol; Cholesterol ester; HDL; LDL; Lipoprotein; NMR; T(2)* relaxation; VLDL
    DOI:  https://doi.org/10.1016/j.chemphyslip.2020.104874
  757. Biochem J. 2020 Jan 31. 477(2): 341-356
    Optimization of nucleotide sugar supply for polysaccharide formation via thermodynamic buffering.
    Kleczkowski LA, Igamberdiev AU.
      Plant polysaccharides (cellulose, hemicellulose, pectin, starch) are either direct (i.e. leaf starch) or indirect products of photosynthesis, and they belong to the most abundant organic compounds in nature. Although each of these polymers is made by a specific enzymatic machinery, frequently in different cell locations, details of their synthesis share certain common features. Thus, the production of these polysaccharides is preceded by the formation of nucleotide sugars catalyzed by fully reversible reactions of various enzymes, mostly pyrophosphorylases. These 'buffering' enzymes are, generally, quite active and operate close to equilibrium. The nucleotide sugars are then used as substrates for irreversible reactions of various polysaccharide-synthesizing glycosyltransferases ('engine' enzymes), e.g. plastidial starch synthases, or plasma membrane-bound cellulose synthase and callose synthase, or ER/Golgi-located variety of glycosyltransferases forming hemicellulose and pectin backbones. Alternatively, the irreversible step might also be provided by a carrier transporting a given immediate precursor across a membrane. Here, we argue that local equilibria, established within metabolic pathways and cycles resulting in polysaccharide production, bring stability to the system via the arrangement of a flexible supply of nucleotide sugars. This metabolic system is itself under control of adenylate kinase and nucleoside-diphosphate kinase, which determine the availability of nucleotides (adenylates, uridylates, guanylates and cytidylates) and Mg2+, the latter serving as a feedback signal from the nucleotide metabolome. Under these conditions, the supply of nucleotide sugars to engine enzymes is stable and constant, and the metabolic process becomes optimized in its load and consumption, making the system steady and self-regulated.
    Keywords:  ADP-glucose pyrophosphorylase; adenylate kinase; nucleoside-diphosphate kinase; starch synthesis; sucrose synthase; thermodynamic buffering
    DOI:  https://doi.org/10.1042/BCJ20190807
  758. J Chromatogr A. 2020 Jan 15. pii: S0021-9673(20)30068-6. [Epub ahead of print] 460891
    Ultrasound-assisted synthesis of clover-shaped nano-titania functionalized covalent organic frameworks for the dispersive solid phase extraction of N-nitrosamines in drinking water.
    Zhang Y, Zhao YG, Muhammad N, Ye ML, Zhu Y.
      In this study, three batches of nano-titania functionalized covalent organic frameworks were acquired depending on different solvothermal reaction stages (24 h, 48 h and 72 h), which were named as single roll-up shaped nano-titania functionalized COFs (SSTF-COFs), double roll-up shaped nano-titania functionalized COFs (DSTF-COFs) and clover-shaped nano-titania functionalized covalent organic framework (CSTF-COFs), respectively. After comparing their extraction performances, the more efficient and stable CSTF-COFs were selected as sorbent for the dispersive solid phase extraction (dSPE) of eight target N-nitrosamines in drinking water, followed by the determination with liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). Owing to the introduction of hydroxy groups, CSTF-COFs showed high extraction efficiency for N-nitrosamines with a wide range of polarities through hydrogen bonding interaction, hydrophobic interaction and hydrophilic interaction. Under optimum conditions, the developed method provided relatively low limits of detection (0.13-2.45 ng/L) and satisfactory recoveries (88.6-105.5%), with relative standard deviations (RSDs) less than 8.3%. Therefore, with the assistance of CSTF-COFs, trace levels of N-nitrosamines were quantitatively and sensitively determined in 31 out of 460 bottled drinking water samples in a sensitive and convenient way.
    Keywords:  Dispersive solid phase extraction; Drinking water; Liquid chromatography-tandem quadrupole mass spectrometry; N-nitrosamines; Nano-titania functionalized covalent organic frameworks
    DOI:  https://doi.org/10.1016/j.chroma.2020.460891
  759. Environ Sci Pollut Res Int. 2020 Jan 20.
    Toxicological responses, bioaccumulation, and metabolic fate of triclosan in Chlamydomonas reinhardtii.
    Wang XD, Lu YC, Xiong XH, Yuan Y, Lu LX, Liu YJ, Mao JH, Xiao WW.
      Triclosan (TCS) is a broad-spectrum antimicrobial agent that is broadly used in personal care products. It has been shown to cause the contamination of a variety of aquatic environments. Since algae has been the primary producers of aquatic ecosystems, understanding the toxicological mechanisms and the metabolic fate of TCS is vital for assessing its risk in an aquatic environment. In our study, 0.5-4 mg L-1 TCS treatments for 72 h in a culture of Chlamydomonas reinhardtii (C. reinhardtii) showed progressive inhibition of cell growth and reduced the chlorophyll content. The EC50 value of C. reinhardtii after 72 h was 1.637 mg L-1, which showed its higher level of resistance to TCS in comparison with other algal species. The exposure to TCS led to oxidative injuries of algae in relation to the increment of malonaldehyde content, cell membrane permeability, and H2O2 levels. Furthermore, the oxidative stress from TCS stimulated a series of antioxidant enzyme activities and their gene expressions. Simultaneously, the accumulated TCS in C. reinhardtii arouses the detoxification/degradation-related enzymes and related gene transcriptions. In the medium, approximately 82% of TCS was removed by C. reinhardtii. Importantly, eight TCS metabolites were identified by ultra-performance liquid chromatography-high-resolution mass spectrometry and their relative abundances were measured in a time-course experiment. Six of these metabolites are reported here for the first time. The metabolic pathways of triclosan via C. reinhardtii including reductive dechlorination, hydroxylation, sulfhydrylation, and binding with thiol/cysteine/GSH/glycosyl were manifested to broaden our understanding of the environmental fate of TCS. Graphical Abstract.
    Keywords:  Biotransformation products; Chlamydomonas reinhardtii; Metabolic pathways; Oxidative stress; Toxicity; Triclosan
    DOI:  https://doi.org/10.1007/s11356-020-07704-9
  760. Endocrinol Diabetes Metab Case Rep. 2019 Sep 12. pii: EDM190044. [Epub ahead of print]2019
    Etomidate in the management of severe Cushing's disease and MRSA bacteraemia in a district general hospital in the United Kingdom.
    Wong SWP, Yap YW, Narayanan RP, Al-Jubouri M, Grossman A, Daousi C, Mahgoub Y.
      Summary: We report our experience on managing a case of florid Cushing's disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital.Learning points: Severe Cushing's syndrome is associated with high morbidity and mortality. Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression. Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital. During treatment with etomidate, accumulation of serum 11β-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.
    Keywords:  2019; ACTH; ACTH stimulation; Adrenal; Adult; Bacteraemia; Blood pressure; C-reactive protein; Citalopram*; Cortisol; Cortisol (serum); Cushing's disease; Deoxycortisol; Dexamethasone suppression; Etomidate; Female; Glucocorticoids; Glucose (blood); Haematoma; Haemoglobin A1c; Histopathology; Hydrocortisone; Hypercortisolaemia; Hyperglycaemia; Hypertension; Hypokalaemia; Hypophysectomy; Hypoxia; Immunoassay*; Insulin; MRI; MRSA*; Mass spectrometry*; Metyrapone; Myasthaenia; Novel treatment; Obesity; Olanzapine ; Pituitary; Pituitary adenoma; Pneumonia; Potassium; Potassium chloride; Ramipril; Resection of tumour; Respiratory failure; Sepsis; September; Spironolactone; Transsphenoidal surgery; United Kingdom; White; White blood cell count
    DOI:  https://doi.org/10.1530/EDM-19-0044
  761. Medicine (Baltimore). 2020 Jan;99(4): e19018
    Metastatic small cell neuroendocrine carcinoma of the submandibular gland from the lung: A case report.
    Lee DH, Kim JH, Yoon TM, Lee JK, Lim SC.
      RATIONALE: Small cell neuroendocrine carcinoma of the salivary gland is an extremely rare condition. To the best of our knowledge, metastasis of small cell neuroendocrine lung cancer to the submandibular gland has not been reported in the literature.PATIENT CONCERN: An 87-year-old female complained of a left neck mass that enlarged from one month ago.
    DIAGNOSIS: The final diagnosis was diagnosed as a metastatic small cell neuroendocrine carcinoma of the submandibular gland from lung by an immunohistochemistry.
    INTERVENTIONS: Left submandibular resection was performed under general anesthesia.
    OUTCOMES: We recommended further evaluation and treatment, but the patient and patient family support team rejected further treatment of her condition. It was confirmed that 3 months after this conclusive diagnosis, the patient died as a result of this condition and disease.
    LESSONS: Small cell neuroendocrine carcinoma of the salivary gland is an extremely rare condition. We report a case of metastatic small cell neuroendocrine carcinoma of the submandibular gland from the lung.
    DOI:  https://doi.org/10.1097/MD.0000000000019018
  762. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31708-5. [Epub ahead of print]30(3): 725-738.e4
    The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis.
    Zhang W, Gong J, Yang H, Wan L, Peng Y, Wang X, Sun J, Li F, Geng Y, Li D, Liu N, Mei G, Cao Y, Yan Q, Li H, Zhang Y, He X, Zhang Q, Zhang R, Wu F, Zhong H, Wei C.
      Recent reports have shown the critical role of the mitochondrial antiviral signaling (MAVS) protein in virus-induced apoptosis, but the involvement of MAVS in tumorigenesis is still poorly understood. Herein, we report that MAVS is a key regulator of p53 activation and is critical for protecting against tumorigenesis. We find that MAVS promotes p53-dependent cell death in response to DNA damage. MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress. Mechanistically, MAVS inhibits p53 ubiquitination by blocking the formation of the p53-murine double-minute 2 (MDM2) complex, leading to the stabilization of p53. Notably, compared with their wild-type littermates, MAVS knockout mice display decreased resistance to azoxymethane (AOM) or AOM/dextran sulfate sodium salt (DSS)-induced colon cancer. MAVS expression is significantly downregulated in human colon cancer tissues. These results unveil roles for MAVS in DNA damage response and tumor suppression.
    Keywords:  MAVS; p53; tumor suppression; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.051
  763. Med Hypotheses. 2020 Jan 02. pii: S0306-9877(19)31228-9. [Epub ahead of print]137 109544
    Inhibitory potential of plant secondary metabolites on anti-Parkinsonian drug targets: Relevance to pathophysiology, and motor and non-motor behavioural abnormalities.
    Mazumder MK, Borah A, Choudhury S.
      Parkinson's disease (PD), a progressive neurodegenerative motor disorder, is caused due to the loss of dopaminergic neurons in the substantia nigra pars compacta region of mid-brain and the resultant depletion of the levels of the neurotransmitter dopamine. Although the pathophysiology of the disease is least understood, studies in animal models revealed oxidative stress, mitochondrial dysfunction and inflammation to be the major contributors. Dopamine replenishment therapy by oral administration of L-DOPA, the precursor of dopamine remains to be the therapeutic gold-standard for symptomatic treatment of PD. In addition, use of inhibitors of dopamine metabolizing enzymes (viz. monoamine oxidase-B: MAO-B; and catechol-O-methyltransferase: COMT) are the other strategies for amelioration of the motor abnormalities. Further, PD is associated with non-motor behavioural abnormalities as well, including cognitive impairment and mood disorders, which are caused due to cholinergic neurodegeneration, and thus inhibition of Acetylcholinesterase (AChE) is suggested. However, the currently used drugs against the three crucial enzymes (MAO-B, COMT and AChE) elicit several side effects, and thus the search for novel compounds continues, and plant-based compounds have promising potential in this regard. In the present study, we have used computational modeling to determine the efficiency of 40 plant-based natural products in inhibiting the three anti-Parkinsonian drug targets. Further, statistical analysis was performed to identify the properties of the compounds which are crucial for inhibition of the enzymes. While all the phytochemicals showed potential in inhibiting the enzymes, Rutin, Demethoxycurcumin and Acteoside were found to be most effective inhibitors of MAO-B, COMT and AChE respectively. Since most of the compounds are established anti-oxidant and anti-inflammatory molecules, they are surmised to confer neuroprotection in PD, and prevent progression of the disease.
    Keywords:  Catechol-O-methyltransferase; Dopamine; Homocysteine; Levodopa; Monoamine oxidase
    DOI:  https://doi.org/10.1016/j.mehy.2019.109544
  764. J Immunol. 2020 Jan 22. pii: ji1901033. [Epub ahead of print]
    TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching.
    Scheraga RG, Abraham S, Grove LM, Southern BD, Crish JF, Perelas A, McDonald C, Asosingh K, Hasday JD, Olman MA.
      Mechanical cell-matrix interactions can drive the innate immune responses to infection; however, the molecular underpinnings of these responses remain elusive. This study was undertaken to understand the molecular mechanism by which the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), alters the in vivo response to lung infection. For the first time, to our knowledge, we show that TRPV4 protects the lung from injury upon intratracheal Pseudomonas aeruginosa in mice. TRPV4 functions to enhance macrophage bacterial clearance and downregulate proinflammatory cytokine secretion. TRPV4 mediates these effects through a novel mechanism of molecular switching of LPS signaling from predominant activation of the MAPK, JNK, to that of p38. This is accomplished through the activation of the master regulator of inflammation, dual-specificity phosphatase 1. Further, TRPV4's modulation of the LPS signal is mechanosensitive in that both upstream activation of p38 and its downstream biological consequences depend on pathophysiological range extracellular matrix stiffness. We further show the importance of TRPV4 on LPS-induced activation of macrophages from healthy human controls. These data are the first, to our knowledge, to demonstrate new roles for macrophage TRPV4 in regulating innate immunity in a mechanosensitive manner through the modulation of dual-specificity phosphatase 1 expression to mediate MAPK activation switching.
    DOI:  https://doi.org/10.4049/jimmunol.1901033
  765. JCI Insight. 2020 Jan 21. pii: 132048. [Epub ahead of print]
    MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis.
    Liu H, Osterburg AR, Flury J, Swank Z, McGraw DW, Gupta N, Wikenheiser-Brokamp KA, Kumar A, Tazi A, Inoue Y, Hirose M, McCormack FX, Borchers M.
      Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking-related, lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of PLCH patients harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models has impeded the study of PLCH pathogenesis. Here, we established a cigarette smoke (CS)-exposed, BRAF-V600E mutant mouse model that recapitulates many hallmark characteristics of PLCH. We show that CD11c-targeted expression of BRAF-V600E increases DC responsiveness to stimuli, including the chemokine CCL20, and that mutant DC accumulation in the lungs of CS-exposed mice is due to both increased cellular viability and enhanced recruitment. Moreover, we report that the chemokine CCL7 is secreted from DCs and human peripheral blood monocytes in a BRAF-V600E-dependent manner, suggesting a possible mechanism for recruitment of cells known to dominate PLCH lesions. Inflammatory lesions and airspace dilation in BRAF-V600E mice in response to CS are attenuated by transitioning animals to filtered air and treatment with a BRAF-V600E inhibitor, PLX4720. Collectively, this model provides mechanistic insights into the role of DCs, the BRAF-V600E mutation and CS exposure in PLCH pathogenesis, and provides a platform to develop therapeutic targets.
    Keywords:  Chemokines; Dendritic cells; Immunology; Molecular pathology; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.132048
  766. Front Aging Neurosci. 2019 ;11 344
    Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia.
    Ettcheto M, Olloquequi J, Sánchez-López E, Busquets O, Cano A, Manzine PR, Beas-Zarate C, Castro-Torres RD, García ML, Bulló M, Auladell C, Folch J, Camins A.
      Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990-2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile.
    Keywords:  Alzheimer's disease; benzodiazepines; cognition; dementia; risk factors
    DOI:  https://doi.org/10.3389/fnagi.2019.00344
  767. An Bras Dermatol. 2019 Dec 18. pii: S0365-0596(19)30172-2. [Epub ahead of print]
    Papillary syringocystadenoma in an uncommon location: a case report.
    Horcel GA, Milhomem J, Mandelbaum SH, Ieiri R.
      
    DOI:  https://doi.org/10.1016/j.abd.2019.02.011
  768. J Proteome Res. 2020 Jan 22.
    Metabolomic Profiling of the Synergistic Effects of Ginsenoside Rg1 in Combination with Neural Stem Cell Transplantation in Ischemic Stroke Rats.
    Gao J, Bai P, Li Y, Li J, Jia C, Wang T, Zhao H, Si Y, Chen J.
      As the greatest medical and socioeconomic problem in developing countries, stroke is the second or third leading cause of death in China and worldwide. In adult organisms suffering from stroke, transplanted stem cell has the ability to repair damaged tissues by regenerating autologous cells, while ginsenoside Rg1 could promote proliferation and differentiation of stem cells. Although obvious anti-stroke effects of ginsenoside Rg1 and transplanted stem cells have been verified in publications, the mechanism exploration remained challenging. Our study was carried out to investigate the synergistic effects of ginsenoside Rg1 and neural stem cell (NSC) transplantation on MCAO rats with a 1H NMR-based non-targeted metabolomics methods to identify potential biomarkers and protein targets and discover the potential mechanism. NSCs transplantation after MCAO combined with ginsenoside Rg1 administration could significantly improve the cerebral infract and neurological deficits. The treatment significant intervened the levels of ten metabolites, and perturbed energy metabolism, amino acids metabolism and lipids metabolism. And 11 enzymes were identified and verified as the targets of NSCs transplantation and ginsenoside Rg1 administration on MCAO rats. Our findings helped to improve the anti-stroke mechanism of NSCs transplantation and ginsenoside Rg1 and supply a theory basis for the combined research of stem cell and Chinese medicine in future.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00639
  769. Int J Mol Sci. 2020 Jan 17. pii: E616. [Epub ahead of print]21(2):
    The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model.
    Gorska-Ponikowska M, Kuban-Jankowska A, Marino Gammazza A, Daca A, Wierzbicka JM, Zmijewski MA, Luu HH, Wozniak M, Cappello F.
      2-Methoxyestradiol is one of the natural 17β-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin.
    Keywords:  2-methoxyestradiol; geldanamycin; neuronal nitric oxide synthase; osteosarcoma
    DOI:  https://doi.org/10.3390/ijms21020616
  770. FEMS Yeast Res. 2020 Jan 25. pii: foaa004. [Epub ahead of print]
    Hexose transport in Torulaspora delbrueckii: identification of Igt1, a new dual-affinity transporter.
    Pacheco A, Donzella L, Hernandez-Lopez MJ, Almeida MJ, Prieto JA, Randez-Gil F, Morrissey JP, Sousa MJ.
      Torulaspora delbrueckii is a yeast species receiving increasing attention from the biotechnology industry, with particular relevance in the wine, beer and baking sectors. However, little is known about its sugar transporters and sugar transport capacity, frequently a rate-limiting step of sugar metabolism and efficient fermentation. Actually, only one glucose transporter, Lgt1, has been characterized so far. Here we report the identification and characterization of a second glucose transporter gene, IGT1, located in a cluster, upstream of LGT1, and downstream of two other putative hexose transporters. Functional characterization of IGT1 in a Saccharomyces cerevisiae hxt-null strain revealed that it encodes a transporter able to mediate uptake of glucose, fructose and mannose and established that its affinity, as measured by Km, could be modulated by glucose concentration in the medium. In fact, IGT1-transformed S. cerevisiae hxt-null cells, grown in 0.1% glucose displayed biphasic glucose uptake kinetics with an intermediate- (Km = 6.5 ± 2.0 mM) and a high-affinity (Km = 0.10 ± 0.01 mM) component, whereas cells grown in 2% glucose displayed monophasic kinetics with an intermediate-affinity (Km of 11.5 ± 1.5 mM). This work contributes to a better characterization of glucose transport in T. delbrueckii, with relevant implications for its exploitation in the food industry.
    Keywords:   Torulaspora delbrueckii ; Glucose transport; dual affinity; glucose transporter gene cluster; hexose transporter; transport kinetics
    DOI:  https://doi.org/10.1093/femsyr/foaa004
  771. Ann Hepatol. 2020 Jan 02. pii: S1665-2681(19)32294-X. [Epub ahead of print]
    NRF-2 and nonalcoholic fatty liver disease.
    Solano-Urrusquieta A, Morales-González JA, Castro-Narro GE, Cerda-Reyes E, Flores-Rangel PD, Fierros-Oceguera R.
      Currently, chronic liver diseases have conditioned morbidity and mortality, many of these with a metabolic, toxicologic, immunologic, viral, or other etiology. Thus, a transcription factor that has been of huge importance for biomedical research is NRF-2. The latter is considered a principal component of the antioxidant mechanism, and it has been acknowledged that it impairs the function of NRF-2 in many liver diseases and that it forms an essential part of the pathologic changes that occur in the liver to contain inflammation and damage. Within the investigations and experiments carried out, there are isolated drugs, many of them related to plants and natural extracts that possess antioxidant properties through the NRF-2 signaling pathway, or even involving the stimulation of the transcription target proteins of NRF-2. Notwithstanding all of these experimental findings, to date there is not sufficient clinical evidence to justify the use of NRF-2 in medical practice.
    Keywords:  Liver antioxidants; NRF-2; Non-alcoholic fatty liver disease and KEAP1; Oxidative stress; Steatohepatitis
    DOI:  https://doi.org/10.1016/j.aohep.2019.11.010
  772. Bioinformatics. 2020 Jan 23. pii: btaa021. [Epub ahead of print]
    Transcompp: Understanding phenotypic plasticity by estimating Markov transition rates for cell state transitions.
    Jagannathan NS, Ihsan MO, Kin XX, Welsch RE, Clement MV, Tucker-Kellogg L.
      MOTIVATION: Gradual population-level changes in tissues can be driven by stochastic plasticity, meaning rare stochastic transitions of single-cell phenotype. Quantifying the rates of these stochastic transitions requires time-intensive experiments, and analysis is generally confounded by simultaneous bidirectional transitions and asymmetric proliferation kinetics. To quantify cellular plasticity, we developed Transcompp, a Markov modeling algorithm that uses optimization and resampling to compute best-fit rates and statistical intervals for stochastic cell-state transitions.RESULTS: We applied Transcompp to time-series datasets in which purified subpopulations of stem-like or non-stem cancer cells were exposed to various cell culture environments, and allowed to re-equilibrate spontaneously over time. Results revealed that commonly-used cell culture reagents hydrocortisone (HC) and cholera toxin (CTX) shifted the cell population equilibrium toward stem-like or non-stem states, respectively, in the basal-like breast cancer cell line MCF10CA1a. In addition, applying Transcompp to patient-derived cells showed that transition rates computed from short-term experiments could predict long-term trajectories and equilibrium convergence of the cultured cell population.
    AVAILABILITY: Freely available for download at http://github.com/nsuhasj/Transcompp.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btaa021
  773. Gastroenterology. 2020 Jan 20. pii: S0016-5085(20)30118-9. [Epub ahead of print]
    High Serum Levels of Cholesterol Increase Anti-tumor Functions of Nature Killer Cells and Reduce Growth of Liver Tumors in Mice.
    Qin WH, Yang ZS, Li M, Chen Y, Zhao XF, Qin YY, Song JQ, Wang BB, Yuan B, Cui XL, Shen F, He J, Bi YF, Ning G, Fu J, Wang HY.
      BACKGROUND AND AIMS: The relationship between serum cholesterol level and development of hepatocellular carcinoma (HCC) remains confusing. We investigated the effects of serum cholesterol level on development of liver tumors in mice.METHODS: We performed studies with C57BL/6J mice, mice with disruption of the low density lipoprotein receptor gene (Ldlr-/-mice)-and mice with conditional deletion of nature killer (NK) cells (NKdele mice). Some C57BL/6J and NKdele, mice were given injections of diethylinitrosamine (DEN) to induce liver tumor formation. Mice were placed on a normal diet (ND) or high-cholesterol diet (HCD) to induce high serum levels of cholesterol. We also studied mice with homozygous disruption of ApoE (ApoE-/- mice), which spontaneously develop high serum cholesterol. C57BL/6J and NKdele mice on the ND or HCD were implanted with Hep1-6 (mouse hepatoma) cells and growth of xenograft tumors and lung metastases were monitored. Blood samples were collected from mice and analyzed by biochemistry and flow cytometry; liver and tumor tissues were collected and analyzed by histology, immunohistochemistry, and RNA-seq analysis. NK cells were isolated from mice and analyzed for cholesterol content, lipid raft formation, immune signaling and changes in functions. We obtained matched tumor tissues and blood samples from 30 patients with HCC and blood samples from 40 healthy volunteers; levels of cholesterol and cytotoxicity of NK cells were measured.
    RESULTS: C57BL/6J mice on HCD and ApoE-/- mice with high serum levels of cholesterol developed fewer and smaller liver tumors and lung metastases after DEN injection or Hep1-6 cells implantation than mice on ND. Liver tumors from HCD-fed mice and ApoE-/- mice had increased numbers of NK cells, compared to tumors from ND-fed mice. NKdele mice or mice with antibody-based depletion for NK cells showed similar tumor number and size in ND and HCD group following DEN injection or Hep1-6 cells implantation. NK cells isolated from C57BL/6J mice fed with HCD had increased expression of NK cell-activating receptors (NCR1 and NKG2D), markers of effector function (granzyme B and perforin), and cytokines and chemokines, compared with NK cells from mice on ND; these NK cells also had enhanced cytotoxic activity against mouse hepatoma cells, accumulated cholesterol, increased lipid raft formation and immune signaling activation. NK cells isolated from HCD-fed Ldlr-/- mice did not have increased cholesterol content or cytotoxic activity against mouse hepatoma cells compared with ND-fed Ldlr-/- mice. Serum levels of cholesterol correlated with number and activity of NK cells isolated from human HCCs.
    CONCLUSION: Mice with increased serum levels of cholesterol, due to an HCD or genetic disruption of ApoE, develop fewer and smaller tumors after injection of hepatoma cells or a chemical carcinogen. We found cholesterol to accumulate in NK cells and activate their effector functions against hepatoma cells. Strategies to increase cholesterol uptake by NK cells might be developed for treatment of HCC.
    Keywords:  anti-tumor immune response; liver cancer; metabolism; signal transduction
    DOI:  https://doi.org/10.1053/j.gastro.2020.01.028
  774. J Biomed Opt. 2020 Jan;25(1): 1-11
    In-vivo full-field measurement of microcirculatory blood flow velocity based on intelligent object identification.
    Ye F, Yin S, Li M, Li Y, Zhong J.
      <p>Microcirculation plays a crucial role in delivering oxygen and nutrients to living tissues and in removing metabolic wastes from the human body. Monitoring the velocity of blood flow in microcirculation is essential for assessing various diseases, such as diabetes, cancer, and critical illnesses. Because of the complex morphological pattern of the capillaries, both <italic>in-vivo</italic> capillary identification and blood flow velocity measurement by conventional optical capillaroscopy are challenging. Thus, we focused on developing an <italic>in-vivo</italic> optical microscope for capillary imaging, and we propose an <italic>in-vivo</italic> full-field flow velocity measurement method based on intelligent object identification. The proposed method realizes full-field blood flow velocity measurements in microcirculation by employing a deep neural network to automatically identify and distinguish capillaries from images. In addition, a spatiotemporal diagram analysis is used for flow velocity calculation. <italic>In-vivo</italic> experiments were conducted, and the images and videos of capillaries were collected for analysis. We demonstrated that the proposed method is highly accurate in performing full-field blood flow velocity measurements in microcirculation. Further, because this method is simple and inexpensive, it can be effectively employed in clinics.</p>.
    Keywords:  biomedical optics; biophotonics; medical imaging
    DOI:  https://doi.org/10.1117/1.JBO.25.1.016003
  775. Sci Rep. 2020 Jan 23. 10(1): 1074
    Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome.
    Hsu WL, Ma YL, Liu YC, Tai DJC, Lee EHY.
      The methyl-CpG-binding protein 2 gene, MECP2, is an X chromosome-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Previous study has shown that re-expression of SUMO-modified MeCP2 in Mecp2-null neurons rescues synaptic and behavioral deficits in Mecp2 conditional knockout mice, whereas about 12-fold decrease in Wnt6 mRNA level was found in MeCP2K412R sumo-mutant mice. Here, we examined the role of Wnt6 in MeCP2 T158A mouse model of RTT. Results show that lentiviral delivery of Wnt6 to the amygdala ameliorates locomotor impairment and social behavioral deficits in these animals. MeCP2 T158A mice show decreased level of GSK-3β phosphorylation and increased level of β-catenin phosphorylation. They also show reduced level of MeCP2 SUMOylation. These alterations were also restored by lenti-Wnt6 transduction. Further, both BDNF and IGF-1 expressions are decreased in MeCP2 T158A mice. Overexpression of Wnt6 increases Bdnf and Igf-1 promoter activity in HEK293T cells in a dose-dependent manner. Lenti-Wnt6 transduction to the amygdala similarly increases the mRNA level and protein expression of BDNF and IGF-1 in MeCP2 T158A mice. Moreover, environmental enrichment (EE) similarly ameliorates the locomotor and social behavioral deficits in MeCP2 T158A mice. One of the mechanisms underlying EE is mediated through enhanced MeCP2 SUMOylation and increased Wnt6 expression in these animals by EE.
    DOI:  https://doi.org/10.1038/s41598-020-57745-w
  776. Disabil Rehabil. 2020 Jan 19. 1-9
    Using a dyadic approach to explore parental support for physical activity among young cancer survivors.
    Price J, Wurz A, Ramphal R, Wilson K, Brunet J.
      Background: Physical activity confers many physical and psychosocial benefits for adolescent and young adult cancer survivors, yet most are not active enough to accrue benefits. Parental support for physical activity may be important to consider when exploring factors that influence physical activity in this population.Purpose: Explore adolescent and young adult cancer survivors' experiences of parental support for physical activity received and their parents' experiences of support provided.Methods: Ten adolescent and young adult cancer survivors (Mage = 17.4 ± 3.2 years; 70% male) and one of their parents (50% fathers) were interviewed separately. Data were analyzed thematically.Results: Participants' experiences were summarized into three main themes: (1) the basics - instrumental, informational, and emotional support, (2) companionship support - doing it together, and (3) role modeling - a double-edged sword. In general, there was congruence between participants' perceptions of the types of support provided and received for physical activity. However, parents felt their role was to provide instrumental, informational, and emotional support, whereas adolescent and young adult cancer survivors emphasized the importance of companionship support.Conclusions: Findings underscore the complexity of parental support for physical activity among adolescent and young adult cancer survivors. Developing and testing resources to empower adolescent and young adult cancer survivors to ask for parental support and to enable parents to support their child's physical activity is imperative.Implications for RehabilitationMany adolescent and young adult cancer survivors do not participate in enough physical activity to acquire physical and psychosocial benefits.Parental support may represent a key factor that influences physical activity participation.Rehabilitation professionals should consider the influence parents may have on adolescent and young adult cancer survivors' physical well-being post-diagnosis.Promoting co-participation may be a viable strategy to enhance physical activity participation among adolescent and young adult cancer survivors.
    Keywords:  Social support; adolescent and young adult cancer survivors; exercise; family; oncology; qualitative research
    DOI:  https://doi.org/10.1080/09638288.2020.1712621
  777. Yeast. 2020 Jan 20.
    Functional inter-relationships between carbohydrate and lipid storage, and mitochondrial activity during sporulation in S. cerevisiae.
    Liu Y, Wood NE, Marchand AJ, Arguello-Miranda O, Doncic A.
      In S. cerevisiae under conditions of nutrient stress, meiosis precedes the formation of spores. Although the molecular mechanisms that regulate meiosis, such as meiotic recombination and nuclear divisions, have been extensively studied, the metabolic factors that determine the efficiency of sporulation are less understood. Here we have directly assessed the relationship between metabolic stores and sporulation in S. cerevisae by genetically disrupting the synthetic pathways for the carbohydrate stores, glycogen (gsy1/2Δ cells), trehalose (tps1Δ cells) or both (gsy1/2Δ, tps1Δ cells). We show that storage carbohydrate-deficient strains are highly inefficient in sporulation. Although glycogen and trehalose stores can partially compensate for each other, they have differential effects on sporulation rate and spore number. Interestingly, deletion of the G1 cyclin, CLN3, which resulted in an increase in cell size, mitochondria and lipid stores, partially rescued meiosis progression and spore ascus formation, but not spore number in storage carbohydrate-deficient strains. Sporulation efficiency in the carbohydrate-deficient strain exhibited a greater dependency on mitochondrial activity and lipid stores than wild-type yeast. Taken together, our results provide new insights into the complex crosstalk between metabolic factors that support gametogenesis.
    Keywords:  cyclin 3; glycogen; lipid droplet; meiosis; trehalose; yeast
    DOI:  https://doi.org/10.1002/yea.3460
  778. Nitric Oxide. 2020 Jan 20. pii: S1089-8603(19)30259-9. [Epub ahead of print]
    Supplementation of dietary nitrate attenuated oxidative stress and endothelial dysfunction in diabetic vasculature through inhibition of NADPH oxidase.
    Tian R, Peng R, Yang Z, Peng YY, Lu N.
      The metabolic disorders in diabetes, which are usually accompanied by oxidative stress and impaired nitric oxide (NO) bioavailability, increase the risk of detrimental cardiovascular complications. Herein, we investigated the therapeutic potential of dietary nitrate, which is found in high content in green leafy vegetables, on vascular oxidative stress and endothelial dysfunction in diabetic mice induced by high-fat diet and streptozotocin injection. Dietary nitrate in drinking water fuelled a nitrate-nitrite-NO pathway, which inhibited vascular oxidative stress, endothelial dysfunction and many features of metabolic syndrome in diabetic mice. These beneficial effects of nitrate on diabetic mice were abolished by PTIO (NO scavenger) treatment and significantly prevented by febuxostat (xanthine oxidoreductase inhibitor), demonstrating the central importance of NO in bioactivation of nitrate. The favorable effects of nitrate were not further influenced by apocynin (NADPH oxidase inhibitor), suggesting NADPH oxidase as a possible target. In high glucose-incubated vascular endothelial cells, NO donor attenuated oxidative stress and endothelial dysfunction via the inhibition of NADPH oxidase, where a heme oxygenase-1 (HO-1)-dependent mechanism was demonstrated for the antioxidant abilities of NO. Altogether, boosting this nitrate-nitrite-NO signaling pathway resulted in the decreases of NADPH oxidase-derived oxidative stress, endothelial dysfunction and metabolic disorders in diabetic vasculature. These findings may have novel implications for the preventive strategy against diabetes-induced vascular dysfunction and associated complications.
    Keywords:  Diabetes; Endothelial dysfunction; NADPH oxidase; Nitrate; Nitric oxide
    DOI:  https://doi.org/10.1016/j.niox.2020.01.007
  779. J Toxicol Environ Health A. 2020 Jan 23. 1-16
    Frequency-dependent changes in mitochondrial number and generation of reactive oxygen species in a rat model of vibration-induced injury.
    Krajnak K.
      Regular use of vibrating hand tools results in cold-induced vasoconstriction, finger blanching, and a reduction in tactile sensitivity and manual dexterity. Depending upon the length and frequency, vibration induces regeneration, or dysfunction and apoptosis, inflammation and an increase in reactive oxygen species (ROS) levels. These changes may be associated with mitochondria, this study examined the effects of vibration on total and functional mitochondria number. Male rats were exposed to restraint or tail vibration at 62.5, 125, or 250 Hz. The frequency-dependent effects of vibration on mitochondrial number and generation of oxidative stress were examined. After 10 days of exposure at 125 Hz, ventral tail arteries (VTA) were constricted and there was an increase in mitochondrial number and intensity of ROS staining. In the skin, the influence of vibration on arterioles displayed a similar but insignificant response in VTA. There was also a reduction in the number of small nerves with exposure to vibration at 250 Hz, and a reduction in mitochondrial number in nerves in restrained and all vibrated conditions. There was a significant rise in the size of the sensory receptors with vibration at 125 Hz, and an elevation in ROS levels. Based upon these results, mitochondria number and activity are affected by vibration, especially at frequencies at or near resonance. The influence of vibration on the vascular system may either be adaptive or maladaptive. However, the effects on cutaneous nerves might be a precursor to loss of innervation and sensory function noted in workers exposed to vibration.
    Keywords:  Hand-arm vibration; biomarkers; neuropathy; peripheral nerve injury; vascular dysfunction
    DOI:  https://doi.org/10.1080/15287394.2020.1718043
  780. Sci Rep. 2020 Jan 21. 10(1): 885
    Describing the fecal metabolome in cryogenically collected samples from healthy participants.
    Trošt K, Ahonen L, Suvitaival T, Christiansen N, Nielsen T, Thiele M, Jacobsen S, Krag A, Rossing P, Hansen T, Dragsted LO, Legido-Quigley C.
      The chemical composition of feces plays an important role in human metabolism. Metabolomics and lipidomics are valuable tools for screening the metabolite composition in feces. Here we set out to describe fecal metabolite composition in healthy participants in frozen stools. Frozen stool samples were collected from 10 healthy volunteers and cryogenically drilled in four areas along the specimen. Polar metabolites were analyzed using derivatization followed by two-dimensional gas chromatography and time of flight mass spectrometry. Lipids were detected using ultra high-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry. 2326 metabolic features were detected. Out of a total of 298 metabolites that were annotated we report here 185 that showed a technical variation of x < 30%. These metabolites included amino acids, fatty acid derivatives, carboxylic acids and phenolic compounds. Lipids predominantly belonged to the groups of diacylglycerols, triacylglycerols and ceramides. Metabolites varied between sampling areas, some were broadly homogeneous, others varied 80%. A LASSO-computed network using metabolites present in all areas showed two main clusters describing the system, DAG lipids and phenyllactic acid. In feces from healthy participants, the main groups detected were phenolic compounds, ceramides, diacylglycerols and triacylglycerols.
    DOI:  https://doi.org/10.1038/s41598-020-57888-w
  781. Int Immunopharmacol. 2020 Jan 21. pii: S1567-5769(19)31997-6. [Epub ahead of print]80 106128
    Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis.
    Liu D, Song G, Ma Z, Geng X, Dai Y, Yang T, Meng H, Gong J, Zhou B, Song Z.
      OBJECTIVE: Bone marrow-derived mesenchymal stem cells (BMSCs) are effective in the treatment of severe acute pancreatitis (SAP), but their therapeutic effects could still be improved. In order to optimize the clinical application of BMSCs, we adopted the strategy of resveratrol (Res) pretreatment of BMSCs (Res-BMSCs) and applied it to a rat model of sodium taurocholate (NaT)-induced acute pancreatitis.METHODS: SAP was induced by injection of 3% NaT into the pancreatic duct and successful induction of SAP occurred after 12 h. Rats were treated with BMSCs, Res or BMSCs primed with Res at 40 mmol/L, Vandetanib (ZD6474) daily oral dosages of 50 mg/kg vandetanib.
    RESULTS: Res stimulated BMSCs to secrete vascular endothelial growth factor A (VEGFA), activated the downstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and inhibited pancreatic cell apoptosis. In addition, conditioned medium (CM) from Res-BMSCs enhanced the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, increased resistance to apoptosis and promoted the expression of angiogenesis-related proteins CD31, VEGF and VEGFR2 in pancreatic tissue, but Vandetanib partly abolished these effects by blocking the VEGFA- mediated pathway.
    CONCLUSION: Resveratrol-preprocessed BMSCs can activate the PI3K/AKT signaling pathway in pancreatic cells and HUVECs through paracrine release of VEGFA; thus, achieving the therapeutic effect of resisting apoptosis of pancreatic cells and promoting regeneration of damaged blood vessels. Res pretreatment may be a new strategy to improve the therapeutic effect of BMSCs on SAP.
    Keywords:  Angiogenesis; Apoptosis; Mesenchymal stem cells; Resveratrol; Severe acute pancreatitis; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1016/j.intimp.2019.106128
  782. J Cell Biochem. 2020 Jan 21.
    The circular RNA HIPK3 reduces hydrogen peroxide-induced injury of PC-12 cells by upregulation of miR-455.
    Chen X, Chen J, Jin S, Yan G, Hu C, Hu S.
      Craniocerebral trauma is a serious disease accompanied with mechanical damage, oxidative damage, and neuronal apoptosis. Circular RNA HIPK3 (circHIPK3), an abundant circRNA, exerts the function in promoting cell growth. Therefore, we aimed to explore the biological roles and mechanism of circHIPK3 on cell damage in craniocerebral trauma. PC-12 cells were cotransfected with PLCDH-cirHIPK3 and microRNA-455 (miR-455) inhibitor and then were treated with H2 O2 for 24 hours. Cell viability, apoptosis and mean fluorescence intensity (MFI) were tested through trypan blue staining, flow cytometry and reactive oxygen species assay, respectively. Expression of circHIPK3 and miR-455 were tested through quantitative reverse transcription polymerase chain reaction. Expression of pro-PARP, cleaved-PARP, pro-caspase-3, cleaved-caspase-3, pro-caspase-9, cleaved-caspase-9, β-actin, beclin-1, p62, light chain 3-I (LC3-I), LC3-II, nuclear factor erythroid 2-related factor 2 (Nrf2), t-extracellular-regulated kinase (t-ERK) and p-ERK were tested via Western blot experiments. The 100 μM H2 O2 -induced cell damage presented as reducing cell viability, increasing apoptosis, autophagy, and MFI. Besides, H2 O2 could downregulate circHIPK3. However, overexpression of circHIPK3 attenuated cell damage caused by H2 O2 that it increased cell viability, decreased apoptosis, autophagy and MFI through upregulating miR-455. Additionally, circHIPK3 overexpression promoted the activation of Nrf2 and ERK signal pathways by upregulating miR-455. Our study demonstrated that circHIPK3 attenuated H2 O2 -induced cell damage and activated Nrf2 and ERK signal pathways by upregulation of miR-455.
    Keywords:  autophagy; craniocerebral trauma; extracellular signal-regulated kinase; mean fluorescence intensity; nuclear factor erythroid 2-related factor 2; viability
    DOI:  https://doi.org/10.1002/jcb.29660
  783. Perfusion. 2020 Jan 21. 267659119900124
    Predictors for unsuccessful weaning from venoarterial extracorporeal membrane oxygenation in patients undergoing coronary artery bypass grafting.
    Shao J, Wang L, Wang H, Hou X.
      BACKGROUND: Studies reporting risk factors associated with unsuccessful weaning for coronary artery bypass grafting patients on venoarterial extracorporeal membrane oxygenation are scarce. This study was designed to identify factors associated with unsuccessful weaning from venoarterial extracorporeal membrane oxygenation.METHODS: Data from 166 coronary artery bypass grafting patients supported with venoarterial extracorporeal membrane oxygenation at the Beijing Anzhen Hospital between February 2004 and March 2017 were retrospectively analyzed. Multivariable logistic regression was performed using bootstrapping methodology to identify factors independently associated with unsuccessful weaning from venoarterial extracorporeal membrane oxygenation.
    RESULTS: A total of 106 patients (64%) could be weaned from venoarterial extracorporeal membrane oxygenation, and 74 patients (45%) were alive at hospital discharge. The 30-day and 60-day survival rates after ECMO weaning were 72% and 70%, respectively. Pre-existing hypertension (odds ratio, 2.54; 95% confidence interval, 1.16-5.56; p = 0.02), serum creatinine (+1 μmol/L; odds ratio, 1.008; 95% confidence interval, 1.003-1.013; p = 0.001), and serum lactate (+1 mmol/L; odds ratio, 1.17; 95% confidence interval, 1.08-1.26; p = 0.001) were independent risk factors associated with unsuccessful weaning from venoarterial extracorporeal membrane oxygenation. Higher platelet count was protective (+1 × 109/L; odds ratio, 0.992; 95% confidence interval, 0.986-0.998; p = 0.011). The area under the receiver operating characteristic curve 0.81 (95% confidence interval, 0.75-0.88) for the logistic regression model was better than those for the survival after VA-ECMO score (p = 0.002), EuroSCORE (p < 0.001), and the prEdictioN of Cardiogenic shock OUtcome foR Acute myocardial infarction patients salvaGed by VA-ECMO scores (p = 0.02) in this population. The pRedicting mortality in patients undergoing venoarterial Extracorporeal MEMBrane oxygenation after coronary artEry bypass gRafting (0.76; 95% confidence interval, 0.68-0.83; p = 0.29) and sepsis-related organ failure assessment score (0.77; 95% confidence interval, 0.70-0.85; p = 0.46) exhibited good performances similar to the logistic regression model.
    CONCLUSION: Pre-existing hypertension, serum creatinine, serum lactate, and low platelet count were independent predictors for unsuccessful weaning from venoarterial extracorporeal membrane oxygenation in patients undergoing coronary artery bypass grafting.
    Keywords:  cardiogenic shock; coronary artery bypass grafting; unsuccessful weaning; venoarterial extracorporeal membrane oxygenation
    DOI:  https://doi.org/10.1177/0267659119900124
  784. RNA Biol. 2020 Jan 19. 1-13
    Pan-cancer analysis of RNA methyltransferases identifies FTSJ3 as a potential regulator of breast cancer progression.
    Manning M, Jiang Y, Wang R, Liu L, Rode S, Bonahoom M, Kim S, Yang ZQ.
      RNA methylation, catalysed by a set of RNA methyltransferases (RNMTs), modulates RNA structures, properties, and biological functions. RNMTs are increasingly documented to be dysregulated in various human diseases, particularly developmental disorders and cancer. However, the genomic and transcriptomic alterations of RNMTs, as well as their functional roles in human cancer, are limited. In this study, we utilized an unbiased approach to examine copy number alterations and mutation rates of 58 RNMTs in more than 10,000 clinical samples across 32 human cancer types. We also investigated these alterations and RNMT expression level as they related to clinical features such as tumour subtype, grade, and survival in a large cohort of tumour samples, focusing on breast cancer. Loss-of-function analysis was performed to examine RNMT candidates with important roles in growth and viability of breast cancer cells. We identified a subset of RNMTs, notably TRMT12, NSUN2, TARBP1, and FTSJ3, that were amplified or mutated in a subset of human cancers. Several RNMTs were significantly associated with breast cancer aggressiveness and poor prognosis. Loss-of-function analysis indicated FTSJ3, a 2'-O-Me methyltransferase, as a candidate RNMT with functional roles in promoting cancer growth and survival. A subset of RNMTs, like FTSJ3, represents promising novel targets for anticancer drug discovery. Our findings provide a framework for further study of the functional consequences of RNMT alterations in human cancer and for developing therapies that target cancer-promoting RNMTs in the future.
    Keywords:  FTSJ3; RNA methyltransferase; amplification; breast cancer; cancer genomics; copy number alteration; mutation
    DOI:  https://doi.org/10.1080/15476286.2019.1708549
  785. Brain Behav Immun. 2020 Jan 20. pii: S0889-1591(19)31179-1. [Epub ahead of print]
    The combined association of depressive symptoms and C-reactive protein for incident disease risk up to 12 years later. Findings from the English Longitudinal of Ageing (ELSA).
    Poole L, Steptoe A.
      BACKGROUND: Depression and inflammation are interrelated, and both are associated with the development of long-term conditions (LTCs). We investigated whether the combination of elevated depressive symptoms and elevated C-reactive protein (CRP) was associated with the rate of onset of a range of LTCs.METHODS: We analysed data from 5360 participants (65.77±9.46 years; 54.1% female) from the English Longitudinal Study of Ageing (ELSA). Depressive symptoms were indicated using the Centre for Epidemiological Studies Depression (CES-D) scale and scores were combined with high sensitivity (hs)-CRP values to reflect the additive interaction between low/high depressive symptoms (CES-D ≥4) and low/high CRP (>3mg/L). Participants were followed-up for up to 12 years to predict incident illness. Cox proportional hazard regression was used controlling for covariates.
    RESULTS: In fully adjusted models, the combination of elevated depressive symptoms and elevated CRP was an independent predictor of CHD (HR = 1.68, 95% C.I. = 1.01-2.78), stroke (HR = 2.02; 95% C.I. = 1.48-2.76), diabetes/high blood glucose (HR = 1.69; 95% C.I. = 1.11-2.57), and pulmonary disease (HR = 1.79; 95% C.I. = 1.02-3.15) relative to low depressive symptoms/low CRP, independently of age, sex, wealth, cohabitation, smoking status, body mass index and hypertension. Elevated depressive symptoms and low CRP was associated with arthritis incidence (HR = 1.49; 95% C.I. = 1.15-1.92). No association was found for cancer incidence.
    CONCLUSION: A combination of depressive symptoms and CRP was implicated in the onset of CHD, stroke, diabetes/high blood glucose, and pulmonary disease up to 12 years later, reflecting the role of psychobiological processes across multiple disease states.
    Keywords:  C-reactive protein; arthritis; cancer; coronary heart disease; depression; diabetes; long-term conditions; pulmonary disease; stroke
    DOI:  https://doi.org/10.1016/j.bbi.2020.01.010
  786. Nat Commun. 2020 Jan 23. 11(1): 442
    NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons.
    Engström Ruud L, Pereira MMA, de Solis AJ, Fenselau H, Brüning JC.
      Activation of Agouti-Related Peptide (AgRP)-expressing neurons promotes feeding and insulin resistance. Here, we examine the contribution of neuropeptide Y (NPY)-dependent signaling to the diverse physiological consequences of activating AgRP neurons. NPY-deficient mice fail to rapidly increase food intake during the first hour of either chemo- or optogenetic activation of AgRP neurons, while the delayed increase in feeding is comparable between control and NPY-deficient mice. Acutely stimulating AgRP neurons fails to induce systemic insulin resistance in NPY-deficient mice, while increased locomotor activity upon AgRP neuron stimulation in the absence of food remains unaffected in these animals. Selective re-expression of NPY in AgRP neurons attenuates the reduced feeding response and reverses the protection from insulin resistance upon optogenetic activation of AgRP neurons in NPY-deficient mice. Collectively, these experiments reveal a pivotal role of NPY-dependent signaling in mediating the rapid feeding inducing effect and the acute glucose regulatory function governed by AgRP neurons.
    DOI:  https://doi.org/10.1038/s41467-020-14291-3
  787. Microorganisms. 2020 Jan 23. pii: E164. [Epub ahead of print]8(2):
    Mbov_0503 Encodes a Novel Cytoadhesin that Facilitates Mycoplasma bovis Interaction with Tight Junctions.
    Zhu X, Dong Y, Baranowski E, Li X, Zhao G, Hao Z, Zhang H, Chen Y, Hu C, Chen H, Citti C, Guo A.
      Molecules contributing to microbial cytoadhesion are important virulence factors. In Mycoplasma bovis, a minimal bacterium but an important cattle pathogen, binding to host cells is emerging as a complex process involving a broad range of surface-exposed structures. Here, a new cytoadhesin of M. bovis was identified by producing a collection of individual knock-out mutants and evaluating their binding to embryonic bovine lung cells. The cytoadhesive-properties of this surface-exposed protein, which is encoded by Mbov_0503 in strain HB0801, were demonstrated at both the mycoplasma cell and protein levels using confocal microscopy and ELISA. Although Mbov_0503 disruption was only associated in M. bovis with a partial reduction of its binding capacity, this moderate effect was sufficient to affect M. bovis interaction with the host-cell tight junctions, and to reduce the translocation of this mycoplasma across epithelial cell monolayers. Besides demonstrating the capacity of M. bovis to disrupt tight junctions, these results identified novel properties associated with cytoadhesin that might contribute to virulence and host colonization. These findings provide new insights into the complex interplay taking place between wall-less mycoplasmas and the host-cell surface.
    Keywords:  Mbov_0503; Mycoplasma bovis; cytoadhesin; epithelial cells; tight junction; translocation; transposon mutagenesis
    DOI:  https://doi.org/10.3390/microorganisms8020164
  788. ACS Synth Biol. 2020 Jan 24.
    Active analyte import improves dynamic range and sensitivity of a Vitamin B12 biosensor.
    McNerney MP, Piorino F, Michel CL, Styczynski MP.
      Cell-free systems provide a versatile platform for the development of low-cost, easy-to-use sensors for diverse analytes. However, sensor affinity dictates response sensitivity, and improving binding affinity can be challenging. Here we describe efforts to address this problem while developing a biosensor for Vitamin B12, a critical micronutrient. We first use a B12-responsive transcription factor to enable B12-dependent output in a cell-free reaction, but the resulting sensor responds to B12 far above clinically relevant concentrations. Surprisingly, when expressed in cells, the same sensor mediates a much more sensitive response to B12. The sensitivity difference is partly due to regulated import that accumulates cytoplasmic B12. Overexpression of importers further improves sensitivity, demonstrating an inherent advantage of whole-cell sensors. The resulting cells can respond to B12 in serum, can be lyophilized, and are functional in a minimal-equipment environment, showing the potential utility of whole-cell sensors as sensitive, field-deployable diagnostics.
    DOI:  https://doi.org/10.1021/acssynbio.9b00429
  789. Obes Rev. 2020 Jan 19.
    Changes in physical activity, diet, and body weight across the education and employment transitions of early adulthood: A systematic review and meta-analysis.
    Winpenny EM, Smith M, Penney T, Foubister C, Guagliano JM, Love R, Clifford Astbury C, van Sluijs EMF, Corder K.
      Early adulthood is a time when individuals go through important life transitions, such as moving from high school into higher education or employment, but the impact of these life transitions on changes in body weight, diet, and physical activity is not known. We searched six electronic databases to July 2019 for longitudinal observational studies providing data on adiposity, diet, and/or physical activity across education or employment transitions in young people aged between 15 and 35 years. We found 19 studies, of which 17 assessed changes in physical activity, three body weight, and five diet or eating behaviours. Meta-analysis (n=9) found that leaving high school was associated with a decrease of -7.04 (95% CI, -11.26, -2.82) min/day of moderate-to-vigorous physical activity. Three studies reported increases in body weight on leaving high school. A small number of studies suggested decreases in diet quality on leaving high school (n=2/4 papers) and leaving university (n=1) but not on starting employment (n=1). Studies suggested no change in physical activity on leaving university (n=4) but decreases in physical activity on starting employment (n=2/3). The transition of leaving high school is an important time to support individuals to prevent decreases in physical activity and gains in body weight.
    Keywords:  obesity; school; university; work
    DOI:  https://doi.org/10.1111/obr.12962
  790. RNA Biol. 2020 Jan 19.
    Molecular Entrapment by RNA: An Emerging Tool for Disrupting Protein-RNA Interactions in vivo.
    Shukla TN, Song J, Campbell ZT.
      mRNA function is controlled by RNA-binding proteins. The specificity of RNA-binding factors for their targets is critical in that it enables all subsequent regulatory control. Despite widespread recognition of the pervasive role RNA-binding proteins play in development and disease, they remain challenging to target with small molecules. A renaissance in RNA therapeutics has led to the identification of modifications that substantially increase RNA stability. When combined with information regarding specificity, a new class of oligonucleotide mimics has emerged as a means to competitively disrupt regulation of endogenous substrates. These decoys have been used to inhibit RNA-binding proteins in living animals. Decoys will likely provide new insights into the expansive roles of RNA-binding proteins in biology and disease. Here, we describe examples where they have been used and discuss how they could be applied to new targets.
    Keywords:  RNA decoys; RNA protein interactions; RNA-binding proteins; Specificity
    DOI:  https://doi.org/10.1080/15476286.2020.1717059
  791. Redox Biol. 2020 Jan 20. pii: S2213-2317(19)31517-4. [Epub ahead of print]30 101430
    Effect of ER stress on sphingolipid levels and apoptotic pathways in retinal pigment epithelial cells.
    Afşar E, Kırımlıoglu E, Çeker T, Yılmaz Ç, Demir N, Aslan M.
      BACKGROUND: We aimed to determine sphingolipid levels and examine apoptotic pathways in human retinal pigment epithelial cells (ARPE-19) undergoing endoplasmic reticulum (ER) stress.METHODS: Cells were treated with tunicamycin (TM) to induce ER stress and tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was administered to decrease cytotoxicity. Cell viability was measured by MTT assay. Levels of C16-C24 sphingomyelins (SM) and C16-C24 ceramides (CERs) were determined by LC-MS/MS. Glucose-regulated protein 78-kd (GRP78) and nuclear factor kappa-b subunit 1 (NFκB1) gene expressions were evaluated by quantitative PCR analysis, while GRP 78, NF-κB p65, cleaved caspase-3 and caspase-12 protein levels were assesed by immunofluorescence. Ceramide-1-phosphate (C1P) levels were determined by immunoassay, while caspase -3 and -12 activity in cell lysates were measured via a fluorometric method.
    RESULTS: Induction of ER stress in TM treated groups were confirmed by significantly increased mRNA and protein levels of GRP78. TM significantly decreased cell viability compared to controls. Treatment with TUDCA along with TM significantly increased cell viability compared to the TM group. A significant increase was observed in C22-C24 CERs, C1P, caspase-3, caspase-12, NFκB1 mRNA and NF-κB p65 protein levels in cells treated with TM compared to controls. Administration of TUDCA lead to a partial decrease in GRP78 expression, NFκB1 mRNA, NF-κB p65 protein, C22-C24 CERs and C1P levels along with a decrease in caspase-3 and -12 activity.
    CONCLUSIONS: The results of this study reveal the presence of increased long chain CERs, C1P and apoptotic markers in retinal cells undergoing ER stress.
    Keywords:  Retinal pigment epithelial cells; Sphingolipid; Tunicamycin
    DOI:  https://doi.org/10.1016/j.redox.2020.101430
  792. Cell Death Dis. 2020 Jan 23. 11(1): 55
    B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression.
    Wang R, Ma Y, Zhan S, Zhang G, Cao L, Zhang X, Shi T, Chen W.
      Tumor angiogenesis is a hallmark of cancer and is involved in the tumorigenesis of solid tumors. B7-H3, an immune checkpoint molecule, plays critical roles in proliferation, metastasis and tumorigenesis in diverse tumors; however, little is known about the biological functions and molecular mechanism underlying B7-H3 in regulating colorectal cancer (CRC) angiogenesis. In this study, we first demonstrated that the expression of B7-H3 was significantly upregulated and was positively associated with platelet endothelial cell adhesion molecule-1 (CD31) level in tissue samples from patients with CRC. In addition, a series of in vitro and in vivo experiments showed that conditioned medium from B7-H3 knockdown CRC cells significantly inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas overexpression of B7-H3 had the opposite effect. Furthermore, B7-H3 promoted tumor angiogenesis by upregulating VEGFA expression. Recombinant VEGFA abolished the inhibitory effects of conditioned medium from shB7-H3 CRC cells on HUVEC angiogenesis, while VEGFA siRNA or a VEGFA-neutralizing antibody reversed the effects of conditioned medium from B7-H3-overexpressing CRC cells on HUVEC angiogenesis. Moreover, we verified that B7-H3 upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Collectively, our findings identify the B7-H3/NF-κB/VEGFA axis in promoting CRC angiogenesis, which serves as a promising approach for CRC treatment.
    DOI:  https://doi.org/10.1038/s41419-020-2252-3
  793. Semergen. 2020 Jan 21. pii: S1138-3593(19)30447-2. [Epub ahead of print]
    [Lung ultrasound in a patient with dyspnoea and fever in primary care].
    Muñoz Bueno C, Gómez Sánchez L, Alonso Roca R.
      
    DOI:  https://doi.org/10.1016/j.semerg.2019.10.012
  794. Rev Port Cardiol. 2020 Jan 16. pii: S0870-2551(19)30571-2. [Epub ahead of print]
    Effect of lifestyle on blood pressure in patients under antihypertensive medication: An analysis from the Portuguese Health Examination Survey.
    Salvador MR, Cunha Gonçalves S, Quinaz Romana G, Nunes B, Kislaya I, Matias Dias C, Rodrigues AP.
      INTRODUCTION AND OBJECTIVES: Hypertension is one of the main risk factors for disability and death from cardiovascular disease. Current guidelines include initiatives to control blood pressure in hypertensive patients that focus on lifestyle changes. The main objective of this study was to analyze the association between lifestyle and blood pressure in patients under antihypertensive medication.METHODS: Data collected in the Portuguese National Health Examination Survey (INSEF) were analyzed. Individuals who met INSEF inclusion criteria and reported being under antihypertensive medication in the two weeks prior to the questionnaire were studied. Lifestyle variables (alcohol consumption, smoking, added salt intake, fruit and vegetable consumption, and physical activity) were assessed by questionnaire, and systolic and diastolic blood pressure were measured by physical examination. Associations between lifestyle factors and blood pressure, stratified by gender and adjusted for sociodemographic variables and obesity, were estimated through a multiple linear regression model.
    RESULTS: Alcohol consumption (beta=6.31, p=0.007) and smoking (beta=4.72, p=0.018) were positively associated with systolic blood pressure in men. Added salt intake, fruit and vegetable consumption, and physical activity were not associated with blood pressure in men. In women, no association was observed for any behavioral variable.
    CONCLUSIONS: These conclusions highlight the need in the population under antihypertensive medication, particularly in men, to focus on the fight against high systolic blood pressure in the two modifiable and preventable behaviors of smoking and alcohol consumption.
    Keywords:  Alcohol; Atividade física; Blood pressure; Diet; Dieta; Physical activity; Pressão arterial; Smoking; Tabaco; Álcool
    DOI:  https://doi.org/10.1016/j.repc.2018.12.006
  795. Cancer. 2020 Jan 24.
    Electrocautery ablation of anal high-grade squamous intraepithelial lesions: Effectiveness and key factors associated with outcomes.
    Gaisa MM, Liu Y, Deshmukh AA, Stone KL, Sigel KM.
      BACKGROUND: Electrocautery ablation (EA) is a common treatment modality for patients with anal high-grade squamous intraepithelial lesions (HSILs), but to the authors' knowledge its effectiveness has been understudied. The objective of the current study was to determine ablation outcomes and to identify clinicopathological factors associated with postablation disease recurrence.METHODS: A total of 330 people living with HIV with de novo intra-anal HSIL who were treated with EA from 2009 to 2016 were studied retrospectively. Using long-term, surveillance high-resolution anoscopy biopsy data, treatment failures were classified as local recurrence (HSIL noted at the treated site at the time of surveillance) or overall recurrence (HSIL noted at treated or untreated sites). The associations between these outcomes and clinical factors were analyzed using Cox proportional hazards models.
    RESULTS: Approximately 88% of participants were men who have sex with men. The median age of study  participants was 45.5 years (range, 35-51 years) and approximately 49% had multiple index HSILs (range, 2-6 index HSILs). At a median of 12.2 months postablation (range, 6.3-20.9 months postablation), approximately 45% of participants had developed local recurrence whereas 60% had developed overall recurrence. Current cigarette smoking, HIV viremia (HIV-1 RNA ≥100 copies/mL), and multiple index HSILs were found to be predictive of local recurrence. Overall recurrence was more common in current smokers and those with multiple index lesions. In multivariable models that included human papillomavirus (HPV) genotypes, baseline and persistent infections with HPV-16 and/or HPV-18 were found to be significantly associated with both local and overall recurrence.
    CONCLUSIONS: EA is an effective treatment modality for anal HSIL in people living with HIV, but rates of disease recurrence are substantial. Multiple index HSILs, HIV viremia, current cigarette smoking, and both baseline and persistent infection with HPV-16 and/or HPV-18 appear to negatively impact treatment success. Ongoing surveillance is imperative to capture recurrence early and improve long-term treatment outcomes.
    Keywords:  HIV; anal cancer precursors; electrocautery ablation; high-grade squamous intraepithelial lesion (HSIL); outcomes; recurrence
    DOI:  https://doi.org/10.1002/cncr.32581
  796. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30042-5. [Epub ahead of print]
    Protein kinase A accelerates the rate of early stage differentiation of pluripotent stem cells.
    Minakawa T, Kanki Y, Nakamura K, Yamashita JK.
      In normal development, the rate of cell differentiation is tightly controlled and critical for normal development and stem cell differentiation. However, the underlying mechanisms regulating the rate of the differentiation are unknown, and manipulation of the rate of the stem cell differentiation is currently difficult. Here we show that activation of protein kinase A (PKA) accelerates the rate of mouse embryonic stem cell (ESC) differentiation through an early loss of ESC pluripotency markers and early appearance of mesodermal and other germ layer cells. The activation of PKA hastened differentiation by increasing the expression of a histone H3 lysine 9 (H3K9) dimethyltransferase, G9a protein, and the level of a negative epigenetic histone mark, H3K9 dimethylation (H3K9me2), in the promoter regions of the pluripotency markers Nanog and Oct4. These results elucidate a novel role of PKA on ESC differentiation and offer an experimental model for controlling the rate of ESC differentiation.
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.098
  797. Food Chem. 2020 Jan 11. pii: S0308-8146(20)30043-1. [Epub ahead of print]314 126196
    Identification of sesamol byproducts produced by plasma treatment with inhibition of advanced glycation endproducts formation and ONOO- scavenging activities.
    Jeong YH, Jeong GH, Jeong YH, Kim TH.
      Little is known of plasma-mediated relations between major food components and their biological capacities. In the present work, the effects of dielectric barrier discharge (DBD) plasma irradiation on pure sesamol and sesame oil were investigated using spectroscopic (LC-MS, NMR) and bioassay methods. Sesamol was degraded when subjected to plasma irradiation for 40 min, and the exposed products exhibited improved anti-glycation capacities against advanced glycation end products (AGEs) formation and better ONOO- scavenging ability. Structures of newly formed compounds were determined spectroscopically. Quantitative LC-MS analysis of the major products generated in sesamol and sesame oil was achieved using isolates 1-4 of purified sesamol plasma treated for 40 min. These results indicate that the predominant chemical changes induced in sesamol and sesame oil by DBD plasma treatment might enhance biological properties.
    Keywords:  Anti-diabetic complications; Dielectric barrier discharge plasma; Dimerization; Sesame oil; Sesamol
    DOI:  https://doi.org/10.1016/j.foodchem.2020.126196
  798. Adv Med Sci. 2020 Jan 20. pii: S1896-1126(19)30018-5. [Epub ahead of print]65(1): 163-169
    Single-cell analysis on stromal fibroblasts in the microenvironment of solid tumours.
    Musa M.
      Besides malignant cells, the tumour microenvironment consists of various stromal cells such as cancer-associated fibroblasts (CAFs) and myofibroblasts. Accumulation of heterogeneous populations of stromal cells in solid tumours is associated with lower survival rates and cancer recurrence in patients. Certain limitations presented by conventional experimental designs and techniques in cancer research have led to poor understanding of the fundamental basis of cancer niche. Recent developments in single-cell techniques allow more in-depth studies of the tumour microenvironment. Analyses at the single-cell level enables the detection of rare cell types, characterization of intra-tumour cellular heterogeneity and analysis of the lineage output of malignant cells. This subsequently, provides valuable insights on better diagnostic methods and treatment avenues for cancer. This review explores the recent advancements and applications of single-cell technologies in cancer research pertaining to the study of stromal fibroblasts in the microenvironment of solid tumours.
    Keywords:  Cancer; Microenvironment; Single-cell analysis; Solid tumour; Stromal fibroblast
    DOI:  https://doi.org/10.1016/j.advms.2019.12.001
  799. J Nutr. 2020 Jan 21. pii: nxz301. [Epub ahead of print]
    Regulation of mTORC1 by Small GTPases in Response to Nutrients.
    Zhu M, Wang XQ.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a highly evolutionarily conserved serine/threonine kinase that regulates cell growth and metabolism in response to multiple environmental cues, such as nutrients, hormones, energy, and stress. Deregulation of mTORC1 can lead to diseases such as diabetes, obesity, and cancer. A series of small GTPases, including Rag, Ras homolog enriched in brain (Rheb), adenosine diphosphate ribosylation factor 1 (Arf1), Ras-related protein Ral-A, Ras homolog (Rho), and Rab, are involved in regulating mTORC1 in response to nutrients, and mTORC1 is differentially regulated via these small GTPases according to specific conditions. Leucine and arginine sensing are considered to be well-confirmed amino acid-sensing signals, activating mTORC1 via a Rag GTPase-dependent mechanism as well as the Ragulator complex and vacuolar H+-adenosine triphosphatase (v-ATPase). Glutamine promotes mTORC1 activation via Arf1 independently of the Rag GTPase. In this review, we summarize current knowledge regarding the regulation of mTORC1 activity by small GTPases in response to nutrients, focusing on the function of small GTPases in mTORC1 activation and how small GTPases are regulated by nutrients.
    Keywords:  arginine; glutamine; leucine; mTORC1; small GTPases
    DOI:  https://doi.org/10.1093/jn/nxz301
  800. Appetite. 2020 Jan 17. pii: S0195-6663(19)31035-9. [Epub ahead of print] 104611
    Do perceived norms of social media users' eating habits and preferences predict our own food consumption and BMI?
    Hawkins LK, Farrow C, Thomas JM.
      In laboratory studies, exposure to social norm messages conveying the typical eating behaviour of others has influenced participants' own consumption of food. Given the widespread use of social media, it is plausible that we are implicitly exposed to norms in our wider social circles, and that these influence our eating behaviour, and potentially, Body Mass Index (BMI). This study examined whether four perceived norms (perceived descriptive, injunctive, liking and frequency norms) about Facebook users' eating habits and preferences predicted participants' own food consumption and BMI. In a cross-sectional survey, men and women university students (n = 369; mean age = 22.1 years; mean BMI = 23.7) were asked to report their perceptions of Facebook users' consumption of, and preferences for, fruit, vegetables, energy-dense snacks and sugar sweetened beverages (SSBs), their own consumption of and preferences for these foods, and their BMI. Multiple linear regression revealed that perceived descriptive norms and perceived frequency norms about Facebook users' fruit and vegetable consumption were significant positive predictors of participants' own fruit and vegetable consumption (both ps < .01). Conversely, perceived injunctive norms about Facebook users' energy-dense snack and SSB consumption were significant positive predictors of participants' own snack and SSB consumption (both ps < .05). However, perceived norms did not significantly predict BMI (all ps > .05). These findings suggest that perceived norms concerning actual consumption (descriptive and frequency) and norms related to approval (injunctive) may guide consumption of low and high energy-dense foods and beverages differently. Further work is required to establish whether these perceived norms also affect dietary behaviour over time.
    Keywords:  BMI; Facebook; Food; Perceptions; Social media; Social norms
    DOI:  https://doi.org/10.1016/j.appet.2020.104611
  801. Sci Rep. 2020 Jan 20. 10(1): 634
    Cathepsin B overexpression induces degradation of perilipin 1 to cause lipid metabolism dysfunction in adipocytes.
    Mizunoe Y, Kobayashi M, Hoshino S, Tagawa R, Itagawa R, Hoshino A, Okita N, Sudo Y, Nakagawa Y, Shimano H, Higami Y.
      Obesity, caused by the dysfunction of white adipose tissue (WAT), is reportedly accompanied by exacerbation of lipolysis. Perilipin 1 (PLIN1), which forms a coat around lipid droplets, interacts with several lipolysis proteins to regulate lipolysis. While it is known that perilipin family proteins are degraded in lysosomes, the underlying molecular mechanisms related to the downregulated expression of PLIN1 in obese WAT remain unknown. Recently, we found that lysosomal dysfunction originating from an abnormality of cathepsin B (CTSB), a lysosomal representative protease, occurs in obese WAT. Therefore, we investigated the effect of CTSB alterations on PLIN1 expression in obese WAT. PLIN1 protein disappeared and CTSB protein appeared in the cytoplasm of adipocytes in the early stage of obese WAT. Overexpression of CTSB reduced PLIN1 protein in 3T3L1 adipocytes, and treatment with a CTSB inhibitor significantly recovered this reduction. In addition, CTSB overexpression induced the dysfunction of lipolysis in 3T3L1 adipocytes. Therefore, we concluded that upregulation of CTSB induced the reduction of PLIN1 protein in obese WAT, resulting in lipolysis dysfunction. This suggests a novel pathology of lipid metabolism involving PLIN1 in adipocytes and that CTSB might be a therapeutic candidate molecule for obese WAT.
    DOI:  https://doi.org/10.1038/s41598-020-57428-6
  802. NPJ Genom Med. 2020 ;5 2
    Proneural and mesenchymal glioma stem cells display major differences in splicing and lncRNA profiles.
    Guardia GDA, Correa BR, Araujo PR, Qiao M, Burns S, Penalva LOF, Galante PAF.
      Therapy resistance and recurrence in high-grade gliomas are driven by their populations of glioma stem cells (GSCs). Thus, detailed molecular characterization of GSCs is needed to develop more effective therapies. We conducted a study to identify differences in the splicing profile and expression of long non-coding RNAs in proneural and mesenchymal GSC cell lines. Genes related to cell cycle, DNA repair, cilium assembly, and splicing showed the most differences between GSC subgroups. We also identified genes distinctly associated with survival among patients of mesenchymal or proneural subgroups. We determined that multiple long non-coding RNAs with increased expression in mesenchymal GSCs are associated with poor survival of glioblastoma patients. In summary, our study established critical differences between proneural and mesenchymal GSCs in splicing profiles and expression of long non-coding RNA. These splicing isoforms and lncRNA signatures may contribute to the uniqueness of GSC subgroups, thus contributing to cancer phenotypes and explaining differences in therapeutic responses.
    Keywords:  Cancer genomics; Cancer stem cells; Gene expression analysis; Gene regulatory networks
    DOI:  https://doi.org/10.1038/s41525-019-0108-5
  803. Int J Mol Sci. 2020 Jan 16. pii: E582. [Epub ahead of print]21(2):
    Influence of Sex on Urinary Organic Acids: A Cross-Sectional Study in Children.
    Caterino M, Ruoppolo M, Villani GRD, Marchese E, Costanzo M, Sotgiu G, Dore S, Franconi F, Campesi I.
      The characterization of urinary metabolome, which provides a fingerprint for each individual, is an important step to reach personalized medicine. It is influenced by exogenous and endogenous factors; among them, we investigated sex influences on 72 organic acids measured through GC-MS analysis in the urine of 291 children (152 males; 139 females) aging 1-36 months and stratified in four groups of age. Among the 72 urinary metabolites, in all age groups, 4-hydroxy-butirate and homogentisate are found only in males, whereas 3-hydroxy-dodecanoate, methylcitrate, and phenylacetate are found only in females. Sex differences are still present after age stratification being more numerous during the first 6 months of life. The most relevant sex differences involve the mitochondria homeostasis. In females, citrate cycle, glyoxylate and dicarboxylate metabolism, alanine, aspartate, glutamate, and butanoate metabolism had the highest impact. In males, urinary organic acids were involved in phenylalanine metabolism, citrate cycle, alanine, aspartate and glutamate metabolism, butanoate metabolism, and glyoxylate and dicarboxylate metabolism. In addition, age specifically affected metabolic pathways, the phenylalanine metabolism pathway being affected by age only in males. Relevantly, the age-influenced ranking of metabolic pathways varied in the two sexes. In conclusion, sex deeply influences both quantitatively and qualitatively urinary organic acids levels, the effect of sex being age dependent. Importantly, the sex effects depend on the single organic acid; thus, in some cases the urinary organic acid reference values should be stratified according the sex and age.
    Keywords:  GC; mass spectrometry; sex-specific reference values; urine metabolome
    DOI:  https://doi.org/10.3390/ijms21020582
  804. Rocz Panstw Zakl Hig. 2019 ;70(4): 337-345
    Importance of diet in reducing cancer incidence in Poland: a review
    Zych M, Stec K, Bąblewska A, Pilis K.
      Cancer is one of the leading causes of death in most countries in the world. In Poland, after cardiovascular disease, cancer is the leading cause of death, and the number of malignant tumors has more than doubled in the last three decades. Increased cancer mortality in the immediate future is expected to be mainly associated with lung cancer caused by smoking (both sexes), colorectal cancer (both sexes), breast cancer in women, and prostate cancer in men. It is estimated that 20 to 30% of all malignant tumors are diet-dependent, in which cases the cancer-inducing factors are the nutritional components of the food and the ‘hygiene’ of eating. Research by the Institute of Food and Nutrition in Warsaw indicates that an important factor in the prevention of cancer is also the individual’s state of awareness concerning diet. It is emphasized that running nutritional education programs, especially for children and adolescents, may help to limit the occurrence of diet-dependent cancers in Poland over the next few decades. The aim of this review is to assist the promulgation of knowledge about the importance of a high-quality diet in the prevention of cancer. The need for such knowledge is indicated by the upward trend in the incidence of these types of disease in Poland.
    Keywords:  nutrition; diet; cancer; prevention
  805. J Neurotrauma. 2020 Jan 23.
    Acute Cardiovascular Responses to Vagus Nerve Stimulation Following Experimental Spinal Cord Injury.
    Sachdeva R, Krassioukov AV, Bucksot JE, Hays SA.
      Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to enhance plasticity and improve recovery in a range of neurological disorders. A recent study highlights the therapeutic promise of VNS in promoting motor recovery after spinal cord injury (SCI). Here we investigate the safety of acute VNS in a rat model of chronic SCI. We measured the cardiovascular response to various VNS paradigms following chronic high-thoracic SCI that is known to deleteriously impact cardiovascular control. Dose-response experiments with continuous VNS revealed an SCI-dependent increase in sensitivity for heart rate (HR) and blood pressure (BP) compared to controls. A clinically-relevant intermittent VNS resulted in transient reduction in HR in rats with SCI, however BP remained unaltered. In all experiments, the effect lasted only while the VNS stimulus train was present, as HR and BP restored to baseline values as soon as VNS ended. No prolonged episodes of persisting hypotension were seen in either group. Furthermore, VNS did not trigger autonomic dysreflexia or exacerbate the severity of autonomic dysreflexia when induced during or after stimulation sessions. Overall, these findings provide initial evidence that intermittent VNS at parameters used for targeted plasticity therapy (30 Hz, 0.8mA) appears safe and supports further investigation of this potential therapy for use following SCI.
    Keywords:  ANIMAL STUDIES; THERAPEUTIC APPROACHES FOR THE TREATMENT OF CNS INJURY; spinal cord injury
    DOI:  https://doi.org/10.1089/neu.2019.6828
  806. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30060-7. [Epub ahead of print]
    Protein complexes including PGRMC1 and actin-associated proteins are disrupted by AG-205.
    Teakel SL, Ludescher M, Thejer BM, Poschmann G, Forwood JK, Neubauer H, Cahill MA.
      PGRMC1 is a protein from the MAPR family with a range of cellular functions. PGRMC1 has been described to play a role in fertility, neuroprotection, steroidogenesis, membrane trafficking and in cancer cell biology. PGRMC1 represents a likely key regulator of cell metabolism and proliferation, as well as a potential target for anti-cancer therapies. To further understand the functions of PGRMC1 and the mechanism of the small molecule inhibitor of PGRMC1, AG-205, proteins differentially bound to PGRMC1 were identified following AG-205 treatment of MIA PaCa-2 cells. Our results suggest that AG-205 influences PGRMC1 interactions with the actin cytoskeleton. The binding of two PGRMC1-associated proteins that support this, RACK1 and alpha-Actinin-1, was reduced following AG-205 treatment. The biology associated with PGRMC1 binding partners identified here merits further investigation.
    Keywords:  Actin cytoskeleton; Affinity proteomics; Cytochrome b5 domain; MAPR; Membrane trafficking; Membrane-associated progesterone receptor
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.108
  807. Neuron. 2020 Jan 22. pii: S0896-6273(19)31041-4. [Epub ahead of print]105(2): 207-209
    Greasing the Wheels of Regeneration.
    Kohen R, Giger RJ.
      In this issue of Neuron, Yang et al. (2020) identify glycerolipid metabolism as a neuron-intrinsic mechanism that regulates axonal growth and regeneration. Shifting glycerolipid metabolism toward increased triglyceride synthesis blocks PNS neuron regeneration, whereas shifting it toward membrane phospholipid synthesis overcomes regeneration failure in CNS neurons.
    DOI:  https://doi.org/10.1016/j.neuron.2019.11.032
  808. Sci Rep. 2020 Jan 20. 10(1): 702
    The Adaptive and Innate Immune Cell Landscape of Uterine Leiomyosarcomas.
    Manzoni M, Bolognesi MM, Antoranz A, Mancari R, Carinelli S, Faretta M, Bosisio FM, Cattoretti G.
      Reactivation of the anti-tumor response has shown substantial progress in aggressive tumors such as melanoma and lung cancer. Data on less common histotypes are scanty. Immune checkpoint inhibitor therapy has been applied to few cases of uterine leiomyosarcomas, of which the immune cell composition was not examined in detail. We analyzed the inflammatory infiltrate of 21 such cases in high-dimensional, single cell phenotyping on routinely processed tissue. T-lymphoid cells displayed a composite phenotype common to all tumors, suggestive of antigen-exposure, acute and chronic exhaustion. To the contrary, myelomonocytic cells had case-specific individual combinations of phenotypes and subsets. We identified five distinct monocyte-macrophage cell types, some not described before, bearing immunosuppressive molecules (TIM3, B7H3, VISTA, PD1, PDL1). Detailed in situ analysis of routinely processed tissue yields comprehensive information about the immune status of sarcomas. The method employed provides equivalent information to extractive single-cell technology, with spatial contexture and a modest investment.
    DOI:  https://doi.org/10.1038/s41598-020-57627-1
  809. J Agric Food Chem. 2020 Jan 22.
    Optimization and multiomic basis of phenyllactic acid overproduction by Lactobacillus plantarum.
    Wu W, Deng G, Liu C, Gong X, Ma G, Yuan Q, Yang E, Li XR, Luo YY.
      The goal of this study was to explore the regulatory mechanisms of phenyllactic acid (PLA) overaccumulation in Lactobacillus plantarum. The dynamics of PLA production revealed that 24 h was a suitable fermentation time, at which one of the largest differences in PLA content between strains S1 and YM-4-3 was 22.42 mg/L. Additionally, an optimization experiment showed that PLA production under the optimal condition (sample YM-4-3y) was up to 400.74 mg/L, 7.61-13.26 times as those of YM-4-3 and S1. Subsequently, an integrated analysis of genomic, transcriptomic and metabolomic data revealed that, YM-4-3 and YM-4-3y, compared with S1, although lacking a complete de novo biosynthetic pathway, increased PLA production by strengthening the core pathway and central carbon metabolism, and weakening the biosynthesis pathway of amino acids and their derivatives. These changes can provide sufficient precursors and compensate for or balance the energy consumed by the reinforced core pathway.
    DOI:  https://doi.org/10.1021/acs.jafc.9b07136
  810. Mult Scler. 2020 Jan 22. 1352458519876020
    Metabolomics in multiple sclerosis disease course and progression.
    Bhargava P, Anthony D.
      Multiple sclerosis (MS) is associated with changes in the metabolome. Numerous studies employing varying metabolomics platforms have examined a range of biological material ranging from brain tissue to urine and demonstrated consistently alterations in multiple metabolic pathways in MS. We review not only the studies that describe the ability of metabolomics to differentiate MS patients from healthy controls and other neurological disease but also discuss the potential of metabolomics-based methods to build predictive models that are able to stage disease, monitor progression, and select the most appropriate therapy. The increasing number of impressive claims for the capacity of metabolomics to distinguish between different types of demyelinating disease suggests that the provision of such tests may be close at hand. Besides the ability to provide potential diagnostic and prognostic biomarkers, metabolomics also provides us with unique insights into the pathophysiology of the disease and helps identify metabolic pathways that may be potential therapeutic targets. Future studies will integrate metabolomics data with other omics techniques to provide further insight into the source of these metabolic abnormalities and help with identification of the most promising targets for therapeutic intervention.
    Keywords:  Metabolomics; mass spectrometry; multiple sclerosis; nuclear magnetic resonance; tryptophan
    DOI:  https://doi.org/10.1177/1352458519876020
  811. J Reprod Dev. 2020 Jan 19.
    Retinoblastoma binding protein 7 is involved in Kiss1 mRNA upregulation in rodents.
    Horihata K, Inoue N, Uenoyama Y, Maeda KI, Tsukamura H.
      Kisspeptin, encoded by Kiss1, is essential for reproduction in mammals. Kiss1 expression is regulated by estrogen via histone acetylation in the Kiss1 promotor region. Thus, elucidation of histone modification factor(s) involved in the regulation of Kiss1 expression is required to gain further understanding of the mechanisms of its control. The RNA-seq analysis of isolated kisspeptin neurons, obtained from the arcuate nucleus (ARC) of female rats, revealed that Rbbp7, encoding retinoblastoma binding protein 7 (RBBP7), a member of histone modification and chromatin remodeling complexes, is highly expressed in the ARC kisspeptin neurons. Thus, the present study aimed to investigate whether RBBP7 is involved in Kiss1 expression. Histological analysis using in situ hybridization (ISH) revealed that Rbbp7 expression was located in several hypothalamic nuclei, including the ARC and the anteroventral periventricular nucleus (AVPV), where kisspeptin neurons are located. Double ISH for Rbbp7 and Kiss1 showed that a majority of kisspeptin neurons (more than 85%) expressed Rbbp7 mRNA in both the ARC and the AVPV of female rats. Further, Rbbp7 mRNA knockdown significantly decreased in vitro expression of Kiss1 in a mouse immortalized kisspeptin neuronal cell line (mHypoA-55). Estrogen treatment significantly decreased and increased Kiss1 mRNA levels in the ARC and AVPV of ovariectomized female rats, respectively, but failed to affect Rbbp7 mRNA levels in both the nuclei. Taken together, these findings suggest that RBBP7 is involved in the upregulation of Kiss1 expression in kisspeptin neurons of rodents in an estrogen-independent manner.
    Keywords:  Kiss1; Kisspeptin neuron; Retinoblastoma binding protein 7
    DOI:  https://doi.org/10.1262/jrd.2019-149
  812. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30098-2. [Epub ahead of print]49(1): xiii-xiv
    Technological Advances in Management of Diabetes Mellitus.
    Ioachimescu AG.
      
    DOI:  https://doi.org/10.1016/j.ecl.2019.11.004
  813. Clin Diabetes. 2020 Jan;38(1): 9
    It's That Time of Year Again.
    Brunton SA.
      
    DOI:  https://doi.org/10.2337/cd19-0081
  814. J Diabetes Investig. 2020 Jan 25.
    Is visceral abdominal fat area a better indicator for hyperglycemic risk? Results from the Pinggu Metabolic Disease Study.
    Zhang F, Li Y, Zhao Y, Zhou X, Ji L.
      AIM: To analyze the strength of association between fasting plasma glucose (FPG), 2h-postprandial glucose (2hPPG), hemoglobin A1c (HbA1c), disposition index (DI) and nine anthropometrics measures, to explore the best indicator for hyperglycemia.MATERIALS AND METHODS: Analyses were based on the cross-sectional data of 3 572 adults from the Pinggu Metabolic Disease study. Anthropometrics were measured, visceral fat area (VFA) and subcutaneous fat area (SFA) were calculated using abdominal CT scan. Linear regression was used to analyze the association between FPG, 2hPPG, HbA1c, DI and nine anthropometrics measures (height, weight, waist circumference (WC), body mass index (BMI) and waist to hip ratio (WHR), waist to height ratio, VFA, SFA, and visceral to subcutaneous ratio (VSR)). Logistic regression was further performed to understand the association between per standard increase and risk for hyperglycemia.
    RESULTS: Higher VFA and SFA were associated with higher FPG, 2hPPG, HbA1c and DI after adjusting for other covariates. The strongest association observed after adjustment was WC for FPG, with one standard deviation (SD) greater WC associated with 1.70 increased odds; WHR for 2h PPG, with one SD greater WHR associated with 1.83 increased odds. The strength of association between VFA and FPG, 2h PPG, HbA1c and DI was less than WHR and WC, but slightly stronger than BMI. Stratified analyses showed that VFA perform better as an anthropometrics indicator in predicting hyperglycaemic risk in female than male.
    CONCLUSION: WHR and WC remains the best indicators for hyperglycemic risk among healthy Chinese population.
    Keywords:  Visceral fat; body mass index; diabetes
    DOI:  https://doi.org/10.1111/jdi.13217
  815. Geroscience. 2020 Jan 20.
    Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice.
    Yabluchanskiy A, Tarantini S, Balasubramanian P, Kiss T, Csipo T, Fülöp GA, Lipecz A, Ahire C, DelFavero J, Nyul-Toth A, Sonntag WE, Schwartzman ML, Campisi J, Csiszar A, Ungvari Z.
      Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~ 50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI-treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte-dependent NVC responses (whisker-stimulation-induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC-related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post-irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI-induced senescence and NVC dysfunction, senescent cells were depleted from WBI-treated animals (at 3 months post-WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL-2/BCL-xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI-treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses, and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.
    Keywords:  Aging; Dementia; Functional hyperemia; Radiation; Senescence; Vascular cognitive impairment; WBI; WBRT; Whole brain radiation therapy
    DOI:  https://doi.org/10.1007/s11357-020-00154-8
  816. Int J Mol Sci. 2020 Jan 20. pii: E682. [Epub ahead of print]21(2):
    STVNa Attenuates Isoproterenol-Induced Cardiac Hypertrophy Response through the HDAC4 and Prdx2/ROS/Trx1 Pathways.
    Liu F, Su H, Liu B, Mei Y, Ke Q, Sun X, Tan W.
      Recent data show that cardiac hypertrophy contributes substantially to the overall heart failure burden. Mitochondrial dysfunction is a common feature of cardiac hypertrophy. Recent studies have reported that isosteviol inhibits myocardial ischemia-reperfusion injury in guinea pigs and H9c2 cells. This work investigated the protective mechanisms of isosteviol sodium (STVNa) against isoproterenol (Iso)-induced cardiac hypertrophy. We found that STVNa significantly inhibited H9c2 cell and rat primary cardiomyocyte cell surface, restored mitochondrial membrane potential (MMP) and morphological integrity, and decreased the expression of mitochondrial function-related proteins Fis1 and Drp1. Furthermore, STVNa decreased reactive oxygen species (ROS) levels and upregulated the expression of antioxidant factors, Thioredoxin 1 (Trx1) and Peroxiredoxin 2 (Prdx2). Moreover, STVNa restored the activity of histone deacetylase 4 (HDAC4) in the nucleus. Together, our data show that STVNa confers protection against Iso-induced myocardial hypertrophy primarily through the Prdx2/ROS/Trx1 signaling pathway. Thus, STVNA is a potentially effective treatment for cardiac hypertrophy in humans.
    Keywords:  ROS; cardiac hypertrophy; isosteviol sodium; peroxiredoxin; thioredoxin
    DOI:  https://doi.org/10.3390/ijms21020682
  817. J Clin Med. 2020 Jan 20. pii: E286. [Epub ahead of print]9(1):
    Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response.
    Xiao Q, Nobre A, Piñeiro P, Berciano-Guerrero MÁ, Alba E, Cobo M, Lauschke VM, Barragán I.
      Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.
    Keywords:  epigenetics; immunotherapy; melanoma; non-small-cell lung cancer; predictor; resistance; stroma
    DOI:  https://doi.org/10.3390/jcm9010286
  818. J Bioenerg Biomembr. 2020 Jan 21.
    Artesunate targets oral tongue squamous cell carcinoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition.
    Xiao Q, Yang L, Hu H, Ke Y.
      Although mitochondrial metabolism has recently gained attention as a promising therapeutic strategy in cancer, little is known on the impact of mitochondrial respiration inhibition on oral tongue squamous cell carcinoma (OTSCC). Using in vitro and in vivo OTSCC models, our work demonstrates that inducing mitochondrial dysfunction by anti-malarial drug artesunate is effective in targeting OTSCC stem-cell like and bulk cells. Artesunate inhibits anchorage-independent colony formation, proliferation and survival in all tested OTSCC cell lines although with varying efficacy. Artesunate displays preferential anti-OTSCC activity by sparing normal cells. Mechanism analysis indicates that artesunate inhibits mitochondrial respiration via suppressing mitochondrial complex I and II but not IV or V, resulting in oxidative stress and damage. Interestingly, OTSCC cells that are more sensitive to artesunate have higher level of basal mitochondrial respiration and reversed respiratory capacity compared to those with less sensitivity to artesunate, suggesting the varying dependence on mitochondrial respiration among OTSCC cell lines. In addition, artesunate induces oxidative stress and damage in cells with low sensitivity to a less extent than in those with high sensitivity. We confirm that mitochondrial respiration inhibition is required for the action of artesunate in OTSCC. Mitochondrial dysfunction by artesunate further activates AMPK and suppresses Akt/mTOR. Importantly, the in vitro observations are reproducible in vivo OTSCC xenograft mouse model. Our findings provide pre-clinical evidence on the efficacy of artesunate and emphasize the therapeutic value of targeting mitochondrial respiration in OTSCC.
    Keywords:  AMPK/mTOR; Artesunate; Complex II; Mitochondrial respiration; OTSCC
    DOI:  https://doi.org/10.1007/s10863-020-09823-x
  819. Cancer Discov. 2020 Jan 23. pii: CD-19-0608. [Epub ahead of print]
    Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing.
    Fan JB, Miyauchi S, Xu HZ, Liu D, Kim LJY, Burkart C, Cheng H, Arimoto KI, Yan M, Zhou Y, Gyorffy B, Knobeloch KP, Rich JN, Cang H, Fu XD, Zhang DE.
      Type I interferons (IFNs), which activate many IFN-stimulated genes (ISGs), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing anti-tumor effects. Here we report that the ISG, UBA7, is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins in a process known as "ISGylation". ISGylation of other ISGs, including STAT1 and STAT2, synergistically facilitates production of chemokine-receptor ligands to attract cytotoxic T cells. These gene activation events are further linked to clustering and nuclear relocalization of STAT1/2 within IFN-induced PML bodies. Importantly, this coordinated ISG-ISGylation network plays a central role in suppressing murine breast cancer growth and metastasis, which parallels improved survival in breast cancer patients. These findings reveal a cooperative IFN-inducible gene network in orchestrating a tumor suppressive microenvironment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-0608
  820. Cells. 2020 Jan 21. pii: E261. [Epub ahead of print]9(2):
    Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes.
    Mytych J, Sołek P, Będzińska A, Rusinek K, Warzybok A, Tabęcka-Łonczyńska A, Koziorowski M.
      Immunosenescence in monocytes has been shown to be associated with several biochemical and functional changes, including development of senescence-associated secretory phenotype (SASP), which may be inhibited by klotho protein. To date, it was believed that SASP activation is associated with accumulating DNA damage. However, some literature data suggest that endoplasmic reticulum and Golgi stress pathways may be involved in SASP development. Thus, the aim of this study was to investigate the role of klotho protein in the regulation of immunosenescence-associated Golgi apparatus and ER stress response induced by bacterial antigens in monocytes. We provide evidence that initiation of immunosenescent-like phenotype in monocytes is accompanied by activation of CREB34L and TFE3 Golgi stress response and ATF6 and IRE1 endoplasmic reticulum stress response, while klotho overexpression prevents these changes. Further, these changes are followed by upregulated secretion of proinflammatory cytokines, which final modification takes place exclusively in the Golgi apparatus. In conclusion, we provide for the first time evidence of klotho involvement in the crosstalk on the line ER-Golgi, which may, in turn, affect activation of SASP. This data may be useful for a novel potential target for therapy in age-related and chronic inflammatory conditions.
    Keywords:  ER stress response; Golgi apparatus/complex stress response; SASP; immunosenescence; klotho; monocytes
    DOI:  https://doi.org/10.3390/cells9020261
  821. AoB Plants. 2020 Feb;12(1): plz078
    Continuous variation in herkogamy enhances the reproductive response of Lonicera implexa to spatial variation in pollinator assemblages.
    Lázaro A, Seguí J, Santamaría L.
      Herkogamy, the spatial separation of sex organs in hermaphroditic plants, has been proposed as a mechanism to reduce self-pollination and the associated processes of inbreeding and gamete wastage. Longitudinal herkogamy is the most frequent type, with two subtypes: approach herkogamy (anthers below the stigma), which is associated with diverse pollinator arrays, and reverse herkogamy (anthers above the stigma), associated with specialized, long-tongued pollinators. By using a herkogamy index that varied continuously from negative (reverse herkogamy) to positive (approach herkogamy) values, we studied the effect of continuous variation in herkogamy on pollinator attraction, selfing capability and plant fitness across three populations of Lonicera implexa differing in the relative abundance of long-tongued vs. short-tongued pollinators. Reverse herkogamy was significantly more frequent in the population where long-tongued pollinators were dominant than in the other two populations. Agreeing with this, the main floral visitors of L. implexa individuals with small and large herkogamy index were, respectively, long-tongued and short-tongued pollinators. Spontaneous selfing was low and increased with increasing herkogamy index (i.e. with approach herkogamy), although most of it occurred when there was close distance between anthers and stigma. Fruit production was unrelated to the herkogamy index in the population with long-tongued pollinators, but it increased with approach herkogamy (higher herkogamy index) in the other two populations. In contrast, seeds of individuals with reverse herkogamy (smaller herkogamy indices) germinated better. In this species, continuous variation in herkogamy might function as a reproductive strategy, as different morphotypes might be favoured by different pollinator assemblages.
    Keywords:  Corolla length; Macroglossum stellatarum; fruit set; pollinator visitation; seed germination; seed set; seed weight; selfing capability; stigma-anthers distance
    DOI:  https://doi.org/10.1093/aobpla/plz078
  822. Front Psychol. 2019 ;10 2904
    Universal and Specific Predictors of Chinese Children With Dyslexia - Exploring the Cognitive Deficits and Subtypes.
    Song S, Zhang Y, Shu H, Su M, McBride C.
      While previous studies have shown that the impact of phonological awareness (PA) and rapid automatized naming (RAN) on dyslexia depends on orthographic complexity in alphabetic languages, it remains unclear whether this relationship generalizes to the more complex orthography of Chinese. We investigated the predictive power of PA, RAN, and morphological awareness (MA) in dyslexia diagnosis status in a sample of 241 typically developing and 223 dyslexic Chinese-speaking children. Compared with the control group, children with dyslexia performed notably worse on character reading and all three cognitive measures. A logistic regression analysis showed that PA and RAN were both significant predictors, while MA also played a relatively important role for predicting dyslexia status in Chinese children. In the next step, we used multigroup analyses to test if these three cognitive predictors were of the same importance in predicting reading variance in different reading proficiency groups. And the results showed that the regression coefficient of MP is stronger for the control group than the dyslexia group, while the regression coefficient of PD tends to be stronger for the dyslexic group. Further cluster analysis identified four subtypes of dyslexia in this sample: a global deficit group, a phonological deficit group, a RAN deficit group, and a mild morphological deficit group. Our findings are largely consistent with previous studies of predictors of dyslexia, while uniquely demonstrating the differences in predictive power of these three cognitive variables on reading, as well as the unique contribution of MA in Chinese reading.
    Keywords:  Chinese; dyslexia; morphology; phonology; subtypes
    DOI:  https://doi.org/10.3389/fpsyg.2019.02904
  823. Ambio. 2020 Jan 21.
    Correction to: Status and trends of circumpolar peregrine falcon and gyrfalcon populations.
    Franke A, Falk K, Hawkshaw K, Ambrose S, Anderson DL, Bente PJ, Booms T, Burnham KK, Carrière S, Ekenstedt J, Fufachev I, Ganusevich S, Johansen K, Johnson JA, Kharitonov S, Koskimies P, Kulikova O, Lindberg P, Lindström BO, Mattox WG, McIntyre CL, Mechnikova S, Mossop D, Møller S, Nielsen ÓK, Ollila T, Østlyngen A, Pokrovsky I, Poole K, Restani M, Robinson BW, Rosenfield R, Sokolov A, Sokolov V, Swem T, Vorkamp K.
      While collating contributions and comments from 36 researchers, the coordinating authors accidentally omitted Dr. Suzanne Carrière from the list of contributing co-authors. Dr. Carrière's data are described in Tables 1 and 3, Figure 2 and several places in the narrative.The new author list is thus updated in this article.
    DOI:  https://doi.org/10.1007/s13280-019-01314-7
  824. J Cell Mol Med. 2020 Jan 19.
    Treatment of hypoxia-dependent cardiovascular diseases by myo-inositol trispyrophosphate (ITPP)-enhancement of oxygen delivery by red blood cells.
    Oknińska M, El-Hafny-Rahbi B, Paterek A, Mackiewicz U, Crola-Da Silva C, Brodaczewska K, Mączewski M, Kieda C.
      Heart failure is a consequence of progression hypoxia-dependent tissue damages. Therapeutic approaches to restore and/or protect the healthy cardiac tissue have largely failed and remain a major challenge of regenerative medicine. The myo-inositol trispyrophosphate (ITPP) is a modifier of haemoglobin which enters the red blood cells and modifies the haemoglobin properties, allowing for easier and better delivery of oxygen by the blood. Here, we show that this treatment approach in an in vivo model of myocardial infarction (MI) results in an efficient protection from heart failure, and we demonstrate the recovery effect on post-MI left ventricular remodelling in the rat model. Cultured cardiomyocytes used to study the molecular mechanism of action of ITPP in vitro displayed the fast stimulation of HIF-1 upon hypoxic conditions. HIF-1 overexpression was prevented by ITPP when incorporated into red blood cells applied in a model of blood-perfused cardiomyocytes coupling the dynamic shear stress effect to the enhanced O2 supply by modification of haemoglobin ability to release O2 in hypoxia. ITPP treatment appears a breakthrough strategy for the efficient and safe treatment of hypoxia- or ischaemia-induced injury of cardiac tissue.
    Keywords:  cardiomyocytes; haemoglobin; hypoxia; myocardial infarction; oxygen delivery
    DOI:  https://doi.org/10.1111/jcmm.14909
  825. Lipids Health Dis. 2020 Jan 18. 19(1): 12
    Associations between age and dyslipidemia are differed by education level: The Cardiovascular and Metabolic Diseases Etiology Research Center (CMERC) cohort.
    Cho SMJ, Lee HJ, Shim JS, Song BM, Kim HC.
      BACKGROUND: Dyslipidemia is a multifactorial disorder, which arises from complex interactions among genetic and environmental risk factors. Previous studies have established the deteriorating effect of aging on lipid profiles. However, little is known about the role of education level, a stable marker of socioeconomic status, which reflect modifiability of lifestyle risk factors. Therefore, we examined the association between age and individual dyslipidemia parameter across education level among healthy, middle-aged Korean women.METHODS: From 2049 middle-aged women, education attainment was classified into completion of elementary school or below, middle school, high school, college or above. Dyslipidemia was assessed in adherence to the 2018 Korean Dyslipidemia Treatment Guideline. Multivariable logistic regression and generalized linear model tested for associations between age and dyslipidemia parameter across education level and other known risk factors, including menopause, obesity, and current drinking and smoking.
    RESULTS: In this cross-sectional analysis, the prevalence of each dyslipidemia parameter was significantly different by age and education level. The odds ratio (OR) for dyslipidemia was higher among participants who were older and had received higher education (OR = 2.31, p for interaction = 0.008) than younger and low education counterpart. The interaction between age and education level remained significant for hypercholesterolemia (p for interaction = 0.003) and hyper-LDL-cholesterolemia (p for interaction = 0.002).
    CONCLUSIONS: Separate examination of individual dyslipidemia parameter indicated varying degree of interaction with age and education level. Such results imply that each type of lipid abnormality may arise from and be exacerbated by heterogeneous composition of biological and lifestyle risk factors, which may be reflected by education level.
    Keywords:  Aging; Dyslipidemias; Education; Risk factors
    DOI:  https://doi.org/10.1186/s12944-020-1189-y
  826. Blood Adv. 2020 Jan 28. 4(2): 296-300
    Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia.
    McCalmont H, Li KL, Jones L, Toubia J, Bray SC, Casolari DA, Mayoh C, Samaraweera SE, Lewis ID, Prinjha RK, Smithers N, Wang S, Lock RB, D'Andrea RJ.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2019000586
  827. Nat Commun. 2020 Jan 24. 11(1): 515
    CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint.
    Yu M, Guo G, Huang L, Deng L, Chang CS, Achyut BR, Canning M, Xu N, Arbab AS, Bollag RJ, Rodriguez PC, Mellor AL, Shi H, Munn DH, Cui Y.
      CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73hi population in human colorectal cancers (CRCs) and two CD73- murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A2A and A2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A2B-mediated ADO-CAF-CD73 feedforward circuit and A2A-mediated immune suppression is crucial for improving therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s41467-019-14060-x
  828. Sci Rep. 2020 Jan 23. 10(1): 1051
    Mass spectrometry-based metabolomics approach in the isolation of bioactive natural products.
    Demarque DP, Dusi RG, de Sousa FDM, Grossi SM, Silvério MRS, Lopes NP, Espindola LS.
      Metabolomics is a powerful tool in the analysis and identification of metabolites responsible for biological properties. Regarding natural product chemistry, it constitutes a potential strategy to streamline the classic and laborious process of isolating natural products, which often involves the re-isolation and identification of known compounds. In this contribution, we establish a mass spectrometry-based metabolomics strategy to discover compounds with larvicidal activity against Aedes aegypti. We analyse the Brazilian plant Annona crassiflora using different platforms to annotate the active compounds in different extracts/fractions of various plant parts. The MetaboAnalyst and GNPS platforms, which consider LC-MS and LC-MS/MS data, respectively, were chosen to identify compounds that differentiate active and inactive samples. Bio-guided isolation was subsequently performed to confirm compound activity. Results proved the capacity of metabolomics to predict metabolite differences between active and inactive samples using LC-MS and LC-MS/MS data. Moreover, we discuss the limitations, possibilities, and strategies to have a broad view of vast data.
    DOI:  https://doi.org/10.1038/s41598-020-58046-y
  829. Pestic Biochem Physiol. 2020 Feb;pii: S0048-3575(19)30469-9. [Epub ahead of print]163 64-75
    Fenoxycarb and methoxyfenozide (RH-2485) affected development and chitin synthesis through disturbing glycometabolism in Lymantria dispar larvae.
    Zhang G, Zou H, Geng N, Ding N, Wang Y, Zhang J, Zou C.
      Fenoxycarb as a juvenile hormone analogue and methoxyfenozide (RH-2485) as a 20-hydroxyecdysone (20E) agonist are two main insect growth regulators (IGRs) used for pest control, whose insecticidal mechanisms had been widely reported in past decades. However, there were few studies focused on their effects on the carbohydrate metabolism of insects. Here, we reported that two IGRs (fenoxycarb and RH-2485) significantly affected growth and development of L. dispar larvae and caused larval lethality. Furthermore, both contens of three sugars (glycogen, threhalose, glucose) in four tissues (fat body, midgut, hemolymph and epidermis) and trehalase activity in three tissues (fat body, midgut and hemolymph) of L. dispar larvae were markedly affected by these two IGRs. Moreover, we found that mRNA expression levels of LdTPS, LdTre1 and LdTre2 in L. dispar larvae were dramatically suppressed by two IGRs. Additionally, chitin content in both midgut and epidermis decreased significantly after L. dispar larvae treated with fenoxycarb or RH-2485. Summarily, these results indicated that these two IGRs disturbed glycometabolism in L. dispar larvae, resulting in impeding chitin synthesis, generating new epidermis failure, disrupting molting and larval lethality in the end.
    Keywords:  Chitin synthesis; Fenoxycarb; Glycometabolism; Insect growth regulators (IGRs); Lymantria dispar; methoxyfenozide (RH-2485)
    DOI:  https://doi.org/10.1016/j.pestbp.2019.10.009
  830. Biochem Pharmacol. 2020 Jan 16. pii: S0006-2952(20)30023-X. [Epub ahead of print] 113813
    The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences.
    Nguyen PH, Sigdel KP, Schaefer GAK, Mensah KG, King GM, Roberts AG.
      P-glycoprotein (Pgp) is an ATP-dependent efflux transporter and plays a major role in anti-cancer drug resistance by pumping a chemically diverse range of cytotoxic drugs from cancerous tumors. Despite numerous studies with the transporter, the molecular features that drive anti-cancer drug efflux are not well understood. Even subtle differences in the anti-cancer drug molecular structure can lead to dramatic differences in their transport rates. To unmask these structural differences, this study focused on two closely-related anthracycline drugs, daunorubicin (DNR), and doxorubicin (DOX), with mouse Pgp. While only differing by a single hydroxyl functional group, DNR has a 4 to 5-fold higher transport rate than DOX. They both non-competitively inhibited Pgp-mediated ATP hydrolysis below basal levels. The Km of Pgp-mediated ATP hydrolysis extracted from the kinetics curves was lower for DOX than DNR. However, the dissociation constants (KDs) for these drugs determined by fluorescence quenching were virtually identical. Acrylamide quenching of Pgp tryptophan fluorescence to probe the tertiary structure of Pgp suggested that DNR shifts Pgp to a "closed" conformation, while DOX shifts Pgp to an "intermediate" conformation. The effects of these drugs on the Pgp conformational distributions in a lipid bilayer were also examined by atomic force microscopy (AFM). Analysis of AFM images revealed that DNR and DOX cause distinct and significant shifts in the conformational distribution of Pgp. The results were combined to build a conformational distribution model for anthracycline transport by Pgp.
    Keywords:  anti-cancer drug resistance; atomic force microscopy (AFM); multidrug resistance transporters; protein conformation
    DOI:  https://doi.org/10.1016/j.bcp.2020.113813
  831. J Assoc Physicians India. 2020 Jan;68(1): 49
    Correlation Study of Apolipoprotein'a' with Diabetic Retinopathy in Patients of Type 2 Diabetes Mellitus with Retinopathy.
    Singh PK, Tandon R.
      
  832. Chempluschem. 2018 May;83(5): 318
    Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.
    Kahremany S, Babaev I, Hasin P, Tamir TY, Ben-Zur T, Cohen G, Jiang Z, Weintraub S, Offen D, Rahimipour S, Major MB, Senderowitz H, Gruzman A.
      Invited for this month's cover is Prof. Arie Gruzman (Bar-Ilan University) and collaborators who have developed an Nrf2 enhancer. This compound activated the Nrf2 transduction pathway and because of this the translation of dozens of antioxidant cytoprotective proteins in a dose- and time-dependent manner and protected PC-12 cells against oxidative stress. Considering the imbalance between production and elimination of oxidative species involved in the pathophysiology of many human diseases, this compound is a promising starting point for the development of novel therapeutics for the treatment of oxidative-stress-related diseases. Read the full text of the article at 10.1002/cplu.201700539.
    DOI:  https://doi.org/10.1002/cplu.201800155
  833. J Dairy Sci. 2020 Jan 15. pii: S0022-0302(20)30024-2. [Epub ahead of print]
    Proteasome activity and expression of mammalian target of rapamycin signaling factors in skeletal muscle of dairy cows supplemented with conjugated linoleic acids during early lactation.
    Yang Y, Sadri H, Prehn C, Adamski J, Rehage J, Dänicke S, von Soosten D, Metges CC, Ghaffari MH, Sauerwein H.
      The mammalian target of rapamycin (mTOR) is a major regulator of protein synthesis via its main downstream effectors, ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein (4EBP1). The ubiquitin-proteasome system (UPS) is the main proteolytic pathway in muscle, and the muscle-specific ligases tripartite motif containing 63 (TRIM63; also called muscle-specific ring-finger protein 1, MuRF-1) and F-box only protein 32 (FBXO32; also called atrogin-1) are important components of the UPS. We investigated 20S proteasome activity and mRNA expression of key components of mTOR signaling and UPS in skeletal muscle of dairy cows during late gestation and early lactation and tested the effects of dietary supplementation (from d 1 in milk) with conjugated linoleic acids (sCLA; 100 g/d; n = 11) compared with control fat-supplemented cows (CTR; n = 10). Blood and muscle tissue (semitendinosus) samples were collected on d -21, 1, 21, and 70 relative to parturition. Dry matter intake increased with time of lactation in both groups. It was lower in sCLA than in CTR on d 21, which resulted in a reduced calculated metabolizable protein balance. Most serum and muscle concentrations of AA followed time-related changes but were unaffected by CLA supplementation. In both groups, serum and muscle 3-methylhistidine (3-MH) concentrations and the ratio of 3-MH:creatinine increased from d -21 to d 1, followed by a decline on d 21. The mRNA abundance of MTOR on d 21 and 70 was greater in sCLA than in CTR. The abundance of 4EBP1 mRNA did not differ between groups but was upregulated in both on d 1. The mRNA abundance of S6K1 on d 70 was greater in CTR than in sCLA, but remained unchanged over time in both groups. The mRNA abundance of FBXO32 (encoding atrogin-1) on d 21 was greater in sCLA than in CTR. The mRNA abundance of TRIM63 (also known as MuRF1) showed a similar pattern as FBXO32 in both groups: an increase from d -21 to d 1, followed by a decline. The mRNA for the α (BCKDHA) and β (BCKDHB) polypeptide of branched-chain α-keto acid dehydrogenase was elevated in sCLA and CTR cows on d 21, respectively, suggesting a role of CLA in determining the metabolic fate of branched-chain AA. For the mTOR protein, no group differences were observed. The abundance of S6K1 protein was greater across all time points in sCLA versus CTR. The antepartum 20S proteasome activity in muscle was elevated in both groups compared with postpartum, probably reflecting the start of protein mobilization before parturition. Plasma insulin concentrations decreased in both groups postpartum but to a greater extent in CTR than in sCLA, resulting in greater insulin concentrations in sCLA than in CTR. Thus, the greater abundance of MTOR mRNA and S6K1 protein in sCLA compared with CTR might be mediated by the greater plasma insulin postpartum. The upregulation of MTOR mRNA in sCLA cows on d 21, despite greater FBXO32 mRNA abundance, may reflect a simultaneous activation of both anabolic and catabolic signaling pathways, likely resulting in greater protein turnover.
    Keywords:  conjugated linoleic acid; dairy cow; mammalian target of rapamycin; muscle; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3168/jds.2019-17244
  834. Chem Biol Interact. 2020 Jan 21. pii: S0009-2797(19)31745-4. [Epub ahead of print] 108961
    Enolate-forming compounds provide protection from platinum neurotoxicity.
    Geohagen BC, Weiser DA, Loeb DM, Nordstroem LU, LoPachin RM.
      Cisplatin (CisPt) and other platinum (Pt)-based antineoplastic drugs (e.g., carboplatin, oxaliplatin) are highly effective and widely used in the treatment of solid tumors in both pediatric and adult patients. Although considered to be life-saving as a cancer treatment, Pt-based drugs frequently result in dose-limiting toxicities such as chemotherapy-induced peripheral neuropathies (CIPN). Specifically, irreversible damage to outer hair cells and injury of sensory neurons are linked to profound sensorineural hearing loss (ototoxicity), which complicates tumor management and can lead to a poor clinical prognosis. Given the severity of CIPN, substantial effort has been devoted to the development of neuroprotective compounds, regardless clinical results have been underwhelming. It is noteworthy that Pt is a highly reactive electrophile (electron deficient) that causes toxicity by forming adducts with nucleophilic (electron rich) targets on macromolecules. In this regard, we have discovered a series of carbon-based enol nucleophiles; e.g., N-(4-acetyl-3,5-dihydroxyphenyl)-2-oxocytclopentane-1-carboxamide (Gavinol), that can prevent neurotoxicity by scavenging the platinum ion. The chemistry of enol compounds is well understood and mechanistic research has demonstrated the role of this chemistry in cytoprotection. Our cell-derived data were corroborated by calculations of hard and soft, acids and bases (HSAB) parameters that describe the electronic character of interacting electrophiles and nucleophiles. Together, these observations indicate that the respective mechanisms of Pt neurotoxicity and antitumor activity are separable and can therefore be affected independently.
    Keywords:  Chemotherapy-induced peripheral neuropathies (CIPN); Enol neuroprotection; HSAB parameters; Platinum electrophile
    DOI:  https://doi.org/10.1016/j.cbi.2020.108961
  835. NPJ Biofilms Microbiomes. 2020 ;6 3
    Biofilm formation displays intrinsic offensive and defensive features of Bacillus cereus.
    Caro-Astorga J, Frenzel E, Perkins JR, Álvarez-Mena A, de Vicente A, Ranea JAG, Kuipers OP, Romero D.
      Biofilm formation is a strategy of many bacterial species to adapt to a variety of stresses and has become a part of infections, contaminations, or beneficial interactions. In this study, we demonstrate that profound physiological changes permit Bacillus cereus to switch from a floating to a sessile lifestyle, to undergo further maturation of the biofilm and to differentiate into the offensive or defensive features. We report that floating and biofilm cells are populations that differentiate metabolically, with members of each subpopulation developing different branches of certain metabolic pathways. Secondly, biofilm populations rearrange nucleotides, sugars, amino acids, and energy metabolism. Thirdly, this metabolic rearrangement coexists with: the synthesis of the extracellular matrix, sporulation, reinforcement of the cell wall, activation of the ROS detoxification machinery and production of secondary metabolites. This strategy contributes to defend biofilm cells from competitors. However, floating cells maintain a fermentative metabolic status that ensures a higher aggressiveness against hosts, evidenced by the production of toxins. The maintenance of the two distinct subpopulations is an effective strategy to face different environmental conditions found in the life styles of B. cereus.
    Keywords:  Biofilms; Next-generation sequencing
    DOI:  https://doi.org/10.1038/s41522-019-0112-7
  836. Diabetes Obes Metab. 2020 Jan 22.
    The relationship between hypoglycaemia, body mass index and quality of life among patients with type 1 diabetes: observations from the DEPICT clinical trial programme.
    Gordon J, Beresford-Hulme L, Bennett H, Tank A, Edmonds C, McEwan P.
      AIMS: This study aimed to demonstrate the relationships between hypoglycaemia, body mass index (BMI) and quality of life, and examine the impact of dapagliflozin on patient-reported treatment satisfaction in type 1 diabetes mellitus (T1DM) patients, using data from the DEPICT clinical trial programme.METHODS: A two-stage modelling approach, using a linear regression framework, was adopted to evaluate the relationship between hypoglycaemia, BMI and quality of life. Hypoglycaemia fear score (HFS) was modelled as a function of hypoglycaemic events (non-severe documented symptomatic and severe) and subsequently quality of life (as measured by EQ-5D) was modelled as a function of HFS and BMI. A linked evidence approach correlated the relationship between treatment, hypoglycaemic events and HbA1c, to the relationships captured within the regression models. The proportion of patients achieving increased patient-reported treatment satisfaction, as measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) total score, was compared between study arms.
    RESULTS: Incident severe hypoglycaemia was associated with significantly increased HFS (coefficient estimate (CE): 14.62, p=0.004). The frequency of symptomatic hypoglycaemic events was associated with significantly increase HFS (log transposed, CE: 1.32, p=0.026). Increased HFS and increased BMI were both independently associated with a significant reduction in EQ-5D (HFS: CE -0.0024, p<0.001; BMI: CE -0.0026, p=0.016). Significantly higher proportions of dapagliflozin-treated patients achieved ≥3-point increases in DTSQ total score compared to placebo.
    DISCUSSION: The results of this study demonstrate that increases in hypoglycaemia and BMI were associated with reduced quality of life in T1DM patients. Dapagliflozin treated patients achieved a reduction in HbA1c whilst avoiding an increase in hypoglycaemic events. The results also showed that treatment with dapagliflozin was associated with an improvement in treatment satisfaction. This article is protected by copyright. All rights reserved.
    Keywords:  Body Mass Index; Diabetes Mellitus, Type 1; Hypoglycaemia; Quality of Life; dapagliflozin; insulin
    DOI:  https://doi.org/10.1111/dom.13972
  837. Bioorg Med Chem Lett. 2020 Jan 07. pii: S0960-894X(20)30010-X. [Epub ahead of print] 126957
    Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors.
    He H, Hu X, Teng F, Liu Z, Zhang Q, Feng Z, Feng Q, Yu L.
      Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the "tail" region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.
    Keywords:  (E)-1,2-Diphenylethenem; EZH2; H3K27Me3; PRC2; SKLB1049
    DOI:  https://doi.org/10.1016/j.bmcl.2020.126957
  838. Int J Environ Res Public Health. 2020 Jan 16. pii: E594. [Epub ahead of print]17(2):
    Associations between Physical Activity and Comorbidities in People with COPD Residing in Spain: A Cross-Sectional Analysis.
    Sánchez Castillo S, Smith L, Díaz Suárez A, López Sánchez GF.
      There is a high prevalence of comorbidities among patients with chronic obstructive pulmonary disease (COPD). Comorbidities are likely common in patients with any COPD degree and are associated with increased mortality. The aim of this study was to determine the prevalence of thirty-one different COPD comorbidities and to evaluate the association between physical activity (PA) levels in people with COPD residing in Spain. Cross-sectional data from the Spanish National Health Survey 2017 were analysed. A total of 601 adults (52.2% females) with COPD aged 15 to 69 participated in this study. PA (exposure) was measured with the International Physical Activity Questionnaire (IPAQ) short form and comorbidities (outcomes) were self-reported in response to the question "Have you ever been diagnosed with…?" Multivariable logistic regression, in three different models, was used to assess this association. Results showed a high prevalence of comorbidities (94%), these being chronic lumbar back pain (38.9%), chronic allergy (34.8%), arthrosis (34.1%), chronic cervical back pain (33.3%), asthma (32.9%) and hypertension (32.8%) the most prevalent. Low PA level was significantly associated with urinary incontinence (2.115[1.213-3.689]), chronic constipation (1.970[1.119-3.459]), cataracts (1.840[1.074-3.153]), chronic anxiety (1.508[1.002-2.269]) and chronic lumbar back pain (1.489[1.044-2.125]). Therefore, people with COPD should increase their PA levels in order to reduce their risk of comorbidities and increase their quality of life.
    Keywords:  adults; lung disease; physical exercise; prevalence
    DOI:  https://doi.org/10.3390/ijerph17020594
  839. Eur J Sport Sci. 2020 Jan 20. 1-22
    A multilevel hypernetworks approach to capture properties of team synergies at higher complexity levels.
    Ribeiro J, Silva P, Davids K, Araújo D, Ramos J, Lopes R, Garganta J.
      Previous work has sought to explain team coordination using insights from theories of synergy formation in collective systems. Under this theoretical rationale, players are conceptualised as independent degrees of freedom, whose interactions can become coupled to produce team synergies, guided by shared affordances. Previous conceptualisation from this perspective has identified key properties of synergies, the measurement of which can reveal important aspects of team dynamics. However, some team properties have been measured through implementation of a variety of methods, while others have only been loosely addressed. Here, we show how multilevel hypernetworks comprise an innovative methodological framework that can successfully capture key properties of synergies, clarifying conceptual issues concerning team collective behaviours based on team synergy formation. Therefore, this study investigated whether different synergy properties could be operationally related utilising hypernetworks. Thus, we constructed a multilevel model composed of three levels of analysis. Level N captured changes in tactical configurations of teams during competitive performance. While Team A changed from an initial 1-4-3-3 to a 1-4-4-2 tactical configuration, Team B altered the dynamics of the midfielders. At Level N + 1, the 2vs.1 (1vs.2) and 1vs.1 were the most frequently emerging simplices, both behind and ahead of the ball line for both competing teams. Level N + 2 allowed us to identify the prominent players (a6, a8, a12, a13) and their interactions, within and between simplices, before a goal was scored. These findings showed that different synergy properties can be assessed through hypernetworks, which can provide a coherent theoretical understanding of competitive team performance.
    Keywords:  Association football; Dynamics; Multilevel hypernetworks; Performance analysis; Team collective behaviour; Team synergies
    DOI:  https://doi.org/10.1080/17461391.2020.1718214
  840. J Neurosci. 2020 Jan 20. pii: 1010-19. [Epub ahead of print]
    Age-dependent remarkable regenerative potential of the dentate gyrus provided by intrinsic stem cells.
    Licht T, Kreisel T, Biala Y, Mohan S, Yaari Y, Anisimov A, Alitalo K, Keshet E.
      Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.SIGNIFICANCE STATEMENTAdult hippocampal neurogenesis has been extensively studied in the context of its role in cognitive enhancement but whether, and to what extent can dentate gyrus (DG)-resident neural stem cells drive regeneration of an injured DG has remained unclear. Here we show that DG neurogenesis act to replace lost neurons and restore lost functions even following massive (>50%) neuronal loss. Age-related decline of neurogenesis is paralleled by a progressive decline of regenerative capacity. Considering also the exceptional vulnerability of the DG to insults, these findings provide a further rationale for maintaining DG neurogenesis in adult life.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1010-19.2019
  841. Curr Biol. 2020 Jan 16. pii: S0960-9822(19)31664-1. [Epub ahead of print]
    Binocular Encoding in the Damselfly Pre-motor Target Tracking System.
    Supple JA, Pinto-Benito D, Khoo C, Wardill TJ, Fabian ST, Liu M, Pusdekar S, Galeano D, Pan J, Jiang S, Wang Y, Liu L, Peng H, Olberg RM, Gonzalez-Bellido PT.
      Akin to all damselflies, Calopteryx (family Calopterygidae), commonly known as jewel wings or demoiselles, possess dichoptic (separated) eyes with overlapping visual fields of view. In contrast, many dragonfly species possess holoptic (dorsally fused) eyes with limited binocular overlap. We have here compared the neuronal correlates of target tracking between damselfly and dragonfly sister lineages and linked these changes in visual overlap to pre-motor neural adaptations. Although dragonflies attack prey dorsally, we show that demoiselles attack prey frontally. We identify demoiselle target-selective descending neurons (TSDNs) with matching frontal visual receptive fields, anatomically and functionally homologous to the dorsally positioned dragonfly TSDNs. By manipulating visual input using eyepatches and prisms, we show that moving target information at the pre-motor level depends on binocular summation in demoiselles. Consequently, demoiselles encode directional information in a binocularly fused frame of reference such that information of a target moving toward the midline in the left eye is fused with information of the target moving away from the midline in the right eye. This contrasts with dragonfly TSDNs, where receptive fields possess a sharp midline boundary, confining responses to a single visual hemifield in a sagittal frame of reference (i.e., relative to the midline). Our results indicate that, although TSDNs are conserved across Odonata, their neural inputs, and thus the upstream organization of the target tracking system, differ significantly and match divergence in eye design and predatory strategies. VIDEO ABSTRACT.
    Keywords:  TSDN; demoiselle; evolution; flight; invertebrate; jewel wing; predation; reference frame; summation; vision
    DOI:  https://doi.org/10.1016/j.cub.2019.12.031
  842. J Asthma. 2020 Jan 20. 1-19
    Cross-sectional phenotyping of small airway dysfunction in preschool asthma using the Impulse Oscillometry System.
    Bokov P, Bafunyembaka G, Medjahdi N, Bernard A, Essalhi M, Houdouin V, Peiffer C, Delclaux C.
      Objective. Asthma is a chronic inflammatory airway disorder known to induce small-airways dysfunction (SAD). It is important to develop tools to assess the presence and extent of SAD in daily clinical practice. An Impulse Oscillometry System (IOS) might detect SAD, but the validity of the underlying model (serial Resistive airway and Compliant tissue model: RC model) in diseased lungs remains questionable.Methods. Our objective was to evaluate the usefulness of parameters obtained from six electrical circuit models that were fitted to the measurements of impedance obtained with IOS in asthmatic children characterized by an abnormal lung function defined by an increased baseline interrupter resistance (Rint, z-score > +1.645).Results. The six models were tested in 102 asthmatic children (median age: 5.5 years). Two models allowed the description of 92/102 (90%) children: 74 by the extended RIC model (central and peripheral Resistance, Inertance and peripheral airway Compliance) and 18 by the Mead1969 model (extended RIC plus lung compliance). Thus, peripheral airway compliance and resistance were essential to describe lung function abnormalities of these asthmatic children. Parenchyma impairment (increased lung compliance) which was responsive to salbutamol was present in 18% of asthmatic children. After salbutamol, peripheral airway resistance decreased while peripheral airway compliance increased, arguing for asthma related SAD. R5-20Hz independently correlated with the two latter parameters but was increased in two thirds of children with increased Rint only.Conclusion. Additional modeling of IOS results can be a reliable tool to assess the presence and extent of SAD in young asthmatic children.
    Keywords:  Interrupter resistance; airway compliance; lung compliance; modeling; peripheral airway resistance
    DOI:  https://doi.org/10.1080/02770903.2020.1719133
  843. J Cancer Res Clin Oncol. 2020 Jan 20.
    TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma.
    Boscolo-Rizzo P, Giunco S, Rampazzo E, Brutti M, Spinato G, Menegaldo A, Stellin M, Mantovani M, Bandolin L, Rossi M, Del Mistro A, Tirelli G, Dei Tos AP, Guerriero A, Niero M, Da Mosto MC, Polesel J, De Rossi A.
      PURPOSE: To evaluate the prevalence of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of the gene encoding telomerase reverse transcriptase (TERT) as well as their relationship with TERT level, telomeres length, and outcome in patients with head and neck squamous cell carcinomas (HNSCCs).METHODS: We evaluate the prevalence of TERT promoter mutations, TERT levels, and telomere length in paired cancer tissue and adjacent mucosa (AM) in a series of HNSCCs.
    RESULTS: Cancer tissue and AM specimens from 105 patients were analyzed. Telomere length and TERT mRNA levels were estimated using real-time polymerase chain reaction. TERT promoter mutations were assessed using Sanger sequencing. Out of 105 cases, 101 were considered suitable for the analysis. TERT promoter harbored mutations in 12 tumors (11.9%), with -124 C>T and -146 C>T accounting for 83.3% and 16.7% of the alterations, respectively. No mutations were detected in AM samples. The prevalence of TERT promoter mutations was significantly higher in oral cavity SCCs (10 out of 27 tumors; 37%), and telomere length in AM was shorter in patients with tumors carrying TERT promoter mutations than in patients with unmutated TERT promoter cancers (p = 0.023). TERT levels in tumor did not significantly differ according to the mutational status of TERT promoter. No significant association was found between TERT promoter status and overall survival.
    CONCLUSION: TERT promoter mutations are most likely a late event in tumor development, occurring in a context of critically short telomeres, mostly in patients with oral cavity SCC. TERT levels, but not TERT promoter mutational status impact clinical outcome.
    Keywords:  Head and neck squamous cell carcinoma; Mutation; Promoter; Telomerase reverse transcriptase; Telomere
    DOI:  https://doi.org/10.1007/s00432-020-03130-z
  844. Immunol Lett. 2020 Jan 16. pii: S0165-2478(19)30159-2. [Epub ahead of print]
    Sensitivity and specificity of Interleukin 29 in patients with rheumatoid arthritis and other rheumatic diseases.
    da Rocha Junior LF, Angela Luzia Branco PD, de Melo Rêgo MJB, de Almeida AR, de Melo Vilar K, de Lima HD, Andréa Tavares D, de Ataíde Mariz H, da Rocha Pitta I, da Rocha Pitta MG.
      BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and progressive inflammation that can cause a high degree of disability in affected individuals. Proinflammatory cytokines play central roles in the development of degradative and inflammatory responses in RA. IL-29 has been identified in RA and reported as a biomarker of the disease.OBJECTIVE: To analyze serum levels and accuracy of IL-29 in RA patients compared to healthy subjects and patients with other rheumatic diseases.
    METHODS: IL-29 serum levels were measured in 121 patients with RA, 53 patients with systemic lupus erythematosus (SLE), 60 patients with systemic sclerosis (SSc), 29 patients with fibromyalgia (FM), 50 patients with osteoarthritis (OA) and 68 healthy individuals as controls. IL-29 levels in serum were investigated by ELISA. Sensitivity, specificity and likelihood ratios (LR) for having RA were calculated.
    RESULTS: Serum levels of IL-29 were increased in RA patients 113.6 (IQR = 31.25-308.5) pg/ml compared to non-RA patients (SLE, SSc, OA, and FM) (31.25 pg/ml) and healthy controls (31.25 pg/ml, p < 0.001). The IL-29 cut-off values to distinguish patients with RA from non-RA patients were 61.11 pg/ml (sensitivity 57.02, specificity 92.71, LR: 7.82) and for all subjects 32.96 pg/ml (sensitivity 64.46, specificity 87.31, LR: 5.08). Additionally, IL-29 correlated negatively with age (r=-0189, p = 0.038) and disease duration (-0.192, p = 0.037). Interestingly, IL-29 correlated positively with neutrophil count in RA patients positive for rheumatoid factor (r = 0.259, p = 0.022).
    CONCLUSION: IL-29 is higher in the serum of patients with RA compared to non-RA subjects and may have potential for use as a biological marker.
    Keywords:  accuracy; autoimmunity; diagnosis; interleukin; rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.imlet.2020.01.004
  845. Curr Opin Biotechnol. 2020 Jan 15. pii: S0958-1669(19)30146-6. [Epub ahead of print]63 111-117
    Metabolic regulation of epigenetic remodeling in immune cells.
    Britt EC, John SV, Locasale JW, Fan J.
      Immune cells are capable of sensing various signals in the microenvironment and turning on specific immune functions in response. The appropriate transition of immune cells into diverse functional states, which is crucial for immunity, involves complex and well-regulated changes in transcriptional program. Accumulating evidence shows that epigenetic remodeling plays a central role in mediating the transcriptional program for immune cell activation and immunological memory. Concurrently, immune cells undergo significant metabolic reprogramming during immune response. Here we review recent studies that demonstrate shifts in metabolic state can orchestrate immune cell functions through its impact on epigenetic remodeling, and the microenvironment can exert its influence on immune cells through the metabolic regulation of epigenetics. We also discuss the systems biology approaches that enabled these discoveries.
    DOI:  https://doi.org/10.1016/j.copbio.2019.12.008
  846. BMC Genomics. 2020 Jan 20. 21(1): 63
    Differential basal expression of immune genes confers Crassostrea gigas resistance to Pacific oyster mortality syndrome.
    de Lorgeril J, Petton B, Lucasson A, Perez V, Stenger PL, Dégremont L, Montagnani C, Escoubas JM, Haffner P, Allienne JF, Leroy M, Lagarde F, Vidal-Dupiol J, Gueguen Y, Mitta G.
      BACKGROUND: As a major threat to the oyster industry, Pacific Oyster Mortality Syndrome (POMS) is a polymicrobial disease affecting the main oyster species farmed across the world. POMS affects oyster juveniles and became panzootic this last decade, but POMS resistance in some oyster genotypes has emerged. While we know some genetic loci associated with resistance, the underlying mechanisms remained uncharacterized. So, we developed a comparative transcriptomic approach using basal gene expression profiles between different oyster biparental families with contrasted phenotypes when confronted to POMS (resistant or susceptible).RESULTS: We showed that POMS resistant oysters show differential expression of genes involved in stress responses, protein modifications, maintenance of DNA integrity and repair, and immune and antiviral pathways. We found similarities and clear differences among different molecular pathways in the different resistant families. These results suggest that the resistance process is polygenic and partially varies according to the oyster genotype.
    CONCLUSIONS: We found differences in basal expression levels of genes related to TLR-NFκB, JAK-STAT and STING-RLR pathways. These differences could explain the best antiviral response, as well as the robustness of resistant oysters when confronted to POMS. As some of these genes represent valuable candidates for selective breeding, we propose future studies should further examine their function.
    Keywords:  Antiviral molecular pathways; Invertebrate immunity; OsHV-1; Oyster disease; Pacific oyster; Resistance
    DOI:  https://doi.org/10.1186/s12864-020-6471-x
  847. iScience. 2020 Jan 24. pii: S2589-0042(19)30528-0. [Epub ahead of print]23(1): 100783
    OptFill: A Tool for Infeasible Cycle-Free Gapfilling of Stoichiometric Metabolic Models.
    Schroeder WL, Saha R.
      Stoichiometric metabolic modeling, particularly genome-scale models (GSMs), is now an indispensable tool for systems biology. The model reconstruction process typically involves collecting information from public databases; however, incomplete systems knowledge leaves gaps in any reconstruction. Current tools for addressing gaps use databases of biochemical functionalities to address gaps on a per-metabolite basis and can provide multiple solutions but cannot avoid thermodynamically infeasible cycles (TICs), invariably requiring lengthy manual curation. To address these limitations, this work introduces an optimization-based multi-step method named OptFill, which performs TIC-avoiding whole-model gapfilling. We applied OptFill to three fictional prokaryotic models of increasing sizes and to a published GSM of Escherichia coli, iJR904. This application resulted in holistic and infeasible cycle-free gapfilling solutions. In addition, OptFill can be adapted to automate inherent TICs identification in any GSM. Overall, OptFill can address critical issues in automated development of high-quality GSMs.
    Keywords:  Bioinformatics; Metabolic Engineering; Metabolic Flux Analysis; Systems Biology
    DOI:  https://doi.org/10.1016/j.isci.2019.100783
  848. ACS Chem Neurosci. 2020 Jan 21.
    Test-retest repeatability of [18F]MC225-PET in rodents: A tracer for imaging of P-gp function.
    García-Varela L, Vállez García D, Rodríguez-Pérez M, van Waarde A, Sijbesma JWA, Schildt A, Kwizera C, Aguiar P, Sobrino T, Dierckx RAJO, Elsinga PH, Luurtsema G.
      In longitudinal PET studies, animals are repeatedly anesthetized which may affect the repeatability of PET measurements. The aim of this study was to assess the effect of anesthesia on the P-gp function as well as the reproducibility of [18F]MC225 PET scans. Thus, dynamic PET scans with blood sampling were made in 13 Wistar rats. Seven animals were exposed to isoflurane anesthesia one week before the PET scan ("Anesthesia-exposed" PET). A second group of six animals was used to evaluate the reproducibility of measurements of P-gp function at the blood-brain barrier (BBB) with [18F]MC225. In this group, two PET scans were made with a 1-week interval ("Test" and "Retest" PET). Pharmacokinetic parameters were calculated using compartmental models and metabolite-corrected plasma as input function. "Anesthesia-exposed" animals showed a 28% decrease in whole-brain volume of distribution (VT) (p<0.001) compared to "Test", where the animals were not previously anesthetized. The VT at "Retest" also decreased (19%) compared to "Test" (p<0.001). The k2 values in whole-brain were significantly increased by 18% in "Anesthesia-exposed" (p=0.005) and by 15% in "Retest" (p=0.008) compared to Test. However, no significant differences were found in the influx rate constant K1, which is considered as the best parameter to measure the P-gp function. Moreover, Western Blot analysis did not find significant differences in the P-gp expression of animals no pre-exposed to anesthesia ("Test") or pre-exposed animals ("Retest"). To conclude, anesthesia may affect the brain distribution of [18F]MC225 but it does not affect the P-gp expression or function.
    DOI:  https://doi.org/10.1021/acschemneuro.9b00682
  849. J Vasc Surg. 2020 Jan 18. pii: S0741-5214(19)32782-X. [Epub ahead of print]
    Quantitative evaluation of postintervention foot blood supply in patients with peripheral artery disease by computed tomography perfusion.
    Gao P, Li Z, Jin L, Li L, Zhao W, Zhang W, Sun Y, Zhao Y, Cui J, Li M.
      OBJECTIVE: The aim of this study was to quantitatively evaluate the changes of the foot's blood supply after endovascular treatment in patients with peripheral artery disease (PAD) using foot computed tomography (CT) perfusion.METHODS: Nineteen patients who underwent endovascular treatment for PAD between January 2018 and November 2018 were included in the study. Perfusion CT scanning was performed before and after intervention with the measurement of ankle-brachial index. Regions of interest were selected from two arteries and four different tissues per foot. Perfusion maps of blood volume, blood flow, permeability surface area product, time to peak (TTP), mean transit time (MTT), mean slope of increase (MSI), Tmax, and impulse response function (IRFt0) were constructed and calculated by the perfusion analysis software. Wilcoxon signed rank test was performed on the eight parameter pairs of the limbs on the treated and untreated sides before and after intervention in the 19 patients.
    RESULTS: Differences in blood flow, MTT, TTP, Tmax, MSI, and IRFt0 on the treated side of the tissue perfusion group and statistical difference in blood flow, MTT, and MSI on the treated side of the arterial perfusion group were observed (all P < .05). Ankle-brachial index improved from 0.41 ± 0.11 to 0.76 ± 0.10 (P < .001). For the untreated side, TTP of the tissue perfusion group was significantly shortened (by 7.71 seconds) after surgery (P = .006), whereas there were no differences in the other parameters. In addition, no significant differences in parameters were observed on the untreated side of the arterial perfusion group. The average radiation dose per phase of perfusion scan was 0.00097 mSv. Moreover, the hyperperfusion zone in the plantar dermis and periosteum reappeared after revascularization.
    CONCLUSIONS: Perfusion CT is a feasible and repeatable approach for quantifying blood supply in patients with PAD. The increase of blood flow, MSI, and MTT shortening suggest blood supply improvement after revascularization in both arterial perfusion and tissue perfusion. In addition, TTP may be a sensitive indicator of blood supply changes in tissue perfusion.
    Keywords:  Blood supply; Perfusion; Peripheral artery disease; Quantitative assessment; Tomography; X-ray computed
    DOI:  https://doi.org/10.1016/j.jvs.2019.11.030
  850. Biochim Biophys Acta Mol Cell Res. 2020 Jan 21. pii: S0167-4889(20)30017-3. [Epub ahead of print] 118659
    GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer.
    Lin J, Song T, Li C, Mao W.
      Glycogen synthase kinase-3β (GSK-3β) is an evolutionarily conserved serine/threonine kinase, functioning in numerous cellular processes including cell proliferation, DNA repair, cell cycle, signaling and metabolic pathways. GSK-3β is implicated in different diseases including inflammation, neurodegenerative disease, diabetes and cancers. GSK-3β is involved in biological processes of tumorigenesis, therefore, it is rational that GSK-3β inhibitors were employed to target malignant tumors. The effects of GSK-3β inhibitors in combination of radiation and chemotherapeutic drugs have been reported in various types of cancers, suggesting GSK-3β would play important roles in cancer treatments. GSK-3β is involved in multiple signal pathway including Wnt/β-catenin, PI3K/PTEN/AKT and Notch. GSK-3β also functions in DNA repair through phosphorylation of DNA repair factors and affecting their binding to chromatin. This review focuses on the molecular mechanism of GSK-3β in DNA repair, special in base excision repair and double-strands break repair, the roles of GSK-3β in inhibition of apoptosis through activation of NF-κB, and the effects of GSK-3β inhibitors on radio- and chemosensitization of various types of cancers. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.
    Keywords:  Apoptosis; Chemoresistance; DNA repair; GSK-3β; Radioresistance
    DOI:  https://doi.org/10.1016/j.bbamcr.2020.118659
  851. J Drug Target. 2020 Jan 21. 1-46
    Biointerface: A nano-modulated way for biological transportation.
    Shende P, Wakade VS.
      The concept of biointerface emerges in the fields of biochemistry, genomics, cellular biology and life science. The integration of nanoparticles and biointerfaces creates the scope in different areas like biology, biochemistry, biotechnology and microbiology. The mode of action of nanoparticles through biointerface involves the formation of the protein corona, cellular contact, endocytosis and intracellular transport. The article highlights the complexation of host-guest and types of biointerfaces based on the principles of light, pH, redox reaction and competitive binding. Three major theories include Arrhenius theory, interfacial theory and electron theory. Apart from electron transfer, polymer complexation and kinetic drug release, the energy of activation play an important role in the formation of biointerface. The applications of nano-biointerface include cell patterning, gene delivery, blood-contacting device and cancer therapy. The review article focuses on the potential of biointerface in nano-based systems due to longer contact time, higher surface area, better drug loading efficiency and adhesion for increasing lift-off force, cell penetration, drug delivery of nanocarriers and on-targeting effect to the infected cells. Further, advancement in this field will increase the efficiency of gaseous systems like nanobubbles, nanodroplets, nanoshells, nanocages and nanopopcorn.
    Keywords:  Host-guest complex; blood-contacting device; cell signaling; molecular recognition; nano-based delivery; nanoparticles
    DOI:  https://doi.org/10.1080/1061186X.2020.1720218
  852. J Phys Chem Lett. 2020 Jan 24.
    The Ionization Energy of Liquid Water Revisited.
    Perry CF, Zhang P, Nunes FB, Jordan I, von Conta A, Wörner HJ.
      The ionization energy of liquid water is one of its most fundamental properties, an important benchmark for first-principles electronic-structure calculations and a crucial reference in the growing field of liquid-phase photoelectron spectroscopy. In spite of this significance, a consensus on its value appears to be missing in the literature. Therefore, we use a monochromatized high-harmonic light source to perform detailed measurements of the ionization energy of liquid water in the presence of a tunable bias voltage applied to the liquid jet. We show that this simple method is sufficient to simultaneously compensate the effects of the streaming potential and that of the vacuum-level offset between the liquid and the photoelectron spectrometer. Our measurements yield corrected values of the vertical and adiabatic ionization energies of the 1b$_1$ band of bulk liquid water of 11.67(15) eV and 10.19(9) eV, respectively. Our method is broadly applicable and is likely to result in corrections of the measured ionization energies of solvated species as well.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03391
  853. J Cyst Fibros. 2020 Jan 21. pii: S1569-1993(19)30996-8. [Epub ahead of print]
    Glycemic control and FEV1 recovery during pulmonary exacerbations in pediatric cystic fibrosis-related diabetes.
    Okoniewski W, Hughan KS, Weiner GA, Weiner DJ, Forno E.
      RATIONALE: Whether short-term glucose control in cystic fibrosis-related diabetes (CFRD) is associated with FEV1 recovery during acute pulmonary exacerbations is unclear.METHODS: Data from all patients with CFRD ages 6-21 years hospitalized in 2010-2016 for pulmonary exacerbations at our CF Center were analyzed, including CFRD status at each encounter, all FEV1 recorded during each exacerbation, and relevant clinical covariates. Glucose control was analyzed using meter blood glucose area under the curve (AUC) indices. The primary outcome was FEV1 recovery.
    RESULTS: Patients with CFRD who finished IV antibiotics at home were treated for longer than those fully treated in the hospital (22.2 vs. 13.8 days). In those who finished treatment at home, poor inpatient glycemic control was associated with lower lung function improvement: when comparing the 75th to the 25th percentile of each glycemic index (i.e., "poorer" vs. "better" glycemic control), FEV1 recovery at discharge was 20.1% lower for glucose AUC (95%CI -0.4%, -39.9%); 20.9% lower for 48-h AUC (95%CI -2.7%, -39.1%); and 28.2% lower for AUC/day (95%CI -7.1%, -49.3%). Similar results were found at the end of IV antibiotics and at clinic follow-up. Likewise, patients with poor glycemic control had a lower slope of inpatient FEV1 recovery. Analysis in patients with normal glucose tolerance was largely non-significant. No associations were found between hemoglobin A1c and FEV1 recovery.
    CONCLUSIONS: In patients with CFRD who complete IV antibiotic treatment at home, poor inpatient glycemic control is associated with worse FEV1 recovery despite longer duration of treatment.
    Keywords:  Cystic fibrosis; Cystic fibrosis-related diabetes; Glycemic control; Lung function
    DOI:  https://doi.org/10.1016/j.jcf.2019.12.016
  854. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30092-1. [Epub ahead of print]49(1): 95-107
    HbA1c: The Glucose Management Indicator, Time in Range, and Standardization of Continuous Glucose Monitoring Reports in Clinical Practice.
    Carlson AL, Criego AB, Martens TW, Bergenstal RM.
      Continuous glucose monitoring (CGM) use is growing rapidly among people with diabetes and beginning to be standard of care for managing glucose levels in insulin therapy. With this increased use, there is a need to standardize CGM data. CGM standardization has been set forth by expert panels. The Glucose Management Indicator is a concept using the CGM-derived mean glucose to provide a value that can be understood similarly to hemoglobin A1c. The times an individual spends in various glucose ranges is emerging as an important set of metrics. Metrics derived from patient CGM data are changing the way diabetes is managed.
    Keywords:  Ambulatory glucose profile; Continuous glucose monitoring; Glucose management indicator; Time in range
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.010
  855. Int J Pharm. 2020 Jan 21. pii: S0378-5173(20)30030-2. [Epub ahead of print] 119048
    Drug-loaded implantable surgical cavity-adaptive hydrogels for prevention of local tumor recurrence.
    Zhuang B, Chen T, Xiao Z, Jin Y.
      High local post-surgical cancer recurrence severely impairs the patients' prognosis and survival rates. Here, an injectable in situ forming hydrogel was designed to locally controlled release gemcitabine (GEM) and doxorubicin (DOX) to prevent local cancer recurrence. The hydrogel was rapidly formed at the post-surgical cavity after the aldehyde hyaluronic acid (HA-CHO) and the carboxymethyl chitosan (CM-CS) were mixed and immediately injected. Meanwhile, DOX was conjugated to HA-CHO and GEM was doped in CM-CS to obtain GD-HA/CS-Gel. The drug-free hydrogels showed low cytotoxicity on L929 cells and good in vivo biocompatibility. The hydrogels had appropriate viscoelasticity and rapid self-healing ability, favoring long-term local residence at the injected site where GEM quickly released and DOX slowly released. GEM and DOX showed the synergistic anticancer effect on 4T1 cells. Breast cancer 4T1-cell xenograft models were established and the tumors were surgically resected. GD-HA/CS-Gel was implanted in the post-surgical cavity and cancer recurrence and distant lung metastasis were completely prevented in comparison with the single drug-loaded hydrogel or drug solutions. The locally implanted dual drug-loaded cavity-adaptive hydrogel is a promising medication for prevention of post-surgical tumor recurrence.
    Keywords:  controlled release; hydrogel; post-surgical; recurrence; synergistic effect
    DOI:  https://doi.org/10.1016/j.ijpharm.2020.119048
  856. J Clin Med. 2020 Jan 21. pii: E289. [Epub ahead of print]9(2):
    Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia.
    Borgatti M, Altamura E, Salvatori F, D'Aversa E, Altamura N.
      Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary.
    Keywords:  nonsense mediated mRNA decay; nonsense suppression; premature termination codon; readthrough molecules; β0-thalassemia
    DOI:  https://doi.org/10.3390/jcm9020289
  857. J Phys Condens Matter. 2020 Jan 24.
    Ab Initio molecular dynamics and high dimensional neural network potential study of VZrNbHfTa melt.
    Balyakin I, Yuryev A, Gelchinski B, Rempel A.
      The structural and dynamics properties of melts are directly related to their solidification processes, and consequently to the properties of as-cast solid alloys. Ab initio molecular dynamics is a powerful tool that can study both of these factors. However, the main disadvantage of this method is its low performance which is critical for simulation of the multicomponent liquids. In the same time the atomistic simulation of multicomponent liquids has found its application for prediction of the formation of high-entropy alloys - novel class of materials with enhanced mechanical properties. An effective method to solve the problem of ab initio molecular dynamics low performance may be the design of pair or many-body potentials for classical molecular dynamics. One of promising approaches is high-dimensional neural network - the method of constructing many-body potentials for classical molecular dynamics from ab initio data. Thus at this work high-dimensional neural network potential for multicomponent liquid VZrNbHfTa melt was constructed. It was shown that structure and dynamics are reproduced well by high-dimensional neural network potential. Some differences between high dimensional neural network potential- and ab initio molecular dynamics-obtained structure and dynamics are explained by finite-size effect and lack of statistics in ab initio molecular dynamics simulation along with inherent errors in energy and force estimations made by high dimensional neural network potentials. Analysis of melt structure via partial radial distribution functions and chemical short range order parameters led to the conclusion that the system VZrNbHfTa can't form single-phase disordered solid solution during solidification due to repulsion of vanadium by other components. Diffusivity in multicomponent melt was found to decrease with increasing of mass and size of an atom.
    Keywords:  ab initio molecular dynamics; classical molecular dynamics; diffusivity; high dimensional neural network potential; high entropy alloy; pair distribution function
    DOI:  https://doi.org/10.1088/1361-648X/ab6f87
  858. Exp Brain Res. 2020 Jan 20.
    Associations between catechol-O-methyltransferase (COMT) genotypes at rs4818 and rs4680 and gene expression in human dorsolateral prefrontal cortex.
    Dean B, Parkin GM, Gibbons AS.
      Having reported associations between catechol-O-methyltransferase (COMT) genotypes at SNPs rs4818 and rs4680 with levels of soluble COMT (S-COMT) in human dorsolateral prefrontal cortex (DLPFC), we postulated that changes in the levels of cortical S-COMT could impact on behavioural abilities associated with COMT genotype through S-COMT-mediated changes in gene expression. To test this hypothesis, we have examined the relationships between COMT genotypes and gene expression measured using the Affymetrix™ Human Exon 1.0 ST Array in the DLPFC from 141 individuals, some of whom had had a psychiatric disorder. There were significant differences in levels of expression of 15 genes between individuals with a homozygous genotype at rs4818 (GG vs CC), compared to differences in levels of expression of 6 genes between homozygotes at rs4680 (GG vs AA); levels of expression of CEP128, EFCAB13, and FAM133A differed between homozygotes at both SNPs. Fourteen of the genes differentially expressed in the DLPFC according to COMT genotypes have oestrogen receptor elements and their expression could, therefore, be regulated by catecholestrogens, which are substrates for COMT that occupy and activate oestrogen receptors. In addition, the changes in gene expression between the homozygotes at rs4818 or rs4680 would be expected to impact on neuronal function, synaptic plasticity, cognition, and attention. These data would support a hypothesis that the mechanism underlying the association between COMT genotype and cognition involves differential changes in cortical gene expression.
    Keywords:  Catechol-O-methyltransferase; Dorsolateral prefrontal cortex; Gene expression; Human postmortem CNS
    DOI:  https://doi.org/10.1007/s00221-020-05730-0
  859. Nitric Oxide. 2020 Jan 16. pii: S1089-8603(19)30339-8. [Epub ahead of print]96 35-43
    Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases.
    Liu Y, Croft KD, Hodgson JM, Mori T, Ward NC.
      Within the body, NO is produced by nitric oxide synthases via converting l-arginine to citrulline. Additionally, NO is also produced via the NOS-independent nitrate-nitrite-NO pathway. Unlike the classical pathway, the nitrate-nitrite-NO pathway is oxygen independent and viewed as a back-up function to ensure NO generation during ischaemia/hypoxia. Dietary nitrate and nitrite have emerged as substrates for endogenous NO generation and other bioactive nitrogen oxides with promising protective effects on cardiovascular and metabolic function. In brief, inorganic nitrate and nitrite can decrease blood pressure, protect against ischaemia-reperfusion injury, enhance endothelial function, inhibit platelet aggregation, modulate mitochondrial function and improve features of the metabolic syndrome. However, many questions regarding the specific mechanisms of these protective effects on cardiovascular and metabolic diseases remain unclear. In this review, we focus on nitrate/nitrite bioactivation, as well as the potential mechanisms for nitrate/nitrite-mediated effects on cardiovascular and metabolic diseases. Understanding how dietary nitrate and nitrite induce beneficial effect on cardiovascular and metabolic diseases could open up novel therapeutic opportunities in clinical practice.
    Keywords:  Cardiovascular disease; Metabolic disease; Nitrate; Nitric oxide; Nitrite
    DOI:  https://doi.org/10.1016/j.niox.2020.01.006
  860. Cell. 2020 Jan 23. pii: S0092-8674(19)31397-2. [Epub ahead of print]180(2): 296-310.e18
    Cysteine Toxicity Drives Age-Related Mitochondrial Decline by Altering Iron Homeostasis.
    Hughes CE, Coody TK, Jeong MY, Berg JA, Winge DR, Hughes AL.
      Mitochondria and lysosomes are functionally linked, and their interdependent decline is a hallmark of aging and disease. Despite the long-standing connection between these organelles, the function(s) of lysosomes required to sustain mitochondrial health remains unclear. Here, working in yeast, we show that the lysosome-like vacuole maintains mitochondrial respiration by spatially compartmentalizing amino acids. Defects in vacuole function result in a breakdown in intracellular amino acid homeostasis, which drives age-related mitochondrial decline. Among amino acids, we find that cysteine is most toxic for mitochondria and show that elevated non-vacuolar cysteine impairs mitochondrial respiration by limiting intracellular iron availability through an oxidant-based mechanism. Cysteine depletion or iron supplementation restores mitochondrial health in vacuole-impaired cells and prevents mitochondrial decline during aging. These results demonstrate that cysteine toxicity is a major driver of age-related mitochondrial deterioration and identify vacuolar amino acid compartmentation as a cellular strategy to minimize amino acid toxicity.
    Keywords:  V-ATPase; aging; amino acid; cysteine; iron; lysosome; mitochondria; vacuole; yeast
    DOI:  https://doi.org/10.1016/j.cell.2019.12.035
  861. AMB Express. 2020 Jan 18. 10(1): 11
    Enhancement of pullulanase production from recombinant Bacillus subtilis by optimization of feeding strategy and fermentation conditions.
    Zhang Y, Nie Y, Zhou X, Bi J, Xu Y.
      Pullulanase is an important starch-debranching enzyme mostly used in starch processing-related food industries. However, the levels of pullulanase produced from recombinant Bacillus subtilis, a Generally Recognized as Safe (GRAS) host, are generally limited. To enhance the activity of pullulanase, batch fermentation and fed-batch fermentation were systematically investigated. The overall purpose is to improve the fermentation yield by optimizing the feeding strategy in the fermentation process, thereby increasing the enzyme activity of pullulanase. Therefore, in this study, the feeding methods, the feeding ingredients, the feeding concentration, and pH values were studied in detail. The optimized fermentation conditions for pullulanase production from recombinant B. subtilis were determined as following: inoculum volume 7%, pH 6.5, the dissolved oxygen level 30%, and constant-rate feeding of 100 mL glucose solution (400 g L-1) in late logarithmic growth. The OD600 of recombinant B. subtilis and enzyme activity were 84.54 and 102.75 U mL-1, which were respectively 141% and 144% higher than that before optimization. These findings provided a prerequisite for further amplification of the fermentation system to obtain higher enzyme activity.
    Keywords:  Bacillus subtilis; Feeding strategy; Fermentation process; Optimization; Pullulanase
    DOI:  https://doi.org/10.1186/s13568-020-0948-5
  862. Phys Rev E. 2019 Dec;100(6-1): 063302
    Model reduction of rigid-body molecular dynamics via generalized multipole potentials.
    Patrone PN, Dienstfrey A, McFadden GB.
      Motivated by the challenges of uncertainty quantification for coarse-grained (CG) molecular dynamics, we investigate the role of perturbation theory in model reduction of classical systems. In particular, we consider the task of coarse-graining rigid bodies in the context of generalized multipole potentials that have controllable levels of accuracy relative to their atomistic counterparts. We show how the multipole framework yields a hierarchy of models that systematically connects a CG "point molecule" approximation to the exact dynamics. We use these results to understand when and how the CG models fail to describe atomistic dynamics at the trajectory level and develop asymptotic error estimates for approximate molecular potential energies. Implications for other model-reduction strategies are also discussed. Key findings of this work are that (i) omitting rotational energy introduces significant error when coarse-graining and (ii) attention to symmetry can improve accuracy of "point-molecule" approximations. Analytical derivations and numerical results support these conclusions. Relevance to nonrigid bodies is also discussed.
    DOI:  https://doi.org/10.1103/PhysRevE.100.063302
  863. Molecules. 2020 Jan 23. pii: E503. [Epub ahead of print]25(3):
    White Matter and Neuroprotection in Alzheimer's Dementia.
    Lorenzini L, Fernandez M, Baldassarro VA, Bighinati A, Giuliani A, Calzà L, Giardino L.
      Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer's dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.
    Keywords:  amyloid; drug screening; oligodendrocyte precursor cells; oxygen-glucose deprivation
    DOI:  https://doi.org/10.3390/molecules25030503
  864. Clin Nucl Med. 2020 Jan 17.
    Re: A Prospective Head-to-Head Comparison of 18F-Fluciclovine With 68Ga-PSMA-11 in Biochemical Recurrence of Prostate Cancer in PET/CT.
    Evangelista L, Sepulcri M.
      
    DOI:  https://doi.org/10.1097/RLU.0000000000002907
  865. J Cell Physiol. 2020 Jan 24.
    Sclerostin antibody treatment rescues the osteopenic bone phenotype of TGFβ inducible early gene-1 knockout female mice.
    Gingery A, Subramaniam M, Pitel KS, Li X, Ke HZ, Turner RT, Iwaniec UT, Hawse JR.
      Deletion of TGFβ inducible early gene-1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl-Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl-Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl-Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl-Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl-Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX-1 serum levels were unaffected by Scl-Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl-Ab therapy elicits potent bone-forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.
    Keywords:  Krüppel-like transcription factor 10 (KLF10); TGFβ inducible early gene-1 (TIEG); bone; osteoporosis; sclerostin
    DOI:  https://doi.org/10.1002/jcp.29500
  866. iScience. 2020 Jan 02. pii: S2589-0042(19)30562-0. [Epub ahead of print]23(1): 100816
    Toward an MRI-Based Mesoscale Connectome of the Squid Brain.
    Chung WS, Kurniawan ND, Marshall NJ.
      Using high-resolution diffusion magnetic resonance imaging (dMRI) and a suite of old and new staining techniques, the beginnings of a multi-scale connectome map of the squid brain is erected. The first of its kind for a cephalopod, this includes the confirmation of 281 known connections with the addition of 145 previously undescribed pathways. These and other features suggest a suite of functional attributes, including (1) retinotopic organization through the optic lobes and into other brain areas well beyond that previously recognized, (2) a level of complexity and sub-division in the basal lobe supporting ideas of convergence with the vertebrate basal ganglia, and (3) differential lobe-dependent growth rates that mirror complexity and transitions in ontogeny.
    Keywords:  Biological Sciences; Neuroscience; Systems Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2019.100816
  867. Am J Emerg Med. 2020 Jan 07. pii: S0735-6757(20)30006-1. [Epub ahead of print]
    Fluid resuscitation following rib fractures.
    Cakmak F.
      
    DOI:  https://doi.org/10.1016/j.ajem.2020.01.006
  868. J Assoc Physicians India. 2020 Jan;68(1): 87
    Comparison of Capillary Blood Glucose Versus Arterial Blood Glucose in Diabetic Patients Admitted in ICU on Vasopressor Support.
    Gupta K, Cs K, Patil P.
      
  869. Hepatology. 2020 Jan 21.
    Bespoken nanoceria: A new effective treatment in experimental hepatocellular carcinoma.
    Fernández-Varo G, Perramón M, Carvajal S, Oró D, Casals E, Boix L, Oller L, Macías-Muñoz L, Marfà S, Casals G, Morales-Ruiz M, Casado P, Cutillas PR, Bruix J, Navasa M, Fuster J, Garcia-Valdecasas JC, Pavel MC, Puntes V, Jiménez W.
      BACKGROUND & AIMS: Despite the availability of new generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeO2 NPs) have emerged as a novel antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2 NPs as therapeutic agent in HCC.APPROACH & RESULTS: HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2 NPs at the week 16 and 17. At the 18th week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2 NPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2 NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2 NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2 NPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeO2 NPs reduced serum alpha-protein levels and improved the survival of HCC-rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated.
    CONCLUSIONS: These data indicate that CeO2 NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC-rats, suggesting that they could be effective in patients with HCC.
    Keywords:  antioxidants; cerium oxide nanoparticles; diethylnitrosamine; hepatic phosphoproteome; tyrosine kinases inhibitors
    DOI:  https://doi.org/10.1002/hep.31139
  870. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19890. [Epub ahead of print]24(1): 11-17
    MiR-7a ameliorates spinal cord injury by inhibiting neuronal apoptosis and oxidative stress.
    Ding LZ, Xu J, Yuan C, Teng X, Wu QM.
      OBJECTIVE: The aim of this study was to investigate the therapeutic effect of microRNA-7a (miR-7a) on spinal cord injured rats and to explore its underlying mechanism in vivo.MATERIALS AND METHODS: The spinal cord injury (SCI) model was first established in adult rats. The epicenter of the lesion was treated with miR-7a mimics via intrathecal injection. The Basso-Beattie-Bresnahan (BBB) locomotor rating scale was used to evaluate the functional recovery of hindlimbs in rats within 4 weeks following SCI. Western blotting and qPCR were utilized to detect the apoptosis and oxidative stress in rats treated with or without miR-7a. In addition, the neuron survival and neuro-filament amount were determined using immunofluorescence.
    RESULTS: After SCI and miR-7a treatment, the locomotor recovery of treated rats was significantly improved when compared with rats without treatment. The mitochondrial disorder and cell death were significantly reduced in miR-7a treated rats. Meanwhile, the nuclear transcription factor-κB (NF-κB) pathway was significantly reduced as well. Contrarily, the expression of anti-apoptotic protein Bcl-2 and NF-κB inhibitor I-κB was remarkably elevated in miR-7a treated rats. In addition, up-regulation of miR-7a rescued neurons and maintained the neural structure.
    CONCLUSIONS: The up-regulation of miR-7a alleviated the injury-induced oxidative stress and inhibited apoptosis by down-regulating NF-κB pathway in SCI rats.
    DOI:  https://doi.org/10.26355/eurrev_202001_19890
  871. Spine Deform. 2018 May;6(3): 220-225
    The Use of Arm Span as a Substitute for Height in Calculating Body Mass Index (BMI) for Spine Deformity Patients.
    Opoku H, Yirerong T, Osei-Onwona B, Boachie-Adjei O, .
      OBJECTIVE: To compare arm span and height in body mass index (BMI) calculation in patients with spinal curvature and investigate their impact on interpretation of BMI.STUDY DESIGN: Prospective case-control cohorts. The BMI value is based on weight to height ratio. Spine deformity patients experience height loss and its use in calculating BMI is likely to produce errors. A surrogate for height should therefore be sought in BMI determination.
    METHODS: Ninety-three spine deformity patients were matched with 64 normal children. Anthropometric values (height, arm span, and weight) and spinal curve were obtained. BMIs using arm span and height were calculated, and statistical analysis performed to assess the relationship between BMI/height and BMI/arm span in both groups as well as the relationship between these values and Arm Span to Height difference (Delta AH).
    RESULTS: There were 46 males and 47 females, the average age was 15.5 years in Group 1 versus 33 males and 31 females, average age 14.8 years in Group 2. Major scoliosis in Group 1 averaged 125.7° (21° to 252°). The extreme curves show vertebral transposition, with overlapping segments making it more than 180°. A logistic regression showed that there was linearity in BMI scores (R2 = 0.97) for both arm span and height (R2 = 0.94) in group 2 patients. For group 1 patients there was a significant difference in the BMI values when comparing BMI/arm span versus BMI/height (p < .0001). Mean BMI values using height was overstated by 2.8 (18.6%). The threshold at which BMI score must be calculated using arm span as opposed to the height (Delta AH) was determined to be 3 cm.
    CONCLUSIONS: Spine deformity patients experience height loss, which can impact their true BMI values thereby giving an erroneous impression of their nutritional status. The arm span should be used in patients with Delta AH >3 cm to properly assess nutritional status.
    Keywords:  Arm span; BMI; Height; Nutrition assessment; Spine deformity
    DOI:  https://doi.org/10.1016/j.jspd.2017.09.052
  872. J Cell Physiol. 2020 Jan 20.
    miR-885 mediated cardioprotection against hypoxia/reoxygenation-induced apoptosis in human cardiomyocytes via inhibition of PTEN and BCL2L11 and modulation of AKT/mTOR signaling.
    Meng X, Mei L, Zhao C, Chen W, Zhang N.
      Ischemia/reperfusion (I/R) injury could cause the enhanced cell apoptosis of cardiomyocytes, which is one of key contributors for the development of ischemic heart disease. Recent studies emphasized the role of microRNAs (miRNAs) in regulating cardiomyocyte apoptosis. The study planned to elucidate the molecular actions of miR-885 on mediating human cardiomyocytes (HCMs) apoptosis induced by hypoxia/reoxygenation (H/R) and to explore the potential molecular mechanisms. The present data revealed that H/R stimulation inhibited HCM viability and potentiated HCM apoptosis, and more importantly, the expression of miR-885 in HCMs was markedly repressed after H/R stimulation. Further experimental examinations demonstrated that overexpression of miR-885 attenuated H/R-induced increased in HCM apoptotic rates, while miR-885 knockdown impaired HCM viability and increased HCM apoptotic rates. Moreover, the mechanistic studies showed that miR-885 inversely regulated the expression of phosphatase and tensin homolog (PTEN) and BCL2 like 11 (BCL2L11) in HCMs, and enforced expression of PTEN and BCL2L11 partially antagonized the protective actions of miR-885 overexpression on H/R-induced HCM injury. Moreover, H/R suppressed AKT/mTOR signaling, which was attenuated by miR-885 overexpression in HCMs. In conclusion, the present study for the first time showed the downregulation of miR-885 induced by H/R in HCMs, and provided the evidence that miR-885 attenuated H/R-induced cell apoptosis via inhibiting PTEN and BLC2L11 and modulation of AKT/mTOR signaling in HCMs.
    Keywords:  BCL2L11; PTEN; apoptosis; human cardiomyocytes; hypoxia/reoxygenation; miR-885
    DOI:  https://doi.org/10.1002/jcp.29460
  873. Mar Pollut Bull. 2020 Jan 20. pii: S0025-326X(20)30015-1. [Epub ahead of print]152 110897
    Is Laguncularia racemosa more invasive than Sonneratia apetala in northern Fujian, China in terms of leaf energetic cost?
    Li FL, Zhong L, Cheung SG, Wong YS, Shin PKS, Lei AP, Zhou HC, Song X, Tam NFY.
      Laguncularia racemosa and Sonneratia apetala are fast-growing exotic mangrove species in Southern China and widely used for afforestation. However, the invasiveness of the two exotic species is still unclear. We compared structural and physiological traits and energy-use related traits between L. racemosa and S. apetala, and with two natives (Kandelia obovata and Aegiceras corniculatum) in northern Fujian. Results showed that leaf construction cost based on mass (CCM) and caloric values of L. racemosa were significantly lower than S. apetala, and the two natives had highest CCM. Because lower CCM, L. racemosa grew faster with a taller height (4.83 m) and wider ground diameter circumference (40.03 cm) than S. apetala (4.43 m tall and 35.63 cm wide) and the two natives (2.42 m tall and 26.78 cm wide). These findings indicated that L. racemosa could be more invasive than S. apetala in mangrove forests in northern Fujian, China where it still grew well, which deserves more attention.
    Keywords:  Construction cost (CC); Invasiveness; Laguncularia racemosa; Mangroves; Sonneratia apetala
    DOI:  https://doi.org/10.1016/j.marpolbul.2020.110897
  874. J Phys Chem Lett. 2020 Jan 20.
    Hot Electron Cooling in Silicon Nanoclusters via Landau-Zener Non-Adiabatic Molecular Dynamics: Size Dependence and Role of Surface Termination.
    Smith B, Akimov AV.
      We develop a new express-methodology for modeling excited states dynamics occurring in dense manifolds of electronic states in atomistic systems. The approach leverages a modified Landau-Zener formula, the neglect of back-reaction approximation, and the highly efficient density functional tight-binding method. We study the hot electron dynamics in a series of H- and F-terminated silicon nanocrystals (NCs) containing up to several hundreds of atoms. We explain the slower electron cooling dynamics in F-terminated NCs by the larger energy gaps between the adjacent electronic states in these systems, as well as their slower fluctuations. We conclude that both the mass and chemical identity of the surface termination groups equally influence the electron dynamics, on average. However, the mass effect becomes dominant for higher-energy excitations. We find that the electron decay dynamics in F-terminated NCs has a greater sensitivity to the mass of the surface ligands than do the H-terminated NCs, and explain this observation by the details of the electron-phonon coupling in the systems. We find that in the H-terminated NCs, electronic transitions in the cooling process occur predominantly between the surface states, whereas in F-terminated Si NCs, both surface and NC core states are coupled to the nuclear vibrations. We find that electron energy relaxation is accelerated in larger NCs and attribute this effect to the higher densities of states and smaller energy gaps in these systems.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03687
  875. J Cancer. 2020 ;11(5): 1104-1114
    Comparison of different images in gross target volume delineating on VX2 nasopharyngeal transplantation tumor models.
    Xiang ZQ, Imani S, Hu Y, Ding RL, Pang HW, Chen Y, Fu SZ, Xie F, He WF, Wen QL.
      Background: To determine the optimum conditions for diagnosis of nasopharyngeal carcinoma, we established VX2 rabbit model to delineate gross target volume (GTV) in different imaging methods. Methods: The orthotopic nasopharyngeal carcinoma (NPC) was established in sixteen New Zealand rabbits. After 7-days inoculation, the rabbits were examined by CT scanning and then sacrificed for pathological examination. To achieve the best delineation, different GTVs of CT, MRI, 18F-FDG PET/CT, and 18F-FLT PET/CT images were correlated with pathological GTV (GTVp). Results: We found 45% and 60% of the maximum standardized uptake value (SUVmax) as the optimal SUV threshold for the target volume of NPC in 18F-FDG PET/CT and 18F-FLT PET/CT images, respectively (GTVFDG45% and GTVFLT60%). Moreover, the GTVMRI and GTVCT were significantly higher than the GTVp (P ≤ 0.05), while the GTVFDG45% and especially GTVFLT60% were similar to the GTVp (R = 0.892 and R = 0.902, respectively; P ≤ 0.001). Conclusions: Notably, the results suggested that 18F-FLT PET/CT could reflect the tumor boundaries more accurately than 18F-FDG PET/CT, MRI and CT, which makes 18F-FLT PET-CT more advantageous for the clinical delineation of the target volume in NPC.
    Keywords:  18F-FDG PET/CT.; 18F-FLT PET/CT; Gross tumor volume; Magnetic resonance imaging, Computed tomography; Nasopharyngeal carcinoma
    DOI:  https://doi.org/10.7150/jca.36076
  876. J Pharm Sci. 2020 Jan 15. pii: S0022-3549(20)30015-0. [Epub ahead of print]
    The role of Self Nano Emulsifying drug delivery systems of CDODA-Me in sensitizing Erlotinib resistant Nonsmall cell lung cancer.
    Nottingham E, Sekar V, Mondal A, Safe S, Rishi A, Singh M.
      In this study we have investigated the effects of combination treatment involving ERL (Erlotinib) with a glycyrrhetinic acid analog, CDODA-Me in overcoming ERL resistance, and to improve the oral bioavailability of this treatment using self-Nano-emulsifying drug delivery systems (SNEDDS). A Qbd (quality by design) approach was used to prepare CDMS (CDODA-SNEDDS, 2μΜ), which were characterized using surface response methodology to optimize drug content, particle size, as well as drug release. CDMS/ERL combinations showed synergism in wild type and resistant H1975 and HCC827 cell lines with combination index values less than 1. Increased apoptosis, mitochondrial membrane potential depletion and enhanced intracellular ROS levels were also observed in combination therapy. Western blot analysis showed that combination therapy inhibited phosphorylation of epidermal growth factor receptor (EGFR) (p<0.01 in all cell lines) and Met receptor tyrosine kinase (MET) (p<0.01 in all cell lines). In vivo, the relative bioavailability of CDMS increased significantly from 22.13μg/ml to 151.76μg/ml compared to the dosing of oral suspension (dose equivalent). Our results demonstrate that combination therapy involving ERL and CDODA-Me overcomes resistance through dual inhibition of p-EGFR and p-MET leading to the induction of apoptosis, intracellular ROS accumulation and decreased mitochondrial potential. Further, CDMS improved the oral bioavailability of CDODA-Me.
    DOI:  https://doi.org/10.1016/j.xphs.2020.01.010
  877. Nat Chem. 2020 Jan 20.
    Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids.
    Li J, Li F, King-Smith E, Renata H.
      Meroterpenoids are natural products of hybrid biosynthetic origins-derived from both terpenoid and polyketide pathways-with a wealth of biological activities. Given their therapeutic potential, a general strategy to access these natural products in a concise and divergent fashion is highly desirable. Here, we report a modular synthesis of a suite of oxidized meroterpenoids using a hybrid synthetic strategy that is designed to harness the power of both biocatalytic and radical-based retrosynthetic logic. This strategy enables direct introduction of key hydroxyl groups and rapid construction of key bonds and stereocentres, facilitating the development of a concise route (7-12 steps from commercial materials) to eight oxidized meroterpenoids from two common molecular scaffolds. This work lays the foundation for rapid access to a wide range of oxidized meroterpenoids through the use of similar hybrid strategy that combines two synthetic approaches.
    DOI:  https://doi.org/10.1038/s41557-019-0407-6
  878. Curr Opin Biotechnol. 2020 Jan 15. pii: S0958-1669(19)30150-8. [Epub ahead of print]62 228-238
    Harnessing ecological and evolutionary principles to guide the design of microbial production consortia.
    Giri S, Shitut S, Kost C.
      Bacteria are widely used for commercially producing biomolecules. However, attempts to rationally design production strains and optimize cultivation conditions are frequently counteracted by the emergence of mutants with reduced production characteristics that decrease overall process yield. The reason why these mutants arise is likely because of a mismatch between the ecological conditions under which bacteria evolved in nature and the situation they experience in an industrial setting. Thus, there is a great potential for improving biotechnological production processes by implementing eco-evolutionary knowledge. However, this is often limited by a lack of effective communication between process engineers and microbial ecologists/evolutionary biologists. Here, we highlight recent findings in the field of microbial ecology and evolution and suggest implementation of this knowledge can significantly enhance microbial bioproduction.
    DOI:  https://doi.org/10.1016/j.copbio.2019.12.012
  879. PLoS Genet. 2020 Jan 21. 16(1): e1008537
    Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation.
    Keele GR, Quach BC, Israel JW, Chappell GA, Lewis L, Safi A, Simon JM, Cotney P, Crawford GE, Valdar W, Rusyn I, Furey TS.
      Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. Here we characterize expression and chromatin state dynamics across three tissues-liver, lung, and kidney-in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 genes and 133 chromatin regions. Also detected were eQTL and cQTL whose allelic effects differed across tissues, including local-eQTL for Pik3c2g detected in all three tissues but with distinct allelic effects. Leveraging overlapping measurements of gene expression and chromatin accessibility on the same mice from multiple tissues, we used mediation analysis to identify chromatin and gene expression intermediates of eQTL effects. Based on QTL and mediation analyses over multiple tissues, we propose a causal model for the distal genetic regulation of Akr1e1, a gene involved in glycogen metabolism, through the zinc finger transcription factor Zfp985 and chromatin intermediates. This analysis demonstrates the complexity of transcriptional and chromatin dynamics and their regulation over multiple tissues, as well as the value of the CC and related genetic resource populations for identifying specific regulatory mechanisms within cells and tissues.
    DOI:  https://doi.org/10.1371/journal.pgen.1008537
  880. Cell Stress Chaperones. 2020 Jan 22.
    Consequences of mutations in the genes of the ER export machinery COPII in vertebrates.
    Lu CL, Kim J.
      Coat protein complex II (COPII) plays an essential role in the export of cargo molecules such as secretory proteins, membrane proteins, and lipids from the endoplasmic reticulum (ER). In yeast, the COPII machinery is critical for cell viability as most COPII knockout mutants fail to survive. In mice and fish, homozygous knockout mutants of most COPII genes are embryonic lethal, reflecting the essentiality of the COPII machinery in the early stages of vertebrate development. In humans, COPII mutations, which are often hypomorphic, cause diseases having distinct clinical features. This is interesting as the fundamental cellular defect of these diseases, that is, failure of ER export, is similar. Analyses of humans and animals carrying COPII mutations have revealed clues to why a similar ER export defect can cause such different diseases. Previous reviews have focused mainly on the deficit of secretory or membrane proteins in the final destinations because of an ER export block. In this review, we also underscore the other consequence of the ER export block, namely ER stress triggered by the accumulation of cargo proteins in the ER.
    Keywords:  COPII; Cell death; ER export defect; Endoplasmic reticulum; Secretion; Stress; Unfolded protein response
    DOI:  https://doi.org/10.1007/s12192-019-01062-3
  881. J Affect Disord. 2020 Jan 13. pii: S0165-0327(19)31349-7. [Epub ahead of print]265 10-17
    Dysfunctional pain perception and modulation among torture survivors: The role of pain personification.
    Tsur N, Defrin R, Shahar G, Solomon Z.
      OBJECTIVE: Individuals exposed to trauma, especially those who develop posttraumatic stress disorder (PTSD), are at a higher risk of suffering from chronic pain as well as altered pain perception and modulation. However, the underlying mechanisms of these processes are yet to be established. Recent findings have indicated that trauma survivors tend to personify chronic pain that is developed after the exposure, in a way that resonates with the traumatic experience. The aim of this study was to test whether pain personification plays a significant role in explaining the long-term links between trauma, PTSD and pain.METHODS: This study is part of a large-scale longitudinal study on ex-prisoners of war (ex-POWs) from the 1973 Yom-Kippur war, who were followed over 35 years after the war. Fifty-nine ex-POWs who were exposed to torture and 44 matched combatants were assessed for PTSD at 18, 30, and 35 post-war. Quantitative somatosensory testing of heat-pain threshold, pain tolerance, conditioned pain modulation (CPM), and temporal summation of pain (TSP), as well as torturing personification, were assessed at 35 years after the war.
    RESULTS: Sequential mediation analyses revealed that the associations between torture and heat pain threshold, as well as pain tolerance were mediated by PTSD at several time-points (-1.43<indirect effect < 1.47). Torturing personification significantly mediated the associations between torture, PTSD, CPM and TSP (-0.16 < indirect effect).
    CONCLUSIONS: These findings point to the effect of trauma on the subjective orientation towards bodily signals as a key factor in dysfunctional pain modulation.
    Keywords:  PTSD; Pain modulation; Pain perception; Pain personification; Torture; Trauma
    DOI:  https://doi.org/10.1016/j.jad.2020.01.031
  882. J Med Chem. 2020 Jan 24.
    Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies.
    Dunlap LE, Azinfar A, Ly C, Cameron LP, Viswanathan J, Tombari RJ, Myers-Turnbull D, Taylor JC, Grodzki AC, Lein PJ, Kokel D, Olson DE.
      Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.
    DOI:  https://doi.org/10.1021/acs.jmedchem.9b01404
  883. Cancer Metastasis Rev. 2020 Jan 20.
    piRNAs: biogenesis and their potential roles in cancer.
    Guo B, Li D, Du L, Zhu X.
      With the length of about 26-31 nt, PIWI-interacting RNA (piRNA) is a small non-coding RNA (ncRNA) that interacts with PIWI proteins to form the piRNA silencing complex (piRISC). PIWI is a subfamily of Argonaute, and piRNA must bind to PIWI to exert its regulatory role. Current studies indicated that piRNA and PIWI are significantly abnormally expressed in gastric, breast, kidney, colon, and lung cancers, and are involved in the initiation, progression, and metastasis of cancers, which may be the potential diagnostic tools, prognostic markers, and therapeutic targets for cancers. By reviewing piRNA recent studies, this research summarized the mechanism of piRNA generation and the functions of piRNA/PIWI in gastric, breast, kidney, colon, and lung cancers, providing a reference value for further piRNA research.
    Keywords:  Biogenesis; Cancer metastasis; PIWI; piRISC; piRNAs
    DOI:  https://doi.org/10.1007/s10555-020-09863-0
  884. Curr Opin HIV AIDS. 2020 Jan 20.
    HIV, aging, and adherence: an update and future directions.
    Mann SC, Castillo-Mancilla JR.
      PURPOSE OF REVIEW: To highlight recent data on antiretroviral adherence in older people living with HIV (PLWH), describe the most relevant pharmacokinetic antiretroviral studies, and identify critical research gaps in this population.RECENT FINDINGS: Overall, studies have found that older PLWH are more likely to be adherent to antiretroviral therapy (ART). Although multiple methods to measure adherence are available (self-report, pharmacy refills, electronic device monitors, drug concentrations), there is currently no 'gold standard' adherence measure or sufficient evidence to suggest a preferred method in older patients. Recently, studies evaluating antiretroviral concentrations in hair and dried blood spots in older patients identified no major differences when compared with younger individuals. Similarly, although pharmacokinetic studies in older PLWH are scarce, most data reveal no significant pharmacokinetic differences in the aging population. Furthermore, no specific guidelines or treatment recommendations regarding ART dose modification or long-term toxicity in aging PLWH are available, mostly because of the exclusion of this population in clinical trials.
    SUMMARY: How aging influences adherence and pharmacokinetics remains poorly understood. As the population of older PLWH increases, research focusing on adherence, toxicity, drug--drug interactions, and the influence of comorbidities is needed.
    DOI:  https://doi.org/10.1097/COH.0000000000000615
  885. Sci Total Environ. 2020 Jan 02. pii: S0048-9697(19)36385-5. [Epub ahead of print]713 136389
    Sedimentary phosphorus cycling and budget in the seasonally hypoxic coastal area of Changjiang Estuary.
    Liu J, Krom MD, Ran X, Zang J, Liu J, Yao Q, Yu Z.
      Anthropogenic activities have greatly accelerated phosphorus (P) inputs from land to coastal seas. The increased P inputs from major rivers can cause adjacent coastal areas to experience seasonal hypoxia with the enhancing coastal eutrophication, which can subsequently increase P cycling and alter long term preservation. Analysis of sediment core measurements including SEDEX P speciation coupled with diagenetic kinetic models were performed on two cores in the coastal area under the Changjiang river plume, that experiences seasonal hypoxia. It was found that the benthic flux of dissolved reactive phosphate (DRP) in the Changjiang Estuary (CJE) was higher than that of adjacent areas of the Chinese coastal shelf. Sedimentary phosphorus transformations of Fe-bound P and organic P resulted in the in-situ formation of authigenic P (probably apatite), which was the major form of reactive P buried in the sediment. P burial efficiency (PBE) was lower than that of the oxic Chinese shelf but higher than that of other seasonally hypoxic areas in the world away from major river inputs. An exponential relationship between PBE and bottom water dissolved oxygen was developed, which suggested a positive feedback mechanism of increased hypoxia increasing P recycling, and hence intensifying eutrophication. The relatively high input of sediment including detrital P from the adjacent major river can explain many of the observed differences in P cycling from other seasonally hypoxic areas.
    Keywords:  Anthropogenic activities; Changjiang River Estuary; Phosphorus cycling; Seasonal hypoxia
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.136389
  886. Curr Biol. 2020 Jan 20. pii: S0960-9822(19)31592-1. [Epub ahead of print]30(2): R89-R91
    Amino Acid Sensing: Architecture of mTORC1 on the Lysosome Surface.
    Peng W, Jewell JL.
      Amino acid signaling through the Rag GTPases promotes mTORC1 lysosomal localization and subsequent activation. Two new cryo-EM structures examine the architecture of the Rag GTPase heterodimers complexed with mTORC1.
    DOI:  https://doi.org/10.1016/j.cub.2019.11.087
  887. Inflammopharmacology. 2020 Jan 20.
    Low-dose curcumin reduced TNBS-associated mucin depleted foci in mice by scavenging superoxide anion and lipid peroxides, rebalancing matrix NO synthase and aconitase activities, and recoupling mitochondria.
    Mouzaoui S, Banerjee S, Djerdjouri B.
      BACKGROUND: The role of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseases (IBD) is still being investigated. This study evaluated the therapeutic effect of curcumin (Cur), a polyphenolic electrophile in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis and mitochondrial dysfunction, in mice.METHODS: Colitis was induced by rectal instillation to mice of 30 mg kg-1 TNBS, alone or followed by daily intraperitoneal injections of Cur 25 mg kg-1. Animals were euthanized at days 3, 7, and 14, post TNBS challenge. Colon mitochondria of control mice were treated with 5 µM Cur, and TNBS (50, 100 µM)-toxicity was evaluated by measuring swelling, respiration, and aconitase and fumarase activities. Redox status was evaluated in colon mucosa and in mitochondria.
    RESULTS: In vitro, a short-term Cur treatment controlled the dose and time dependent mitochondrial toxicity induced by TNBS, by collapsing the generation of superoxide anion and hydroperoxy lipids, rebalancing nitric oxide synthase and aconitase activities, and recoupling mitochondria. In vivo, a daily low-dose Cur abolished mice mortality which reached 27% in model group. Cur improved in a time dependent manner mucosal redox homeostasis, cell apoptosis, mucin depleted crypts and crypt abscesses by controlling prooxidant activity of myeloperoxidase and NO synthase associated to phagocytes influx, quenching hydroperoxy lipids, and reboosting GSH levels.
    CONCLUSION: Cur, by quenching intra and extra mitochondrial ROS generation, rebalancing aconitase/fumarase and MDA/GSH ratios, and recoupling mitochondria, may support mithormesis priming and remitting in IBD.
    Keywords:  Aconitase; Curcumin; Electrophile; MDA/GSH; Mucin depleted crypts; TNBS
    DOI:  https://doi.org/10.1007/s10787-019-00684-4
  888. J Bacteriol. 2020 Jan 21. pii: JB.00711-19. [Epub ahead of print]
    Dysregulation of magnesium transport protects Bacillus subtilis against manganese and cobalt intoxication.
    Pi H, Wendel BM, Helmann JD.
      Transition metals are essential for life, but are toxic when in excess. Metal ion intoxication may result from the mismetallation of essential metal-dependent enzymes with a non-cognate metal. To begin to identify enzymes and processes that are susceptible to mismetallation, we have selected for strains with increased resistance to Mn(II) and Co(II). In Bacillus subtilis, cells lacking the MntR metalloregulator are exquisitely sensitive to Mn(II), but can easily become resistant by acquiring mutations affecting the MntH Mn(II) importer. Using transposon mutagenesis, and starting with an mntR mntH strain, we recovered mariner insertions that inactivated the mpfA gene encoding a putative Mg(II) efflux system. Loss of MpfA leads to elevated intracellular Mg(II), increased sensitivity to high Mg(II), and reduced Mn(II) sensitivity. Consistently, we also recovered an insertion disrupting the mgtE riboswitch, which normally restricts expression of the major Mg(II) importer. These results suggest that Mn(II) intoxication results from disruption of a Mg(II)-dependent enzyme or process. Mutations that inactivate MpfA were also recovered in a selection for Co(II) resistance beginning with sensitized strains lacking the major Co(II) efflux pump, CzcD. Since both Mn(II) and Co(II) may mismetallate iron-dependent enzymes, we repeated the selections under conditions of iron-depletion imposed by expression of the Listeria monocytogenes FrvA iron exporter. Under conditions of iron depletion, a wider variety of suppressor mutations was recovered, but they still point to a central role for Mg(II) in maintaining metal ion homeostasis.Importance Cellular metal ion homeostasis is tightly regulated. When metal ion levels are imbalanced, or when one metal is at toxic levels, enzymes may bind to the wrong metal cofactor. Enzyme mismetallation can impair metabolism, lead to new and deleterious reactions, and cause cell death. Beginning with Bacillus subtilis strains genetically sensitized to metal intoxication, through loss of efflux or by lowering intracellular iron, we have identified mutations that suppress the deleterious effects of excess Mn(II) or Co(II). For both metals, mutations in mpfA, encoding a Mg(II) efflux pump, suppressed toxicity. These mutant strains have elevated intracellular Mg(II), suggesting that Mg(II)-dependent processes are very sensitive to disruption by transition metals.
    DOI:  https://doi.org/10.1128/JB.00711-19
  889. Health Expect. 2020 Jan 21.
    Mapping the spectrum of psychological and behavioural responses to low-dose CT lung cancer screening offered within a Lung Health Check.
    Kummer S, Waller J, Ruparel M, Cass J, Janes SM, Quaife SL.
      BACKGROUND: Research on the psychological impact of low-dose computed tomography (LDCT) lung cancer screening has typically been narrow in scope and restricted to the trial setting.OBJECTIVE: To explore the range of psychological and behavioural responses to LDCT screening offered as part of a Lung Heath Check (LHC), including lung cancer risk assessment, spirometry testing, a carbon monoxide reading and smoking cessation advice.
    METHODS: Semi-structured interviews were carried out with 28 current and former smokers (aged 60-75), who had undergone LDCT screening as part of a LHC appointment and mostly received an incidental or indeterminate result (n = 23). Framework analysis was used to map the spectrum of responses participants had across the LHC appointment and screening pathway, to their LDCT results and to surveillance.
    RESULTS: Interviewees reported a diverse range of both positive and negative psychological responses, beginning at invitation and spanning the entire LHC appointment (including spirometry) and LDCT screening pathway. Similarly, positive behavioural responses extended beyond smoking cessation to include anticipated implications for other cancer prevention and early detection behaviours, such as symptom presentation. Individual differences in responses appeared to be influenced by smoking status and LDCT result, as well as modifiable factors including perceived risk and health status, social support, competing priorities, fatalism and perceived stigma.
    CONCLUSIONS: The diverse ways in which participants responded to screening, both psychologically and behaviourally, should direct a broader research agenda to ensure all stages of screening delivery and communication are designed to promote well-being, motivate positive behaviour change and maximize patient benefit.
    Keywords:  behavioural sciences; early detection of cancer; lung cancer; mass screening; psychology; smoking
    DOI:  https://doi.org/10.1111/hex.13030
  890. J Thorac Cardiovasc Surg. 2019 Nov 28. pii: S0022-5223(19)33492-0. [Epub ahead of print]
    Commentary: Taking matters into your own hands: Venoarterial extracorporeal membrane oxygenation for controlled reperfusion during lung transplantation.
    Mitzman B.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.11.037
  891. Semin Oncol Nurs. 2020 Jan 16. pii: S0749-2081(19)30156-1. [Epub ahead of print] 150974
    The Who, What, Why, When, Where, and How of Team-Based Interdisciplinary Cancer Rehabilitation.
    Raj VS, Pugh TM, Yaguda SI, Mitchell CH, Mullan SS, Garces NS.
      OBJECTIVE: To review the key components necessary for successful application of rehabilitation principles to oncology survivors.DATA SOURCES: Validated databases, including PubMed, MEDLINE, and Scopus.
    CONCLUSION: Rehabilitation is an essential component of cancer care that addresses functional needs for oncology survivors and is best accomplished via an interdisciplinary team. Interdisciplinary care, provided by nursing, physiatry, rehabilitation therapy, and exercise physiology, are critical components for comprehensive intervention. Challenges exist in implementing services, but opportunity also exists within the post-acute care sector.
    IMPLICATIONS FOR NURSING PRACTICE: Nurses play an important role in the screening, assessment, and treatment of cancer-related functional impairments.
    Keywords:  Neoplasms; Nursing; Physical and Rehabilitation Medicine; Recovery of Function; Rehabilitation
    DOI:  https://doi.org/10.1016/j.soncn.2019.150974
  892. Benef Microbes. 2019 Oct 14. 10(7): 801-810
    Analysis of hypoxia-associated dendritic cells in colitic mice and effects of probiotics on IL-10 production in inflammatory dendritic-cells under hypoxia.
    Ogita T, Miyamoto J, Hirabayashi Y, Rossi M, Mazzarella G, Takahashi I, Tanabe S, Suzuki T.
      The aim of this study was to analyse hypoxia-associated dendritic cells (DCs) in colitic mice and the effects of probiotics on interleukin (IL)-10 production in inflammatory DCs under hypoxic conditions. Extensive hypoxia was observed in the colonic mucosa of dextran sodium sulphate-induced colitic mice. Flow cytometric analysis demonstrated that hypoxia-inducible factor-1α+ DCs in colonic lamina propria (CLP) lymphocytes and mesenteric lymph nodes (MLN) were more abundant in colitic mice than those in controls. Among three subsets of DCs, i.e. plasmacytoid DCs, conventional DCs (cDCs), and monocyte-derived DCs (mDCs), cDCs and mDCs were more abundant in CLP of colitic mice. Bone marrow-derived Flt-3L-induced DCs (Flt-DCs) but not bone marrow-derived GM-CSF-induced DCs (GM-DCs), incubated with 1% O2 exhibited an inflammatory phenotype, with higher CD86, IL-6, and tumour necrosis factor-α expression, and lower IL-10 levels than those in Flt-DCs incubated with 21% O2. The hypoxia-induced decrease in IL-10 expression in Flt-DCs was restored by Bifidobacterium bifidum JCM 1255T promoted IL-10 expression through the p38 pathway under normoxic conditions. The anti-inflammatory effects of B. bifidum JCM 1255T in Flt-DCs were mediated through different cellular mechanisms under hypoxic and normoxic conditions. B. bifidum JCM 1255T could be used therapeutically for its anti-inflammatory effects.
    Keywords:  immunology; lactic acid bacteria; mechanism of action; oxygen environment; probiotics
    DOI:  https://doi.org/10.3920/BM2018.0171
  893. Cancer Med. 2020 Jan 24.
    Profiles of prognostic alternative splicing signature in hepatocellular carcinoma.
    Wu F, Chen Q, Liu C, Duan X, Hu J, Liu J, Cao H, Li W, Li H.
      Previous studies have demonstrated the role of abnormal alternative splicing (AS) in tumor progression. This study examines the prognostic index (PI) of alternative splices (ASs) in patients with hepatocellular carcinoma (HCC). The clinical features and splicing events of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed AS (DEAS) were compared between HCC and adjacent normal samples. Univariate Cox regression analysis was used to determine changes in DEAS associated with overall survival (OS). A PI was generated from OS-associated DEASs using Kaplan-Meier curves, receiver operating characteristic (ROC) curves, multivariate Cox regression, and cluster analysis. Then, the correlation between DEASs and splicing factors was assessed, followed by functional and pathway enrichment analysis. We identified 34 163 ASs of 8985 genes in HCC, and 153 OS-ASs were identified using univariate Cox regression analysis. Low- and high-PI groups were determined based on the median "PI-ALL" value according to significantly different survival (P = 2.2e - 16). The ROC curve of all PI (PI-ALL) had an area under the curve (AUC) of 0.993 for survival status in patients with HCC. A potential regulatory network associated with prognosis of patients with HCC was established. Enrichment analysis also resulted in the identification of several pathways potentially associated with carcinogenesis and progression of HCC. Four clusters were identified that were associated with clinical features and prognosis. Our study generated comprehensive profiles of ASs in HCC. The interaction network and functional connections were used to elucidate the underlying mechanisms of AS in HCC.
    Keywords:  TCGA; alternative splicing; hepatocellular carcinoma; prognosis; survival
    DOI:  https://doi.org/10.1002/cam4.2875
  894. Med Mycol. 2020 Jan 21. pii: myz137. [Epub ahead of print]
    Acid and heat fastness in microsporidia: How acid fast are acid fast microsporidium?
    Mittal R, Agarwal S, Muduli KC, Sahu S, Das S.
      Microsporidia are obligate spore-forming microorganisms with strong resemblance to fungi and can affect almost every organ system in immunocompetent or immunocompromised individuals. Mixed infections are also reported in immunocompromised hosts. Microsporidial spores show marked morphological variations and the small and slender forms can resemble bacilli. Modified Zeihl Neelsen (ZN) stain, cold method demonstrates them as bright red in color, leaving several spores blue or incompletely stained; thus, they are reported as weakly or variably acid fast. Variability in staining results with ZN stain and considering the fact that Mycobacterium tuberculosis, the commoner bug in developing countries is identified by its resistance to stronger acids on ZN staining, authors wished to demonstrate acid and heat fastness in microsporidium using corneal tissue specimens. Microsporidial spores stained bright red in color with conventional ZN stain, demonstrated strong acid fastness, and interestingly the staining results improved on heating. Thus, the authors conclude that they are strongly acid and heat fast and care must be warranted so that they are not misdiagnosed as Mycobacterium or other acid-fast organisms. Careful observation of morphology, battery of special stains, and molecular diagnostics should be advocated for diagnostic confirmation. To the best of the authors' knowledge, this is the first explicit report on acid and heat fastness on microsporidial spores.
    Keywords:   Mycobacterium ; Microsporidia; Zeihl Neelsen stain; acid fast bacilli; histopathology
    DOI:  https://doi.org/10.1093/mmy/myz137
  895. J Cell Physiol. 2020 Jan 20.
    Gli1 interacts with YAP1 to promote tumorigenesis in esophageal squamous cell carcinoma.
    Wang C, Cheng L, Song S, Wu S, Sun G.
      Esophageal squamous cell carcinoma (ESCC) is the predominant esophageal cancer type in China. The aberrant activation of glioma-associated oncogene homolog1 (Gli1), a key factor in Hedgehog (Hh) signaling pathway, has been found in esophageal carcinoma. Moreover, Yes-associated protein 1 (YAP1), the major mediator of Hippo signaling pathway, has been linked to esophageal carcinoma progression. However, the precise roles and the underlying mechanism of both Gli1 and YAP1 in ESCC are unclear. Here, we found that Gli1 and YAP1 are overexpressed in ESCC and are associated with poor prognosis. In addition, we confirmed that knockdown of Gli1 or YAP1 suppresses ESCC cell growth, migration, and invasion in ESCC TE1 and EC109 cells. Significantly, Gli1 interacts with YAP1 in ESCC cells. Both Gli1 and YAP1 proteins are closely correlated with each other in human ESCC samples. Mechanistically, Gli1 upregulates YAP1 in a LATS1-independent manner. Conversely, YAP1 induces Gli1 by regulating phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Most importantly, we demonstrated that the interaction between Gli1 and YAP1 promotes ESCC tumor growth in vitro and in vivo. Our findings established a novel signaling mechanism by which the interaction between Gli1 and YAP1 promotes ESCC cell growth. This signaling regulation of the tumorigenesis provides a new therapeutic strategy for highly lethal ESCC.
    Keywords:  Gli1; YAP1; esophageal squamous cell carcinoma; tumorigenesis
    DOI:  https://doi.org/10.1002/jcp.29477
  896. J Clin Med. 2020 Jan 22. pii: E311. [Epub ahead of print]9(2):
    Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases.
    Alfatni A, Riou M, Charles AL, Meyer A, Barnig C, Andres E, Lejay A, Talha S, Geny B.
      Cardiovascular diseases (CVDs) are devastating disorders and the leading cause of mortality worldwide. The pathophysiology of cardiovascular diseases is complex and multifactorial and, in the past years, mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) have gained growing attention. Indeed, CVDs can be considered as a systemic alteration, and understanding the eventual implication of circulating blood cells peripheral blood mononuclear cells (PBMCs) and or platelets, and particularly their mitochondrial function, ROS production, and mitochondrial DNA (mtDNA) releases in patients with cardiac impairments, appears worthwhile. Interestingly, reports consistently demonstrate a reduced mitochondrial respiratory chain oxidative capacity related to the degree of CVD severity and to an increased ROS production by PBMCs. Further, circulating mtDNA level was generally modified in such patients. These data are critical steps in term of cardiac disease comprehension and further studies are warranted to challenge the possible adjunct of PBMCs' and platelets' mitochondrial dysfunction, oxidative stress, and circulating mtDNA as biomarkers of CVD diagnosis and prognosis. This new approach might also allow further interesting therapeutic developments.
    Keywords:  PBMCS; biomarkers; cardiovascular diseases; circulating cells; herat failure; mitochondrial DNA (mtDNA); mitochondrial dysfunction; oxidative stress; platelets; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/jcm9020311
  897. J Cell Physiol. 2020 Jan 22.
    ROCK-TAZ signaling axis regulates mechanical tension-induced osteogenic differentiation of rat cranial sagittal suture mesenchymal stem cells.
    Li W, Zhao J, Wang J, Sun L, Xu H, Sun W, Pan Y, Wang H, Zhang WB.
      Mechanical force across sutures is able to promote suture osteogenesis. Orthodontic clinics often use this biological characteristic of sutures to treat congenital cranio-maxillofacial malformations. However, the underlying mechanisms still remain poorly understood. Craniofacial sutures provide a special growth source and support primary sites of osteogenesis. Here, we isolated rat sagittal suture cells (rSAGs), which had mesenchymal stem cell characteristics and differentiating abilities. Cells were then subjected to mechanical tension (5% elongation, 0.5 Hz; sinusoidal waveforms) showing that mechanical tension could enhance osteogenic differentiation but hardly affect proliferation of rSAGs. Besides, mechanical tension could increase Rho-associated kinase (ROCK) expression and enhance transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation. Inhibiting ROCK expression could suppress tension-induced osteogenesis and block tension-induced upregulation of nuclear TAZ. In addition, our results indicated that TAZ had direct combination sites with runt-related transcription factor 2 (Runx2) in rSAGs, and knock-downed TAZ simultaneously decreased the expression of Runx2 no matter with or without mechanical tension. In summary, our findings demonstrated that the multipotency of rSAGs in vitro could give rise to early osteogenic differentiation under mechanical tension, which was mediated by ROCK-TAZ signal axis.
    Keywords:  Rho-associated kinase; mechanical tension; osteogenesis; sagittal suture cells; transcriptional coactivator with PDZ-binding motif
    DOI:  https://doi.org/10.1002/jcp.29522
  898. J Assoc Physicians India. 2020 Jan;68(1): 46
    Effect of Nutritional Anaemia on HbA1c Levels in Type 2 Diabates.
    Hemachoudary Y, Kumari P.
      
  899. FASEB J. 2020 Jan 19.
    Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells.
    Wang F, Wu H, Fan M, Yu R, Zhang Y, Liu J, Zhou X, Cai Y, Huang S, Hu Z, Jin X.
      Bladder cancer is one of the most frequently occurring malignant tumors in the urinary system. Sodium butyrate (NaB) is a histone deacetylase inhibitor and exerts remarkable antitumor effects in various cancer cells. MicroRNAs (miRNAs) and autophagy play crucial roles in cancer occurrence and development. In the present study, we evaluated the anticancer effects, including cell migration inhibition and the apoptotic effects of NaB in human bladder cancer cells. Furthermore, we found that NaB inhibited migration and induced AMPK/mTOR pathway-activated autophagy and reactive oxygen species (ROS) overproduction via the miR-139-5p/Bmi-1 axis. In addition, we found that ROS overproduction contributed to NaB-induced caspase-dependent apoptosis and autophagy. The interplay between autophagy and apoptosis in NaB treatment was clarified. Our findings provide a further understanding of EMT reversion, apoptosis and autophagy induced by antitumor drugs and a novel perspective and alternative strategy for bladder cancer chemotherapy.
    Keywords:  apoptosis; autophagy; bladder cancer; miR-139-5p/Bmi-1 axis; migration; reactive oxygen species (ROS); sodium butyrate
    DOI:  https://doi.org/10.1096/fj.201902626R
  900. Pflugers Arch. 2020 Jan 18.
    Mechanisms underlying suppression of noradrenaline-induced contraction by prolonged treatment with advanced glycation end-products in organ-cultured rat carotid artery.
    Matsumoto T, Takayanagi K, Kojima M, Taguchi K, Kobayashi T.
      We investigated the direct effects of prolonged exposure to advanced glycation end-products (AGEs) on noradrenaline-induced contraction of rat carotid artery smooth muscle. Noradrenaline-induced contraction of endothelium-denuded carotid artery rings was suppressed by AGE-bovine serum albumin (AGE-BSA) pretreatment (0.01 and 0.1 mg/mL for 23 ± 1 h) compared with vehicle pretreatment (control), whereas isotonic-K+-induced contraction was not significantly altered by AGE-BSA pretreatment. This reduction in noradrenaline-induced contraction by AGE-BSA (0.1 mg/mL) was reversed by iberiotoxin, an inhibitor of large-conductance calcium-activated potassium (BKCa) channels, but not by inhibitors of other K channels [4-AP (Kv inhibitor), TRAM-34 (IKCa inhibitor), or glibenclamide (KATP inhibitor)]. Acute incubation of carotid arterial rings with H2O2 had also reduced noradrenaline-induced contraction in control arteries, but it had no effect on noradrenaline-induced contraction in AGE-BSA-pretreated arteries. Alternatively, acute incubation with the H2O2 scavenger catalase increased noradrenaline-induced contraction of AGE-BSA-pretreated arteries but had no effect on noradrenaline-induced contraction of control arteries. Noradrenaline-induced contraction in the presence of H2O2 was increased by co-treatment with iberiotoxin. The AGE-BSA-mediated suppression of noradrenaline-induced contraction was prevented by the organic cation transporter 3 (OCT3) inhibitor corticosterone, whereas the expression of OCT3 protein was similar between control and AGE-BSA-treated endothelium-denuded carotid arteries. These findings suggest that noradrenaline-induced arterial contraction is reduced by prolonged AGE-BSA exposure due to activation of BKCa channels via H2O2 generation and increased OCT3-mediated noradrenaline transport activity.
    Keywords:  Advanced glycation end-products; Carotid artery; Contraction; Noradrenaline; Vascular smooth muscle
    DOI:  https://doi.org/10.1007/s00424-020-02349-6
  901. Anal Chem. 2020 Jan 21.
    CUPRA-ZYME: An assay for measuring carbohydrate-active enzyme activities, pathways and substrate specificities.
    Li Z, Kitov PI, Kitova EN, Mozenah F, Rodrigues E, Chapla DG, Moremen KW, Macauley MS, Klassen JS.
      Carbohydrate-Active enZymes (CAZymes) are involved in the synthesis, degradation and modification of carbohydrates. They play critical roles in diverse physiological and pathophysiological processes, have important industrial and biotechnological applications, are important drug targets and represent promising biomarkers for the diagnosis of a variety of diseases. Measurements of their activities, catalytic pathways and substrate specificities are essential to a comprehensive understanding of the biological functions of CAZymes and exploiting these enzymes for industrial and biomedical applications. For glycosyl hydrolases a variety of sensitive and quantitative spectrophotometric techniques are available. However, measuring the activity of glycosyltransferases is considerably more challenging. Here, we introduce CUPRA-ZYME, a versatile and quantitative electrospray ionization mass spectrometry (ESI-MS) assay for measuring the kinetic parameters of CAZymes, monitoring reaction pathways and profiling substrate specificities. The method employs the recently developed competitive universal proxy receptor assay (CUPRA), implemented in a time-resolved manner. Measurements of the hydrolysis kinetics of CUPRA substrates containing ganglioside oligosaccharides by the glycosyl hydrolase human neuraminidase 3 served to validate the reliability of kinetic parameters measured by CUPRA-ZYME and highlight its use in establishing catalytic pathways. Applications to libraries of substrates demonstrate the potential of the assay for quantitative profiling of the substrate specificities glycosidases and glycosyltransferases. Finally, we show how the comparison of the reactivity of CUPRA substrates and glycan substrates present on glycoproteins, measured simultaneously, affords a unique opportunity to quantitatively study how the structure and protein environment of natural glycoconjugate substrates influences CAZyme activity.
    DOI:  https://doi.org/10.1021/acs.analchem.9b05007
  902. Front Neurosci. 2019 ;13 1381
    Vesicular Dysfunction and the Pathogenesis of Parkinson's Disease: Clues From Genetic Studies.
    Ebanks K, Lewis PA, Bandopadhyay R.
      Parkinson's disease (PD) is a common age-related neurodegenerative disorder with disabling motor symptoms and no available disease modifying treatment. The majority of the PD cases are of unknown etiology, with both genetics and environment playing important roles. Over the past 25 years, however, genetic analysis of patients with familial history of Parkinson's and, latterly, genome wide association studies (GWAS) have provided significant advances in our understanding of the causes of the disease. These genetic insights have uncovered pathways that are affected in both genetic and sporadic forms of PD. These pathways involve oxidative stress, abnormal protein homeostasis, mitochondrial dysfunction, and lysosomal defects. In addition, newly identified PD genes and GWAS nominated genes point toward synaptic changes involving vesicles. This review will highlight the genes that contribute PD risk relating to intracellular vesicle trafficking and their functional consequences. There is still much to investigate on this newly identified and converging pathway of vesicular dynamics and PD, which will aid in better understanding and suggest novel therapeutic strategies for PD patients.
    Keywords:  Parkinson’s disease; Rab proteins; alpha-synuclein; genetics; genome wide association studies; leucine-rich repeat kinase 2; lysosomal dysfunction; vesicular dysfunction
    DOI:  https://doi.org/10.3389/fnins.2019.01381
  903. Cancer Med. 2020 Jan 20.
    Causes of death among cancer patients in the era of cancer survivorship in Korea: Attention to the suicide and cardiovascular mortality.
    Oh CM, Lee D, Kong HJ, Lee S, Won YJ, Jung KW, Cho H.
      BACKGROUND: Improved cancer survival is expected to increase noncancer deaths; however, detailed causes of death have rarely been discussed. Changing landscapes in mortality patterns and noncancer mortality risks in patients with cancer require evaluation.METHODS: We identified cancer and noncancer-related causes of death using data from the 2000-2016 national cancer registry in Korea (n = 2 707 520), and we characterized the leading causes of death and proportionate mortalities over time. Risks of noncancer deaths relative to the general population were estimated using standardized mortality ratios (SMRs).
    RESULTS: Of 1 105 607 identified deaths, 87% were due to the primary cancer. Proportionate mortalities of primary cancer among overall deaths remained high in patients with liver (86%) and lung (70%) cancers and in female patients with breast cancer (77%), even 5 to 10 years following diagnosis, whereas proportionate mortalities reduced to ≤50% in patients with stomach (men, 39%; women, 48%), prostate (47%), and female thyroid (27%) cancers. Despite the predominance of index cancer deaths, the proportion of noncancer deaths among all deaths increased over time. There was a 20-fold increase in cardiovascular disease deaths among patients with cancer from 2000 to 2016, and the risk of suicide among patients with cancer was higher than that among the general population (SMR: 1.68 [95% confidence interval (CI): 1.63-1.74] in men, SMR: 1.42 [95% CI: 1.33-1.55] in women).
    CONCLUSIONS: Deaths from primary cancer remain a major concern; however, follow-up is required for both cancer and noncancer-related health issues in cancer survivors, especially concerning suicide and cardiovascular deaths.
    Keywords:  cancer survivorship; cardiovascular diseases; cause of death; neoplasms; noncancer mortality; suicide
    DOI:  https://doi.org/10.1002/cam4.2813
  904. Neuroscience. 2020 Jan 16. pii: S0306-4522(20)30018-X. [Epub ahead of print]
    The differential effect of treadmill exercise intensity on hippocampal soluble aβ and lipid metabolism in APP/PS1 mice.
    Zeng B, Zhao G, Liu HL.
      Alzheimer's disease (AD) is characterized clinically by progressive impairments in learning and memory. Accumulating evidence suggests that regular exercise plays a neuroprotective role in aging-associated memory loss. Our previous study has confirmed that long-term treadmill exercise initiated either before or during the onset of β-amyloid (Aβ) pathology, was beneficial for reducing the levels of soluble Aβ and further improved cognition. In this study, in APP/PS1 mice, we assessed changes in soluble Aβ, and various blood biochemistry and molecular biological indices to assess whether exercise modulated lipid metabolism and thereby decelerated AD progression. Our results show that long-term treadmill exercise reduced the total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, and increased the level of high-density lipoprotein cholesterol. Exercise also decreased the levels of soluble Aβ1-40 and Aβ1-42, down-regulated retinoid X receptor expression, and up-regulated liver X receptor, Apolipoprotein E, Low density lipoprotein receptor, Low density lipoprotein receptor-related protein 1, and ATP-binding cassette transporter A1 expression. This indicates that long-term treadmill exercise alters the lipoprotein content, increases lipid metabolism and cholesterol transportation, reduces the soluble Aβ, and therein plays an important neuroprotective role and delays AD progression. We further show that medium exercise intensity (60%-70% of maximal oxygen uptake) was more efficacious in increasing lipid metabolism and reducing blood lipid levels and soluble Aβ levels, than low-intensity exercise (45-55% of maximal oxygen uptake). This research has broad prospects and implications, and offers a theoretical basis for the prevention of AD.
    Keywords:  Alzheimer's disease; exercise intensity; lipid metabolism; soluble Aβ
    DOI:  https://doi.org/10.1016/j.neuroscience.2020.01.005
  905. Reprod Fertil Dev. 2020 Jan 21.
    Effects of treatment with a microRNA mimic or inhibitor on the developmental competence, quality, epigenetic status and gene expression of buffalo (Bubalus bubalis) somatic cell nuclear transfer embryos.
    Sah S, Sharma AK, Singla SK, Singh MK, Chauhan MS, Manik RS, Palta P.
      Expression levels of 13 microRNAs (miRNAs) were compared between buffalo blastocysts produced by somatic cell nuclear transfer through hand-made cloning and IVF to improve cloning efficiency. Expression of miR-22, miR-145, miR-374a and miR-30c was higher, whereas that of miR-29b, miR-101, miR-302b, miR-34a, miR-21 and miR-25 was lower, in nuclear transferred (NT) than IVF embryos; the expression of miR-200b, miR-26a and miR-128 was similar between the two groups. Based on these, miR-145, which is involved in the regulation of pluripotency, was selected for further investigation of NT embryos. miR-145 expression was lowest at the 2-cell stage, increased through the 4-cell stage and was highest at the 8-cell or morula stage in a pattern that was similar between NT and IVF embryos. miR-145 expression was higher in NT than IVF embryos at all stages examined. Treatment of reconstructed embryos 1h after electrofusion with an inhibitor of miR-145 for 1h decreased the apoptotic index and increased the blastocyst rate, total cell number, ratio of cells in the inner cell mass to trophectoderm, global levels of acetylation of histone 3 at lysine 18 and expression of Krueppel-like factor 4 (KLF4), octamer-binding transcription factor 4 (OCT4) and SRY (sex determining region Y)-box 2 (SOX2) in blastocysts. Treatment with an miR-145 mimic had the opposite effects. In conclusion, treatment of NT embryos with an miR-145 inhibitor improves the developmental competence and quality, and increases histone acetylation and expression of pluripotency-related genes.
    DOI:  https://doi.org/10.1071/RD19084
  906. Drug Metab Pharmacokinet. 2019 Dec 31. pii: S1347-4367(19)30243-5. [Epub ahead of print]
    mRNA levels of drug-metabolizing enzymes in 11 brain regions of cynomolgus macaques.
    Uno Y, Yamazaki H.
      The cynomolgus macaque is an important nonhuman primate species in drug metabolism studies, in part because of its evolutionary closeness to humans. Cytochromes P450 (P450s) have been investigated in the major drug-metabolizing organs, i.e., the liver and small intestine, but have not been fully investigated in the brain. However, recent investigations have indicated possible important roles for P450s in the brain. In this study, by using the quantitative polymerase chain reaction, we measured the mRNA levels of 38 cynomolgus drug-metabolizing enzymes, including 19 P450s, 10 UDP-glycosyltransferases, and 9 other enzymes, in 11 brain regions. Among these drug-metabolizing enzymes, expression of 32 enzyme mRNAs were detected in one or more brain regions, indicating their possible roles in the brain. Further investigation of metabolic activities would facilitate better understanding of the importance of these enzymes in the brain.
    Keywords:  Brain; Cynomolgus monkey; Cytochrome P450; Drug metabolism; Tissue expression
    DOI:  https://doi.org/10.1016/j.dmpk.2019.12.003
  907. J Popul Ther Clin Pharmacol. 2020 Jan 18. 27(1): e32-e47
    Validation of predictive equations for resting energy expenditure in treatment-seeking adults with overweight and obesity: Measured versus estimated.
    Itani L, Tannir H, Kreidieh D, El Masri D, El Ghoch M.
      The quantification of resting energy expenditure (REE) in patients with obesity is an important measure. We aimed to evaluate the validity of predictive equations in estimating REE compared with indirect calorimetry (IC) in treatment-seeking Arab adults with overweight or obesity. Twenty-three predictive equations were compared with REE values measured by IC (Vmax Encore 229) in 89 adult participants with overweight or obesity (mean age = 40.62 ± 15.96 years and mean body mass index [BMI] = 35.02 ± 4.60 kg/m2) referred to the Department of Nutrition and Dietetics of Beirut Arab University (Lebanon). The accuracy of the predictive equations was evaluated on the basis of whether the percentage prediction was within 10% of the measured REE, and the mean difference between predicted and measured values (bias). The Bland-Altman method was used to assess the agreement between the predicted and measured values. The equations that demonstrated the closest agreement with IC were the De La Cruz equation in males (accurate predictions: 68.2%; bias: -19.52 kcal/day) and the Mifflin equation in females (accurate prediction: 61.2%; bias: -36.43 kcal/day). In conclusion, we suggest that these two equations produce the least biased estimations for REE in this population.
    Keywords:  indirect calorimetry; obesity; predictive equations; resting energy expenditure
    DOI:  https://doi.org/10.15586/jptcp.v27i1.653
  908. Chem Commun (Camb). 2020 Jan 21.
    Small-sized copolymeric nanoparticles for tumor penetration and intracellular drug release.
    Zhu CN, Zang LY, Zheng DY, Cao HM, Liu XJ.
      Poor solid-tumor penetration of nanocarriers limits the drug efficacy. Herein, small-sized copolymeric nanoparticles are prepared for delivering the chemotherapeutic drug DOX into solid tumors deeply and releasing the drug effectively. These small-sized copolymeric nanoparticles represent substantial potential for clinical translation.
    DOI:  https://doi.org/10.1039/c9cc09716c
  909. J Clin Lab Anal. 2020 Jan;34(1): e22980
    Circular RNA VRK1 correlates with favourable prognosis, inhibits cell proliferation but promotes apoptosis in breast cancer.
    Li Y, Li H.
      OBJECTIVE: This study aimed to evaluate the correlation between the circular RNA VRK serine/threonine kinase 1 (circ-VRK1) and the clinicopathological features and survival outcomes of breast cancer patients and determine its effects on breast cancer cell proliferation and apoptosis.METHODS: A total of 350 breast cancer tissues and 163 breast cancer adjacent tissues, as controls, were acquired from Specimen House. Circ-VRK1 expression was measured using qPCR. The correlations between circ-VRK1 expression and demographic characteristics, tumour features and overall survival were analysed. In vitro, the effects of circ-VRK1 on breast cancer cell proliferation and apoptosis were measured by upregulating and downregulating circ-VRK1 expression via plasmid transfection.
    RESULTS: Circ-VRK1 was downregulated in breast cancer tissues compared with adjacent tissues and represented a good value in distinguishing breast cancer tissues from the adjacent tissues. Circ-VRK1 was associated with smaller tumour size, reduced T stage and lower TNM stage, and circ-VRK1 was also an independent predictor of better overall survival. According to the in vitro experiments, circ-VRK1 expression was lower in breast cancer cell lines (including BT474, MDA-MB-453 and MDA-MB-231) than in a normal breast epithelial cell line (MCF10A), and circ-VRK1 inhibited cell proliferation but promoted cell apoptosis in MDA-MB-231 cells.
    CONCLUSION: Circ-VRK1 is downregulated in tumour tissues and associated with reduced tumour stage as well as better survival, and it inhibits cell proliferation but promotes cell apoptosis in breast cancer.
    Keywords:  Circ-VRK1; breast cancer; cell activities; clinicopathological features; survival
    DOI:  https://doi.org/10.1002/jcla.22980
  910. J Mater Chem B. 2020 Jan 23.
    A highly sensitive red-emitting probe for the detection of viscosity changes in living cells, zebrafish, and human blood samples.
    Fu M, Shen W, Chen Y, Yi W, Cai C, Zhu L, Zhu Q.
      Intracellular viscosity can be measured to reflect the state of living cells. Fluorescent probes are powerful tools for viscosity detection in vivo. Herein, we report on a novel red-emitting viscosity-sensitive probe DJH with a large Stokes shift of 165 nm, showing a 400-fold fluorescence enhancement from PBS solution to 90% glycerol. The probe was suitable for the visualization of the changes in viscosity within living cells and also in zebrafish treated with microplastics for the first time. Furthermore, the viscosity of fresh blood from diabetic mice and hypertensive and diabetic patients was first evaluated by using DJH. These results showed that the probe has a wide range of potential applications in basic research on environmental pollution and in the pre-diagnosis of patients.
    DOI:  https://doi.org/10.1039/c9tb02023c
  911. Biochem Biophys Res Commun. 2020 Jan 18. pii: S0006-291X(20)30094-2. [Epub ahead of print]
    Ubiquitin-specific protease 14 promotes prostate cancer progression through deubiquitinating the transcriptional factor ATF2.
    Geng L, Chen X, Zhang M, Luo Z.
      Activating Transcription Factor 2 (ATF2) is a member of the ATF/CREB bZIP family of transcription factors and an oncogene in prostate cancer. ATF2 has been reported to be a critical substrate of the CUL3-SPOP-RBX1 E3 ubiquitin ligase complex and the recurrent somatic mutation of SPOP has been believed to be a key feature of prostate cancer. However, the deubiquitinating enzyme required for ATF2 stabilization is still unknown. Here, we show that ATF2 is associated with ubiquitin-specific protease 14 (USP14), which increased the protein abundance and transcriptional activity of ATF2. Pharmacologic inhibition or siRNA-mediated depletion of USP14 resulted in the decline and inactivation of ATF2. USP14 deubiquitinates and activates ATF2, resulting in enhanced prostate cancer cells proliferation both in vitro and in vivo. Importantly, silencing of ATF2 largely attuned USP14-mediated prostate cancer cells proliferation. Thus, our data revealed a critical role of USP1-ATF2 axis in the progress of prostate cancer and the inhibition of USP14 might be a promising strategy against prostate cancer.
    Keywords:  ATF2; Deubiquitination; Prostate cancer; USP14
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.128
  912. Chin Clin Oncol. 2019 Dec;8(6): 64
    Advances in percutaneous lung tumor therapy: 2019 update.
    Kodama H, Yamakado K, Taniguchi J, Ogasawara A, Kako Y, Takaki H, Kobayashi K.
      
    DOI:  https://doi.org/10.21037/cco.2019.12.09
  913. Sci Rep. 2020 Jan 21. 10(1): 802
    HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA.
    Chong CK, Cheng CYS, Tsoi SYJ, Huang FY, Liu F, Fung J, Seto WK, Lai KK, Lai CL, Yuen MF, Wong DK.
      The hepatitis B X protein (HBx) plays a role in the epigenetic regulation of hepatitis B virus (HBV) replication. This study investigated the effects of HBx mutations on HBV transcription and the recruitment of HBx, histone acetyl-transferase P300 and histone deacetylase 1 (HDAC1) to circularized HBV DNA (which resembles covalently closed circular DNA [cccDNA]). Compared with wild type, majority of mutants had lower levels of intracellular HBV RNA (44-77% reduction) and secretory HBsAg (25-81% reduction), and 12 mutants had a reduction in intracellular encapsidated HBV DNA (33-64% reduction). Eight mutants with >70% reduction in HBV RNA and/or HBsAg were selected for chromatin immunoprecipitation analysis. Four HBx mutants with mutations in amino acid residues 55-60 and 121-126 had a lower degree of HBx-cccDNA association than wild type HBx (mean % input: 0.02-0.64% vs. 3.08% in wild type). A reduced association between cccDNA and P300 (mean % input: 0.69-1.81% vs. 3.48% in wild type) and an augmented association with HDAC1 (mean % input: 4.01-14.0% vs. 1.53% in wild type) were detected. HBx amino acid residues 55-60 and 121-126 may play an important role in HBV transcription regulation, via their impeded interaction with cccDNA and altered recruitment of histone modifying enzymes to cccDNA.
    DOI:  https://doi.org/10.1038/s41598-020-57637-z
  914. Sci Rep. 2020 Jan 24. 10(1): 1125
    Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy.
    Timpani CA, Goodman CA, Stathis CG, White JD, Mamchaoui K, Butler-Browne G, Gueven N, Hayes A, Rybalka E.
      Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD) is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca2+) buffering within, and the regenerative capacity of, dystrophic muscle. Therefore, increasing the metabogenic potential could represent an effective treatment avenue. The aim of our study was to determine the efficacy of adenylosuccinic acid (ASA), a purine nucleotide cycle metabolite, to stimulate metabolism and buffer skeletal muscle damage in the mdx mouse model of DMD. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were treated with ASA (3000 µg.mL-1) in drinking water. Following the 8-week treatment period, metabolism, mitochondrial density, viability and superoxide (O2-) production, as well as skeletal muscle histopathology, were assessed. ASA treatment significantly improved the histopathological features of murine DMD by reducing damage area, the number of centronucleated fibres, lipid accumulation, connective tissue infiltration and Ca2+ content of mdx tibialis anterior. These effects were independent of upregulated utrophin expression in the tibialis anterior. ASA treatment also increased mitochondrial viability in mdx flexor digitorum brevis fibres and concomitantly reduced O2- production, an effect that was also observed in cultured immortalised human DMD myoblasts. Our data indicates that ASA has a protective effect on mdx skeletal muscles.
    DOI:  https://doi.org/10.1038/s41598-020-57610-w
  915. Part Fibre Toxicol. 2020 Jan 20. 17(1): 4
    Mechanisms of lung toxicity induced by biomass burning aerosols.
    Pardo M, Li C, He Q, Levin-Zaidman S, Tsoory M, Yu Q, Wang X, Rudich Y.
      BACKGROUND: Carbonaceous aerosols emitted from indoor and outdoor biomass burning are major risk factors contributing to the global burden of disease. Wood tar aerosols, namely, tar ball particles, compose a substantial fraction of carbonaceous emissions, especially from biomass smoldering. However, their health-related impacts and toxicity are still not well known. This study investigated the toxicity of the water-soluble fraction of pyrolyzed wood tar aerosols in exposed mice and lung epithelial cells.RESULTS: Mice exposed to water-soluble wood tar aerosols showed increased inflammatory and oxidative stress responses. Bronchial epithelial cells exposed to the same water-soluble wood tar aerosols showed increased cell death with apoptotic characteristics. Alterations in oxidative status, including changes in reactive oxygen species (ROS) levels and reductions in the expression of antioxidant genes related to the transcription factor Nrf2, were observed and were confirmed by increased levels of MDA, a lipid peroxidation adduct. Damage to mitochondria was observed as an early event responsible for the aforementioned changes.
    CONCLUSIONS: The toxicity and health effect-related mechanisms of water-soluble wood tar were investigated for the first time in the context of biomass burning. Wood tar particles may account for major responses such as cell death, oxidative stress, supression of protection mechnaisms and mitochondrial damaged cause by expsoure to biomass burning aerosols.
    Keywords:  Apoptosis; Biomass burning; Health effects; Inflammation; Mitochondria; Nrf2; Oxidative stress; Wood tar particles
    DOI:  https://doi.org/10.1186/s12989-020-0337-x
  916. Cancer Med. 2020 Jan;9(2): 783-796
    Antitumor activity of celastrol by inhibition of proliferation, invasion, and migration in cholangiocarcinoma via PTEN/PI3K/Akt pathway.
    Zhu B, Wei Y.
      AIM: Cholangiocarcinoma is a malignant tumor originating from bile duct epithelium. Currently, the treatment strategy is very limited and the prognosis is poor. Recent studies reported celastrol exhibits antigrowth and antimetastasis properties in many tumors. Our study aimed to assess the anti-CCA effects of cholangiocarcinoma (CCA) and the mechanisms involved in it.METHODS: In this study, the long-term and short-term antiproliferation effects was determined using colony formation and Cell Counting Kit-8 (CCK-8) assays, respectively. Flow cytometry was performed to quantify apoptosis. Furthermore, wound healing and transwell assays were performed to determine the cell migration and invasion capabilities, respectively. To further find the mechanism involved in the celastrol-induced biological functions, LY204002, a PI3K/Akt signaling inhibitor, and an Akt-1 overexpression plasmid were employed to find whether PI3K/Akt pathway was involved in the celastrol-induced CCA cell inhibition. Additionally, short interfering RNA (siRNA) was also used to investigate the mechanism involved in the celastrol-induced PI3K/Akt signaling inhibition. Western blotting and immunofluorescence assays were also performed to detect the degree of relative proteins. Moreover, we validated the antiproliferation and antimetastasis effects of celastrol in vivo by constructing subcutaneous and lung metastasis nude mice models.
    RESULTS: We discovered that celastrol effectively induced apoptotic cell death and inhibited the capacity of migration and invasion in CCA cells. Further mechanistic study identified that celastrol regulated the PI3K/Akt signaling pathway, and the antitumor efficacy was likely due to the upregulation of PTEN, a negative regulator of PI3K/Akt. Blockage of PTEN abolished the celastrol-induced PI3K/Akt signaling inhibition. Additionally, in vivo experiments conformed celastrol inhibited the tumor growth and lung metastasis with no serious side effects.
    CONCLUSIONS: Overall, our study elucidated a mechanistic framework for the anti-CCA effects of celastrol via PTEN/PI3K/Akt pathway.
    Keywords:  Akt; apoptosis; celastrol; epithelial-to-mesenchymal transition; phosphatase and tensin homolog
    DOI:  https://doi.org/10.1002/cam4.2719
  917. Int J Mol Sci. 2020 Jan 23. pii: E755. [Epub ahead of print]21(3):
    Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis.
    Srivastava S, Zahra FT, Gupta N, Tullar PE, Srivastava SK, Mikelis CM.
      : Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood-brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.
    Keywords:  angiogenesis; breast cancer; penfluridol
    DOI:  https://doi.org/10.3390/ijms21030755
  918. Sensors (Basel). 2020 Jan 19. pii: E554. [Epub ahead of print]20(2):
    Research on Target Deviation Measurement of Projectile Based on Shadow Imaging Method in Laser Screen Velocity Measuring System.
    Chu W, Zhao D, Liu B, Zhang B, Gui Z.
      In the laser screen velocity measuring (LSVM) system, there is a deviation in the consistency of the optoelectronic response between the start light screen and the stop light screen. When the projectile passes through the light screen, the projectile's over-target position, at which the timing pulse of the LSVM system is triggered, deviates from the actual position of the light screen (i.e., the target deviation). Therefore, it brings errors to the measurement of the projectile's velocity, which has become a bottleneck, affecting the construction of a higher precision optoelectronic velocity measuring system. To solve this problem, this paper proposes a method based on high-speed shadow imaging to measure the projectile's target deviation, ΔS, when the LSVM system triggers the timing pulse. The infrared pulse laser is collimated by the combination of the aspherical lens to form a parallel laser source that is used as the light source of the system. When the projectile passes through the light screen, the projectile's over-target signal is processed by the specially designed trigger circuit. It uses the rising and falling edges of this signal to trigger the camera and pulsed laser source, respectively, to ensure that the projectile's over-target image is adequately exposed. By capturing the images of the light screen of the LSVM system and the over-target projectile separately, this method of image edge detection was used to calculate the target deviation, and this value was used to correct the target distance of the LSVM to improve the accuracy of the measurement of the projectile's velocity.
    Keywords:  beam collimation; sequential control; shadow imaging; target deviation measurement; triggering; velocity measurement
    DOI:  https://doi.org/10.3390/s20020554
  919. Int J Mol Sci. 2020 Jan 17. pii: E618. [Epub ahead of print]21(2):
    Effect of Drought Stress during Soybean R2-R6 Growth Stages on Sucrose Metabolism in Leaf and Seed.
    Du Y, Zhao Q, Chen L, Yao X, Zhang H, Wu J, Xie F.
      Sucrose is the main photosynthesis product of plants and the fundamental carbon skeleton monomer and energy supply for seed formation and development. Drought stress induces decreased photosynthetic carbon assimilation capacity, and seriously affects seed weight in soybean. However, little is known about the relationship between decreases in soybean seed yield and disruption of sucrose metabolism and transport balance in leaves and seeds during the reproductive stages of crop growth. Three soybean cultivars with similar growth periods, "Shennong17", "Shennong8", and "Shennong12", were subjected to drought stress during reproductive growth for 45 days. Drought stress significantly reduced leaf photosynthetic rate, shoot biomass, and seed weight by 63.93, 33.53, and 41.65%, respectively. Drought stress increased soluble sugar contents, the activities of sucrose phosphate synthase, sucrose synthase, and acid invertase enzymes, and up-regulated the expression levels of GmSPS1, GmSuSy2, and GmA-INV, but decreased starch content by 15.13% in leaves. Drought stress decreased the contents of starch, fructose, and glucose in seeds during the late seed filling stages, while it induced sucrose accumulation, which resulted in a decreased hexose-to-sucrose ratio. In developing seeds, the activities of sucrose synthesis and degradation enzymes, the expression levels of genes related to metabolism, and the expression levels of sucrose transporter genes were enhanced during early seed development under drought stress; however, under prolonged drought stress, all of them decreased. These results demonstrated that drought stress enhances the capacity for unloading sucrose into seeds and activated sucrose metabolism during early seed development. At the middle and late seed filling stages, sucrose flow from leaves to seeds was diminished, and the balance of sucrose metabolism was impaired in seeds, resulting in seed mass reduction. The different regulation strategies in sucrose allocation, metabolism, and transport during different seed development stages may be one of the physiological mechanisms for soybean plants to resist drought stress.
    Keywords:  Glycine max; drought; source–sink relationship; sucrose metabolism; sucrose transporter
    DOI:  https://doi.org/10.3390/ijms21020618
  920. Mol Ther Methods Clin Dev. 2020 Jun 12. 17 246-257
    Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model.
    Keeler AM, Zieger M, Semple C, Pucci L, Veinbachs A, Brown RH, Mueller C, ElMallah MK.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in death from respiratory failure. No cure exists for this devastating disease, but therapy that directly targets the respiratory system has the potential to prolong survival and improve quality of life in some cases of ALS. The objective of this study was to enhance breathing and prolong survival by suppressing superoxide dismutase 1 (SOD1) expression in respiratory motor neurons using adeno-associated virus (AAV) expressing an artificial microRNA targeting the SOD1 gene. AAV-miRSOD1 was injected in the tongue and intrapleural space of SOD1G93A mice, and repetitive respiratory and behavioral measurements were performed until the end stage. Robust silencing of SOD1 was observed in the diaphragm and tongue as well as systemically. Silencing of SOD1 prolonged survival by approximately 50 days, and it delayed weight loss and limb weakness in treated animals compared to untreated controls. Histologically, there was preservation of the neuromuscular junctions in the diaphragm as well as the number of axons in the phrenic and hypoglossal nerves. Although SOD1 suppression improved breathing and prolonged survival, it did not ameliorate the restrictive lung phenotype. Suppression of SOD1 expression in motor neurons that underlie respiratory function prolongs survival and enhances breathing until the end stage in SOD1G93A ALS mice.
    DOI:  https://doi.org/10.1016/j.omtm.2019.12.007
  921. ChemSusChem. 2020 Jan 22.
    Molecular design strategy towards high-redox-potential and low soluble n-type phenazine derivatives as cathode materials for lithium batteries.
    Chen J, Miao L, Liu L, Zhang K.
      N-type phenazine (PZ) derivatives represent an emerging class of cathode materials in lithium batteries for low-cost and sustainable energy storage. However, the low redox potential (< 2 V) and high solubility severely plague their application to battery systems. To explore and solve such problems in lithium batteries, we here systematically investigate the redox characteristics of 13 types of n-type PZ derivatives and their dissolution behavior in 7 organic electrolytes using density functional theory (DFT) calculations, and then summarize their rules. Two decisive factors are observed to tune the redox potentials for these molecules: one is the electron density around N active sites, the other is the chelation on lithium by both active N and substituent group. Specific approaches including reducing aromatic rings and introducing functional groups at β sites in n-type PZ derivatives can improve the redox potential to ~3 V. In addition, we develop a new index denoted as Ediff to investigate the solubility of n-type PZ derivatives. The most effective way to reduce the dissolution of electrodes in solvents is accordingly proposed as to improve intermolecular attraction between electrode molecules through introducing π-π stacking and hydrogen bonds. Such an all-around guideline should enlighten and promote the application of n-type PZ-based organic cathodes with high-redox potential and low electrode solubility for lithium batteries.
    Keywords:  n-type phenazine derivative * lithium battery * DFT * redox potential * solubility
    DOI:  https://doi.org/10.1002/cssc.202000004
  922. J Basic Clin Physiol Pharmacol. 2020 Jan 23. pii: /j/jbcpp.ahead-of-print/jbcpp-2019-0238/jbcpp-2019-0238.xml. [Epub ahead of print]
    Correlation of chemotherapy costs with quality of life in nasopharyngeal cancer patients.
    Romdhoni AC, Aulia R, Utaminingtyas RP, , Alderman CP.
      Background Nasopharyngeal cancer (NPC) is the most common neck/head cancer occurring in Indonesia and is the fourth most malignant after breast cancer, cervical cancer, and lung cancer. It is known that the cost of chemotherapy may not be separated from quality of life (QoL) to reflect the success of therapy, especially in cancer patients. Thus, studies on the correlation between chemotherapy cost and the QoL in NPC patients are needed. Methods The participants were recruited by a consecutive sampling method. All patients diagnosed with NPC using a paclitaxel-cisplatin chemotherapy regimen in August-March 2019 for first until the third chemotherapy cycle were assessed for their the chemotherapy cost and QoL before the first chemotherapy cycle and after the third cycle using the EORTC QLQ-C30 questionnaire. Chemotherapy cost and QoL were analyzed using SPSS version 20 to find out the correlation. Results Data from 26 patients showed a notable increase in the QoL after the third chemotherapy cycle. Thus, there was a relationship between chemotherapy cost and QoL in NPC patients. The total cost of chemotherapy increased with the increase in cycles of chemotherapy. We further analyzed the correlation between QoL and the cost of chemotherapy. We found that there was a correlation between the cost and the aspects of global health status, the QoL. Conclusions It is concluded that chemotherapy that is followed by the increase in cost in chemotherapy improves the QoL.
    Keywords:  QoL; chemotherapy; cisplatin; cost; nasopharyngeal cancer; paclitaxel
    DOI:  https://doi.org/10.1515/jbcpp-2019-0238
  923. Ann Neurol. 2020 Jan 24.
    Mendelian randomization study of obesity and cerebrovascular disease.
    Marini S, Merino J, Montgomery BE, Malik R, Sudlow CL, Dichgans M, Florez JC, Rosand J, Gill D, Anderson CD, .
      OBJECTIVE: To systematically investigate causal relationships between obesity and cerebrovascular disease, and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.METHODS: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR) and multiple cerebrovascular disease phenotypes. We explored causal associations with two-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR; and assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels respectively.
    RESULTS: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval (CI)=44%-113%) in risk for large artery ischemic stroke, a 57% (CI=29%-91%) increase in risk for small vessel ischemic stroke, a 197% increase (CI=59%-457%) in risk of intracerebral hemorrhage, as well as an increase in white matter hyperintensity volume (β=0.11; CI=0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (12%; CI=4%-20%), but no evidence of mediation was found for average blood glucose.
    INTERPRETATION: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ana.25686
  924. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019 Dec 25. 48(6): 668-673
    [Research progress on the effects of plateau hypoxia on blood-brain barrier structure and drug permeability].
    Ding Y, Li W, Wang R, Zhang J.
      Drugs for the treatment of central nervous system diseases need to enter the brain tissue through the blood-brain barrier to function. In high altitude hypoxic environment, there are changes in tight junction proteins of blood-brain barrier tissue structure, transporters in astrocytes and endothelial cells and ATP in endothelial cells; at the same time the permeability of the blood-brain barrier is increased. These changes are an important reference for rational drug use in patients with central nervous system disease in the plateau region. This article reviews the research progress on the effects of plateau hypoxia on the structure of the blood-brain barrier and related drug permeability.
  925. J Cell Physiol. 2020 Jan 22.
    Mechanical stretch regulates the expression of specific miRNA in extracellular vesicles released from lung epithelial cells.
    Najrana T, Mahadeo A, Abu-Eid R, Kreienberg E, Schulte V, Uzun A, Schorl C, Goldberg L, Quesenberry P, Sanchez-Esteban J.
      The underlying mechanism of normal lung organogenesis is not well understood. An increasing number of studies are demonstrating that extracellular vesicles (EVs) play critical roles in organ development by delivering microRNAs (miRNA) to neighboring and distant cells. miRNAs are important for fetal lung growth; however, the role of miRNA-EVs (miRNAs packaged inside the EVs) during fetal lung development is unexplored. The aim of this study was to examine the expression of miRNA-EVs in MLE-12, a murine lung epithelial cell line subjected to mechanical stretch in vitro with the long-term goal to investigate their potential role in the fetal lung development. Both cyclic and continuous mechanical stretch regulate miRNA differentially in EVs released from MLE-12 and intracellularly, demonstrating that mechanical signals regulate the expression of miRNA-EVs in lung epithelial cells. These results provide a proof-of-concept for the potential role that miRNA-EVs could play in the development of fetal lung.
    Keywords:  MLE-12; extracellular vesicles; mechanical stretch; miRNA
    DOI:  https://doi.org/10.1002/jcp.29476
  926. Sci Rep. 2020 Jan 24. 10(1): 1160
    Structural characterization and in-silico analysis of Momordica charantia 7S globulin for stability and ACE inhibition.
    Kesari P, Pratap S, Dhankhar P, Dalal V, Mishra M, Singh PK, Chauhan H, Kumar P.
      Momordica charantia (Mc) seeds are widely used edible crop with high nutritional quality. The food and pharmaceutical industries use it as a natural anti-oxygenic agent. Herein, a ~52 kDa protein, which is a major part of seed proteome has been purified, biochemically characterized and structure has been determined. MALDI-ESI-MS identified peptide fragments and contig-deduced sequence suggested the protein to be homologous to 7S globulins. The crystal structure shows that protein has a bicupin fold similar to 7S globulins and the electron density for a copper and acetate ligand were observed in the C-terminal barrel domain. In silico study reveals that a tripeptide (VFK) from Mc7S possess a higher binding affinity for angiotensin converting enzyme (ACE) than already reported drug Lisinopril (LPR). The protein is a glycoprotein and highly stable under varying thermal and pH conditions due to its secondary structures. The DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay showed the protein to have an anti-oxygenic nature and can aid in scavenging free radical from sample. The protein can assist to enhance the nutritional and functional value of food by acting as a food antioxidant. Further, characterization of Mc7S required which might add in importance of Mc7S as antioxidant, anti-diabetic and anti-hypertensive.
    DOI:  https://doi.org/10.1038/s41598-020-58138-9
  927. Sci Rep. 2020 Jan 20. 10(1): 734
    TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency.
    Fukushima H, Iwata Y, Watanabe S, Saito K, Tanaka Y, Hasegawa Y, Akiyama M, Sugiura K.
      Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36Ra) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn-/- mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn-/- mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn-/- mice. These data indicate that Il36rn-/- mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response.
    DOI:  https://doi.org/10.1038/s41598-020-57550-5
  928. Biomedicines. 2020 Jan 21. pii: E19. [Epub ahead of print]8(2):
    A Multi-Omics Analysis of Bone Morphogenetic Protein 5 (BMP5) mRNA Expression and Clinical Prognostic Outcomes in Different Cancers Using Bioinformatics Approaches.
    Karim MA, Samad A, Adhikari UK, Kader MA, Kabir MM, Islam MA, Hasan MN.
      Cumulative studies have provided controversial evidence for the prognostic values of bone morphogenetic protein 5 (BMP5) in different types of cancers such as colon, breast, lung, bladder, and ovarian cancer. To address the inconsistent correlation of BMP5 expression with patient survival and molecular function of BMP5 in relation to cancer progression, we performed a systematic study to determine whether BMP5 could be used as a prognostic marker in human cancers. BMP5 expression and prognostic values were assessed using different bioinformatics tools such as ONCOMINE, GENT, TCGA, GEPIA, UALCAN, PrognoScan, PROGgene V2 server, and Kaplan-Meier Plotter. In addition, we used cBioPortal database for the identification and analysis of BMP5 mutations, copy number alterations, altered expression, and protein-protein interaction (PPI). We found that BMP5 is frequently down-regulated in our queried cancer types. Use of prognostic analysis showed negative association of BMP5 down-regulation with four types of cancer except for ovarian cancer. The highest mutation was found in the R321*/Q amino acid of BMP5 corresponding to colorectal and breast cancer whereas the alteration frequency was higher in lung squamous carcinoma datasets (>4%). In PPI analysis, we found 31 protein partners of BMP5, among which 11 showed significant co-expression (p-value < 0.001, log odds ratio > 1). Pathway analysis of differentially co-expressed genes with BMP5 in breast, lung, colon, bladder and ovarian cancers revealed the BMP5-correlated pathways. Collectively, this data-driven study demonstrates the correlation of BMP5 expression with patient survival and identifies the involvement of BMP5 pathways that may serve as targets of a novel biomarker for various types of cancers in human.
    Keywords:  BMP5; BMP5 mutations; bioinformatics; cancer prognostic biomarkers; cancer progression; multi-omics analysis; protein–protein interaction
    DOI:  https://doi.org/10.3390/biomedicines8020019
  929. Orig Life Evol Biosph. 2020 Jan 25.
    Reactivity of Metabolic Intermediates and Cofactor Stability under Model Early Earth Conditions.
    Maltais TR, VanderVelde D, LaRowe DE, Goldman AD, Barge LM.
      Understanding the emergence of metabolic pathways is key to unraveling the factors that promoted the origin of life. One popular view is that protein cofactors acted as catalysts prior to the evolution of the protein enzymes with which they are now associated. We investigated the stability of acetyl coenzyme A (Acetyl Co-A, the group transfer cofactor in citric acid synthesis in the TCA cycle) under early Earth conditions, as well as whether Acetyl Co-A or its small molecule analogs thioacetate or acetate can catalyze the transfer of an acetyl group onto oxaloacetate in the absence of the citrate synthase enzyme. Several different temperatures, pH ranges, and compositions of aqueous environments were tested to simulate the Earth's early ocean and its possible components; the effect of these variables on oxaloacetate and cofactor chemistry were assessed under ambient and anoxic conditions. The cofactors tested are chemically stable under early Earth conditions, but none of the three compounds (Acetyl Co-A, thioacetate, or acetate) promoted synthesis of citric acid from oxaloacetate under the conditions tested. Oxaloacetate reacted with itself and/or decomposed to form a sequence of other products under ambient conditions, and under anoxic conditions was more stable; under ambient conditions the specific chemical pathways observed depended on the environmental conditions such as pH and presence/absence of bicarbonate or salt ions in early Earth ocean simulants. This work demonstrates the stability of these metabolic intermediates under anoxic conditions. However, even though free cofactors may be stable in a geological environmental setting, an enzyme or other mechanism to promote reaction specificity would likely be necessary for at least this particular reaction to proceed.
    Keywords:  Acetyl coenzyme a; Early earth; Metabolism; Oxaloacetate; TCA cycle
    DOI:  https://doi.org/10.1007/s11084-019-09590-9
  930. Brain Behav. 2020 Jan 22. e01527
    Duloxetine and pregabalin in neuropathic pain of lung cancer patients.
    Gül ŞK, Tepetam H, Gül HL.
      INTRODUCTION: Neuropathic pain occurs in 1% of the population and is difficult to manage. This chronic pain causes psychological distress and impacts patient's quality of life, especially in cancer patients. The aim of this study was to show and compare the efficacy of pregabalin and duloxetine, which are reported in the group of first-line treatment at European Federation of Neurological Societies (EFNS) guidelines on the pharmacological treatment of neuropathic pain (2010 revision) in lung cancer patients by using visual analogue scale (VAS) and Leeds Assessment of Neuropathic Symptoms and Sign (LANSS).PATIENTS AND METHODS: A prospective, randomized, open label, 3 month of study was conducted. A total of 44 patients that were diagnosed with neuropathic pain (14 women and 30 men) were included in the study. Patient's LANSS and VAS values were recorded before treatment. Then, 22 patients undergo pregabalin and 22 patients undergo duloxetine therapy. But due to side effects (dizziness, constipation), two patients had stopped to use pregabalin. Their LANSS and VAS values were recorded after 1 and 3 months of therapy.
    RESULTS: When we compare LANSS and VAS scores before treatment, after 1 and 3 months of treatment with pregabalin and duloxetine, a significant decrease was observed in both groups at the 1 and 3 months (p < .01). Duloxetine is superior to pregabalin in reducing the LANSS scores when we compare two groups.
    CONCLUSIONS: Both duloxetine and pregabalin are effective in the treatment of neuropathic pain of lung cancer patients. And as far as we know, this is the first study comparing the efficacy of duloxetine and pregabalin in the neuropathic pain of lung cancer patients.
    Keywords:  cancer; duloxetine; efficacy; neuropathic pain; pregabalin
    DOI:  https://doi.org/10.1002/brb3.1527
  931. Naunyn Schmiedebergs Arch Pharmacol. 2020 Jan 23.
    Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice.
    Kondo M, Tahara A, Hayashi K, Inami H, Ishikawa T, Tomura Y.
      Renal inflammation is a final common pathway of chronic kidney disease including diabetic nephropathy, which is the leading cause of end-stage renal disease and is associated with high cardiovascular risk and significant morbidity and mortality. Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4) is a pivotal molecule for IL-1 receptor- and Toll-like receptor-induced activation of proinflammatory mediators. In this study, we investigated the renoprotective properties of IRAK-4 inhibitor AS2444697 in KK/Ay type 2 diabetic mice. Four-week repeated administration of AS2444697 dose-dependently and significantly improved albuminuria; hyperfiltration, as measured by creatinine clearance; renal injury, including glomerulosclerosis; tubular injury markers, including urinary N-acetyl-β-D-glucosaminidase activity; and glomerular podocyte injury markers, including urinary nephrin excretion. In addition, AS2444697 attenuated plasma levels of proinflammatory cytokines, including IL-6; plasma levels of endothelial dysfunction markers, including intercellular adhesion molecule-1; and plasma levels and renal contents of oxidative stress markers. In contrast, AS2444697 did not significantly affect food intake or blood glucose levels. These results suggest that AS2444697 attenuates the progression of diabetic nephropathy mainly via anti-inflammatory mechanisms through inhibition of IRAK-4 activity under diabetic conditions and may represent a promising therapeutic option for the treatment of type 2 diabetic nephropathy.
    Keywords:  AS2444697; IRAK-4 inhibitor; Inflammation; Nephropathy; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s00210-020-01816-2
  932. J Reprod Immunol. 2020 Jan 15. pii: S0165-0378(20)30002-4. [Epub ahead of print]137 103081
    The effect of prednisolone on endometrial VGEF concentrations, Gene polymorphisms and pregnancy outcome in women with polycystic ovary syndrome: A retrospective cohort study.
    Bi H, Aldakheel FM, Sawsan Aloahd M.
      PCOS (Polycystic Ovary Syndrome) occurs due to hyperandrogenism, excessive androgen, abnormal growth, steroidogenesis and seems to be associated with abnormal Vascular endothelial growth factor (VEGF) level in serum. The treatment is provided on the basis of body symptoms to mute the excess production of hormone. The study assessed the effect of prednisolone treatment on the concentration of VEGF, pregnancy outcomes and variants of VEGF SNPs. In the current retrospective study, the samples were collected from PCOS female patients who received prednisolone and those who did not received it, were compared along with control, in terms of pregnancy results and the association complications. The results inferred that the prednisolone made the concentration of VEGF significantly to normal levels along with other pregnancy-related and growth-related hormones. But the reduced normal limits were achieved only among few patients whereas no significant improvement found in the women who received prednisolone and control, in terms of pregnancy outcomes or complications. Further, there were no relations between the impact of treatment and the variants of VEGF SNPs. To conclude, there is no solid evidence found in the current study with regards to notable beneficial effect when the patients were treated with prednisolone, either in pregnancy outcomes or VEGF SNPs. The current study results should be considered only as a preliminary one since the genetic polymorphisms tend to exhibit different results based on population, ethnic groups etc. The results yielded may not be generalized due to differences in genetic background.
    Keywords:  Endometrial cells; Endothelial growth factor (VEGF); Gene polymorphisms; Genetic variation; Polycystic ovary syndrome (PCOS); Prednisolone; Serum VEGF levels; Single nucleotide polymorphism; Vascular
    DOI:  https://doi.org/10.1016/j.jri.2020.103081
  933. Cancer Lett. 2020 Jan 16. pii: S0304-3835(20)30017-3. [Epub ahead of print]
    The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction.
    Huang H, Zepp M, Georges R, Jarahian M, Kazemi M, Eyol E, Berger MR.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and novel therapeutic strategies are urgently needed. Recently, expression of the C-C chemokine receptor 5 (CCR5) and its ligands has been found to play an important role in cancer progression and metastasis. In this study, we blocked the CCR5 receptor by the FDA approved antagonist maraviroc (MVC) in Suit2-007 and MIA-PaCa-2 human PDAC cells. The treatment significantly inhibited their proliferation and induced apoptosis of exposed cells as evidenced by caspases activation and increased Bax levels. Moreover, MVC inhibited the cell cycle by down regulating the proteins of the complexes of cyclin dependent kinase (CDK) 4/6 - Cyclin D and CDK2 - Cyclin E, as well as by increasing the protein levels of CDK inhibitors p18, p21 and p27. In line with this, MVC caused significant retardation of Suit2-007 cells growing in a PDAC liver metastasis xenograft model (p<0.05). These results suggest that maraviroc could be a promising treatment strategy for PDAC patients with liver metastases.
    Keywords:  C-C chemokine receptor 5; G1 phase arrest; MIA-PaCa-2; Pancreatic ductal adenocarcinoma; Suit2-007
    DOI:  https://doi.org/10.1016/j.canlet.2020.01.009
  934. Sci Total Environ. 2020 Feb 25. pii: S0048-9697(19)35815-2. [Epub ahead of print]705 135820
    The paradox between the environmental appeal of bio-based plastic packaging for consumers and their disposal behaviour.
    Taufik D, Reinders MJ, Molenveld K, Onwezen MC.
      To realize the potential environmental benefits that recycling and/or composting bio-based plastic packages can deliver, it is important that consumers view bio-based packaging as environmentally-friendly, but also correctly dispose of the packaging. The current experimental lab-in-the-field study was conducted among German consumers (n = 281) and explores whether consumers' perceived environmental benefits of recyclable and compostable bio-based plastic packages match with how consumers dispose of these packages. The results show that consumers only perceive compostable bio-based packages to have more environmental benefits than fossil-based packages. However, consumers dispose of compostable bio-based packages in an incorrect manner (not in line with what is communicated on the packaging label) relatively often. Consumers with a stronger familiarity with bio-based products more often correctly dispose of compostable bio-based packages, but not recyclable bio-based packages, relative to fossil-based packages. Thus, although mainly compostable bio-based plastic packages have strong environmental appeal to consumers, paradoxically this does not translate in the proper disposal actions to fully capitalize on the environmental benefits that bio-based packages can actually deliver. Increasing consumers' bio-based product familiarity might be an avenue to increase the levels of sustainable disposal.
    Keywords:  Bio-based; Consumer behaviour; Disposal; Environmental benefits; Packaging; Plastic
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.135820
  935. J Med Microbiol. 2020 Jan 21.
    Metabolic manipulation by Pseudomonas fluorescens: a powerful stratagem against oxidative and metal stress.
    MacLean A, Bley AM, Appanna VP, Appanna VD.
      Metabolism is the foundation of all living organisms and is at the core of numerous if not all biological processes. The ability of an organism to modulate its metabolism is a central characteristic needed to proliferate, to be dormant and to survive any assault. Pseudomonas fluorescens is bestowed with a uniquely versatile metabolic framework that enables the microbe to adapt to a wide range of conditions including disparate nutrients and toxins. In this mini-review we elaborate on the various metabolic reconfigurations evoked by this microbial system to combat reactive oxygen/nitrogen species and metal stress. The fine-tuning of the NADH/NADPH homeostasis coupled with the production of α-keto-acids and ATP allows for the maintenance of a reductive intracellular milieu. The metabolic networks propelling the synthesis of metabolites like oxalate and aspartate are critical to keep toxic metals at bay. The biochemical processes resulting from these defensive mechanisms provide molecular clues to thwart infectious microbes and reveal elegant pathways to generate value-added products.
    Keywords:  NADH; NADPH; Pseudomonas fluorescens; metabolic networks; metal toxicity; oxidative stress
    DOI:  https://doi.org/10.1099/jmm.0.001139
  936. Sci Rep. 2020 Jan 20. 10(1): 718
    Novel invasion indices quantify the feed-forward facilitation of tumor invasion by macrophages.
    Lim GJ, Kang SJ, Lee JY.
      Quantitative and reliable measurement of cellular invasion is important to understand a range of biological processes such as cancer metastasis and angiogenesis. Spheroid invasion assays are an attractive in vitro platform because they effectively mimic the tumor cell invasion of solid tissues. Here, we developed an image analysis-based method to quantify the invasiveness of HT1080 human fibrosarcoma tumor cell spheroids. We segmented a cell-covered area into three subareas using objectively set threshold pixel intensities and calculated invasion indices using these subareas. Comparison with conventional parameters for spheroid invasion assays, such as area, length, and detached cells, showed that our indices present the invasion event at an early time and without being convoluted by proliferation. As an application, we then examined paracrine interactions between LLC1 mouse lung carcinoma cells and Raw264.7 mouse macrophage cells with our developed analysis method. We found that the invasion of tumor spheroids was increased by a macrophage-conditioned medium, concomitantly with a decrease in tumor cell proliferation. Importantly, invasion was further enhanced by a conditioned medium from activated macrophages by co-culture with tumor cells. Thus, our indices reveal that tumor cell invasion is facilitated in a feed-forward manner by communication between tumor cells and macrophages in the tumor microenvironment.
    DOI:  https://doi.org/10.1038/s41598-020-57517-6
  937. Int Immunopharmacol. 2020 Jan 20. pii: S1567-5769(19)32488-9. [Epub ahead of print]80 106179
    Prediction of triptolide targets in rheumatoid arthritis using network pharmacology and molecular docking.
    Song X, Zhang Y, Dai E, Wang L, Du H.
      Network pharmacology is a novel approach that uses bioinformatics to predict and identify multiple drug targets and interactions in disease. Here, we used network pharmacology to investigate the mechanism by which triptolide acts in rheumatoid arthritis (RA). We first searched public databases for genes and proteins known to be associated with RA, as well as those predicted to be targets of triptolide, and then used Ingenuity Pathway Analysis (IPA) to identify enriched gene pathways and networks. Networks and pathways that overlapped between RA-associated proteins and triptolide target proteins were then used to predict candidate protein targets of triptolide in RA. The following proteins were found to occur in both RA-associated networks and triptolide target networks: CD274, RELA, MCL1, MAPK8, CXCL8, STAT1, STAT3, c-JUN, JNK, c-Fos, NF-κB, and TNF-α. Docking studies suggested that triptolide can fit in the binding pocket of the six top candidate triptolide target proteins (CD274, RELA, MCL1, MAPK8, CXCL8 and STAT1). The overlapping pathways were activation of Th1 and Th2 cells, macrophages, fibroblasts and endothelial cells in RA, while the overlapping networks were involved in cellular movement, hematological system development and function, immune cell trafficking, cell-to-cell signaling and interaction, inflammatory response, cellular function and maintenance, and cell death and survival. These results show that network pharmacology can be used to generate hypotheses about how triptolide exerts therapeutic effects in RA. Network pharmacology may be a useful method for characterizing multi-target drugs in complex diseases.
    Keywords:  Ingenuity pathway analysis; Molecular docking; Network pharmacology; Rheumatoid arthritis; Triptolide
    DOI:  https://doi.org/10.1016/j.intimp.2019.106179
  938. Nat Rev Endocrinol. 2020 Jan 23.
    Role of thyroid hormones in craniofacial development.
    Leitch VD, Bassett JHD, Williams GR.
      The development of the craniofacial skeleton relies on complex temporospatial organization of diverse cell types by key signalling molecules. Even minor disruptions to these processes can result in deleterious consequences for the structure and function of the skull. Thyroid hormone deficiency causes delayed craniofacial and tooth development, dysplastic facial features and delayed development of the ossicles in the middle ear. Thyroid hormone excess, by contrast, accelerates development of the skull and, in severe cases, might lead to craniosynostosis with neurological sequelae and facial hypoplasia. The pathogenesis of these important abnormalities remains poorly understood and underinvestigated. The orchestration of craniofacial development and regulation of suture and synchondrosis growth is dependent on several critical signalling pathways. The underlying mechanisms by which these key pathways regulate craniofacial growth and maturation are largely unclear, but studies of single-gene disorders resulting in craniofacial malformations have identified a number of critical signalling molecules and receptors. The craniofacial consequences resulting from gain-of-function and loss-of-function mutations affecting insulin-like growth factor 1, fibroblast growth factor receptor and WNT signalling are similar to the effects of altered thyroid status and mutations affecting thyroid hormone action, suggesting that these critical pathways interact in the regulation of craniofacial development.
    DOI:  https://doi.org/10.1038/s41574-019-0304-5
  939. ACS Appl Mater Interfaces. 2020 Jan 24.
    Differential work-function enabled bifunctional switching in strontium titanate flexible resistive memories.
    Rahman MA, Tawfik SA, Ahmed T, Spencer MJS, Walia S, Sriram S, Bhaskaran M.
      Multifunctional electronic memories capable of demonstrating both analog and digital switching on-demand are extremely attractive for miniaturization of electronics without significant drain on energy consumption. Simultaneously translating functionality onto mechanically conformable platforms will further enhance their suitability. Here, we demonstrate the ability to engineer multi-functionality in strontium titanate (STO) based resistive random-access memories (ReRAM) on a flexible polyimide (PI) platform. By utilising different bottom electrodes of various work functions while the top electrode is fixed, differential work-functions are induced in STO, to induce bipolar (BP) or complementary (CS) switching behaviours whenever required. This work-functions difference induced bifunctional switching on flexible platform reveals a streamlined route for achieving flexible artificial neural networks, high density integration, and logic operation using a single ReRAM.
    DOI:  https://doi.org/10.1021/acsami.9b20585
  940. Lung. 2020 Jan 24.
    Discriminating Between Non-Specific Interstitial Pneumonia and Idiopathic Pulmonary Fibrosis at Early Stages: When CPET is Enough?
    Boutou AK.
      
    DOI:  https://doi.org/10.1007/s00408-019-00316-2
  941. J Cell Physiol. 2020 Jan 24.
    LncRNA H19 is involved in myocardial ischemic preconditioning via increasing the stability of nucleolin protein.
    Chen C, Liu M, Tang Y, Sun H, Lin X, Liang P, Jiang B.
      Myocardial ischemic preconditioning (IP) is defined as a brief period of myocardial ischemia/reperfusion (I/R) that significantly reduces injury during the subsequent exposure to long-term I/R. However, the underlying mechanisms of myocardial IP are yet to be elucidated. This study investigated the expression and roles of long noncoding RNA (lncRNA) H19 in myocardial IP in vitro and in vivo. LncRNA H19 expression levels were analyzed by quantitative reverse-transcription polymerase chain reaction, cell viability was determined by the Cell Counting Kit-8 assay, apoptosis was evaluated based on the caspase 3 activity, and RNA immunoprecipitation was performed to examine the interaction between lncRNA H19 and nucleolin. The results of this study showed that lncRNA H19 expression was significantly upregulated in mouse hearts subjected to myocardial IP, in rat H9C2 cells exposed to H2 O2 preconditioning (H2 O2 -PC), and in neonatal rat cardiomyocytes subjected to hypoxia preconditioning. H19 knockdown abrogated the H2 O2 -PC-mediated protection in cardiomyocytes evidenced by the decreased cell viability and increased caspase-3 activity. Conversely, H19 overexpression enhanced the protective role of H2 O2 -PC in cardiomyocytes. In addition, H19 overexpression increased the expression of nucleolin, whereas H19 ablation abrogated H2 O2 -PC-induced upregulation of nucleolin in cardiomyocytes. Furthermore, H19 overexpression increased the stabilization of nucleolin; an interaction between H19 and nucleolin was identified using the RNA-protein interaction studies. Furthermore, nucleolin small interfering RNA relieved the protective role of lncRNA H19. These findings demonstrated that the lncRNA H19 is involved in myocardial IP via increasing the stability of nucleolin protein and lncRNA H19 may represent a potential therapeutic target for the treatment of the myocardial injury.
    Keywords:  lncRNA H19; myocardial ischemic preconditioning; nucleolin; stability of protein
    DOI:  https://doi.org/10.1002/jcp.29524
  942. Am J Nucl Med Mol Imaging. 2019 ;9(6): 255-273
    An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases.
    Kung BT, Seraj SM, Zadeh MZ, Rojulpote C, Kothekar E, Ayubcha C, Ng KS, Ng KK, Au-Yong TK, Werner TJ, Zhuang H, Hunt SJ, Hess S, Alavi A.
      For decades, conventional nuclear medicine techniques have been utilized for the assessment of many infectious and inflammatory diseases. Most of these techniques have limitations such as the relatively low spatial resolution, being time consuming and low sensitivity or specificity. In recent years, FDG-PET/CT has shown promising role in the management of such diseases. An expanding set of studies illustrate the multifarious roles of FDG-PET/CT in the assessment of these conditions, both systemic diseases and more regional. Specifically, PET can provide vital information at a molecular level and consequently detect the disease activity at their earliest manifestation. With the continuing research on the diagnosis and treatment monitoring of patients with infectious and inflammatory diseases, the role of PET/CT can be further extended.
    Keywords:  FDG PET/CT; HIV; bone infection; fever of unknown origin; infectious disease; inflammatory disease; sarcoidosis; tuberculosis; vasculitis
  943. Andrology. 2020 Jan 18.
    Simvastatin alleviated diabetes mellitus-induced erectile dysfunction in rats by enhancing AMPK pathway-induced autophagy.
    Ding F, Shan C, Li H, Zhang Y, Guo C, Zhou Z, Zheng J, Shen W, Dai Q, Ouyang Q, Wu X.
      BACKGROUND: Diabetes mellitus-induced erectile dysfunction (DMED) is a common diabetic complication, and new therapeutics and the pathogenesis of DMED need to be investigated.OBJECTIVES: The aim was to investigate the pathogenesis of DMED and the pharmacological mechanism of simvastatin treatment in DMED model rats.
    MATERIALS AND METHODS: A total of 86 male Sprague-Dawley (SD) rats aged 8 weeks old were used in this study. The rats were divided into 3 groups: control (normal), DMED (streptozotocin (STZ) -injected), and DMED+simvastatin (sim). Each group was subdivided into 2 subgroups for in vitro and in vivo analyses. A bioinformatics method was used to detect differences in gene expression in the corpus cavernosum between normal and DMED rats. Erectile function was measured by a cavernous nerve (CN) electrostimulation test. Corpus cavernosum fibrosis was assessed by Masson staining and Western blotting. Immunofluorescence and Western blotting were performed to explore the differential expression of autophagy-related genes and the AMPK-SKP2-CARM1 pathway genes in rat cavernous smooth muscle cells (CSMCs) and the corpus cavernosum. The autophagosomes of the corpus cavernosum tissue were observed by transmission electron microscopy.
    RESULTS: Autophagy-related genes and pathways (the AMPK and FoxO pathway) were identified by bioinformatics analysis and confirmed at the protein level. Simvastatin, an AMPK agonist, was used to treat DMED rats for 8 weeks, demonstrating that erectile function was improved for 80.5% (P < 0.05) of rats. Corpus cavernosum fibrosis was alleviated (P < 0.05), and autophagy was further enhanced (P < 0.05); these results might be partially caused by AMPK-SKP2-CARM1 pathway activation (P < 0.05).
    DISCUSSION AND CONCLUSION: Simvastatin could enhance protective autophagy by activating the AMPK-SKP2-CARM1 pathway to improve erectile function in DMED rats.
    DOI:  https://doi.org/10.1111/andr.12758
  944. Am J Cardiol. 2020 Jan 08. pii: S0002-9149(20)30011-4. [Epub ahead of print]
    Relation of Hypocholesterolemia With Diabetes Mellitus in Patients With Coronary Artery Disease.
    Ndrepepa G, Cassese S, Xhepa E, Fusaro M, Laugwitz KL, Schunkert H, Kastrati A.
      The association between hypocholesterolemia and diabetes mellitus (DM) in patients with coronary artery disease (CAD) remains poorly investigated. We undertook this study to investigate whether there is an association between hypocholesterolemia and odds of DM in these patients. This observational study included 14,952 patients with CAD: 8,592 without statins (statin-naive group) and 6,360 with statins on admission (statin-treated group). Hypocholesterolemia was defined as a total cholesterol within the first quintile of the total cholesterol concentration (total cholesterol <157 mg/dl). The primary outcome measure of this study was presence of DM. Hypocholesterolemia was present in 2,926 patients (20%; 1,102 statin-naive patients and 1,824 statin-treated patients). DM was present in 1,029 patients with hypocholesterolemia and 2,793 patients without hypocholesterolemia (35% vs 23%; odds ratio [OR] 1.79, 95% confidence interval [CI] 1.64 to 1.96; p <0.001). After adjustment, hypocholesterolemia was independently associated with the odds of DM in all patients (adjusted OR 1.55 [1.38 to 1.74]; p <0.001), statin-naive patients (adjusted OR 1.51 [1.25 to 1.82]; p <0.001) and statin-treated patients (adjusted OR 1.64 [1.41 to 1.91]; p <0.001). For every 20 mg/dl lower total cholesterol, the odds of being with DM increased by 14% (adjusted OR 1.14 [1.11 to 1.16]; p <0.001) with no cholesterol-by-statin interaction (Pint = 0.803). The association between hypocholesterolemia and odds of DM was entirely driven by low-density lipoprotein-cholesterol. For every 20 mg/dl lower low-density lipoprotein-cholesterol, the odds of DM increased by 14 % (adjusted OR 1.14 [1.11 to 1.16]; p <0.001). In conclusion, in patients with CAD, hypocholesterolemia was independently associated with the odds of DM with a dose-response relation and no cholesterol-by-statin interaction.
    DOI:  https://doi.org/10.1016/j.amjcard.2019.12.044
  945. Curr Nutr Rep. 2020 Jan 20.
    The Role of General Parenting Style in Child Diet and Obesity Risk.
    Kiefner-Burmeister A, Hinman N.
      PURPOSE OF REVIEW: The childhood obesity epidemic is widely considered to have reached pandemic proportions. Across the world, children with obesity are facing numerous psychological and physiological issues that follow them into adulthood, frequently leading to chronic illness and early death. In an effort to combat the compounding effects of childhood overweight, researchers are attempting to identify biological and environmental contributors to child weight. Parenting styles are one recognized influence on child diet and body mass index (BMI). This review is a comprehensive examination of the literature on the influence of parenting style on childhood diet and BMI over the past 5 years.RECENT FINDINGS: Current research continues to support the use of traditional parenting style categories (i.e., authoritative, authoritarian, permissive, uninvolved/neglectful): however, newer subcategories of Baumrind's styles and the inclusion of previously underrepresented groups (e.g., fathers, cross cultural comparison studies) are shedding more light on the nuance of parenting's relationship with child weight. Parenting styles that focus on the balance of warmth and control (e.g., authoritative) in contrast to the styles dedicated to only one of these constructs (e.g., permissive, authoritarian) seem to promote the healthiest dietary habits and may be protective of child BMI.
    Keywords:  BMI; Child diet; Childhood obesity; Eating behaviors; Parenting style
    DOI:  https://doi.org/10.1007/s13668-020-00301-9
  946. Cancer. 2019 Dec 15. 125 Suppl 24 4609-4615
    Treatment of recurrent epithelial ovarian cancer.
    Pignata S, Pisano C, Di Napoli M, Cecere SC, Tambaro R, Attademo L.
      The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.
    Keywords:  BRCA; bevacizumab; ovarian cancer; poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors; recurrence
    DOI:  https://doi.org/10.1002/cncr.32500
  947. Spine Deform. 2019 Jul;7(4): 517-524
    In Vivo Assessment of Thoracic Vertebral Shape From MRI Data Using a Shape Model.
    Meakin JR, Hopkins SJ, Clarke A.
      STUDY DESIGN: Feasibility study on characterizing thoracic vertebral shape from magnetic resonance images using a shape model.OBJECTIVES: Assess the reliability of characterizing thoracic vertebral shape from magnetic resonance images and estimate the normal variation in vertebral shape using a shape model. The characterization of thoracic vertebra shape is important for understanding the initiation and progression of deformity and in developing surgical methods. Methods for characterizing shape need to be comprehensive, reliable, and suitable for use in vivo.
    METHODS: Magnetic resonance images of the thoracic vertebrae were acquired from 20 adults. Repeat scans were acquired, after repositioning the participants, for T4, T8, and T12. Landmark points were placed around the vertebra on the images and used to create a shape model. The reliability was assessed using relative error (E%) and intraclass correlation (ICC). The effect of vertebral level, sex and age on vertebral shape was assessed using repeated measures analysis of variance.
    RESULTS: Five modes of variation were retained from the shape model. Reliability was excellent for the first two modes (mode 1: E% = 7, ICC = 0.98; mode 2: E% = 11, ICC = 0.96). These modes described variation in the vertebral bodies, the pedicle width and orientation, and the facet joint position and orientation with respect to the pedicle axis. Variation in vertebral shape was found along the thoracic spine and between individuals, but there was little effect of age and sex.
    CONCLUSIONS: Magnetic resonance images and shape modeling provides a reliable method for characterizing vertebral shape in vivo. The method is able to identify differences between vertebral levels and between individuals. The use of these methods may be advantageous for performing repeated measurements in longitudinal studies.
    LEVEL OF EVIDENCE: N/A.
    Keywords:  Anatomy; Magnetic resonance imaging; Reliability of results; Statistical shape model; Thoracic vertebrae
    DOI:  https://doi.org/10.1016/j.jspd.2018.10.005
  948. Eur J Heart Fail. 2020 Jan 23.
    Atrial fibrillation and remote monitoring through cardiac implantable electronic devices in heart failure patients.
    Boriani G, Imberti JF, Vitolo M.
      
    DOI:  https://doi.org/10.1002/ejhf.1745
  949. Nat Commun. 2020 Jan 20. 11(1): 381
    Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy.
    Huhn O, Ivarsson MA, Gardner L, Hollinshead M, Stinchcombe JC, Chen P, Shreeve N, Chazara O, Farrell LE, Theorell J, Ghadially H, Parham P, Griffiths G, Horowitz A, Moffett A, Sharkey AM, Colucci F.
      During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal cells and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: decidual NK cells (dNK)1-3, ILC3s and proliferating NK cells. Following stimulation, dNK2 and dNK3 produce more chemokines than dNK1 including XCL1 which can act on both maternal dendritic cells and fetal EVT. In contrast, dNK1 express receptors including Killer-cell Immunoglobulin-like Receptors (KIR), indicating they respond to HLA class I ligands on EVT. Decidual NK have distinctive organisation and content of granules compared with peripheral blood NK cells. Acquisition of KIR correlates with higher granzyme B levels and increased chemokine production in response to KIR activation, suggesting a link between increased granule content and dNK1 responsiveness. Our analysis shows that dILCs are unique and provide specialised functions dedicated to achieving placental development and successful reproduction.
    DOI:  https://doi.org/10.1038/s41467-019-14123-z
  950. J Clin Anesth. 2020 Jan 15. pii: S0952-8180(19)31958-0. [Epub ahead of print] 109704
    Anatomical considerations in Pecs blocks.
    Raghuraman MS, Surya R.
      
    DOI:  https://doi.org/10.1016/j.jclinane.2020.109704
  951. Curr Org Synth. 2019 ;16(1): 112-129
    3,4-Dihydroisocoumarins, Interesting Natural Products: Isolation, Organic Syntheses and Biological Activities.
    Ortiz A, Castro M, Sansinenea E.
      BACKGROUND: 3,4-dihydroisocoumarins are an important small group belonging to the class of naturally occurring lactones isolated from different bacterial strains, molds, lichens, and plants. The structures of these natural compounds show various types of substitution in their basic skeleton and this variability influences deeply their biological activities. These lactones are structural subunits of several natural products and serve as useful intermediates in the synthesis of different heterocyclic molecules, which exhibit a wide range of biological activities, such as anti-inflammatory, antiplasmodial, antifungal, antimicrobial, antiangiogenic and antitumoral activities, among others. Their syntheses have attracted attention of many researchers reporting many synthetic strategies to achieve 3,4-dihydroisocoumarins and other related structures.OBJECTIVE: In this context, the isolation of these natural compounds from different sources, their syntheses and biological activities are reviewed, adding the most recent advances and related developments.
    CONCLUSION: This review aims to encourage further work on the isolation and synthesis of this class of natural products. It would be beneficial for synthetic as well as the medicinal chemists to design selective, optimized dihydroisocoumarin derivatives as potential drug candidates, since dihydroisocoumarin scaffolds have significant utility in the development of therapeutically relevant and biologically active compounds.
    Keywords:  Isocoumarins; dihydroisocoumarins; isolation; lactones; microorganisms; natural products
    DOI:  https://doi.org/10.2174/1570179415666180924123439
  952. Hum Reprod Open. 2020 ;2020(1): hoz042
    Type 2 diabetes mellitus in women with polycystic ovary syndrome during a 24-year period: importance of obesity and abdominal fat distribution.
    Forslund M, Landin-Wilhelmsen K, Trimpou P, Schmidt J, Brännström M, Dahlgren E.
      STUDY QUESTION: What are the predictive factors for later development of type 2 diabetes (T2DM) in women with polycystic ovary syndrome (PCOS)?SUMMARY ANSWER: Obesity and abdominal fat distribution in women with PCOS in the mid-fertile years were the major risk factors for T2DM development 24 years later when lifestyle factors were similar to controls.
    WHAT IS KNOWN ALREADY: Women with PCOS have an increased prevalence of T2DM.
    STUDY DESIGN SIZE DURATION: A longitudinal and cross-sectional study was performed. Women with PCOS were examined in 1992 and in 2016. Randomly selected, age-matched women from the general population served as controls.
    PARTICIPANTS/MATERIALS SETTING METHODS: Women with PCOS (n = 27), attending an outpatient clinical at a tertiary care centre for infertility or hirsutism were diagnosed in 1992 (mean age 30 years) and re-examined in 2016 (mean age 52 years). Women from the World Health Organization MONItoring of trends and determinants for CArdiovascular disease (WHO MONICA-GOT) 2008, aged 38-68 years, served as controls (n = 94), and they were previously examined in 1995. At both at baseline and at follow-up, women had blood samples taken, underwent a clinical examination and completed structured questionnaires, and the women with PCOS also underwent a glucose clamp test at baseline.
    MAIN RESULTS AND THE ROLE OF CHANCE: None of women with PCOS had T2DM at baseline. At the 24-year follow-up, 19% of women with PCOS had T2DM versus 1% of controls (P < 0.01). All women with PCOS who developed T2DM were obese and had waist-hip ratio (WHR) >0.85 at baseline. No difference was seen between women with PCOS and controls regarding use of high-fat diet, Mediterranean diet or amount of physical activity at follow-up at peri/postmenopausal age. However, women with PCOS had a lower usage of a high-sugar diet as compared to controls (P = 0.01). The mean increases in BMI and WHR per year were similar in women with PCOS and controls during the follow-up period.
    LIMITATIONS REASONS FOR CAUTION: The small sample size of women with PCOS and the fact that they were recruited due to infertility or hirsutism make generalization to women with milder forms of PCOS uncertain.
    WIDER IMPLICATIONS OF THE FINDINGS: Obesity and abdominal fat distribution, but not hyperandrogenism per se, in women with PCOS in the mid-fertile years were the major risk factors for T2DM development 24 years later when peri/postmenopausal. Lifestyle factors were similar to controls at that time.
    STUDY FUNDING/COMPETING INTERESTS: The study was financed by grants from the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement (ALFGBG-718611), the Gothenburg Medical Association GLS 694291 and 780821, the Swedish Heart Lung Foundation and Hjalmar Svensson Foundation. The authors have no conflict of interest.
    Keywords:  diet; menopausal; obesity; polycystic ovary syndrome; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1093/hropen/hoz042
  953. Case Rep Pathol. 2020 ;2020 5845394
    Pulmonary Mucormycosis: A Case Report of a Rare Infection with Potential Diagnostic Problems.
    Mekki SO, Hassan AA, Falemban A, Alkotani N, Alsharif SM, Haron A, Felemban B, Iqbal MS, Tabassum A.
      Pulmonary mucormycosis is a relatively rare pulmonary fungal disease, which is difficult to diagnose early and lacks effective treatment. It is seen in patients with hematological malignancies, diabetes mellitus, and immunocompromised states. The diagnosis depends primarily on the detection of fungi in lung tissue. Here, we present a case of a 52-year-old male who has type 2 diabetes mellitus and a past history of treated pulmonary tuberculosis. Clinical diagnosis is difficult in pulmonary mucormycosis, and early diagnosis is needed for this life-threatening infection. Histopathological examination of a resected cavity confirmed the diagnosis of pulmonary mucormycosis. This report highlights the difficulty of diagnosis and the importance of histological examination in detecting mucormycosis which will help for early management.
    DOI:  https://doi.org/10.1155/2020/5845394
  954. IEEE Trans Neural Netw Learn Syst. 2020 Jan 20.
    Synchronization of Delayed Neural Networks via Integral-Based Event-Triggered Scheme.
    Zhang L, Nguang SK, Ouyang D, Yan S.
      This article investigates the event-triggered synchronization of delayed neural networks (NNs). A novel integral-based event-triggered scheme (IETS) is proposed where the integral of the system states, and past triggered data over a period of time are used. With the proposed IETS, the integral event-triggered synchronization problem becomes a distributed delay problem. Using the Bessel-Legendre inequalities, sufficient conditions for the existence of a controller that ensures asymptotic synchronization are provided in the form of linear matrix inequalities (LMIs). Illustrative examples are used to demonstrate the advantages of the proposed IETS method over other event-triggered scheme (ETS) methods. Moreover, this IETS method is applied to the image encryption and decryption. A novel encryption algorithm is proposed to enhance the quality of the encryption process.
    DOI:  https://doi.org/10.1109/TNNLS.2019.2963146
  955. Int J Mol Sci. 2020 Jan 22. pii: E715. [Epub ahead of print]21(3):
    Carbonic Anhydrase XII Expression Is Modulated during Epithelial Mesenchymal Transition and Regulated through Protein Kinase C Signaling.
    Vergara D, Ravaioli S, Fonzi E, Adamo L, Damato M, Bravaccini S, Pirini F, Gaballo A, Barbano R, Pasculli B, Franck J, Fournier I, Salzet M, Maffia M.
      Members of the carbonic anhydrase family are functionally involved in the regulation of intracellular and extracellular pH in physiological and pathological conditions. Their expression is finely regulated to maintain a strict control on cellular homeostasis, and it is dependent on the activation of extracellular and intracellular signaling pathways. Combining RNA sequencing (RNA-seq), NanoString, and bioinformatics data, we demonstrated that the expression of carbonic anhydrase 12 (CAXII) is significantly different in luminal and triple negative breast cancer (BC) models and patients, and is associated with the activation of an epithelial mesenchymal transition (EMT) program. In BC models, the phorbol ester 12-myristate 13-acetate (PMA)-mediated activation of protein kinase C (PKC) induced a down-regulation of CAXII with a concomitant modulation of other members of the transport metabolon, including CAIX and the sodium bicarbonate cotransporter 3 (NBCn1). This is associated with a remodeling of tumor glycolytic metabolism induced after PKC activation. Overall, this analysis highlights the dynamic nature of transport metabolom and identifies signaling pathways finely regulating this plasticity.
    Keywords:  PKC; breast cancer; carbonic anhydrase; epithelial mesenchymal transition; metabolism; proteomics; transport metabolon
    DOI:  https://doi.org/10.3390/ijms21030715
  956. J Phys Chem Lett. 2020 Jan 22.
    Nanoscale Surface-induced Unfolding of Single Fibronectin is Restricted by Serum Albumin Crowding.
    Warning LA, Zhang Q, Baiyasi R, Landes CF, Link S.
      Understanding nanoscale protein conformational changes at solid-liquid interfaces is critical for predicting how proteins will impact the performance of biomaterials in vivo. Crowding is an important contributor to conformational stability. Here we apply single-molecule high resolution imaging with photobleaching (SHRImP) to directly measure dye-conjugated fibronectin's unfolding in varying conditions of crowding with human serum albumin on aminosilanized glass. Using this approach, we identify serum albumin's crowding mechanism. We find that fibronectin achieves larger degrees of unfolding when not crowded by co-adsorbed serum albumin. Serum albumin does not as effectively constrict fibronectin's conformation if it is sequentially, rather than simultaneously, introduced, suggesting that serum albumin's crowding mechanism is dependent on its ability to sterically block fibronectin's unfolding during the process of adsorption. Because fibronectin's conformation is dependent on interfacial macromolecular crowding under in vitro conditions, it is important to consider the role of in vivo crowding on protein activity.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03446
  957. Am J Physiol Gastrointest Liver Physiol. 2020 Jan 21.
    Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma.
    Nabeshima T, Hamada S, Taguchi K, Tanaka Y, Matsumoto R, Yamamoto M, Masamune A.
      The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad up-regulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/p53 expressing livers, accompanied by up-regulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma.
    DOI:  https://doi.org/10.1152/ajpgi.00296.2019
  958. Neuroimage Clin. 2020 Jan 11. pii: S2213-1582(20)30005-X. [Epub ahead of print]25 102166
    A 7 Tesla fMRI investigation of human tinnitus percept in cortical and subcortical auditory areas.
    Berlot E, Arts R, Smit J, George E, Gulban OF, Moerel M, Stokroos R, Formisano E, De Martino F.
      Tinnitus is a clinical condition defined by hearing a sound in the absence of an objective source. Early experiments in animal models have suggested that tinnitus stems from an alteration of processing in the auditory system. However, translating these results to humans has proven challenging. One limiting factor has been the insufficient spatial resolution of non-invasive measurement techniques to investigate responses in subcortical auditory nuclei, like the inferior colliculus and the medial geniculate body (MGB). Here we employed ultra-high field functional magnetic resonance imaging (UHF-fMRI) at 7 Tesla to investigate the frequency-specific processing in sub-cortical and cortical regions in a cohort of six tinnitus patients and six hearing loss matched controls. We used task-based fMRI to perform tonotopic mapping and compared the magnitude and tuning of frequency-specific responses between the two groups. Additionally, we used resting-state fMRI to investigate the functional connectivity. Our results indicate frequency-unspecific reductions in the selectivity of frequency tuning that start at the level of the MGB and continue in the auditory cortex, as well as reduced thalamocortical and cortico-cortical connectivity with tinnitus. These findings suggest that tinnitus may be associated with reduced inhibition in the auditory pathway, potentially leading to increased neural noise and reduced functional connectivity. Moreover, these results indicate the relevance of high spatial resolution UHF-fMRI for the investigation of the role of sub-cortical auditory regions in tinnitus.
    Keywords:  Auditory pathway; Resting-state connectivity; Tinnitus; Tonotopic maps; Ultra-high field MRI
    DOI:  https://doi.org/10.1016/j.nicl.2020.102166
  959. Eur J Pharmacol. 2020 Jan 17. pii: S0014-2999(20)30016-9. [Epub ahead of print] 172924
    The role of circadian clock gene BMAL1 in vascular proliferation.
    Takaguri A, Sasano J, Akihiro O, Satoh K.
      Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, is implicated in the development of cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysms. However, the role of BMAL1 in vascular proliferation associated with vascular remodeling is unknown. In the present study, we investigated the mechanisms underlying BMAL1 expression in vascular smooth muscle cells (VSMCs) and the role of BMAL1 in VSMC proliferation. BMAL1 expression significantly increased in injured carotid arteries in C57BL/6J mice and platelet-derived growth factor (PDGF)-BB-stimulated VSMC cultures. Pretreatment with diphenyleneiodonium (an NADPH oxidase inhibitor) and U0126 or PD98059 (MEK Inhibitors) inhibited PDGF-BB-induced BMAL1 expression in a dose-dependent manner in VSMCs. In addition, the knockdown of early growth factor protein-1 (Egr-1) significantly inhibited PDGF-BB-induced BMAL1 mRNA or protein expression in VSMCs, and the knockdown of BMAL1 significantly decreased PDGF-BB-induced cell proliferation and extracellular signal-regulated kinase (ERK) phosphorylation but not Akt phosphorylation in VSMCs. The results demonstrate that PDGF-BB up-regulates BMAL1 expression through reactive oxygen species/ERK/Egr-1 pathways and that BMAL1 is involved in PDGF-BB-induced cell proliferation partially through ERK in VSMCs. Thus, BMAL1 may be a novel therapeutic target for the treatment of atherosclerosis including vascular remodeling.
    Keywords:  BMAL1; Cell proliferation; Egr-1; PDGF-BB; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1016/j.ejphar.2020.172924
  960. Semin Roentgenol. 2020 Jan;pii: S0037-198X(19)30076-8. [Epub ahead of print]55(1): 41-50
    Classification and Imaging Findings of Lung Neoplasms.
    Altmayer S, Verma N, Francisco MZ, Almeida RF, Mohammed TL, Hochhegger B.
      
    DOI:  https://doi.org/10.1053/j.ro.2019.10.002
  961. Am J Cardiol. 2020 Jan 08. pii: S0002-9149(20)30003-5. [Epub ahead of print]
    Impact of Malnutrition on Outcomes Following Transcatheter Aortic Valve Implantation (from a National Cohort).
    Emami S, Rudasill S, Bellamkonda N, Sanaiha Y, Cale M, Madrigal J, Christian-Miller N, Benharash P.
      Malnutrition is associated with increased mortality in open cardiac surgery, but its impact on transcatheter aortic valve implantation (TAVI) is unknown. This study utilized the National Readmissions Database to evaluate the impact of malnutrition on mortality, complications, length of stay (LOS), 30-day readmission, and total charges following TAVI. Adult patients undergoing isolated TAVI for severe aortic stenosis were identified using the 2011 to 2016 National Readmissions Database, which accounts for 56.6% of all US hospitalizations. The malnourished cohort included patients with nutritional neglect, cachexia, protein calorie malnutrition, postsurgical nonabsorption, weight loss, and underweight status. Multivariable models were utilized to evaluate the impact of malnutrition on selected outcomes. Of 105,603 patients, 5,280 (5%) were malnourished. Malnourished patients experienced greater mortality (10.4% vs 2.2%, p <0.001), postoperative complications (49.2% vs 22.6%, p <0.001), 30-day readmission rates (21.4 vs 14.9%, p <0.001), index hospitalization charges ($331,637 vs $208,082, p <0.001), and LOS (16.4 vs 6.2 days, p <0.001) relative to their nourished counterparts. On multivariable analysis, malnutrition remained a significant, independent predictor of increased index mortality (Adjusted odds ratio (AOR) = 2.68, p <0.001), complications (AOR = 2.09, p <0.001), and 30-day readmission rates (AOR = 1.34, p <0.001). Malnutrition was most significantly associated with infectious complications at index hospitalization (AOR = 3.88, p <0.001) and at 30-day readmission (AOR = 1.43, p <0.027). In conclusion, malnutrition is independently associated with increased mortality, complications, readmission, and resource utilization in patients undergoing TAVI. Preoperative risk stratification and malnutrition modification may improve outcomes in this vulnerable population.
    DOI:  https://doi.org/10.1016/j.amjcard.2019.12.038
  962. Toxics. 2020 Jan 20. pii: E4. [Epub ahead of print]8(1):
    A Method for the Evaluation of Site-Specific Nephrotoxic Injury in the Intact Rat Kidney.
    Edwards J, Kowal M, VanDreel A, Lamar P, Prozialeck W.
      In a previously published report we detailed an in situ method to quantify cell death in the renal cortex by perfusing the cell membrane impermeable fluorochrome, ethidium homodimer in situ. The objective of the present study was to use this in situ viability assay to examine cell death following the administration of nephrotoxic drugs known to produce cell death and/or injury in specific segments of the nephron. Male Sprague/Dawley rats were treated with the following nephrotoxicants: Gentamicin, amphotericin-B, and indomethacin. Results of the in situ viability assay indicated that gentamicin and amphotericin-B treatment caused cell death localized in the kidney cortex and medulla, respectively. The urinary biomarker kidney injury molecule-1 (Kim-1) showed significant increases in both gentamicin (20 fold increase) and amphotericin-B-treated (9.2 fold increase) animals. Urinary alpha glutathione-S-transferase (GST) showed significant increases for gentamicin (6.2 fold increase) only and mu GST for amphotericin-B-treated (19.1 fold increase) animals only. These results show that this in situ viability assay provides a sensitive method to identify cell death in different regions of the kidney. Furthermore, urinary alpha GST and mu GST are specific for proximal and distal tubule injury, respectively; urinary Kim-1 demonstrated greater sensitivity to both proximal and distal tubule injury.
    Keywords:  amphotericin; cell viability; drug toxicity; gentamicin; indomethacin; nephrotoxicity
    DOI:  https://doi.org/10.3390/toxics8010004
  963. J Nurs Manag. 2020 Jan 24.
    Fatigue in new registered nurses: A 12-month cross-lagged analysis of its association with work motivation, engagement, sickness absence, and turnover intention.
    Austin S, Fernet C, Trépanier SG, Lavoie-Tremblay M.
      AIM: This longitudinal study examines the motivational factors that explain why and how fatigue acts on new nurses' affective (work engagement), attitudinal (intention to leave the occupation), and behavioral (sickness absence) work outcomes.BACKGROUND: Growing nurse shortage makes it crucial to understand how and why fatigue can cut short the career of nurses.
    METHODS: This two-wave longitudinal study (baseline, 12-month follow-up) was conducted among 630 French-speaking new registered nurses from Canada. The proposed cross-lagged model was analysed using the EQS statistical software package for structural equation modeling (SEM).
    RESULTS: Time 1 fatigue was positively related to time 2 controlled motivation (working under internal or external pressure). Taking into account the cross-lagged effects of T1 fatigue on T2 outcomes, T1 controlled motivation was positively associated to T2 sickness absence, whereas T1 autonomous motivation (working because the activity is valued or inherently interesting) was related to all T2 outcomes.
    CONCLUSION: These findings provide insights into the motivational processes that affect nurses' early career functioning, revealing that distinct forms of motivation explain how fatigue relates to work outcomes.
    IMPLICATIONS FOR NURSING MANAGEMENT: Organizational efforts to strengthen autonomous over controlled motivation constitute a promising strategy to improve new nurses' well-being and retention in the occupation.
    Keywords:  Fatigue; engagement; motivation; sickness absence; turnover intention
    DOI:  https://doi.org/10.1111/jonm.12962
  964. Front Cardiovasc Med. 2019 ;6 186
    SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function.
    Maejima Y.
      Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.
    Keywords:  NHE; SGLT2; fission; fusion; ketone body; mitochondria
    DOI:  https://doi.org/10.3389/fcvm.2019.00186
  965. J Eukaryot Microbiol. 2020 Jan 23.
    De novo Sequencing, Assembly and Annotation of the Transcriptome for the Free-Living Testate Amoeba Arcella intermedia.
    Ribeiro GM, Porfírio-Sousa AL, Maurer-Alcalá XX, Katz LA, Lahr DJG.
      Arcella, a diverse understudied genus of testate amoebae is a member of Tubulinea in Amoebozoa group. Transcriptomes are a powerful tool for characterization of these organisms as they are an efficient way of characterizing the protein-coding potential of the genome. In this work, we employed both single-cell and clonal populations transcriptomics to create a reference transcriptome for Arcella. We compared our results with annotations of Dictyostelium discoideum, a model Amoebozoan. We assembled a pool of 38 Arcella intermedia transcriptomes, which after filtering are composed of a total of 14,712 translated proteins. There are GO categories enriched in Arcella including mainly intra-cellular signal transduction pathways; We also used KEGG to annotate 11,546 contigs, which also have similar distribution to Dictyostelium. A large portion of data are still impossible to assign to a gene family, probably due to a combination of lineage-specific genes, incomplete sequences in the transcriptome and rapidly evolved genes. Some absences in pathways could also be related to low expression of these genes. We provide a reference database for Arcella and we highlight the emergence of the need for further gene discovery in Arcella.
    Keywords:   Arcella ; gene discovery; next generation sequencing; pathways description
    DOI:  https://doi.org/10.1111/jeu.12788
  966. Nutr Metab (Lond). 2020 ;17 7
    S-Equol ameliorates insulin secretion failure through Chrebp/Txnip signaling via modulating PKA/PP2A activities.
    Chen K, Lang H, Wang L, Liu K, Zhou Y, Mi M.
      Background: S-Equol, produced from daidzein by gut microbiota, has been suggested as an potential anti-diabetic agent, but the underlying mechanisms remain unclear. Recent evidences demonstrated that carbohydrate response element-binding protein (Chrebp)/Thioredoxin-interacting protein (Txnip) signaling played central roles on diabetes progression, particularly in relation to the function maintenance and apoptosis of pancreatic β-cell. Here, we investigated the effects of S-Equol on β-cell function and Chrebp/Txnip signaling.Methods: Zucker diabetic fatty rats were treated with racemic Equol (120 mg/kg.BW.d) for 6 weeks. The glucose and lipid metabolism were monitored during the supplementation, and the Chrebp and Txnip expression were measured by using Western blotting. INS-1 cells were incubated with high glucose (26.2 mM) with or without S-Equol (0.1 μM, 1 μM, 10 μM) for 48 h. Glucose-stimulated insulin secretion (GSIS) was evaluated by radioimmunoassay, and the apoptosis of INS-1 cells was analyzed using Annexin V-FITC/PI and TUNEL assay. The dual luciferase reporter assay, chromatin immunoprecipitation assay and Western-blotting followed by Chrebp small interfering RNAs were utilized to clarify the mechanism of transcriptional regulation of S-Equol on Chrebp/Txnip signaling and the activities of protein kinase A (PKA) and protein phophatase (PP2A) were also detected.
    Results: In vivo, Equol supplementation delayed the onset of the hyperglycemia and hyperlipemia, ameliorated insulin secretion failure, enhanced GSIS in isolated islets, and significantly reduced Chrebp and Txnip expression in islets. In vitro, S-Equol treatment enhanced GSIS of high glucose cultured INS-1 cell, and reduced apoptosis of INS-1 cells were also observed. Moreover, S-Equol dramatically suppressed Txnip transcription, as evident by the reduction of Txnip protein and mRNA levels and decrease in the Txnip promoter-driven luciferase activity. Meanwhile, S-Equol significantly inhibited Chrebp/Mlx expression and decreased occupancy of Chrebp on the Txnip promoter, and combined with siChrebp, we confirmed that S-Equol improvement of insulin secretion was partially through the Chrebp/Txnip pathway. Furthermore, S-Equol significantly decrease nuclear translocation of Chrebp, which was related with the decrease activity of protein kinase A (PKA) and the increase activity of protein phophatase (PP2A).
    Conclusions: S-Equol could ameliorate insulin secretion failure, which was dependent on the suppression of Chrebp/Txnip signaling via modulating PKA/PP2A activities.
    Keywords:  Chrebp; Diabetes; Insulin secretion; PKA; PP2A; S-Equol; Txnip
    DOI:  https://doi.org/10.1186/s12986-020-0426-8
  967. Cell Mol Life Sci. 2020 Jan 23.
    A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane.
    Loureiro CA, Pinto FR, Barros P, Matos P, Jordan P.
      Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the recessive genetic disease cystic fibrosis, where the chloride transport across the apical membrane of epithelial cells mediated by the CFTR protein is impaired. CFTR protein trafficking to the plasma membrane (PM) is the result of a complex interplay between the secretory and membrane recycling pathways that control the number of channels present at the membrane. In addition, the ion transport activity of CFTR at the PM is modulated through post-translational protein modifications. Previously we described that spleen tyrosine kinase (SYK) phosphorylates a specific tyrosine residue in the nucleotide-binding domain 1 domain and this modification can regulate the PM abundance of CFTR. Here we identified the underlying biochemical mechanism using peptide pull-down assays followed by mass spectrometry. We identified in bronchial epithelial cells that the adaptor protein SHC1 recognizes tyrosine-phosphorylated CFTR through its phosphotyrosine-binding domain and that the formation of a complex between SHC1 and CFTR is induced at the PM in the presence of activated SYK. The depletion of endogenous SHC1 expression was sufficient to promote an increase in CFTR at the PM of these cells. The results identify a SYK/SHC1 pathway that regulates the PM levels of CFTR channels, contributing to a better understanding of how CFTR-mediated chloride secretion is regulated.
    Keywords:  CFTR; Chloride co-transport; Membrane traffic; Protein phosphorylation; SHC1; SYK
    DOI:  https://doi.org/10.1007/s00018-020-03448-4
  968. Int J Genomics. 2020 ;2020 7415909
    MicroRNA Biomarker hsa-miR-195-5p for Detecting the Risk of Lung Cancer.
    Li L, Feng T, Zhang W, Gao S, Wang R, Lv W, Zhu T, Yu H, Qian B.
      Background: Lung cancer is one of the leading diagnosed cancers worldwide, and microRNAs could be used as biomarkers to diagnose lung cancer. hsa-miR-195 has been demonstrated to affect the prognosis of NSCLC (non-small-cell lung cancer) in a previous study. However, the diagnostic value of hsa-miR-195-5p in lung cancer has not been investigated.Methods: To evaluate the ability of hsa-miR-195-5p to diagnose lung cancer, we compared the expression of hsa-miR-195-5p in lung cancer patients, COPD patients, and normal controls. Receiver operating characteristic (ROC) curve analysis was performed to investigate the sensitivity and specificity of hsa-miR-195-5p. Coexpression network and pathway analysis were carried out to explore the mechanism.
    Results: We found that hsa-miR-195-5p had lower expression in lung cancer and COPD patients than in normal controls, and the AUC was 0.92 for diagnosing lung cancer. hsa-miR-143 correlated with hsa-miR-195-5p, and by combining these two microRNAs, the AUC was 0.97 for diagnosing lung cancer.
    Conclusions: hsa-miR-195-5p may act as a biomarker that contributes to the diagnosis of lung cancer and the detection of its high-risk population.
    DOI:  https://doi.org/10.1155/2020/7415909
  969. Adv Respir Med. 2019 ;87(6): 258-264
    Difficulties in recognizing granulomatosis with polyangiitis (GPA) in elderly patients undergoing diagnostic thoracotomy twice - a report of two cases.
    Fijołek J, Wiatr E, Gawryluk D, Langfort R, Roszkowski-Śliż K.
      Granulomatosis with polyangiitis (GPA) is defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract with necrotizing vasculitis affecting predominantly small to medium vessels. Because of non-specific symptoms, its radiological presentation, and the diversity of its clinical expression, it is not uncommon to for it to be misdiagnosed, especially in the elderly. Although biopsy and histological examination seem to be essential for GPA diagnosis, their results are sometimes ambiguous and not helpful in making a decision. In this report, we present difficulties in the recognition of GPA in two elderly patients in whom, despite twice performing a diagnostic thoracotomy, GPA was recognized almost 4 and 6 years after the first symptoms.
    Keywords:  GPA; diagnostic difficulties; elderly patients
    DOI:  https://doi.org/10.5603/ARM.2019.0064
  970. Eur J Phys Rehabil Med. 2020 Jan 23.
    Occupational performance in multiple sclerosis and its relationship with quality of life and fatigue.
    Pérez de Heredia-Torres M, Huertas-Hoyas E, Sánchez-Camarero C, Máximo-Bocanegra N, Alegre-Ayala J, Sánchez-Herrera-Baeza P, Martínez-Piédrola RM, García-Bravo C, Mayoral-Martín A, Serrada-Tejeda S.
      BACKGROUND: Performance and perceived satisfaction of daily occupations in people with multiple sclerosis (MS) can affect the perception of their quality of life and be impacted by the level of fatigue.AIM: To describe the performance and occupational self-perception, as well as to analyze whether there is a relationship between the perception of occupational performance and the quality of life and perceived fatigue.
    DESIGN: A descriptive cross-sectional study.
    SETTING: Participants were referred by the services of Neurology of the various hospitals in Madrid. The assessment process was performed either at the MS' associations, in the participants' home, or at the Laboratory of Cognitive Intervention of the Health Sciences Faculty of the University.
    POPULATION: A total sample of 30 people with MS (pwMS) selected by non-probabilistic consecutive sampling during a three-months uptake patient recruitment period.
    METHOD: The outcome measures used were the Canadian Occupational Performance Measure (COPM), the Modified Fatigue Impact Scale (MFIS) and the Multiple Sclerosis Quality of Life 54 (MSQoL-54). Descriptive analysis, parametric and non-parametric tests and multiple linear regression models were used.
    RESULTS: A statistically significant positive correlation was found between occupational performance and physical and mental health. Also, high physical health scores were associated with high satisfaction scores. Multiple regression models indicated that high levels of satisfaction were associated with high levels of physical health (p = 0.013).
    CONCLUSIONS: The better the perception of the physical aspects that influence the quality of life, the better the perceived satisfaction of pwMS. Fatigue may not influence self-perceived satisfaction and performance.
    CLINICAL REHABILITATION IMPACT: The physical factors affecting perceived satisfaction should be considered when planning interventions to promote quality of life in pwMS. Although fatigue associated with MS may influence perceived performance and satisfaction, no relevant associations were found between variables.
    DOI:  https://doi.org/10.23736/S1973-9087.20.05914-6
  971. J Cell Biol. 2020 Mar 02. pii: e201904090. [Epub ahead of print]219(3):
    A reference library for assigning protein subcellular localizations by image-based machine learning.
    Schormann W, Hariharan S, Andrews DW.
      Confocal micrographs of EGFP fusion proteins localized at key cell organelles in murine and human cells were acquired for use as subcellular localization landmarks. For each of the respective 789,011 and 523,319 optically validated cell images, morphology and statistical features were measured. Machine learning algorithms using these features permit automated assignment of the localization of other proteins and dyes in both cell types with very high accuracy. Automated assignment of subcellular localizations for model tail-anchored proteins with randomly mutated C-terminal targeting sequences allowed the discovery of motifs responsible for targeting to mitochondria, endoplasmic reticulum, and the late secretory pathway. Analysis of directed mutants enabled refinement of these motifs and characterization of protein distributions in within cellular subcompartments.
    DOI:  https://doi.org/10.1083/jcb.201904090
  972. Expert Opin Drug Metab Toxicol. 2020 Jan 24.
    Pharmacodynamics of current and emerging PD-1 and PD-L1 inhibitors for the treatment of non-small cell lung cancer.
    Rocco D, Malapelle U, Del Re M, Della Gravara L, Pepe F, Danesi R, Troncone G, Gridelli C.
      Introduction: As of today, one of the cornerstones of NSCLC treatment is represented by Immune Checkpoint Inhibitors (ICI) treatment in the form of anti PD-1/PD-L1 monoclonal antibodies. However, apart from currently approved, recommended and employed agents (nivolumab, pembrolizumab, atezolizumab, durvalumab), several new agents are currently under development and investigation both in monotherapy and in combinational settings.Areas covered: This paper aims to discuss both the current state of the art and the most interesting emerging PD-1 and PD-L1 inhibitors and their present and future role in metastatic NSCLC treatment.Expert opinion: Great scientific interest lies in combinational settings, involving both already developed FDA and EMA approved and not approved agents and anti PD-1 and PD-L1 inhibitors, that will certainly provide data about pharmacodynamic and clinical properties of these associations, enhancing our understanding of ICIs and cancer immunotherapy. Moreover, new potential predictive biomarkers are much needed, especially considering the less decisive role of PD-L1 in treatment algorithms involving chemo-immune combinations and the current lack of other validated predictive biomarkers.
    Keywords:  Atezolizumab; Cemiplimab; Immunotherapy; Nivolumab; Pembrolizumab; Pharmacodynamics; Spartalizumab
    DOI:  https://doi.org/10.1080/17425255.2020.1721460
  973. Sci Rep. 2020 Jan 24. 10(1): 1143
    A Small Compound Targeting Prohibitin with Potential Interest for Cognitive Deficit Rescue in Aging mice and Tau Pathology Treatment.
    Guyot AC, Leuxe C, Disdier C, Oumata N, Costa N, Roux GL, Fernandez-Varela P, Duchon A, Charbonnier JB, Herault Y, Pavoni S, Galons H, Andriambeloson E, Wagner S, Meijer L, Lund AK, Mabondzo A.
      Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1β expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.
    DOI:  https://doi.org/10.1038/s41598-020-57560-3
  974. Schizophr Res. 2020 Jan 16. pii: S0920-9964(20)30017-7. [Epub ahead of print]
    A symptom combination predicting treatment-resistant schizophrenia - A strategy for real-world clinical practice.
    Ortiz BB, Higuchi CH, Noto C, Joyce DW, Correll CU, Bressan RA, Gadelha A.
      Early identification of symptoms that can predict treatment-resistant schizophrenia (TRS) could help clinicians to avoid delays in clozapine therapy. This study aims to investigate symptom patterns that could predict TRS using a discovery/replication study design. First, we followed a cohort of inpatients with schizophrenia (n = 164) in which the most discriminative items at baseline of the Positive and Negative Syndrome Scale (PANSS) were determined using logistic regression with TRS status as an outcome. Using Receiver Operating Characteristic (ROC) curves, we tested the prediction performance of multiple combinations of the identified items. The same items' combination was tested in an independent replication sample of (n = 207) outpatients with schizophrenia. In the discovery sample, the best combination to predict TRS at the discharge was the sum of three baseline PANSS items - conceptual disorganization (P2), difficulty in abstract thinking (N5), and unusual thought content (G9). The P2 + N5 + G9 model yielded an area under the curve (AUC) of 0.881, a sensitivity of 77.8%, and a specificity of 83.3%. In the outpatient sample, the model P2 + N5 + G9 predictive accuracy for TRS was only in the range of "acceptable" with an AUC of 0.756 and sensitivity of 72.3% and a specificity of 74.4%. Overall, the P2 + N5 + G9 model corresponds to the construct of formal thought disorder composed of disorganized thinking, concrete thinking, and bizarre-idiosyncratic thinking. Pronounced levels of these symptoms are easily identifiable in clinical practice and may be a feasible strategy in TRS. Replicating in first-episode cohorts is desirable to understand the likely clinical utility.
    Keywords:  Clozapine; Predictors; Schizophrenia; Treatment-resistant schizophrenia
    DOI:  https://doi.org/10.1016/j.schres.2020.01.002
  975. Clin Transplant. 2020 Jan 20. e13781
    Identification and characterisation of chronic lung allograft dysfunction patients with mixed phenotype: A single center study.
    Verleden SE, Von Der Thüsen J, Van Herck A, Weynand B, Verbeken E, Verschakelen J, Dubbeldam A, Vanaudenaerde BM, Vos R, Verleden GM, .
      RATIONALE: Patients can change chronic lung allograft dysfunction (CLAD) phenotype, especially from BOS to mixed phenotype. Our aim was to further characterize these patients.METHOD: Mixed CLAD was defined as a restrictive physiology with persistent CT opacities, after initial bronchiolitis obliterans syndrome (BOS) diagnosis. The incidence, prognosis, pulmonary function, radiology, pathology and airway inflammation were compared between patients with restrictive allograft syndrome (RAS) and mixed CLAD.
    RESULT: 268 (44%) patients developed CLAD of which 47 (18%) were diagnosed with RAS 'ab initio', 215 (80%) with BOS and 6 (2%) an undefined phenotype. Twenty-five patients developed a mixed CLAD phenotype (24 BOS to mixed and 1 RAS to mixed). Survival after mixed phenotype diagnosis, was comparable (p=0.39) to RAS. More emphysema patients developed a mixed phenotype (p=0.020) compared to RAS ab initio, while mixed CLAD patients had a lower FEV1 (p<0.0001) and FEV1 /FVC (p=0.0002) at diagnosis compared to RAS ab initio. CT scans in patients with the mixed phenotype demonstrated apical predominance of the opacities (p=0.0034) with pleuro-parenchymal fibro-elastosis on histopathology.
    CONCLUSION: We further characterized patients with a mixed phenotype of CLAD. Although the survival after diagnosis was comparable to RAS ab initio patients, there was a difference in demography, pulmonary function, radiology and pathology.
    Keywords:  Lung transplantation; bronchiolitis obliterans syndrome; chronic lung allograft dysfunction; mixed CLAD; phenotypes; restrictive allograft syndrome
    DOI:  https://doi.org/10.1111/ctr.13781
  976. J Biosci. 2020 ;pii: 19. [Epub ahead of print]45
    Cellular environment controls the dynamics of histone H3 lysine 56 acetylation in response to DNA damage in mammalian cells.
    Vadla R, Chatterjee N, Haldar D.
      Epigenetic changes play a crucial role in sensing signals and responding to fluctuations in the extracellular environment. How the cellular micro-environment affects DNA damage response signalling in chromatin context is not extensively studied. Histone acetylation is dynamic and very sensitive to changes in the extracellular environment. Existing literature on H3 lysine 56 acetylation (H3K56ac) levels upon DNA damage in mammals presents a conflicting picture. The occurrence of both increased and decreased H3K56ac upon DNA damage in our experiments led us to investigate the role of the micro-environment on H3K56ac. Here, we show that the global levels of H3K56ac increase as cells grow from low density to high density while SIRT1 and SIRT6 expression decrease. Additionally, rising lactic acid levels increase H3K56ac. Our results show that cell density and accumulation of metabolites affect dynamics of H3K56ac in response to DNA damage. Upon DNA damage, H3K56ac increases in low density cells with low initial acetylation, while acetylation decreases in high cell density cells. These results highlight that H3K56ac levels upon DNA damage are dependent on the metabolites in the extracellular milieu which impact chromatin structure by regulating chromatin modifying enzymes. Accumulation of lactic acid at high cell density reflects conditions similar to the tumour micro-environment. As H3K56ac increases in tumours, lactic acid and low pH might alter H3K56ac in tumours, leading to deregulated gene expression, contributing to tumour progression.
  977. Br J Pharmacol. 2020 Jan 23.
    HWL-088, a new highly potent FFAR1 agonist, improves glucolipid metabolism and acts additively with Metformin in ob/ob diabetic mice.
    Chen Y, Ren Q, Zhou Z, Deng L, Hu L, Zhang L, Li Z.
      BACKGROUND AND PURPOSE: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion and therefore become an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2'-methyl-[1,1'- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the chronic effects of HWL-088 mono-therapy and combination therapy with metformin in diabetic mice.EXPERIMENTAL APPROACH: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and rats. Long-term effects on glucose and lipid metabolism were carried out in ob/ob mice.
    KEY RESULTS: HWL-088 is a highly potent FFAR1 agonist (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 570.9 nM), and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of TAK-875, and additive improvements were observed by combination with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue, and alleviated fatty liver in ob/ob mice. The mechanisms of HWL-088 are involved in reduced hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation.
    CONCLUSION AND IMPLICATIONS: These data indicate that HWL-088 is a highly potent FFAR1 agonist that improves glucose and lipid metabolism in long-term treatment, and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with Metformin.
    Keywords:  FFAR1 agonist; Insulin secretion, Metformin; PPAR; Type 2 diabetes
    DOI:  https://doi.org/10.1111/bph.14980
  978. Chirality. 2020 Jan 20.
    New entry to the enantioselective formation of substituted cyclohexenes bearing an all-carbon quaternary stereogenic center.
    Komine K, Urayama Y, Hosaka T, Fukuda H, Hatakeyama S, Ishihara J.
      Enantioselective formation of cyclohexene derivatives bearing an all-carbon quaternary stereogenic center is described. The racemic cyclohexenes are readily transformed to chiral substituted cyclohexenes in good yield with excellent enantioselectivity and diastereoselectivity by a palladium-mediated deracemization. The resulting products are promising synthetic intermediates of biologically active natural products. This protocol provides us with a new entry to the concise and scalable synthesis of multifunctionalized compounds.
    Keywords:  asymmetric allylic alkylation; cyclohexene; palladium-mediated deracemization; quaternary stereogenic center
    DOI:  https://doi.org/10.1002/chir.23173
  979. J Am Heart Assoc. 2020 Jan 21. 9(2): e014276
    Slug, a Cancer-Related Transcription Factor, is Involved in Vascular Smooth Muscle Cell Transdifferentiation Induced by Platelet-Derived Growth Factor-BB During Atherosclerosis.
    Ledard N, Liboz A, Blondeau B, Babiak M, Moulin C, Vallin B, Guillas I, Mateo V, Jumeau C, Blirando K, Meilhac O, Limon I, Glorian M.
      Background Heart attacks and stroke often result from occlusive thrombi following the rupture of vulnerable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) play a pivotal role in plaque vulnerability because of their switch towards a proinflammatory/macrophage-like phenotype when in the context of atherosclerosis. The prometastatic transcription factor Slug/Snail2 is a critical regulator of cell phenotypic transition. Here, we aimed to investigate the role of Slug in the transdifferentiation process of VSMCs occurring during atherogenesis. Methods and Results In rat and human primary aortic smooth muscle cells, Slug protein expression is strongly and rapidly increased by platelet-derived growth factor-BB (PDGF-BB). PDGF-BB increases Slug protein without affecting mRNA levels indicating that this growth factor stabilizes Slug protein. Immunocytochemistry and subcellular fractionation experiments reveal that PDGF-BB triggers a rapid accumulation of Slug in VSMC nuclei. Using pharmacological tools, we show that the PDGF-BB-dependent mechanism of Slug stabilization in VSMCs involves the extracellular signal-regulated kinase 1/2 pathway. Immunohistochemistry experiments on type V and type VI atherosclerotic lesions of human carotids show smooth muscle-specific myosin heavy chain-/Slug-positive cells surrounding the prothrombotic lipid core. In VSMCs, Slug siRNAs inhibit prostaglandin E2 secretion and prevent the inhibition of cholesterol efflux gene expression mediated by PDGF-BB, known to be involved in plaque vulnerability and/or thrombogenicity. Conclusions Our results highlight, for the first time, a role of Slug in aortic smooth muscle cell transdifferentiation and enable us to consider Slug as an actor playing a role in the atherosclerotic plaque progression towards a life-threatening phenotype. This also argues for common features between acute cardiovascular events and cancer.
    Keywords:  atherogenesis; inflammation; vascular smooth muscle
    DOI:  https://doi.org/10.1161/JAHA.119.014276
  980. Int Immunopharmacol. 2020 Jan 16. pii: S1567-5769(19)32548-2. [Epub ahead of print]80 106208
    Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice.
    Liu J, Yuan Y, Gong X, Zhang L, Zhou Q, Wu S, Zhang X, Hu J, Kuang G, Yin X, Wan J, Yuan Y.
      As a natural flavonoid compound, baicalin(BA)has been reported to exhibit hepatoprotective and anti-inflammatory properties. However, the characteristic of poor solubility and low bioavailability greatly limits its application. In addition, the effects and underlying mechanisms of BA in nonalcoholic fatty liver disease (NAFLD) remain elusive. In this study, Methionine and choline deficient diet (MCD)-induced NAFLD mice were treated with baicalin or baicalin-loaded nanoliposomes (BA-NL), then hepatic histopathological changes, biochemical parameters and inflammatory molecules were observed. We found that mice in MCD group showed significant increases in plasma transaminase, hepatocyte apoptosis, hepatic lipid accumulation, liver fibrosis, and infiltration of neutrophils and macrophages compared with control group, however, BA and BA-NL markedly attenuated MCD-induced the above changes. Besides, further analysis indicated that BA and BA-NL also inhibited the up-regulation of toll-like receptor 4 (TLR4) signal and the production of inflammatory mediators in MCD mice. Importantly, BA-NL was found to be more effective than baicalin on MCD-induced NAFLD in mice. These data suggested that BA and its nanoliposomes BA-NL could effectively protect mice against MCD-induced NAFLD, which might be mediated through inhibiting TLR4 signaling cascade.
    Keywords:  Baicalin; Inflammation; Nanoliposomes; Nonalcoholic fatty liver disease; Toll-like receptor 4
    DOI:  https://doi.org/10.1016/j.intimp.2020.106208
  981. J Cell Mol Med. 2020 Jan 19.
    Combined analysis of whole-exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity.
    An T, Zhang J, Liu YF, Wu YX, Lian J, Wang TY, Hu YY, Zhu JJ, Huang J, Zhao DD, Mo FF, Gao SH, Jiang GJ.
      This study sought to find more exon mutation sites and lncRNA candidates associated with type 2 diabetes mellitus (T2DM) patients with obesity (O-T2DM). We used O-T2DM patients and healthy individuals to detect mutations in their peripheral blood by whole-exon sequencing. And changes in lncRNA expression caused by mutation sites were studied at the RNA level. Then, we performed GO analysis and KEGG pathway analysis. We found a total of 277 377 mutation sites between O-T2DM and healthy individuals. Then, we performed a DNA-RNA joint analysis. Based on the screening of harmful sites, 30 mutant genes shared in O-T2DM patients were screened. At the RNA level, mutations of 106 differentially expressed genes were displayed. Finally, a consensus mutation site and differential expression consensus gene screening were performed. In the current study, the results revealed significant differences in exon sites in peripheral blood between O-T2DM and healthy individuals, which may play an important role in the pathogenesis of O-T2DM by affecting the expression of the corresponding lncRNA. This study provides clues to the molecular mechanisms of metabolic disorders in O-T2DM patients at the DNA and RNA levels, as well as biomarkers of the risk of these disorders.
    Keywords:  diabetes; long non-coding RNA; mutation sites; obesity
    DOI:  https://doi.org/10.1111/jcmm.14932
  982. J Mol Cell Cardiol. 2020 Jan 17. pii: S0022-2828(20)30012-2. [Epub ahead of print]
    Osteoprotegerin promotes intimal hyperplasia and contributes to in-stent restenosis: Role of an αVβ3/FAK dependent YAP pathway.
    He Y, Zou P, Lu Y, Jia D, Li X, Yang H, Tang L, Zhu Z, Tu T, Tai S, Xiao Y, Chen M, Lu L, Zhou S.
      OBJECTIVE: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are related to in-stent-restenosis (ISR) following percutaneous coronary intervention (PCI). Osteoprotegerin (OPG) has been implicated in various vascular diseases. However, the effects of OPG on ISR and the underlying mechanism remained elusive. We here investigated the association between OPG and ISR, and to demonstrate the role and potential mechanisms of OPG in neointimal hyperplasia.APPROACH AND RESULTS: From 2962 patients who received coronary angiography and follow-up coronary angiography at approximately one year, 291 patients were diagnosed with ISR, and another 291 gender- and age- matched patients without ISR were selected as controls. Serum OPG levels were significantly increased in patients with ISR. Multivariable logistic regression analysis indicated that OPG level was independently associated with the increased risk of ISR. In a mouse femoral artery wire injury model, upregulated OPG was evidenced in vascular tissue after injury. OPG deletion attenuated the vascular injury-induced neointimal hyperplasia and related gene expression in mice. OPG promoted neointimal hyperplasia and human aortic smooth muscle cell (hASMC) proliferation and migration through activation of yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, whereas knockdown or inhibition of YAP in hASMCs blunted OPG-induced above effects. Moreover, we found that OPG, as a ligand for integrin αVβ3, mediated phosphorylation of focal adhesion kinase (FAK) and actin cytoskeleton reorganization, resulting in YAP dephosphorylation in hASMCs. OPG-dependent YAP and VSMC activation was prevented by treatment with αVβ3-blocking antibodies and inhibitors of FAK and actin stress fibers.
    CONCLUSIONS: Increased serum OPG levels are associated with increased risk of ISR following PCI and OPG could promote neointimal hyperplasia in response to injury through integrin αVβ3 mediated FAK and YAP activation, indicating OPG/YAP inhibition might serve as an attractive novel target for the prevention of ISR after PCI.
    Keywords:  In-stent restenosis; Neointimal hyperplasia; OPG; YAP; αVβ3
    DOI:  https://doi.org/10.1016/j.yjmcc.2020.01.006
  983. Sci Rep. 2020 Jan 24. 10(1): 1167
    Substrate specificity of plastid phosphate transporters in a non-photosynthetic diatom and its implication in evolution of red alga-derived complex plastids.
    Moog D, Nozawa A, Tozawa Y, Kamikawa R.
      The triose phosphate transporter (TPT) is one of the prerequisites to exchange metabolites between the cytosol and plastids. In this study, we demonstrated that the four plastid TPT homologues in the non-photosynthetic diatom Nitzschia sp. NIES-3581 were highly likely integrated into plastid envelope membranes similar to counterparts in the model photosynthetic diatom Phaeodactylum tricornutum, in terms of target membranes and C-terminal orientations. Three of the four Nitzschia TPT homologues are capable of transporting various metabolites into proteo-liposomes including triose phosphates (TPs) and phosphoenolpyruvate (PEP), the transport substrates sufficient to support the metabolic pathways retained in the non-photosynthetic diatom plastid. Phylogenetic analysis of TPTs and closely related transporter proteins indicated that diatoms and other algae with red alga-derived complex plastids possess only TPT homologues but lack homologues of the glucose 6-phosphate transporter (GPT), xylulose 5-phosphate transporter (XPT), and phosphoenolpyruvate transporter (PPT). Comparative sequence analysis suggests that many TPT homologues of red alga-derived complex plastids potentially have the ability to transport mainly TPs and PEP. TPTs transporting both TPs and PEP highly likely mediate a metabolic crosstalk between a red alga-derived complex plastid and the cytosol in photosynthetic and non-photosynthetic species, which explains the lack of PPTs in all the lineages with red alga-derived complex plastids. The PEP-transporting TPTs might have emerged in an early phase of endosymbiosis between a red alga and a eukaryote host, given the broad distribution of that type of transporters in all branches of red alga-derived complex plastid-bearing lineages, and have probably played a key role in the establishment and retention of a controllable, intracellular metabolic connection in those organisms.
    DOI:  https://doi.org/10.1038/s41598-020-58082-8
  984. Spectrochim Acta A Mol Biomol Spectrosc. 2020 Jan 02. pii: S1386-1425(19)31394-0. [Epub ahead of print]230 117995
    A facile microwave assisted synthesis and structure elucidation of (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones by crystallographic, spectroscopic and DFT studies.
    Raza AR, Nisar B, Khalid M, Gondal HY, Khan MU, de Alcântara Morais SF, Tahir MN, Braga AAC.
      The use of microwave (MW) irradiation in organic synthesis has become increasingly popular within the pharmaceutical and academic arenas because it is a new enabling technology for drug discovery and development. It is a rapid way of synthesis, which involves faster reaction rates and high selectivity to conventional heating method of syntheses. The MW-assisted 7-exo-tet cyclization of N-acylanthranilic acids afforded (3R)-3-alkyl-4,1-benzoxazepines-2,5-diones in very short duration (20 min) with extraordinary high yields in comparison to conventional heating mode of synthesis. The method development, comparative yields of MW-assisted and thermal method of syntheses, crystallographic, spectroscopic and density functional theory (DFT) studies are reported herein. Four novel compounds with chemical formulas C10H9BrClNO35m, C19H19NO36e, C13H14ClNO36h and C12H11Br2NO36h were synthesized, validated by 1HNMR, 13CNMR, FT-IR, UVVis, EIMS spectroscopic techniques and confirmed by using single crystal X-ray diffraction (SC-XRD) study. The DFT and TDDFT calculations at B3LYP/6-311 + G(d,p) level of theory were performed for comparative analysis of spectroscopic data, optimized geometries, frontier molecular orbitals (FMOs), natural bond orbital (NBO) analysis and nonlinear optical (NLO) properties of 5m, 6e, 6h and 6o. Overall, experimental findings were supported nicely by corresponding DFT computed results. The NBO analysis confirmed that the presence of non-covalent interactions, hydrogen bonding and hyper- conjugative interactions are pivotal cause for the existence of 5m, 6e, 6h and 6o in the solid-state. NLO analysis showed that 5m, 6e, 6h and 6o have significant NLO properties as compared to prototype standard compound which disclosed their potential for technology related applications.
    Keywords:  (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones; Chiral pool approach; DFT; Microwave irradiation; N-acylanthranilic acids; Spectroscopic data
    DOI:  https://doi.org/10.1016/j.saa.2019.117995
  985. Nutr Rev. 2020 Jan 22. pii: nuz103. [Epub ahead of print]
    Psyllium husk intake and risk of type 2 diabetes: an evidence-based scientific and regulatory review of a qualified health claim conducted by the US Food and Drug Administration.
    Rivers CR, Kantor MA.
      The US Food and Drug Administration (FDA) received a petition from a company requesting that FDA issue an authorized health claim for the relationship between psyllium husk and a reduced risk of type 2 diabetes. After an initial assessment of the available scientific evidence, FDA determined that significant scientific agreement was lacking for this substance-disease relationship, whereupon the company agreed to have its petition reviewed as a qualified health claim. This article describes the process FDA used in conducting an evidence-based review of the science underpinning the proposed claim and addresses certain safety issues associated with psyllium husk that FDA considered in its review of the petition. Of the 6 studies from which scientific conclusions could be drawn, as identified through FDA's review, psyllium husk significantly improved plasma glucose levels and insulin sensitivity in only 1 study. Therefore, FDA's enforcement discretion letter for this qualified health claim stated: "Psyllium husk may reduce the risk of type 2 diabetes, although the FDA has concluded that there is very little scientific evidence for this claim."
    Keywords:  FDA; health claim; psyllium husk; type 2 diabetes
    DOI:  https://doi.org/10.1093/nutrit/nuz103
  986. Hum Exp Toxicol. 2020 Jan 20. 960327119893414
    Sulforaphane attenuates angiotensin II-induced human umbilical vein endothelial cell injury by modulating ROS-mediated mitochondrial signaling.
    Zhang M, Xu Y, Jiang L.
      The study aimed to investigate whether sulforaphane (SFN) protects against angiotensin II (Ang II)-mediated human umbilical vein endothelial cell (HUVEC) injury. Ang II treatment decreased HUVEC viability, increased cell apoptosis, decreased mitochondria membrane potential (MMP), impaired cytochrome c release, activated caspase 3/9, and induced reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate oxidase activity. Moreover, SFN treatment blunted Ang II-stimulated oxidative stress and mitochondria-related apoptosis in HUVECs. The ROS scavenger N-acetyl-l-cysteine reduced Ang II-induced oxidative stress and apoptosis, indicating that ROS generation is involved in the Ang II-induced mitochondria-mediated apoptotic pathway. SFN induced nuclear factor erythroid 2 (Nrf2) activation and expression in Ang II-stimulated HUVECs. Downregulation of Nrf2 expression by a target-specific siRNA revealed an Nrf2-dependent effect on the SFN-mediated attenuation of Ang II-induced apoptosis in HUVECs. Pretreatment with brusatol, an Nrf2-specific inhibitor, reversed the protective effects of SFN on Ang II-induced HUVEC injury. SFN treatment protected HUVECs from Ang II-induced damage by decreasing oxidative stress and ameliorating mitochondrial injury.
    Keywords:  Nrf2; Sulforaphane; angiotensin II; human umbilical vein endothelial cells; oxidative stress
    DOI:  https://doi.org/10.1177/0960327119893414
  987. J Phys Chem Lett. 2020 Jan 24.
    N-H Chirality in Folded Peptide LK7β Is Governed by the Cα-H Chirality.
    Hu X, Fu L, Hou J, Zhang Y, Zhang Z, Wang H.
      Recent chiral sum-frequency generation vibrational spectroscopy (SFG-VS) measurements revealed that two N-H stretching modes in the 3100-3500 cm-1 range in folded peptide LK7β exhibit chiral characteristics. Here we report the first phase-resolved sub-wavenumber high-resolution broadband SFG-VS (HR-BB-SFG-VS) measurement of the folded peptide LK7β. The results show that this chiral N-H band consists of four, instead of two, distinctive peaks, and they are with two groups of opposite spectral phases. Moreover, the phases of these N-H peaks completely flip from the L-LK7β to the D-LK7β peptide, suggesting that the chirality of the N-H in the folded peptide LK7βis completely governed by the chirality of the Cα-H of the amino acids. This discovery provides a clue on why proteins in nature are composed of the α-amino acids rather than β- or γ-amino acids and may help us understand how life works.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03470
  988. SLAS Discov. 2020 Feb;25(2): 115-117
    Advances in Cellular Target Engagement and Target Deconvolution.
    Main MJ, Zhang AX.
      
    DOI:  https://doi.org/10.1177/2472555219897269
  989. Paediatr Drugs. 2020 Jan 22.
    New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management.
    Saraff V, Nadar R, Högler W.
      X-linked hypophosphataemia (XLH) is due to mutations in phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and represents the most common heritable form of rickets. In this condition, the hormone fibroblast growth factor 23 (FGF23) is produced in excessive amounts for still unknown reasons, and causes renal phosphate wasting and suppression of 1,25-dihydroxyvitamin D, leading to low serum phosphate concentrations. Prolonged hypophosphataemia decreases apoptosis of hypertrophic chondrocytes in growth plates (causing rickets) and decreases mineralisation of existing bone (causing osteomalacia). In contrast to historical conventional treatment with oral phosphate supplements and active vitamin D for the last 50 years, the new anti-FGF23 antibody treatment (burosumab) targets the primary pathology by blocking FGF23, thereby restoring phosphate homeostasis. In this review, we describe the changes in treatment monitoring, treatment targets and long-term treatment goals, including future opportunities and challenges in the treatment of XLH in children.
    DOI:  https://doi.org/10.1007/s40272-020-00381-8
  990. Methods Mol Biol. 2020 ;2090 21-48
    Processing and Analyzing Multiple Genomes Alignments with MafFilter.
    Dutheil JY.
      As the number of available genome sequences from both closely related species and individuals within species increased, theoretical and methodological convergences between the fields of phylogenomics and population genomics emerged. Population genomics typically focuses on the analysis of variants, while phylogenomics heavily relies on genome alignments. However, these are playing an increasingly important role in studies at the population level. Multiple genome alignments of individuals are used when structural variation is of primary interest and when genome architecture permits to assemble de novo genome sequences. Here I describe MafFilter, a command-line-driven program allowing to process genome alignments in the Multiple Alignment Format (MAF). Using concrete examples based on publicly available datasets, I demonstrate how MafFilter can be used to develop efficient and reproducible pipelines with quality assurance for downstream analyses. I further show how MafFilter can be used to perform both basic and advanced population genomic analyses in order to infer the patterns of nucleotide diversity along genomes.
    Keywords:  Alignment post-processing; Multiple alignment format; Multiple genome alignment; Quality filtering; Synteny
    DOI:  https://doi.org/10.1007/978-1-0716-0199-0_2
  991. Pediatr Blood Cancer. 2020 Jan 23. e28098
    Preclinical evaluation of the combination of AZD1775 and irinotecan against selected pediatric solid tumors: A Pediatric Preclinical Testing Consortium report.
    Kolb EA, Houghton PJ, Kurmasheva RT, Mosse YP, Maris JM, Erickson SW, Guo Y, Teicher BA, Smith MA, Gorlick R.
      INTRODUCTION: WEE1 is a serine kinase central to the G2 checkpoint. Inhibition of WEE1 can lead to cell death by permitting cell-cycle progression despite unrepaired DNA damage. AZD1775 is a WEE1 inhibitor that is in clinical development for children and adults with cancer.METHODS: AZD1775 was tested using a dose of 120 mg/kg administered orally for days 1 to 5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg for days 1 to 5 (one hour after AZD1775 when used in combination). AZD1775 and irinotecan were studied alone and in combination in neuroblastoma (n = 3), osteosarcoma (n = 4), and Wilms tumor (n = 3) xenografts.
    RESULTS: AZD1775 as a single agent showed little activity. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and two Wilms tumor models (CR and PR). The combination of AZD1775 + irinotecan-induced objective responses in two neuroblastoma lines (PR and CR) and all three Wilms tumor lines (CR and 2 PRs). The objective response measure improved compared with single-agent treatment for one neuroblastoma (PR to CR), two osteosarcoma (PD1 to PD2), and one Wilms tumor (PD2 to PR) xenograft lines. Of note, the combination yielded CR (n = 1) and PR (n = 2) in all the Wilms tumor lines. The event-free survival was significantly longer for the combination compared with single-agent irinotecan in all models tested. The magnitude of the increase was greatest in osteosarcoma and Wilms tumor xenografts.
    CONCLUSIONS: AZD1775 potentiates the effects of irinotecan across most of the xenograft lines tested, with effect size appearing to vary across tumor panels.
    Keywords:  AZD1775; Wilms tumor; irinotecan; neuroblastoma; osteosarcoma; preclinical testing
    DOI:  https://doi.org/10.1002/pbc.28098
  992. Ophthalmic Res. 2020 Jan 17. 1-12
    Effects and Mechanism of Action of PX-478 in Oxygen-Induced Retinopathy in Mice.
    Pan X, Lv Y.
      IMPORTANCE: Retinopathy of prematurity (ROP) is an important risk factor for blindness in children due to neovascularization (NV). Hypoxia stimulates the formation of NV, as retinal hypoxia affects the stability and function of hypoxia-inducible factor (HIF) transcription factors. The purpose of this study is to study the mechanism of ROP and provide theoretical basis for clinical treatment of ROP.OBJECTIVE: In the present study, we used a mouse model of oxygen-induced retinopathy (OIR) to demonstrate the effects of the HIF-1α inhibitor PX-478 on OIR, and to determine its mechanism of action, to provide a theoretical basis for the clinical treatment of ROP.
    MATERIALS AND METHODS: The OIR mouse model was induced by exposing neonatal mouse pups and their mothers to 75 ± 5% oxygen from postnatal day 7 (P7) to P12, before being returned to room air from P12 to P17. Flat mount analyses were performed at P12 and P17. Hif1a, Hif2a, Hif3a, and Vegfa mRNA were detected by reverse transcription-polymerase chain reaction in OIR mice at P12 and P17. Hif1a and Vegfa mRNA were detected in OIR mice at P12 and P17 treatment with PX-478. Western blot analyses were used to assess the levels of HIF-1α, VEGF-A, and EPO before and after treatment with PX-478 at P12 and P17.
    RESULTS: Hif1a mRNA was increased in OIR mice at P12 and P17, while Vegfa mRNA was increased at P12 and P17. HIF-1α, VEGF-A, and EPO protein levels were increased in OIR mice at P12 and P17, as compared to control mice at the same age (all p < 0.05). Inhibition of HIF-1α by injection of PX-478 in OIR mice (P9-P16) caused a decrease in the retinal avascular area at P12 and P17 (both p < 0.05), NV areas at P17 (p < 0.05), Vegfa mRNA decreased at P12 and P17, as compared to control mice (p < 0.05), and VEGF-A and EPO protein levels at P12 and P17, as compared to control mice. Our study found that there were PX-478 both retina and vitreous body of OIR. Inhibition of HIF-1α by injection of PX-478 in OIR mice caused a decrease in the retinal avascular area at P12 and P17, NV areas decreased at P17, VEGF-A and EPO protein levels at P12 and P17. Endothelial cell migration assays and cell tube formation indication PX-478 attenuate cell migration and significantly weakened the cell cavity formation under the condition of hypoxia.
    CONCLUSION: HIF-1α plays a main role in OIR and can be considered a therapeutic target in OIR by suppressing downstream angiogenic factors, PX-478 decreasing the retinal avascular area and NV.
    Keywords:  HIF-1α; Hypoxia; Inhibitor; Neovascularization; Oxygen-induced retinopathy; PX-478
    DOI:  https://doi.org/10.1159/000504023
  993. Eur J Radiol. 2020 Jan 11. pii: S0720-048X(20)30017-6. [Epub ahead of print]124 108828
    Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection.
    Morio K, Kawaoka T, Aikata H, Namba M, Uchikawa S, Kodama K, Ohya K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Tsuge M, Hiramatsu A, Imamura M, Nakamura Y, Akagi M, Awai K, Kobayashi T, Ohdan H, Chayama K.
      PURPOSE: In recent years, it has been reported that use of 18F-FDG PET-CT can reveal the degree of hepatocellular carcinoma malignancy. We evaluate the ability of a preoperative 18F-FDG PET-CT to predict the recurrence of extrahepatic metastasis of HCC after surgery.METHODS: We retrospectively examined 67 patients who received 18F-FDG PET-CT prior to curative hepatic resection for HCC between April 2010 and March 2016. Multivariate Cox regression analysis was performed to identify the factors associated with recurrence of extrahepatic metastasis of HCC after surgery. We also evaluated the sensitivity, specifity, positive predictive value, negative predictive value and accuracy of diagnosis of 18F-FDG PET-CT for recurrent extrahepatic metastasis of HCC after surgery.
    RESULTS: The multivariate analysis identified a tumor-to-normal liver standardized uptake value ratio (TNR) ≥ 1.53 (hazard ratio [HR], 0.037; P = 0.003), multiple tumor nodules (HR, 0.121; P = 0.007), and presence of microvascular invasion (HR, 0.094; P = 0.003) as independent predictors of distant metastasis recurrence. A TNR ≥ 1.53 showed a sensitivity of 91.7 %, specificity of 76.4 %, positive predictive value of 45.8 %, negative predictive value of 97.7 %, and accuracy of 79.1 % for diagnosing distant metastasis recurrence of HCC. In a binomial logistic regression analysis of tumor factors associated with a TNR ≥ 1.53, poor tumor differentiation and large tumor size were significant factors.
    CONCLUSION: 18F-FDG PET-CT and microvascular invasion may be useful for predicting the recurrence of extrahepatic metastasis of HCC after surgery.
    Keywords:  Hepatocellular cancer; Metastasis; PET-CT; Recurrence
    DOI:  https://doi.org/10.1016/j.ejrad.2020.108828
  994. Angew Chem Int Ed Engl. 2020 Jan 22.
    Controlling Single Molecule Conductance by Chemical Reaction.
    Michnowicz T, Borca B, Pétuya R, Schendel V, Pristl M, Pentegov I, Kraft U, Klauk H, Wahl P, Mutombo P, Jelínek P, Arnau A, Schlickum U, Kern K.
      Among the prerequisites for the progress of single-molecule-based electronic devices are a better understanding of the electronic properties at the individual molecular level and the development of methods to tune the charge transport through molecular junctions. Scanning Tunneling Microscopy (STM) is an ideal tool not only for the characterization, but also for the manipulation of single atoms and molecules on surfaces. The conductance through a single molecule can be measured by contacting the molecule with atomic precision and forming a molecular bridge between the metallic STM tip electrode and the metallic surface electrode. The parameters affecting the conductance are mainly related to their electronic structure and to the coupling to the metallic electrodes. Here, the experimental and theoretical analyses are focused on single tetracenothiophene molecules and demonstrate that an in-situ-induced direct desulfurization reaction of the thiophene moiety strongly improves the molecular anchoring by forming covalent bonds between molecular carbon and copper surface atoms. This bond formation leads to an increase of the conductance by about 50% compared to the initial state.
    Keywords:  single-molecule conductance, covalent-bond formation, strong anchoring, STM/AFM, DFT
    DOI:  https://doi.org/10.1002/anie.201915200
  995. Chin J Traumatol. 2019 Dec 27. pii: S1008-1275(19)30239-1. [Epub ahead of print]
    Low expression of vascular endothelial growth factor and high serum level of cyclic guanine monophosphate as the risk factors of femoral head osteonecrosis in alcohol-exposed Wistar rat.
    Suyasa IK, Wiradewi Lestari AA.
      PURPOSE: Severe damage to the femoral head in patients with osteonecrosis has a high impact on morbidity. Despite early diagnosis, the treatment outcome is still unsatisfactory. This study aimed to explore the expression of vascular endothelial growth factor (VEGF) and cyclic guanine monophosphate (cGMP) serum level as the risk factors of femoral head osteonecrosis in alcohol-exposed Wistar rats.METHODS: This was an experimental study using randomized post-test only control group design, with samples using 10-14 weeks Wistar male rats. Rats were then divided into 6 groups: 3 groups without intervention, and 3 groups with intervention using 40% alcohol given perorally. Each one group from intervention and control group was euthanized by the end of the week for 3 consecutive weeks. Proximal femurs were examined under microscope for osteonecrosis, immunohistochemically for VEGF, and blood serum for cGMP levels.
    RESULTS: VEGF expression in the femoral head of alcohol-exposed Wistar rats was lower than those not exposed to alcohol (p < 0.005). Blood serum cGMP levels of alcohol-exposed Wistar rats were higher than those not exposed to alcohol (p < 0.005). The number of necrotic osteocytes in the femoral head of Wistar rats exposed to alcohol was greater than those not exposed to alcohol (p < 0.005). There are significant differences between VEGF, cGMP levels, and number of necrotic osteocytes in the control group and treatment at 1st, 2nd, and 3rd week (p < 0.005).
    CONCLUSIONS: Based on the result of this study, VEGF and cGMP may be considered as diagnostic biomarkers for alcohol-induced femoral head osteonecrosis.
    Keywords:  Cyclic guanosine monophosphate; Osteonecrosis; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1016/j.cjtee.2019.09.003
  996. BMC Pregnancy Childbirth. 2020 Jan 20. 20(1): 44
    Uterine and placental blood flow indexes and antinuclear autoantibodies in unexplained recurrent pregnancy loss: should they be investigated in pregnancy as correlated potential factors? A retrospective study.
    Bruno V, Ticconi C, Martelli F, Nuccetelli M, Capogna MV, Sorge R, Piccione E, Pietropolli A.
      BACKGROUND: The potential role of antinuclear antibodies (ANA) in recurrent pregnancy loss (RPL) pathogenesis is still debated, although some evidences suggest that they could affect pregnancy outcome, leading to a higher miscarriage rate in these patients. A hypothesized mechanism is through changes in uterine flow in pre-conceptional stage, by modifying endometrial receptivity in RPL. However, scant data are available, in pregnancy, about their role in RPL placental perfusion, also in relation to its potential treatments, such as low molecular weight heparin (LMWH). The aim of this study is to retrospectively further investigate the correlation between two-dimensional (2D) and three-dimensional (3D) uterine and placental flow indexes and the presence or the absence of ANA in women with unexplained RPL (uRPL), treated or not treated with LMWH.METHODS: 2D Doppler measurement of pulsatility index (PI) of the uterine arteries and 3D ultrasonography determination of vascularization index (VI), flow index (FI) and vascularization flow index (VFI) was carried out with the aid of the virtual organ computer-aided analysis (VOCAL) technique in LMWH treated (n 24) and not treated-uRPL patients (n 20) and in the relative control group (n 27), each group divided in ANA+ and ANA- subgroups. Serum assay for the presence of ANA was performed in all women.
    RESULTS: No differences were found in PI, VFI and VI values, by comparing the different groups. A difference in VI values was found for ANA- patients between RPL women not treated with LMWH and the treated ones (p = 0,01), which have lower VI values and similar to controls. By considering only ANA- treated and not treated RPL patients, the ROC curve shows an area of 0,80 and at the VI cut-off of 11,08 a sensitivity of 85% and a specificity of 67%.
    CONCLUSIONS: LMWH could exert a potential beneficial effect in restoring the physiological blood flow supply in terms of VI in uRPL ANA- status, suggesting to include ANA and VI investigations in the RPL diagnostic algorithm in a research context, since further studies are needed to clarify this challenging hypothesis in order to try to ameliorate ANA and abnormal placental vascularization negative influence on RPL pregnancy outcome .
    Keywords:  ANA; LMWH; Placental blood flow supply; VOCAL; uRPL
    DOI:  https://doi.org/10.1186/s12884-020-2724-6
  997. J Assoc Physicians India. 2020 Jan;68(1): 50
    Spirometric Analysis in Type 2 Diabetes Mellitus.
    Hazra TK, Kapoor D, Dhir S.
      
  998. Heart Lung Circ. 2019 Dec 09. pii: S1443-9506(19)31493-3. [Epub ahead of print]
    Multivisceral Transplant, The Prince Charles Experience.
    Doig FE, Naidoo R, Hwang J, Frost C, Wall D, Tesar P, Sharma V, Fiene A, Hopkins P.
      BACKGROUND: Multi-visceral organ transplant is uncommon. As a result of the rarity of these surgeries, there are limited studies, making it difficult to interpret outcomes and identify specific patient complications. We aim to assess the indications for multi-organ transplant, the time on the wait-list and evaluate outcomes including patient survival, graft survival and postoperative complications in an Australian context.METHODS: Patients undergoing multi-organ transplant from 1993 to 2018 at The Prince Charles Hospital were retrospectively reviewed, looking at baseline characteristics and post-transplant morbidity, mortality and graft survival.
    RESULTS: A total of 37 patients were included in the study, comprising 22 heart-lung transplants, eight heart-kidney transplants and seven heart-lung-liver transplants. There were six domino heart transplants performed, all in the heart-lung-liver transplant group. The mean age at transplant was 37 years and the mean wait-list time was 10 months. One patient, receiving a heart-lung transplant, required re-transplantation (bilateral lung) at 3 years. One-year (1-year) survival was 91% for heart-lung transplants, 86% for heart-lung-liver transplants and 87.5% for heart-kidney transplants. Five- and ten-year (5- and 10-year) survival was 79% for both in heart-lung transplant, 43% and 29% for heart-lung-liver transplant and 87.5% for both in heart-kidney transplant.
    CONCLUSION: Patients undergoing multi-organ transplant at our unit had long-term survival and organ function comparable to international data. In addition, waitlist time for multi-organ transplant was not found to be excessive.
    Keywords:  Heart transplant; Heart−lung transplant; Multi-organ transplant
    DOI:  https://doi.org/10.1016/j.hlc.2019.10.012
  999. Nucleic Acids Res. 2020 Jan 21. pii: gkaa029. [Epub ahead of print]
    A crucial RNA-binding lysine residue in the Nab3 RRM domain undergoes SET1 and SET3-responsive methylation.
    Lee KY, Chopra A, Burke GL, Chen Z, Greenblatt JF, Biggar KK, Meneghini MD.
      The Nrd1-Nab3-Sen1 (NNS) complex integrates molecular cues to direct termination of noncoding transcription in budding yeast. NNS is positively regulated by histone methylation as well as through Nrd1 binding to the initiating form of RNA PolII. These cues collaborate with Nrd1 and Nab3 binding to target RNA sequences in nascent transcripts through their RRM RNA recognition motifs. In this study, we identify nine lysine residues distributed amongst Nrd1, Nab3 and Sen1 that are methylated, suggesting novel molecular inputs for NNS regulation. We identify mono-methylation of one these residues (Nab3-K363me1) as being partly dependent on the H3K4 methyltransferase, Set1, a known regulator of NNS function. Moreover, the accumulation of Nab3-K363me1 is essentially abolished in strains lacking SET3, a SET domain containing protein that is positively regulated by H3K4 methylation. Nab3-K363 resides within its RRM and physically contacts target RNA. Mutation of Nab3-K363 to arginine (Nab3-K363R) decreases RNA binding of the Nab3 RRM in vitro and causes transcription termination defects and slow growth. These findings identify SET3 as a potential contextual regulator of Nab3 function through its role in methylation of Nab3-K363. Consistent with this hypothesis, we report that SET3 exhibits genetic activation of NAB3 that is observed in a sensitized context.
    DOI:  https://doi.org/10.1093/nar/gkaa029
  1000. Kyobu Geka. 2020 Jan;73(1): 72-75
    [Lung Cancer Accompanied by Sarcoidosis with Mediastinal and Bilateral Hilar Lymphadenopathy;Report of a Case].
    Suzuki H, Shibuya J, Kobayashi K, Handa M, Ishida K, Sugimoto R.
      A 64-year-old woman with complete atrioventricular block caused by sarcoidosis was emergently placed a pacemaker. A 10 mm nodule in the left upper lobe of the lung and the mediastinal and bilateral hilar lymphadenopathy was detected through chest computed tomography. To establish the diagnosis, resection of the tumor and #4L was performed. By intraoperative pathology, the nodule was diagnosed as an adenocarcinoma and #4L was found to be a granuloma without metastasis of carcinoma. Subsequently, left upper lobectomy and lymph node dissection (ND2a-2) was conducted. Pathological stage was stageⅠA1 lung cancer. No recurrence has been noted for a year postoperatively and lymphadenopathy has improved by administering prednisolone medication.
  1001. ACS Omega. 2020 Jan 14. 5(1): 386-393
    Vibrational Spectroscopy and Morphological Studies on Protein-Capped Biosynthesized Silver Nanoparticles.
    Agressott EVH, Blätte D, Cunha FA, Noronha VT, Ciesielski R, Hartschuh A, Paula AJ, Fechine PBA, Souza Filho AG, Paschoal AR.
      Silver nanoparticles (AgNPs) have a large number of applications in technology and physical and biological sciences. These nanomaterials can be synthesized by chemical and biological methods. The biological synthesis using fungi represents a green approach for nanomaterial production that has the advantage of biocompatibility. This work studies silver nanoparticles (AgNPs) produced by fungi Rhodotorula glutinis and Rhodotorula mucilaginosa found in ordinary soil of the Universidade Federal do Ceará campus (Brazil). The biosynthesized AgNPs have a protein-capping layer involving a metallic Ag core. The focus of this paper is to investigate the size and structure of the capping layer, how it interacts with the Ag core, and how sensitive the system (core + protein) is to visible light illumination. For this, we employed SEM, AFM, photoluminescence spectroscopy, SERS, and dark-field spectroscopy. The AgNPs were isolated, and SEM measurements showed the average size diameter between 58 nm for R. glutinis and 30 nm for R. mucilaginosa. These values are in agreement with the AFM measurements, which also provided the average size diameter of 85 nm for R. glutinis and 56 nm for R. mucilaginosa as well as additional information about the average size of the protein-capping layers, whose found values were 24 and 21 nm for R. mucilaginosa and R. glutinis nanoparticles, respectively. The protein-capping layer structure seemed to be easily disturbed, and the SERS spectra were unstable. It was possible to identify Raman peaks that might be related to α-helix, β-sheet, and protein mixed structures. Finally, dark-field microscopy showed that the silver cores are very stable, but some are affected by the laser energy due to heating or melting.
    DOI:  https://doi.org/10.1021/acsomega.9b02867
  1002. Phytopathology. 2020 Jan 21.
    Physiological and transcriptional response of Xanthomonas oryzae pv. oryzae to berberine, an emerging chemical control.
    Yang P, Li FJ, Huang SW, Luo M, Lin W, Yuan GQ, Li QQ.
      Berberine, a botanical drug, has great ability to inhibit the growth of Xanthomonas oryzae pv. oryzae (Xoo). However, the antibacterial mechanism of berberine against Xoo remains poorly understood. In this study, we investigated the physiological and transcriptional response of Xoo to berberine. When strain Xoo-GX13 was treated with berberine (10 μg/mL), the hypersensitive response in tobacco, virulence to rice, pathogen population in the rice xylem, production of extracellular polysaccharide (EPS) and activity of extracellular hydrolases decreased, but the levels of pyruvate and ATP increased. Moreover, biofilm formation was inhibited, and the cell membrane was damaged. Transcriptome sequencing analysis showed downregulated expression of gspD, gspE and gspF, involved in the type II secretion system (T2SS); hrcC, hrcJ, hrcN, etc., involved in the type III secretion system (T3SS); gumB and gumC, associated with EPS; zapE, ftsQ and zapA, associated with cell division; lpxH, lpxK, kdtA, etc., associated with the membrane; and pyk, pgk and mdh, encoding pyruvate kinase, phosphoglycerate kinase and malate dehydrogenase, respectively. Upregulated expression was observed for nuoA, nuoB and nuoH, encoding the NADH dehydrogenase complex, and atpF, atpC and atpB, encoding ATP synthase. An adenylate cyclase (CyaA) fusion assay showed that berberine affects T3E secretion via the T3SS and reduces effector translocation in Xoo. It is speculated that the negative growth and virulence phenotypes of berberine-treated Xoo-GX13 may involve differentially expressed genes associated with cytoarchitecture and energy metabolism, these effects on primary cell function may further dampen virulence and result in differential expression of T3SS- and T2SS-related genes.
    Keywords:  Disease control and pest management
    DOI:  https://doi.org/10.1094/PHYTO-09-19-0327-R
  1003. J Adolesc. 2020 Jan 18. pii: S0140-1971(19)30242-8. [Epub ahead of print]79 128-135
    Factors associated with early sexual initiation and unsafe sex in adolescents: Substance use and parenting style.
    Reis LF, Surkan PJ, Valente JY, Bertolla MHSM, Sanchez ZM.
      
    Keywords:  Adolescence; Alcohol; Drug abuse; Safer sex
    DOI:  https://doi.org/10.1016/j.adolescence.2019.12.015
  1004. Eur J Pharm Biopharm. 2020 Jan 17. pii: S0939-6411(20)30017-5. [Epub ahead of print]
    Nanomedicine in osteosarcoma therapy: micelleplexes for delivery of nucleic acids and drugs for osteosarcoma-targeted therapy.
    Pereira-Silva M, Alvarez-Lorenzo C, Concheiro A, Cláudia Santos A, Veiga F, Figueiras A.
      Osteosarcoma(OS) represents the main cancer affecting bone tissue, and one of the most frequent in children. In this review we discuss the major pathological hallmarks of this pathology, its current therapeutics, new active biomolecules, as well as the nanotechnology outbreak applied to the development of innovative strategies for selective OS targeting. Small RNA molecules play a role as key-regulator molecules capable of orchestrate different responses in what concern cancer proliferation, migration and invasiveness. Frequently associated with lung metastasis, new strategies are urgent to upgrade the therapeutic outcomes and the life-expectancy prospects. Hence, the prominent rise of micelleplexes as multifaceted and efficient structures for small nucleic acid delivery and selective drug targeting is revisited here with special emphasis in ligand-mediated active targeting. Future landmarks towards the development of novel nanostrategies for both OS diagnosis and OS therapy improvements are also discussed.
    Keywords:  Cancer targeting; active targeting; doxorubicin; gene delivery; micelleplexes; osteosarcoma
    DOI:  https://doi.org/10.1016/j.ejpb.2019.10.013
  1005. Rapid Commun Mass Spectrom. 2020 Jan 22. e8735
    Drug Metabolite Identification using UHPLC UV Spectroscopy and Parallelized Scans on a Tribrid Orbitrap Mass Spectrometer.
    Wilkinson SD, Martin S, Orton AL, Markandu R, Jones BC.
      RATIONALE: To capture all metabolites in metabolite identification studies, MS/MS information is required in both positive and negative ionisation modes, usually requiring several sample injections to gain all sample information. A high resolution and high mass accuracy quadrupole/linear trap/Orbitrap tribrid instrument was used to gain all this information in a novel single injection "capture all" approach to metabolite identification.METHODS: Incubations of diclofenac, a model compound, were conducted in human and rat hepatocytes. These were run using UHPLC/UV coupled to a Thermo Fusion tribrid mass spectrometer. Five parallel scans were employed, positive and negative ion full scan, data dependent MS/MS, both high energy dissociation and collision induced dissociation, and data independent all ion fragmentation were collected in positive and negative ion mode.
    RESULTS: Nine metabolites were identified; a metabolite observed in the UV trace, but not positive ion full scan MS was detected in the same sample injection by negative ion full scan MS. This was identified as a sulfate metabolite and the corresponding negative ion all ion fragmentation allowed for some structural elucidation. The use of a photo diode array detector allowed for spectral assessment in case of changes in absorbance spectra, and subsequent metabolite semi-quantification.
    CONCLUSION: This method provided good quality MS/MS data across the m/z range in both positive and negative ion. The addition of both negative ion full scan MS and negative ion MS/MS allowed for the detection and structural elucidation of metabolites not observed in positive ion. Use of the photo diode array detector allowed metabolite semi-quantification.
    DOI:  https://doi.org/10.1002/rcm.8735
  1006. Br J Oral Maxillofac Surg. 2020 Jan 16. pii: S0266-4356(19)30779-X. [Epub ahead of print]
    Oral tyrosine kinase inhibitors in OMFS: a review.
    Shah P, Dylgjeri F, Srinivasan B, Brennan PA.
      It is increasingly common in OMFS to treat patients who are taking therapeutic doses of anticoagulant or antiplatelet drugs, or both. These patients have a high risk of postoperative bleeding ranging from minor oozing that can be managed using local measures, to a major haemorrhage necessitating transfusion. The risk of bleeding associated with tyrosine kinase inhibitors (TKI) taken orally is not well-known in the specialty. We report a case series of two patients treated with them and discuss this group of drugs.
    Keywords:  bleeding; oral and maxillofacial surgery; review; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.bjoms.2019.11.022
  1007. JACC Cardiovasc Imaging. 2020 Jan 09. pii: S1936-878X(19)31157-X. [Epub ahead of print]
    Prognostic Value of 18F-FDG PET Using Texture Analysis in Cardiac Sarcoidosis.
    Manabe O, Koyanagawa K, Hirata K, Oyama-Manabe N, Ohira H, Aikawa T, Furuya S, Naya M, Tsujino I, Tomiyama Y, Otaki Y, Anzai T, Tamaki N.
      
    DOI:  https://doi.org/10.1016/j.jcmg.2019.11.021
  1008. Int J Soc Psychiatry. 2020 Jan 20. 20764019899978
    'I wanted my child dead' - Physical, social, cognitive, emotional and spiritual life stories of Turkish parents who give care to their children with schizophrenia: A qualitative analysis based on empowerment approach.
    Akgül Gök F, Duyan V.
      BACKGROUND: Schizophrenia deeply affects both the lives of patients and their families. The fact that schizophrenic patients in Turkey generally maintain their lives with their families may lead to serious problems for families and parents.AIMS: The main purposes of this research are to determine the physical, social, cognitive, emotional and spiritual lives of parents of children with schizophrenia with the main concepts of the empowerment approach.
    METHOD: The research was carried out with the qualitative research method. In-depth interviews were conducted with 30 parents in total, that is, 15 mothers and 15 fathers, through semi-structured interview form. Maxqda 2018 was used for the analysis of the research data.
    RESULTS: According to the research result, it is determined that the parents have problems due to physical, social, cognitive, emotional and spiritual disease process; gender perspective and roles; domestic functionality; social environment, social perception; and issues related to services.
    CONCLUSION: Considering the parents who are affected by the disease process which is a particularly quite difficult process and who affect the process, to recognize the situations that lead them to gain strength and that make them powerless in personal, interpersonal and political aspects, to activate the existing resources and to create new resources are highly important factors for them to cope with the disease process effectively.
    Keywords:  Empowerment approach; life; parent; schizophrenia
    DOI:  https://doi.org/10.1177/0020764019899978
  1009. J Proteomics. 2020 Jan 17. pii: S1874-3919(20)30021-X. [Epub ahead of print] 103653
    Hepatic proteomic analysis of selenoprotein F knockout mice by iTRAQ: An implication for the roles of selenoprotein F in metabolism and diseases.
    Zheng X, Ren B, Wang H, Huang R, Zhou J, Liu H, Tian J, Huang K.
      Selenoprotein F (Selenof) is an endoplasmic reticulum (ER)-resident protein. It may be functionally linked to glycoprotein folding in the ER but the detail function is not fully understood. To study the function of Selenof, we used CRISPR/Cas9 to generate Selenof knockout mice and performed proteomic analysis of hepatic proteins by iTRAQ. Collectively, 83 differently expressed proteins (DEPs) were identified in the liver of Selenof knockout mice. The changes of mRNA and protein levels of 6 selected DEPs, Fatty acid synthase, ATP-citrate synthase, Glutathione S-transferase P 1, Transformer-2 protein homolog beta, Pyruvate kinase, Metallothionein-2, were further verified by quantitative real-time PCR or Western blot. The roles of 83 DEPs are mainly related to metabolism and cancer. Consistently, the levels of NADPH and ATP, two molecules closely related with energy metabolism, are significantly changed in the livers of Selenof knockout mice. SIGNIFICANCE: Our study identified potential biological pathways and proteins related to Selenof deletion. These findings will provide possible proteins/pathways related to Selenof and help to understand the function of Selenof and its relationship with certain diseases.
    Keywords:  Knockout; Proteomics; Selenoprotein F; iTRAQ
    DOI:  https://doi.org/10.1016/j.jprot.2020.103653
  1010. J Cell Physiol. 2020 Jan 21.
    MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells.
    Bai T, Liang R, Zhu R, Wang W, Zhou L, Sun Y.
      Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre-miR-214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR-214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR-214-induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR-214 elevated the ferroptosis-promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis-promoting effects of miR-214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.
    Keywords:  ATF4; ferroptosis; hepatocellular carcinoma; miR-214
    DOI:  https://doi.org/10.1002/jcp.29496
  1011. World J Transplant. 2019 Dec 20. 9(8): 158-164
    Challenges of pancreas transplantation in developing countries, exploring the Turkey example.
    Cimen SG, Cimen S, Kessaris N, Kahveci E, Tuzuner A.
      Pancreas transplantation significantly improves the quality of life for people with type 1 diabetes, primarily by eliminating the need for insulin and frequent blood glucose measurements. Despite the growing numbers of solid organ transplantations worldwide, number of pancreas transplantations in the developing countries` remain significantly low. This difference of pancreas transplantation practices was striking among the participating countries at the 1st International Transplant Network Meeting which was held in Turkey on 2018. In this meeting more than 40 countries were represented. Most of these counties were developing countries located in Africa, Middle East or Asia. The aim of this article is to identify the challenges and limiting factors for pancreas transplantations in these developing countries, by exploring the Turkish example. The challenges faced by the developing countries are broadly classified in four categories; wait-listing, donor pool, team work and follow up. Under these categorical titles, issues are further discussed in detail, giving examples from Turkish practice of pancreas transplantation. Additionally, several solutions to these challenges have been proposed- some of which have already been undertaken by the Turkish Ministry of Health. With the insight and methods presented in this article, pancreas transplantation should be made possible for the potential recipients in the developing countries.
    Keywords:  Challenges; Developing country; Pancreas transplantation; Quality of life; Transplantation
    DOI:  https://doi.org/10.5500/wjt.v9.i8.158
  1012. Sci Rep. 2020 Jan 22. 10(1): 908
    Circulating miR-330-3p in Late Pregnancy is Associated with Pregnancy Outcomes Among Lean Women with GDM.
    Pfeiffer S, Sánchez-Lechuga B, Donovan P, Halang L, Prehn JHM, Campos-Caro A, Byrne MM, López-Tinoco C.
      Gestational Diabetes Mellitus (GDM) is characterised by insulin resistance accompanied by reduced beta-cell compensation to increased insulin demand, typically observed in the second and third trimester and associated with adverse pregnancy outcomes. There is a need for a biomarker that can accurately monitor status and predict outcome in GDM, reducing foetal-maternal morbidity and mortality risks. To this end, circulating microRNAs (miRNAs) present themselves as promising candidates, stably expressed in serum and known to play crucial roles in regulation of glucose metabolism. We analysed circulating miRNA profiles in a cohort of GDM patients (n = 31) and nondiabetic controls (n = 29) during the third trimester for miRNA associated with insulin-secretory defects and glucose homeostasis. We identified miR-330-3p as being significantly upregulated in lean women with GDM compared to nondiabetic controls. Furthermore, increased levels of miR-330-3p were associated with better response to treatment (diet vs. insulin), with lower levels associated with exogenous insulin requirement. We observed miR-330-3p to be significantly related to the percentage of caesarean deliveries, with miR-330-3p expression significantly higher in spontaneously delivered GDM patients. We report this strong novel association of circulating miR-330-3p with risk of primary caesarean delivery as a pregnancy outcome linked with poor maternal glycaemic control, strengthening the growing body of evidence for roles of diabetes-associated miRNAs in glucose homeostasis and adaptation to the complex changes related to pregnancy.
    DOI:  https://doi.org/10.1038/s41598-020-57838-6
  1013. Respir Res. 2020 Jan 20. 21(1): 26
    Metabolic and cardiorespiratory effects of decreasing lung hyperinflation with budesonide/formoterol in COPD: a randomized, double-crossover, placebo-controlled, multicenter trial.
    Divo MJ, DePietro MR, Horton JR, Maguire CA, Celli BR.
      BACKGROUND: Studies suggest that acute decreases in lung hyperinflation at rest improves cardiac function and increases lung vascular perfusion from decompression of a compromised heart. In those studies, changes in resting oxygen uptake induced by medications, an alternative explanation for compensatory increased cardiac function, were not explored.METHODS: This double-blind, multicenter, double-crossover study enrolled adults with chronic obstructive pulmonary disease, resting hyperinflation, and > 10% improvement in inspiratory capacity after 2 inhalations of budesonide/formoterol 160/4.5 μg. Metabolic, cardiac, and ventilatory function were measured 60 min pre-/post-dose at each visit. Primary endpoint was change in resting oxygen uptake for budesonide/formoterol versus placebo.
    RESULTS: Fifty-one patients (median age: 63 years) received treatment. Compared with placebo, budesonide/formoterol significantly increased resting oxygen uptake (mean change from baseline: 1.25 vs 11.37 mL/min; P = 0.007) as well as tidal volume and minute ventilation. This occurred despite improvements in the inspiratory capacity, forced vital capacity, and expiratory volume in 1 s. No significant treatment differences were seen for oxygen saturation, respiratory rate, and resting dyspnea. There was a numerical increase in oxygen pulse (oxygen uptake/heart rate). Correlations between inspiratory capacity and oxygen pulse were weak.
    CONCLUSIONS: Budesonide/formoterol treatment in resting hyperinflated patients with COPD results in significant deflation. The increase in oxygen uptake and minute ventilation at lower lung volumes, without changes in heart rate and with minimal improvement in oxygen pulse, suggests increased oxygen demand as a contributor to increased cardiac function.
    TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02533505.
    Keywords:  Cardiac output; Oxygen pulse; Oxygen uptake; Stroke volume
    DOI:  https://doi.org/10.1186/s12931-020-1288-3
  1014. Bioorg Chem. 2020 Jan 10. pii: S0045-2068(19)31593-7. [Epub ahead of print]96 103579
    Synthesis of a 1,2,3-bistriazole derivative of embelin and evaluation of its effect on high-fat diet fed-streptozotocin-induced type 2 diabetes in rats and molecular docking studies.
    Stalin A, Kandhasamy S, Kannan BS, Verma RS, Ignacimuthu S, Kim Y, Shao Q, Chen Y, Palani P.
      The embelin derivative 2a was synthesized with the 1,2,3-bistriazole and spectral data confirmed its structural identity. Anti-diabetic and anti-lipidemic effects were evaluated using HFD-STZ induced type 2 diabetic rats. The derivative 2a (30 mg/kg b wt.) supplementation significantly (P ≤ 0.01) normalized the changed biochemical parameters like fasting blood glucose (FBG), body weights, plasma insulin level, total cholesterol (TC), triglycerides (TG) and marker enzymes of carbohydrate metabolism. The derivative 2a (30 mg/kg) also showed a significant effect on oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (ITT). But 15 mg/kg dose of derivative 2a failed to show any significant effects in HFD-STZ induced type2 diabetic rats. Histopathology analysis substantiated the protective effect of this derivative 2a (30 mg/kg b wt.) on the β-cells of the pancreatic, liver and adipose tissues in diabetic treated rats. Further, the expressions of PPARγ and GLUT4 were significantly enhanced in the epididymal adipose tissue. The HOMO and LUMO energies characterized the molecular stability of the derivative 2a with 6-311G++ (d, p) in DFT/B3LYP/LanL2DZ method using Gaussian09 program package. The molecular docking analysis also confirmed the activity of derivative 2a through hydrogen bond interaction with ARG 288, GLU 343, SER 342 and least energy value (-7.72 kcal/mol). Hence, the embelin-1,2,3-bis triazole derivative 2a (30 mg/kg) enhanced the activity of embelin and might be acting as a suitable drug for type 2 diabetes, obesity and its complications.
    Keywords:  Docking; Embelin-1,2,3-bistriazole; Molecular stability; PPARγ partial agonist
    DOI:  https://doi.org/10.1016/j.bioorg.2020.103579
  1015. J Med Chem. 2020 Jan 23.
    Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-Apoptotic Mcl-1 and Bfl-1 Proteins.
    Kump KJ, Miao L, Mady ASA, Ansari NH, Shrestha UK, Yang Y, Pal M, Liao C, Perdih A, Abulwerdi FA, Chinnaswamy K, Meagher JL, Carlson JM, Khanna M, Stuckey JA, Nikolovska-Coleska Z.
      Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure based design was guided by several solved co-crystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.
    DOI:  https://doi.org/10.1021/acs.jmedchem.9b01442
  1016. Arch Pathol Lab Med. 2020 Jan 23.
    "Napoleon Hat" Sign: A Distinctive Cytologic Clue to Reactive Pneumocytes.
    Rekhtman N.
      Various types of acute and subacute lung injury can cause severe reactive pneumocyte atypia, which may mimic malignant proliferations and present a major diagnostic pitfall. This particularly applies to cytologic preparations and frozen sections, where background inflammatory injury may be subtle or not apparent. Although several distinguishing morphologic features of reactive pneumocytes have been suggested, there is significant overlap with neoplastic proliferations. In this article, a highly distinctive but underrecognized feature of reactive pneumocytes is highlighted that can serve as a useful diagnostic clue. The feature refers to the distinctive pinched shape of reactive pneumocytes, for which the author has coined the term "Napoleon hat" sign to draw the analogy with the iconic headwear. The analogy vividly captures the distinctive shape of reactive pneumocytes, and can serve as a useful diagnostic and teaching tool in the interpretation of pulmonary specimens.
    DOI:  https://doi.org/10.5858/arpa.2019-0615-SA
  1017. J Chromatogr A. 2020 Jan 13. pii: S0021-9673(20)30060-1. [Epub ahead of print] 460884
    Cationic polyelectrolyte/graphene oxide as an efficient sorbent for the extraction and analysis of trace acidic herbicides in vegetables.
    Hou X, Yu H, Yan S, Xiao J, Sun M, Wu W.
      The facile preparation and characterization of a cationic polyelectrolyte (polydiallyldimethylammonium chloride, PDDA) fabricated graphene oxide-grafted silica microsphere (PDDA@GO@Sil) with high positive charge density as the sorbent for the high selective capture of acidic herbicides were reported. The theoretical calculation showed that there were strong adsorption energies between the PDDA and analytes, and the main interaction was the hydrogen bonding from OH…Cl and CO…HC. Static- and dynamic- state adsorption results indicated that acidic herbicides were the monolayer coverage onto the PDDA@GO@Sil due to the electrostatic attraction between the sorbent and analytes, and electrostatic repulsion among analytes. Under the optimized conditions obtained with the single-factor experiment and response surface methodology, this established method was used for the enrichment and determination of herbicides in two vegetables. Method detection limits were in the range of 0.75-1.50 µg L-1 indicating that the introduction of PDDA provided the excellent extraction capacity toward acidic herbicides. The obtained results exhibited that the developed method was feasible, reliable, selective and accurate for the determination of acidic herbicides in real samples.
    Keywords:  Acidic herbicide; Cationic polyelectrolyte; Graphene oxide; Matrix effect; Solid-phase extraction
    DOI:  https://doi.org/10.1016/j.chroma.2020.460884
  1018. Sci Rep. 2020 Jan 21. 10(1): 894
    Gαi2+ vomeronasal neurons govern the initial outcome of an acute social competition.
    Pallé A, Montero M, Fernández S, Tezanos P, de Las Heras JA, Luskey V, Birnbaumer L, Zufall F, Chamero P, Trejo JL.
      Pheromone detection by the vomeronasal organ (VNO) mediates important social behaviors across different species, including aggression and sexual behavior. However, the relationship between vomeronasal function and social hierarchy has not been analyzed reliably. We evaluated the role of pheromone detection by receptors expressed in the apical layer of the VNO such as vomeronasal type 1 receptors (V1R) in dominance behavior by using a conditional knockout mouse for G protein subunit Gαi2, which is essential for V1R signaling. We used the tube test as a model to analyze the within-a-cage hierarchy in male mice, but also as a paradigm of novel territorial competition in animals from different cages. In absence of prior social experience, Gαi2 deletion promotes winning a novel social competition with an unfamiliar control mouse but had no effect on an established hierarchy in cages with mixed genotypes, both Gαi2-/- and controls. To further dissect social behavior of Gαi2-/- mice, we performed a 3-chamber sociability assay and found that mutants had a slightly altered social investigation. Finally, gene expression analysis in the medial prefrontal cortex (mPFC) for a subset of genes previously linked to social status revealed no differences between group-housed Gαi2-/- and controls. Our results reveal a direct influence of pheromone detection on territorial dominance, indicating that olfactory communication involving apical VNO receptors like V1R is important for the outcome of an initial social competition between two unfamiliar male mice, whereas final social status acquired within a cage remains unaffected. These results support the idea that previous social context is relevant for the development of social hierarchy of a group. Overall, our data identify two context-dependent forms of dominance, acute and chronic, and that pheromone signaling through V1R receptors is involved in the first stages of a social competition but in the long term is not predictive for high social ranks on a hierarchy.
    DOI:  https://doi.org/10.1038/s41598-020-57765-6
  1019. Sci Rep. 2020 Jan 22. 10(1): 949
    Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids.
    Pawar A, Jha P, Chopra M, Chaudhry U, Saluja D.
      Tuberculosis (TB) is caused by Mycobacterium tuberculosis (MTB), a highly infectious disease accounting for nearly 1.5 million deaths every year and has been a major global concern. Moreover, resistance to anti-TB drugs is an arduous obstacle to effective prevention, TB care and management. Therefore, incessant attempts are being made to identify novel drug targets and newer anti-tubercular drugs to fight with this deadly pathogen. Increasing resistance, adverse effects and costly treatment by conventional therapeutic agents have been inclining the researchers to search for an alternative source of medicine. In this regard natural compounds have been exploited extensively for their therapeutic interventions targeting cellular machinery of MTB. Glutamate racemase (MurI) is an enzyme involved in peptidoglycan (PG) biosynthesis and has become an attractive target due to its moonlighting property. We screened various classes of natural compounds using computational approach for their binding to MTB-MurI. Shortlisted best docked compounds were evaluated for their functional, structural and anti-mycobacterial activity. The results showed that two flavonoids (naringenin and quercetin) exhibited best binding affinity with MTB-MurI and inhibited the racemization activity with induced structural perturbation. In addition, fluorescence and electron microscopy were employed to confirm the membrane and cell wall damages in mycobacterial cells on exposure to flavonoids. Together, these observations could provide impetus for further research in better understanding of anti-tubercular mechanisms of flavonoids and establishing them as lead molecules for TB treatment.
    DOI:  https://doi.org/10.1038/s41598-020-57658-8
  1020. J Assoc Physicians India. 2020 Jan;68(1): 52
    Mean Platelet Volume (MPV) is a Measure of Glycemic Control in Diabetes Mellitus 2.
    Nagiya S.
      
  1021. Life Sci. 2020 Jan 17. pii: S0024-3205(20)30069-2. [Epub ahead of print] 117322
    Parkin overexpression attenuates Aβ-induced mitochondrial dysfunction in HEK293 cells by restoring impaired mitophagy.
    Wang H, Zhang T, Ge X, Chen J, Zhao Y, Fu J.
      AIMS: Mitochondrial dysfunction is an early prominent feature of Alzheimer's disease (AD). In the present study, we sought to investigate whether defective mitophagy is tightly related to amyloid-β (Aβ)-induced mitochondrial dysfunction.MAIN METHODS: Immunofluorescence, western blot and transmission electron microscopy were used to examine mitophagy. Mitochondrial membrane potential was assessed using the JC-1 dye. Mitochondrial ROS was detected using MitoSOX™ Red staining.
    KEY FINDINGS: Aβ induced mitochondrial dysfunction in HEK293 cells. Moreover, Aβ induced an increase in parkin translocation to mitochondria and led to a drastic reduction in cytosolic parkin. Furthermore, Aβ-treated cells displayed a microtubule-associated protein 1 light chain 3 (LC3) punctate pattern and elevated mitochondrial LC3-II levels, suggesting the upregulation of mitophagy. Notably, Aβ induced the accumulation of mitochondrial p62, which was associated with impaired mitophagy. In addition, Aβ-treated cells exhibited fragmented or swollen mitochondria with severely decreased cristae. We then investigated whether overexpression of parkin could protect cells against Aβ-induced mitochondrial dysfunction. Interestingly, parkin overexpression inhibited Aβ-induced mitochondrial dysfunction. Besides, parkin overexpression increased cytosolic and mitochondrial parkin levels as well as mitochondrial LC3-II levels in Aβ-treated cells. Additionally, parkin overexpression reversed the accumulation of p62 in mitochondria, indicating that parkin overexpression restored impaired mitophagy in Aβ-treated cells. Importantly, parkin overexpression remarkably reversed Aβ-induced mitochondrial fragmentation.
    SIGNIFICANCE: Our data demonstrate that overexpression of parkin ameliorates impaired mitophagy and promotes the removal of damaged mitochondria in Aβ-treated cells, indicating that upregulation of parkin-mediated mitophagy may be a potential strategy for the therapy of AD.
    Keywords:  Alzheimer's disease; Amyloid-β; Mitochondrial dysfunction; Mitophagy; Parkin
    DOI:  https://doi.org/10.1016/j.lfs.2020.117322
  1022. Trends Genet. 2020 Jan 18. pii: S0168-9525(19)30268-9. [Epub ahead of print]
    Molecular Mechanisms Driving mRNA Degradation by m6A Modification.
    Lee Y, Choe J, Park OH, Kim YK.
      N6-Methyladenosine (m6A), the most prevalent internal modification associated with eukaryotic mRNAs, influences many steps of mRNA metabolism, including splicing, export, and translation, as well as stability. Recent studies have revealed that m6A-containing mRNAs undergo one of two distinct pathways of rapid degradation: deadenylation via the YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; an m6A reader protein)-CCR4/NOT (deadenylase) complex or endoribonucleolytic cleavage by the YTHDF2-HRSP12-ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some m6A-containing circular RNAs (circRNAs) are also subject to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP. Here, we highlight recent progress on the molecular mechanisms underlying rapid mRNA degradation via m6A and describe our current understanding of the dynamic regulation of m6A-mediated mRNA decay through the crosstalk between m6A (or YTHDF2) and other cellular factors.
    Keywords:  HRSP12; RNase P/MRP; YTHDF2; circular RNA; endoribonucleolytic cleavage; m(6)A modification
    DOI:  https://doi.org/10.1016/j.tig.2019.12.007
  1023. Med J Aust. 2020 Jan 25.
    Childhood cancer: unique opportunities and inherent challenges.
    Manoharan N, O'Brien T.
      
    Keywords:  Cancer; Childhood diseases
    DOI:  https://doi.org/10.5694/mja2.50487
  1024. Chembiochem. 2020 Jan 20.
    Chimeric Interaction of Nitrogenase-like Reductases with the MoFe Protein of Nitrogenase.
    Jasper J, Ramos JV, Trncik C, Jahn D, Einsle O, Layer G, Moser J.
      The engineering of transgenic organisms with the ability to fix nitrogen is an attractive possibility. However, oxygen sensitivity of nitrogenase, mainly conferred by the reductase component (NifH) 2 is an imminent problem. Nitrogenase-like enzymes involved in coenzyme F 430 and chlorophyll biosynthesis utilize the highly homologous reductases (CfbC) 2 and (ChlL) 2 , respectively. Chimeric protein-protein interaction of these reductases with the catalytic component of nitrogenase (MoFe protein) did not support nitrogenase activity. Nucleotide-dependent association and dissociation of these complexes was investigated but (CfbC) 2 and wild type (ChlL) 2 showed no modulation of the binding affinity. By contrast, the interaction between the (ChlL) 2 mutant Y127S and the MoFe protein was markedly increased in the presence of ATP (or ATP analogs) and reduced in the ADP state. Upon formation of the octameric (ChlL) 2 MoFe(ChlL) 2 complex, the ATPase activity of this variant is triggered as seen in the homologous nitrogenase system. Thus, the described reductase(s) might be an attractive tool for further elucidation of the diverse functions of (NifH) 2 and the rational design of a more robust reductase.
    Keywords:  ATPase; DPOR; Protein-protein interaction; metalloproteins; nitrogenases
    DOI:  https://doi.org/10.1002/cbic.201900759
  1025. Sci Total Environ. 2020 Feb 25. pii: S0048-9697(19)35873-5. [Epub ahead of print]705 135878
    Influences of different iron forms activated peroxydisulfate on volatile fatty acids production during waste activated sludge anaerobic fermentation.
    Luo J, Huang W, Zhu Y, Guo W, Yibing L, Wu L, Zhang Q, Wu Y, Fang F, Cao J.
      The treatments of peroxydisulfate (PDS) activated with different iron forms (zero-valent iron (ZVI), ferrous iron (Fe2+) and nano zero-valent iron (NZVI)) all contributed to the generation of volatile fatty acids (VFAs) during waste activated sludge (WAS) anaerobic fermentation. The maximal VFAs generation was 3036, 5537 and 3533 mg COD/L in the PDS/ZVI, PDS/Fe2+ and PDS/NZVI reactors, respectively, while it was only 702 mg COD/L in the control. The enhancing effects followed the order of PDS/Fe2+ > PDS/NZVI > PDS/ZVI. ZVI and NZVI showed no dual promoting effects with PDS on the VFAs production. Mechanisms exploration indicated that the simultaneous improvement of WAS solubilization and hydrolysis (high concentrations of soluble proteins and carbohydrates) and enrichment of fermentative bacteria (i.e. Bacteroides, Clostridium, Fonticella, and etc.) involved in VFAs generation were the main causes of VFAs promotion in the PDS treated systems. However, the reductive ZVI and NZVI partially consumed the generated free radicals (i.e. SO4- and/or OH), which possess strong oxidative potentials and are the main contributors to extracellular polymeric substances disintegration in WAS. This consumption of free radicals accounted for the lower efficiency of solubilization and hydrolysis and consequently reduced VFAs production in the PDS/NZVI and PDS/ZVI reactors compared with that in PDS/Fe2+ reactor. Moreover, the treatment of PDS activated by different forms of iron improved the VSS reduction extent and dewaterability of fermented sludge compared with that of the control, which is advantageous to the ultimate disposal of WAS.
    Keywords:  Anaerobic fermentation; Dewaterability; Iron forms; Peroxydisulfate (PDS); Volatile fatty acids (VFAs); Waste activated sludge (WAS)
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.135878
  1026. Protein Sci. 2020 Jan 24.
    Structural and Functional Characterization of the Dominant Negative P-Loop Lysine Mutation in the Dynamin Superfamily Protein Vps1.
    Tornabene BA, Varlakhanova NV, Hosford CJ, Chappie JS, Ford MGJ.
      Dynamin-superfamily proteins (DSPs) are large self-assembling mechanochemical GTPases that harness GTP hydrolysis to drive membrane remodeling events needed for many cellular processes. Mutation to alanine of a fully conserved lysine within the P-loop of DSP GTPase domains results in abrogation of GTPase activity. This mutant has been widely used in the context of several DSPs as a dominant-negative to impair DSP-dependent processes. However, the precise deficit within the GTPase domain of the P-loop K to A mutation remains an open question. Here, we use biophysical, biochemical and structural approaches to characterize this mutant in the context of the endosomal DSP Vps1. We show that the Vps1 P-loop K to A mutant binds nucleotide with an affinity similar to wild type but exhibits defects in the organization of the GTPase active site that explain the lack of hydrolysis. In cells, Vps1 and Dnm1 bearing the P-loop K to A mutation are defective in disassembly. These mutants become trapped in assemblies at the typical site of action of the DSP. This work provides mechanistic insight into the widely-used DSP P-loop K to A mutation and the basis of its dominant-negative effects in the cell. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/pro.3830
  1027. Calcif Tissue Int. 2020 Jan 24.
    Modulators of Fam210a and Roles of Fam210a in the Function of Myoblasts.
    Tanaka KI, Kanazawa I, Richards JB, Goltzman D, Sugimoto T.
      Fam210a is a novel protein regulating muscle mass and strength in mice in vivo. However, detailed effects of Fam210a on the function of myoblasts as well as modulators of Fam210a are still unknown. We, thus, investigated (1) the roles of Fam210a in myoblast differentiation, proliferation, apoptosis and degradation, and (2) the factors that regulate Fam210a expression in murine C2C12 cells. We found that the level of Fam210a mRNA was reduced during myoblast differentiation. Reduction in endogenous Fam210a levels by siRNA suppressed mRNA levels of myogenic factors (Pax7, Myf5, Myogenin, and Mhc) and a muscle degradation factor (Murf1). On the other hand, Fam210a siRNA did not affect mRNA encoding the apoptotic factors Bcl-2 and Bax and the extent of apoptosis as measured by ELISA in C2C12 cells. In contrast, Fam210a siRNA increased the mRNA level of Mmp-12, which induces osteoclastogenesis. Interestingly, insulin and 1,25(OH)2D, which are known to affect cell metabolism and muscle function, significantly increased the level of Fam210a mRNA in a dose-dependent manner. In addition, a PI3-kinase inhibitor and reduction in endogenous levels of the vitamin D receptor (VDR) by siRNA suppressed insulin- and 1,25(OH)2D-induced expression of Fam210a, respectively. In conclusion, Fam210a might enhance myoblast differentiation and proteolysis. Moreover, insulin and 1,25(OH)2D may induce myoblast differentiation and degradation by enhancing the expression of Fam210a.
    Keywords:  1,25(OH)2 vitamin D3; Fam210a; Insulin; Mmp-12; Myoblast
    DOI:  https://doi.org/10.1007/s00223-020-00661-y
  1028. Nutrients. 2020 Jan 19. pii: E255. [Epub ahead of print]12(1):
    Effects of Lactobacillus plantarum Q180 on Postprandial Lipid Levels and Intestinal Environment: A Double-Blind, Randomized, Placebo-Controlled, Parallel Trial.
    Park YE, Kim MS, Shim KW, Kim YI, Chu J, Kim BK, Choi IS, Kim JY.
      Probiotics can improve the intestinal environment by enhancing beneficial bacteria to potentially regulate lipid levels; however, the underlying mechanisms remain unclear. The aim of this study was to investigate the effect of Lactobacillus plantarum Q180 (LPQ180) on postprandial lipid metabolism and the intestinal microbiome environment from a clinical perspective. A double-blind, randomized, placebo-controlled study was conducted including 70 participants of both sexes, 20 years of age and older, with healthy blood triacylglyceride (TG) levels below 200 mg/dL. Treatment with LPQ180 for 12 weeks significantly decreased LDL-cholesterol (p = 0.042) and apolipoprotein (Apo)B-100 (p = 0.003) levels, and decreased postprandial maximum concentrations (Cmax) and areas under the curve (AUC) of TG, chylomicron TG, ApoB-48, and ApoB-100. LPQ180 treatment significantly decreased total indole and phenol levels (p = 0.019). In addition, there was a negative correlation between baseline microbiota abundance and lipid marker change, which was negatively correlated with metabolites. This study suggests that LPQ180 might be developed as a functional ingredient to help maintain healthy postprandial lipid levels through modulating gut environment.
    Keywords:  LPQ180; correlation; intestinal microbiota; intestinal microbiota metabolites; lipid mechanism; postprandial lipids; probiotics
    DOI:  https://doi.org/10.3390/nu12010255
  1029. Pediatr Diabetes. 2020 Jan 22.
    Decreased markers of bone turnover in children and adolescents with type 1 diabetes.
    Madsen JOB, Herskin CW, Zerahn B, Jørgensen NR, Olsen BS, Pociot F, Johannesen J.
      BACKGROUND AND AIM: Adults with type 1 diabetes (T1D) have increased risk of bone fractures and decreased bone mineral density (BMD). Alterations in bone turnover have been suggested as the link between T1D and the impaired bone health. Furthermore, bone turnover has been suggested to have beneficial effects on glucose metabolism. This study aimed at describing bone turnover markers (BTM), and the relationship with glycemic control, in children and adolescents with T1D.SUBJECTS AND METHODS: 173 (47% girls) children and adolescents aged 7.7-17.5 with T1D for more than one year were included. Participants were evaluated by BMD together with measurements of selected BTM; two formation markers: osteocalcin (OCN) and procollagen type-1 AMino-terminal propeptide (P1NP) and one resorption marker, C-terminal cross-linked telopeptide of type-1 collagen (CTX). BTM were converted into Z-scores utilizing new national references.
    RESULTS: Mean OCN Z-score (-0.68 ± 1.31), P1NP Z-score (-0.33 ± 1.03) and CTX Z-score (-0.43 ± 1.10) were all significantly lower than the reference population (P < 0.001). No associations were seen between BTM and T1D duration. BMD Z-score was comparable to the reference population and associated to none of individual bone turnover markers. CTX Z-score was negatively associated to HbA1c (P = 0.007) independent of both exogeneous and residual endogenous insulin.
    CONCLUSION: Markers of bone formation and resorption were decreased in children and adolescents with T1D. CTX Z-score associated negatively to HbA1c adjusted for insulin treatment and endogenous insulin production indicating a potential association between CTX and insulin sensitivity. The long-term consequences of decreased BTM on BMD needs further attention. This article is protected by copyright. All rights reserved.
    Keywords:  Bone density; Bone remodeling; C-terminal telopeptide of type I collagen; Diabetes Mellitus, Type 1; Osteocalcin
    DOI:  https://doi.org/10.1111/pedi.12987
  1030. Diabetes Res Clin Pract. 2020 Jan 16. pii: S0168-8227(19)31620-1. [Epub ahead of print] 108026
    Insulin pumps use in Greece: efficacy and safety data from 140 patients with type 1 diabetes mellitus.
    Somali M, Paschou SA, Mouslech Z.
      OBJECTIVE: The aim of this study was to investigate the efficacy and safety of continuous subcutaneous insulin infusion (CSII) regarding glycaemic control and quality of life in patients with type 1 diabetes mellitus (T1DM), who were previously treated with a multiple daily injections (MDI).PATIENTS AND METHODS: 140 patients with T1DM [mean age 33.7±22.1 years; 54 males, 76 females, 10 children; duration of diabetes 19.1±8.4 years; total daily insulin usage while on MDI (IU/kg/day) 57.86±15.32; HbA1c at the beginning of CSII treatment 8.67±1.54%] were included in the study. HbA1c, glucose levels, BMI, severe hypoglycemic and diabetic ketoacidosis (DKA) episodes were recorded and compared to the data prior to CSII introduction. The evaluation of the quality of life was assessed with a self-questionnaire adjusted from the SF-12 and diabetes quality of life (DQoL) questionnaires.
    RESULTS: HbA1c was reduced from 8.67±1.54 to 6.85±0.52% (p<0.001). This reduction was independent of age, gender, body mass index (BMI) and diabetes duration. Daily insulin requirements were lower at the end of the follow-up (36.40±12.20 IU/kg/day) compared with the needs during enrolment (57.86±15.32 IU/kg/day) (p<0.001). BMI presented no significant alterations. Ten (10) severe hypoglycemic episodes were recorded but the overall rate was decreased by 71.5% (p<0.001). Only 3 cases of ketoacidosis were recorded. Quality of life parameters were remarkably improved.
    CONCLUSIONS: This study provided evidence that CSII treatment was superior to MDI for patients with T1DM in Greece. CSII offered a safe, effective alternative to MDI schemes, while improving glycaemic control, side-effects and quality of life.
    Keywords:  CSII; DKA; HbA1c; MDI; continuous subcutaneous insulin infusion; diabetic ketoacidosis; hypoglycaemia; insulin pump therapy; mellitus; multiple daily injection; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.diabres.2020.108026
  1031. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30096-9. [Epub ahead of print]49(1): 79-93
    Diabetes Technology in the Inpatient Setting for Management of Hyperglycemia.
    Davis GM, Galindo RJ, Migdal AL, Umpierrez GE.
      In past decades, a rapid evolution of diabetes technology led to increased popularity and use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) in the ambulatory setting for diabetes management, and recently, the artificial pancreas became available. Efforts to translate this technology to the hospital setting have shown accuracy and reliability of CGM, safety of CSII in appropriate populations, improvement of inpatient glycemic control with computerized glycemic management systems, and feasibility of inpatient CGM-CSII closed-loop systems. Several ongoing studies are focusing on continued translation of this technology to improve glycemic control and outcomes in hospitalized patients.
    Keywords:  Diabetes; Glycemic control; Hospital; Inpatient; Technology
    DOI:  https://doi.org/10.1016/j.ecl.2019.11.002
  1032. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30093-3. [Epub ahead of print]49(1): 109-125
    Diabetes Technology and Exercise.
    Riddell MC, Pooni R, Fontana FY, Scott SN.
      Advances in technologies such as glucose monitors, exercise wearables, closed-loop systems, and various smartphone applications are helping many people with diabetes to be more physically active. These technologies are designed to overcome the challenges associated with exercise duration, mode, relative intensity, and absolute intensity, all of which affect glucose homeostasis in people living with diabetes. At present, optimal use of these technologies depends largely on motivation, competence, and adherence to daily diabetes care requirements. This article discusses recent technologies designed to help patients with diabetes to be more physically active, while also trying to improve glucose control around exercise.
    Keywords:  Automated insulin delivery; Closed loop; Diabetes; Exercise; Glucose monitor; Physical activity; Technology; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.011
  1033. J Thorac Cardiovasc Surg. 2019 Dec 20. pii: S0022-5223(19)39875-7. [Epub ahead of print]
    Commentary: Double, double, toil, and trouble: Removing evil humours during ex vivo lung perfusion.
    Rodriguez D, D'Cunha J.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.12.011
  1034. Heart Fail Rev. 2020 Jan 20.
    Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization.
    Hattori Y.
      Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the rate of hospitalization for heart failure in individuals with type 2 diabetes, but the underlying mechanisms remain elusive. Modestly elevated circulating β-hydroxybutyrate (βOHB) during treatment with SGLT2 inhibitors causes different beneficial effects on organs and cells, depending on succinyl-CoA:3-ketoacid CoA transferase (SCOT) levels. In the heart, in which SCOT is highly expressed/up-regulated, βOHB may be an alternative energy source apart from fat and glucose oxidation. The type 2 diabetic failing heart may be energy inefficient. In skeletal muscle, in which SCOT is not highly expressed/down-regulated, βOHB may cause antioxidant effects, resulting in amelioration of insulin resistance, which could lead to improvement in cardiac insulin resistance with metabolic, endocrine, and cytokine alterations. Although various mechanisms have been suggested, we postulate that the potential impact of SGLT2 inhibitors on heart failure lies in fuel energetics and amelioration of insulin resistance with ketone utilization depending upon SCOT levels.
    Keywords:  Heart failure; Insulin resistance; Ketone body; SGLT2 inhibitor
    DOI:  https://doi.org/10.1007/s10741-020-09921-3
  1035. Cancer J. 2020 Jan/Feb;26(1):26(1): 43-47
    Molecular Imaging of Newly Diagnosed Prostate Cancer.
    Williams S.
      Positron emission tomography (PET) is a valuable imaging in evaluating many malignancies. There are various molecular imaging tracers that are currently being utilized with prostate cancer (PC). Several PET agents imaging different molecular processes in PC have reached the clinic. While all of these agents have demonstrated an advantage over conventional imaging, there are considerable differences in the performance of each in staging newly diagnosed PC. In this article, we review the current updates available of different PET tracers, with a strong focus on the emerging role of prostate-specific membrane antigen PET in the management of newly diagnosed PC.
    DOI:  https://doi.org/10.1097/PPO.0000000000000427
  1036. Int Heart J. 2020 Jan 17.
    Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.
    Nakano I, Kinugawa S, Hori H, Fukushima A, Yokota T, Takada S, Kakutani N, Obata Y, Yamanashi K, Anzai T.
      Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (β-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.
    Keywords:  Exercise capacity; Muscle strength
    DOI:  https://doi.org/10.1536/ihj.19-400
  1037. J Med Entomol. 2020 Jan 23. pii: tjaa002. [Epub ahead of print]
    Rhipicephalus (Boophilus) microplus (Ixodida: Ixodidae) Larvae Collected From Vegetation in the Coastal Wildlife Corridor of Southern Texas and Research Solutions for Integrated Eradication.
    Osbrink WLA, Showler AT, Abrigo V, Pérez de León AA.
      The potential for reinvasion of the United States by cattle fever ticks, Rhipicephalus (Boophilus) annulatus and Rhipicephalus microplus (Canestrini), which remain established in Mexico, threatens the viability of the domestic livestock industry because these ticks vector the causal agents (Babesia bovis and Babesia bigemina) of bovine babesiosis. The Cattle Fever Tick Eradication Program safeguards the health of the national cattle herd preventing the reemergence of bovine babesiosis by keeping the United States free of cattle fever ticks. Here, the collection of free-living southern cattle tick, R. microplus, larvae by sweeping flannel flags over vegetation in the wildlife corridor of Cameron and Willacy Counties, TX, is reported. Finding R. microplus larvae on vegetation complements reports of infestations in wildlife hosts inhabiting the southern Texas coastal plains. Land uses and environmental conditions have changed since cattle fever ticks were eradicated from the United States by 1943. These changes complicate efforts by the Cattle Fever Tick Eradication Program to keep cattle in the United States free of the cattle fever tick disease vectors. Current scientific research on technologies that could be used for area-wide management of fever tick larvae in south Texas and how this could be applied to integrated eradication efforts are discussed.
    Keywords:  area-wide management; cattle fever ticks; disease vectors; ecology; integrated eradication
    DOI:  https://doi.org/10.1093/jme/tjaa002
  1038. Analyst. 2020 Jan 23.
    Current developments in LC-MS for pharmaceutical analysis.
    Beccaria M, Cabooter D.
      Liquid chromatography (LC) based techniques in combination with mass spectrometry (MS) detection have had a large impact on the development of new pharmaceuticals in the past decades. Continuous improvements in mass spectrometry and interface technologies, combined with advanced liquid chromatographic techniques for high-throughput qualitative and quantitative analysis, have resulted in a wider scope of applications in the pharmaceutical field. LC-MS tools are increasingly used to analyze pharmaceuticals across a variety of stages in their discovery and development. These stages include drug discovery, product characterization, metabolism studies (in vitro and in vivo) and the identification of impurities and degradation products. The increase in LC-MS applications has been enormous, with retention times and molecular weights (and related fragmentation patterns) emerging as crucial analytical features in the drug development process. The goal of this review is to give an overview of the main developments in LC-MS based techniques for the analysis of small pharmaceutical molecules in the last decade and give a perspective on future trends in LC-MS in the pharmaceutical field.
    DOI:  https://doi.org/10.1039/c9an02145k
  1039. Angew Chem Int Ed Engl. 2020 Jan 23.
    Determination of complex small molecule structures using molecular alignment simulation.
    Ibáñez de Opakua A, Klama F, Ndukwe IE, Martin GE, Williamson TR, Zweckstetter M.
      Correct structural assignment of small molecules and natural products is critical for drug discovery and organic chemistry. Anisotropy-based NMR spectroscopy is a powerful tool for structural assignment of organic molecules, but relies on utilization of a medium that disrupts the isotropic motion of molecules in organic solvents. Here, we establish a quantitative correlation between the atomic structure of the alignment medium, the molecular structure of the small molecule and molecule-specific anisotropic NMR parameters. The quantitative correlation uses an accurate three-dimensional molecular alignment model that predicts residual dipolar couplings of small molecules aligned by poly( γ -benzyl-ʟ-glutamate). The technique facilitates reliable determination of the correct stereoisomer and enables unequivocal, rapid determination of complex molecular structures from extremely sparse NMR   data.
    Keywords:  NMR; configuration; stereochemistry
    DOI:  https://doi.org/10.1002/anie.202000311
  1040. J Clin Med. 2020 Jan 16. pii: E242. [Epub ahead of print]9(1):
    In Vitro Characterization of Dental Pulp Stem Cells Cultured in Two Microsphere-Forming Culture Plates.
    Bu NU, Lee HS, Lee BN, Hwang YC, Kim SY, Chang SW, Choi KK, Kim DS, Jang JH.
      Various three-dimensional (3D) culture methods have been introduced to overcome the limitations of in vitro culture and mimic in vivo conditions. This study aimed to evaluate two microsphere-forming culture methods and a monolayer culture method. We evaluated cell morphology, viability, osteo-, adipo-, and chondrogenic differentiation potential of dental pulp stem cells (DPSCs) cultured in 3D culture plates: ultra-low attachment (ULA) and U-bottomed StemFit 3D (SF) plates, and a two-dimensional (2D) monolayer plate. RNA sequencing (RNA-seq) revealed differentially expressed gene (DEG) profiles of the DPSCs. In contrast to an increasing pattern in the 2D group, cell viability in 3D groups (ULA and SF) showed a decreasing pattern; however, high multilineage differentiation was observed in both the 3D groups. RNA-seq showed significantly overexpressed gene ontology categories including angiogenesis, cell migration, differentiation, and proliferation in the 3D groups. Hierarchical clustering analysis revealed a similar DEG regulation pattern between the 3D groups; however, a comparatively different DEG was observed between the 2D and 3D groups. Taken together, this study shows that DPSCs cultured in microsphere-forming plates present superior multilineage differentiation capacities and demonstrate higher DEG expression in regeneration-related gene categories compared to that in DPSCs cultured in a conventional monolayer plate.
    Keywords:  RNA sequencing; culture method; dental pulp; dental pulp stem cell; microsphere; multilineage differentiation; pulp regeneration
    DOI:  https://doi.org/10.3390/jcm9010242
  1041. Mol Med Rep. 2020 Feb;21(2): 720-730
    Carboxyl terminal activating region 3 of latent membrane protein 1 encoded by the Epstein‑Barr virus regulates cell proliferation and protein expression in NP69 cells.
    Zhang ZW, Zhang HL, Yu YH, Ouyang YM, Chen ZC, He XS, He ZM.
      In the present study, the mechanism by which carboxyl terminal activating region 3 (CTAR3) of latent membrane protein 1 (LMP1), encoded by the Epstein‑Barr virus, regulated cell proliferation and protein expression was investigated in the nasopharyngeal epithelial cell line NP69. The deletion mutant LMP1 (LMP1Δ232‑351; amino acid residues including 232‑351 codons in CTAR3 deleted) was generated by polymerase chain reaction. An NP69‑LMP1Δ232‑351 cell line was established by retroviral infection. Finally, cell proliferation and protein expression of NP69 cells expressing LMP1Δ232‑351 were examined using a cell growth curve and western blot analysis. The results demonstrated: i) The proliferation of NP69‑LMP1Δ232‑351 cells was significantly decreased compared with cells expressing wild type LMP1 (LMP1WT; n=3; P<0.05); ii) 17 proteins exhibited differential protein expression (>2‑fold change) in NP69‑LMP1Δ232‑351 cells compared with NP69‑LMP1WT cells; and iii) LMP1WT was involved in activating the Janus kinase 3 (JAK3) promoter and regulating the expression of JAK3 protein, while LMP1Δ232‑351 was almost defective in ability to activate the JAK promoter. These results suggested that LMP1‑CTAR3 may be an important functional domain for regulating cell proliferation and protein expression in nasopharyngeal epithelial cells.
    DOI:  https://doi.org/10.3892/mmr.2019.10859
  1042. Cold Spring Harb Perspect Med. 2020 Jan 21. pii: a036137. [Epub ahead of print]
    Metabolic Role of PTEN in Insulin Signaling and Resistance.
    Zhe Li Y, Di Cristofano A, Woo M.
      Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified. Through the use of a variety of models, such as tissue-specific knockout (KO) mice and in vitro cell cultures, PTEN's role in regulating insulin action has been elucidated across many cell types. Herein, we will review the recent advancements in the understanding of PTEN's metabolic functions in each of the tissues and cell types that contribute to regulating systemic insulin sensitivity and discuss how PTEN may represent a promising therapeutic strategy for treatment or prevention of T2D.
    DOI:  https://doi.org/10.1101/cshperspect.a036137
  1043. Curr Med Imaging Rev. 2020 Jan 24.
    Quantitative Color Doppler Ultrasonography Measurement of Thyroid Blood Flow in Patients with Graves' Disease.
    Yuksekkaya R, Celikyay F, Gul SS, Yuksekkaya M, Kutluturk F, Ozmen C.
      BACKGROUND: Graves' Disease is an autoimmune disorder characterized by increased levels of thyroid hormones correlated with increased thyroid blood flow. Thyroid scintigraphy is an important and conventional method. However, it has limited accessibility, has ionizing radiation, and is expensive.OBJECTIVES: To investigate the thyroid blood flow in patients with Graves' Disease by color Doppler Ultrasonography and a newly developed software Color Quantification.
    METHODS: Forty-one consecutive subjects with GD and 41 healthy controls were enrolled. Color Doppler ultrasonography parameters of the thyroid arteries and Color Quantification values of the gland were measured by a radiologist. The correlations between thyroid blood flow parameters, levels of 99mTechnetium pertechnetate uptake, thyrotropin, and free thyroxine were evaluated. The diagnostic performances of these parameters were investigated.
    RESULTS: The peak systolic-end diastolic velocities of thyroid arteries and Color Quantification values were increased in the study group (p < 0.05 for all). We observed negative correlations between thyrotropin levels and peak-systolic and end-diastolic velocities of superior thyroid arteries and Color Quantification values. There were positive correlations between 99mTechnetium uptake levels and thyroid blood flow parameters (p < 0.05 for all). In the diagnostic performance of thyroid blood flow parameters, we observed utilities significantly in peak- systolic and end-diastolic velocities of thyroid arteries and Color Quantification values (p < 0.05 for all).
    CONCLUSION: The increased peak-systolic and end-diastolic velocities of thyroid arteries, and increased Color Quantification values might be helpful in the diagnosis of Graves' Disease.
    Keywords:  Autoimmune disorder; Color doppler ultrasonography; Graves disease; Technetium (<sup>99m</sup>Tc) pertechnetate thyroid scintigraphy; Thyroid hormones; Thyrotropin
    DOI:  https://doi.org/10.2174/1573405616666200124121546
  1044. J Comp Physiol B. 2020 Jan 22.
    Growing up gator: a proteomic perspective on cardiac maturation in an oviparous reptile, the American alligator (Alligator mississippiensis).
    Alderman SL, Crossley DA, Elsey RM, Gillis TE.
      We recently described lasting changes in the cardiac proteome of American alligators (Alligator mississippiensis) reared under hypoxic conditions, that resemble what embryos encounter in natural nests. While these changes were consistent with functional differences in cardiac performance induced by developmental hypoxia, the magnitude of this response was dwarfed by a much greater effect of development alone (76% of the total differentially abundant proteins). This means that substantial differences in relative steady-state protein expression occur in the hearts of alligators as they mature from egg-bound embryos to 2-year-old juveniles, and this developmental program is largely resistant to variation in nest conditions. We therefore performed functional enrichment analysis of the 412 DA proteins that were altered by development but not hypoxia, to gain insight into the mechanisms of cardiac maturation in this ectotherm. We found that the cardiac proteome of alligators at 90% of embryonic development retained a considerable capacity for transcription and translation, suggesting the heart was still primarily invested in growth even as the animal approached hatching. By contrast, the cardiac proteome of 2-year-old juveniles was weighted towards structural and energetic processes typical of a working heart. We discuss our results in the context of differences in cardiac development between ectothermic and endothermic oviparous vertebrates, and argue that the robust developmental program of the alligator heart reflects a slow-paced ontogeny, unburdened by the requirement to support the elevated peripheral oxygen demand typical of endothermic animals from a young age.
    Keywords:  Developmental programming; Heart; Oxygen; Phenotypic plasticity; Reptile; iTRAQ
    DOI:  https://doi.org/10.1007/s00360-020-01257-6
  1045. Br J Dermatol. 2020 Jan 18.
    Demographics and Outcomes of Eccrine Porocarcinoma: Results from the National Cancer Database.
    Behbahani S, Malerba S, Karanfilian KM, Warren CJ, Alhatem A, Samie FH.
      Eccrine porocarcinoma (EPC) is a rare, malignant tumour of the eccrine sweat glands. It was first described as "epidermotropic eccrine carcinoma" in 1963 by Pinkus and Mehregan. EPC represents 0.005% to 0.01% of cutaneous tumours, but it is one of the most common malignant cutaneous adnexal tumours.2 Studies have been limited due to its rarity, and controversies regarding tumour behaviour and treatment are present in the literature. Previous studies have been limited to case reports, case series, literature reviews, and meta-analyses. We aim to investigate the association of patient demographics, tumour stage, and treatment modalities with overall survival (OS) in patients with EPC using the National Cancer Database (NCDB) from 2004-2016.
    Keywords:  NCDB; National Cancer Database; eccrine porocarcinoma; skin cancer; survival; sweat gland
    DOI:  https://doi.org/10.1111/bjd.18874
  1046. Eur J Intern Med. 2020 Jan 21. pii: S0953-6205(19)30470-4. [Epub ahead of print]
    Multimorbidity in COPD, does sleep matter?
    Vanfleteren LE, Beghe B, Andersson A, Hansson D, Fabbri LM, Grote L.
      A good night's sleep is a prerequisite for sustainable mental and physical health. Sleep disorders, including sleep disordered breathing, insomnia and sleep related motor dysfunction (e.g., restless legs syndrome), are common in patients with chronic obstructive pulmonary disease (COPD), especially in more severe disease. COPD is commonly associated with multimorbidity, and sleep disorders as a component of this multimorbidity spectrum have a further negative impact on COPD-related comorbidities. Indeed, concomitant diseases in COPD and in obstructive sleep apnea (OSA) are similar, suggesting that the combination of COPD and OSA, the so called OSA-COPD overlap syndrome (OVS), affects patient outcomes. Potential clinically important interactions of OVS exist in cardiovascular and metabolic disease, arthritis, anxiety, depression, neurocognitive disorder and the fatigue syndrome. Correct diagnosis for recognition and treatment of sleep-related disorders in COPD is recommended. However, surprisingly limited information is available and further research and improved diagnostic tools are needed. In the absence of clear evidence, we agree with the recommendation of the Global Initiative on Chronic Obstructive Lung Disease that sleep disorders should be actively searched for and treated in patients with COPD. We believe that both aspects are important components of the holistic approach required in patients with chronic multimorbid conditions.
    Keywords:  Chronic bronchitis; Cognitive dysfunction; Emphysema; Fatigue; Smoking
    DOI:  https://doi.org/10.1016/j.ejim.2019.12.032
  1047. Mutat Res. 2020 Jan 16. pii: S0027-5107(19)30104-6. [Epub ahead of print]819-820 111687
    Mutational landscape screening of methylene tetrahydrofolate reductase to predict homocystinuria associated variants: An integrative computational approach.
    Nagarajan H, Narayanaswamy S, Vetrivel U.
      Methylene tetrahydrofolate reductase (MTHFR) is a flavoprotein, involved in one-carbon pathway and is responsible for folate and homocysteine metabolism. Regulation of MTHFR is pivotal for maintaining the cellular concentrations of methionine and SAM (S-adenosyl methionine) which are essential for the synthesis of nucleotides and amino acids, respectively. Therefore, mutations in MTHFR leads to its dysfunction resulting in conditions like homocystinuria, cardiovascular diseases, and neural tube defects in infants. Among these conditions, homocystinuria has been highly explored, as it manifests ocular disorders, cognitive disorders and skeletal abnormalities. Hence, in this study, we intend to explore the mutational landscape of human MTHFR isoform-1 (h.MTHFR-1) to decipher the most pathogenic variants pertaining to homocystinuria. Thus, a multilevel stringent prioritization of non-synonymous mutations in h.MTHFR-1 by integrative machine learning approaches was implemented to delineate highly deleterious variants based on its pathogenicity, impact on structural stability and functionality. Subsequently, extended molecular dynamics simulations and molecular docking studies were also integrated in order to prioritize the mutations that perturbs structural stability and functionality of h.MTHFR-1. In addition, displacement of Loop (Arg157-Tyr174) and helix α9 (His263-Ser272) involved in open/closed conformation of substrate binding domain were also probed to confirm the functional loss. On juxtaposed analysis, it was inferred that among 126 missense mutations screened, along with known pathogenic mutations (H127 T, A222 V, T227 M, F257 V and G387D) predicted that W500C, P254S and D585 N variants could be potentially driving homocystinuria. Thus, uncovering the prospects for inclusion of these mutations in diagnostic panels based on further experimental validations.
    Keywords:  Homocystinuria; MTHFR; Molecular docking; Molecular dynamics simulation; Molecular modelling; Mutation; SNPs
    DOI:  https://doi.org/10.1016/j.mrfmmm.2020.111687
  1048. Chest. 2020 Jan 16. pii: S0012-3692(20)30017-9. [Epub ahead of print]
    Treatment duration and disease recurrence after the successful treatment of patients with Mycobacterium avium complex lung disease.
    Furuuchi K, Morimoto K, Kurashima A, Fujiwara K, Nakamoto K, Tanaka Y, Tachibana H, Yoshimori K, Sasaki Y, Ohta K.
      
    DOI:  https://doi.org/10.1016/j.chest.2019.12.016
  1049. Comput Struct Biotechnol J. 2020 ;18 125-136
    Inhibition of protein FAK enhances 5-FU chemosensitivity to gastric carcinoma via p53 signaling pathways.
    Hou J, Tan Y, Su C, Wang T, Gao Z, Song D, Zhao J, Liao Y, Liu X, Jiang Y, Feng Q, Wan Z, Yu Y.
      The small molecule drug 5-fluorouracil (5-FU) is widely used in the treatment for gastric cancer (GC), however, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a key role in adhesion, migration, and proliferation of gastric carcinoma cells, suggesting that this kinase may be a promising therapeutic target. Differentially expressed FAK in GC tissue was detected by RT-qPCR and TCGA database analysis. To investigate the biological functions of FAK, loss-of-function experiments were performed. CCK-8 assay, colony formation assay, flow cytometry, dual-luciferase reporter assays, and western blot assays were conducted to determine the underlying mechanisms of FAK in 5-FU chemosensitivity in GC. FAK is overexpressed in GC patients, and positively correlated with poor prognosis. The use of shRNA interference to target FAK decreased proliferation and increased apoptosis of GC cells in vitro. Importantly, FAK silencing enhanced the therapeutic efficacy of 5-FU, leading to reduced tumor growth in vivo. We further demonstrated that FAK silencing increased 5-FU-induced caspase-3 activity, and promoted p53 transcriptional activities. Clinical data also has shown that patients with higher levels of FAK had significantly shorter overall survival (OS) and time to first progression (FP) than those with lower levels of FAK. These findings indicate that FAK plays a critical role in 5-FU chemosensitivity in GC, and the use of FAK inhibitors as an adjunct to 5-FU might be an effective strategy for patients who undergo chemotherapy.
    Keywords:  5-FU; 5-FU, 5-fluorouracil; Chemosensitivity; FAK; FAK, Focal adhesion kinase; FP, first progression; GC, gastric cancer; Gastric carcinoma; OS, Overall survival; RNA interference; shRNA, small hairpin RNA
    DOI:  https://doi.org/10.1016/j.csbj.2019.12.010
  1050. Cells. 2020 Jan 16. pii: E227. [Epub ahead of print]9(1):
    Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor.
    Amrutkar M, Larsen EK, Aasrum M, Finstadsveen AV, Andresen PA, Verbeke CS, Gladhaug IP.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored KRAS and TP53 mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology.
    Keywords:  and cancer cells; human pancreatic ductal adenocarcinoma; pancreatic stellate cells; primary cultures; secretome
    DOI:  https://doi.org/10.3390/cells9010227
  1051. Food Chem Toxicol. 2020 Jan 17. pii: S0278-6915(20)30018-1. [Epub ahead of print] 111131
    The curcumin analogue WZ35 affects glycolysis inhibition of gastric cancer cells through ROS-YAP-JNK pathway.
    Chen T, Zhao L, Chen S, Zheng B, Chen H, Zeng T, Sun H, Zhong S, Wu W, Lin X, Wang L.
      To investigate the anti-tumor activities of WZ35 and its possible molecular mechanism, bioinformatics analysis and the hematoxylin-eosin (HE) staining were applied to evaluate the Yes-associated-protein (YAP) level in gastric cancer. Cell counting kit-8 (CCK-8) was used to examine cell viability. Apoptosis was determined by flow cytometry analysis. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. SiRNA transfection was applied to silence endogenous YAP. Western blot was performed to detect indicated proteins. We found that treatment of gastric cancer cells with WZ35 exerted stronger anti-tumor activities than curcumin. Mechanistically, our research showed that WZ35 inhibited glycolysis, and induced reactive oxygen species (ROS) generation, resulting in Jun N-terminal Kinase (JNK) activation through downregulation of YAP in gastric cancer cells. ROS mediated YAP downregulation and JNK activation was regulated by glycolysis. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP downregulation and JNK activation. Similarly, the JNK inhibitor significantly reversed WZ35 induced anti-tumor activities in gastric cancer cells. Our study reveals a novel anti-gastric cancer mechanism of WZ35 by inhibiting glycolysis through the ROS-YAP-JNK pathway. WZ35 might be a potential therapeutics for the treatment of gastric cancer.
    Keywords:  Curcumin analogue; Gastric cancer; Glycolysis; ROS; YAP
    DOI:  https://doi.org/10.1016/j.fct.2020.111131
  1052. Food Chem. 2020 Jan 13. pii: S0308-8146(20)30050-9. [Epub ahead of print]314 126203
    Comparison of activity, expression and S-nitrosylation of glycolytic enzymes between pale, soft and exudative and red, firm and non-exudative pork during post-mortem aging.
    Wang Y, Liu R, Hou Q, Tian X, Fan X, Zhang W, Zhou G.
      The activity, expression and S-nitrosylation of glycogen phosphorylase (GP), phosphofructokinase (PFK) and pyruvate kinase (PK) was compared between pale, soft and exudative (PSE) and red, firm and non-exudative (RFN) pork. The nitric oxide synthase (NOS) activity of RFN pork was higher than PSE pork (P < 0.05). Glycogen and lactic acid content were significantly different between PSE and RFN samples at 1 h postmortem (P < 0.05). Compared to PSE pork, RFN pork had lower activities and higher S-nitrosylation levels of GP, PFK and PK (P < 0.05). Moreover, GP expression in RFN pork was lower (P < 0.05) while no significant differences of PFK and PK expression were observed between these two groups. These data suggest that protein S-nitrosylation can presumably regulate glycolysis by modulating glycolytic enzymes activities and then regulate the development of PSE pork.
    Keywords:  Glycolytic enzyme; Muscle metabolism; PSE meat; Protein S-nitrosylation
    DOI:  https://doi.org/10.1016/j.foodchem.2020.126203
  1053. Nat Commun. 2020 Jan 24. 11(1): 490
    Pt-O bond as an active site superior to Pt0 in hydrogen evolution reaction.
    Yu FY, Lang ZL, Yin LY, Feng K, Xia YJ, Tan HQ, Zhu HT, Zhong J, Kang ZH, Li YG.
      The oxidized platinum (Pt) can exhibit better electrocatalytic activity than metallic Pt0 in the hydrogen evolution reaction (HER), which has aroused great interest in exploring the role of oxygen in Pt-based catalysts. Herein, we select two structurally well-defined polyoxometalates Na5[H3Pt(IV)W6O24] (PtW6O24) and Na3K5[Pt(II)2(W5O18)2] (Pt2(W5O18)2) as the platinum oxide model to investigate the HER performance. Electrocatalytic experiments show the mass activities of PtW6O24/C and Pt2(W5O18)2/C are 20.175 A mg-1 and 10.976 A mg-1 at 77 mV, respectively, which are better than that of commercial 20% Pt/C (0.398 A mg-1). The in situ synchrotron radiation experiments and DFT calculations suggest that the elongated Pt-O bond acts as the active site during the HER process, which can accelerate the coupling of proton and electron and the rapid release of H2. This work complements the knowledge boundary of Pt-based electrocatalytic HER, and suggests another way to update the state-of-the-art electrocatalyst.
    DOI:  https://doi.org/10.1038/s41467-019-14274-z
  1054. Nature. 2020 Jan 22.
    Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.
    Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC.
      Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics3,4, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.
    DOI:  https://doi.org/10.1038/s41586-020-1935-3
  1055. Nutrients. 2020 Jan 21. pii: E286. [Epub ahead of print]12(2):
    Champ4life Study Protocol: A One-Year Randomized Controlled Trial of a Lifestyle Intervention for Inactive Former Elite Athletes with Overweight/Obesity.
    Silva AM, Nunes CL, Matias CN, Jesus F, Francisco R, Cardoso M, Santos I, Carraça EV, Silva MN, Sardinha LB, Martins P, Minderico CS.
      Preventive and educational programs directed to former elite athletes in the areas of healthy living are required. This is particularly relevant as obesity and health-related problems are observed in retired athletes, especially in those whose current levels of physical activity are below the recommendations. During their sports career, elite athletes are supported by a multidisciplinary team; upon retirement, no support is provided for the transition to a different lifestyle. So far, no program has been implemented to promote sustained healthy lifestyle behaviors in the post-career transition and evidence is lacking for such an intervention. Firstly, we aim to determine if Champ4life, a 1-year lifestyle intervention targeting inactive former athletes with overweight and obesity, is effective for reducing total and abdominal fat. Secondly, our purpose is to assess the effectiveness of the intervention on the levels of physical activity and sedentary behavior, resting energy expenditure, cardio-metabolic markers, physical fitness, energy balance components, eating self-regulation markers, and quality of life over 12 months. Champ4life is an evidence- and theory-based program using a randomized control trial design (intervention vs. control group) that will be conducted on 94 inactive former elite athletes with overweight and obesity. The first four months of the Champ4Life program include a nutritional appointment and 12 weekly, 90-min sessions. Classroom sessions seek to provide participants with key information and a toolbox of behavior change techniques to initiate and sustain long-term lifestyle changes. Participants will undergo baseline, 4-month, and 12-month measurements of body composition (primary outcomes), resting energy expenditure, physical fitness, metabolic markers, energy balance related-markers, and quality of life (secondary outcome). This trial will provide evidence on the effectiveness of the Champ4life program, a pioneer lifestyle intervention for retired athletes, offering tools for sustained changes in physical activity, sedentary behavior and diet, aiming to improve body composition and overall health-related markers.
    Keywords:  behavior change; energy balance regulation; former athletes; obesity; physical activity; sedentary behavior
    DOI:  https://doi.org/10.3390/nu12020286
  1056. New Phytol. 2020 Jan 22.
    Auxin Canalization and Vascular Tissue Formation by TIR1/AFB-Mediated Auxin Signaling in Arabidopsis.
    Mazur E, Kulik I, Hajný J, Friml J.
      Plant survival depends on vascular tissues, which originate in a self-organizing manner as strands of cells co-directionally transporting the plant hormone auxin. The latter phenomenon (a.k.a. auxin canalization) is classically hypothesized to be regulated by auxin itself via the effect of this hormone on the polarity of its own intercellular transport. Correlative observations supported this concept, but molecular insights remain limited. In the current study, we established an experimental system based on the model Arabidopsis thaliana that exhibits auxin transport channels and vasculature strands formation in response to local auxin application. Our methodology permits the genetic analysis of auxin canalization under controllable experimental conditions. By utilizing this opportunity, we confirmed the dependence of auxin canalization on a PIN-dependent auxin transport and nuclear, TIR1/AFB-mediated auxin signaling. We also show that leaf venation and auxin-mediated PIN repolarization in the root require TIR1/AFB signaling. Further studies based on this experimental system are likely to yield better understanding of mechanisms underlying auxin transport polarization in other developmental contexts.
    Keywords:   Arabidopsis thaliana ; PIN1; TIR1/AFB; auxin; auxin canalization; cell polarity
    DOI:  https://doi.org/10.1111/nph.16446
  1057. Gene. 2020 Jan 21. pii: S0378-1119(20)30022-6. [Epub ahead of print] 144353
    Association of dietary intake of fruit and green Vegetables with PTEN and P53 mRNA gene expression in visceral and subcutaneous adipose tissues of obese and non-obese adults.
    Kadkhoda G, Zarkesh M, Saidpour A, Oghaz MH, Hedayati M, Khalaj A.
      OBJECTIVE: The present study investigates the association of dietary intake of fruit and green Vegetables with PTEN and P53 mRNA gene expression in visceral (VAT) and subcutaneous adipose tissues (SAT) of obese and non-obese adults.METHODS: VAT and SAT were obtained from 151 individuals, aged ∼40 years, who had undergone elective abdominal surgery. The participants were grouped according to their body mass index (BMI), as obese (BMI > 30 kg/m2) and non-obese (BMI=18.5-30 kg/m2). Dietary intakes were obtained using a valid and reliable food-frequency questionnaire (FFQ). Real-time PCR was carried out for PTEN and P53 mRNA expressions. Associations between expression levels and dietary parameters were analyzed.
    RESULTS: P53 mRNA expression of obese participants was significantly higher than the non-obese, only in VAT (p<0.001). After adjusting for total energy intake, age and BMI, fruit intake was inversely associated with P53 gene expression in both VAT (β=-0.38, P=0.01) and SAT (β=-0.35, P=0.03) among non-obese participants. Furthermore, fruit consumption was inversely associated with P53 gene expression in obese individuals, only in VAT (β=-0.21, P=0.05). More so, intake of green vegetables in obese subjects was negatively associated with P53 gene expression in VAT (β=-0.27, P=0.01) and SAT (β=-0.28, P<0.001). On the other hand, after adjustment for total energy intake, age and BMI, a positive association was observed between fruit intake and PTEN in VAT (β=0.27, P=0.01) and SAT (β=0.34, P<0.001) among obese participants. In addition, dietary consumption of fruits in non-obese individuals was negatively associated with PTEN expression in SAT (β=-0.48, P<0.001).
    CONCLUSION: Dietary intake of fruit and green vegetables was associated with P53 gene expression in VAT and SAT of obese participants, suggesting their protective role in regulating P53 mRNA expression in adipose tissue. Furthermore, higher fruit intake was inversely associated with PTEN mRNA levels in non-obese participants, implying the anti-adipogenic role of PTEN gene expression.
    Keywords:  P53; PTEN; fruit; gene expression; obesity; vegetables
    DOI:  https://doi.org/10.1016/j.gene.2020.144353
  1058. J Hazard Mater. 2020 Jan 09. pii: S0304-3894(20)30052-2. [Epub ahead of print]388 122066
    Technetium retention by gamma alumina nanoparticles and the effect of sorbed Fe2.
    Mayordomo N, Rodríguez DM, Schild D, Molodtsov K, Johnstone EV, Hübner R, Shams Aldin Azzam S, Brendler V, Müller K.
      Technetium (Tc) retention on gamma alumina nanoparticles (γ-Al2O3 NPs) has been studied in the absence (binary system) and presence (ternary system) of previously sorbed Fe2+ as a reducing agent. In the binary system, γ-Al2O3 NPs sorb up to 6.5% of Tc from solution as Tc(VII). In the ternary system, the presence of previously sorbed Fe2+ on γ-Al2O3 NPs significantly enhances the uptake of Tc from pH 4 to pH 11. Under these conditions, the reaction rate of Tc increases with pH, resulting in a complete uptake for pHs > 6.5. Redox potential (Eh) and X-ray photoelectron spectroscopy (XPS) measurements evince heterogeneous reduction of Tc(VII) to Tc(IV). Here, the formation of Fe-containing solids was observed; Raman and scanning electron microscopy showed the presence of Fe(OH)2, Fe(II)-Al(III)-Cl layered double hydroxide (LDH), and other Fe(II) and Fe(III) mineral phases, e.g. Fe3O4, FeOOH, Fe2O3. These results indicate that Tc scavenging is predominantly governed by the presence of sorbed Fe2+ species on γ-Al2O3 NPs, where the reduction of Tc(VII) to Tc(IV) and overall Tc retention is highly improved, even under acidic conditions. Likewise, the formation of additional Fe solid phases in the ternary system promotes the Tc uptake via adsorption, co-precipitation, and incorporation mechanisms.
    Keywords:  Al(2)O(3); Immobilization; Reduction; Sorption; Technetium
    DOI:  https://doi.org/10.1016/j.jhazmat.2020.122066
  1059. Epilepsia. 2020 Jan 20.
    Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study.
    Somani A, Perry C, Patodia S, Michalak Z, Ellis M, Sisodiya SM, Thom M.
      OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri-ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control.METHODS: In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24 hours prior to death (SUDEP-R).
    RESULTS: Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P < .05 to P < .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P < .05). There was no difference in the LI in the SUDEP-R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P < .005 and P < .05).
    SIGNIFICANCE: A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure-induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period.
    Keywords:  amygdala; galanin; lateral nucleus; neuropeptide Y; somatostatin; sudden unexpected death in epilepsy
    DOI:  https://doi.org/10.1111/epi.16425
  1060. ACS Omega. 2020 Jan 14. 5(1): 597-602
    Dual Modality FeS Nanoparticles with Reactive Oxygen Species-Induced and Photothermal Toxicity toward Pathogenic Bacteria.
    Agnihotri S, Mohan T, Jha D, Gautam HK, Roy I.
      Bacterial infections pose a major threat to human health, primarily because of the evolution of mutated strains that are resistant to antibiotic treatment. As a viable alternative, several nanoparticles have emerged as attractive antibacterial agents. Herein, we report the development of iron sulfide (FeS) nanoparticles that show dual-modality therapy: namely reactive oxygen species (ROS)-induced toxicity and red-laser induced photothermal therapy. The aqueous synthesized nanoparticles have been characterized based on their size, shape, crystallinity, and magnetic and optical properties. These nanoparticles showed sustained release of Fe2+ ions in an aqueous dispersion. They also have a high absorption cross-section in the visible and near infra-red regions and could be excited by a continuous wave diode laser of wavelength 635 nm leading to significant hyperthermia. Nanoparticle treatment, followed by light irradiation, led to significant cell death in two ghastly pathogenic bacterial strains. Stepwise enhancement of intrabacterial ROS levels, as a result of nanoparticle treatment followed by light activation, has been identified as the primary antibacterial mechanism.
    DOI:  https://doi.org/10.1021/acsomega.9b03177
  1061. Biotechnol Bioeng. 2020 Jan 20.
    Influence of cytoskeleton organization on recombinant protein expression by CHO cells.
    Pourcel L, Buron F, Arib G, Le Fourn V, Regamey A, Bodenmann I, Girod PA, Mermod N.
      In this study, we assessed the importance of cytoskeleton organization in mammalian cell used to produce therapeutic proteins. Two cytoskeletal genes, Actin alpha cardiac muscle 1 (ACTC1) and a guanosine triphosphate GTPase-activating protein (TAGAP), were found to be upregulated in highly productive therapeutic protein-expressing CHO cells selected by the deprivation of vitamin B5. We report here that the overexpression of the ACTC1 protein was able to improve significantly recombinant therapeutic production, as well as to decrease the levels of toxic lactate metabolic by-products. ACTC1 overexpression was accompanied by altered as well as decreased polymerized actin, which was associated with high protein production by CHO cell cultured in suspension. We suggest that the depolymerization of actin and the possible modulation of integrin signaling, as well as changes in basal metabolism, may be driving the increase of protein secretion by CHO cells. This article is protected by copyright. All rights reserved.
    Keywords:  CHO cells; actin polymerization; cytoskeleton regulation; recombinant protein production
    DOI:  https://doi.org/10.1002/bit.27277
  1062. J Clin Psychiatry. 2020 Jan 21. pii: 20f13238. [Epub ahead of print]81(1):
    Angiotensin Receptor Blockers and the Risk of Suicide: An Exercise in the Critical Examination of a Case-Control Study.
    Andrade C.
      Angiotensin receptor blockers (ARBs), used in the treatment of hypertension, may modulate neurotransmission in the central nervous system. One previous very small case-control study had suggested that ARBs increase the odds of suicide. In a recent, large, population-based, nested case-control study conducted in Ontario, Canada, completed suicide was associated with significantly increased odds of an ARB prescription during the 100 days preceding the suicide; in this analysis, confounding by indication was reduced by comparing ARB exposure with angiotensin-converting enzyme inhibitor exposure. The results of this new study were widely disseminated in the scientific and mass media. However, at least some of the data presented in the study appeared implausible, and at least one important calculation was incorrect. Furthermore, important subgroup analyses were not conducted. These incongruities diminish the confidence of the reader in the data and in the analyses presented in the study. A generous conclusion is that, at best, ARB use is a marker of suicide risk that merits examination in studies that include a follow-up, in which absolute risks and dose-dependent and treatment duration-dependent effects can be examined. A parsimonious conclusion is that there is no association proven between ARB exposure and suicide.
    DOI:  https://doi.org/10.4088/JCP.20f13238
  1063. Medicine (Baltimore). 2020 Jan;99(4): e19011
    Preliminary study on the clinical significance of kinesin Kif18a in nonsmall cell lung cancer: An analysis of 100 cases.
    Guo W, Zeng H, Zheng J, He Y, Zhuang X, Cai J, Huang H, Huang H, Xu M.
      The aim of this study was to investigate the expression of Kif18A in cancerous and paracancerous tissues from 100 patients with nonsmall cell lung cancer (NSCLC).This was a prospective study of 100 patients with pathologically confirmed NSCLC (adenocarcinoma and squamous cell carcinoma [SCC], n = 50/group) that were operated at the Quanzhou First Hospital Affiliated to Fujian Medical University between June 2015 and December 2016. Kif18A protein expression in cancerous and paracancerous normal tissues was detected by western blot and immunohistochemistry.The expression of the Kif18A protein was higher in adenocarcinoma and SCC tissues than in the corresponding paracancerous normal tissues. The expression of the Kif18A protein was higher in highly differentiated tumors, in patients with lymph node metastasis (vs no lymph node metastasis), adenocarcinoma, and in stage III NSCLC. There were no associations between Kif18A expression and age, gender, and pathologic type.The expression of the Kif18A protein by immunohistochemistry was higher in NSCLC tissues than in normal tissues, and was associated with tumor differentiation, lymph node metastasis, and TNM staging. These results could provide a theoretical basis for novel molecular targeted therapies against NSCLC.
    DOI:  https://doi.org/10.1097/MD.0000000000019011
  1064. Int J Mol Sci. 2020 Jan 19. pii: E661. [Epub ahead of print]21(2):
    Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells.
    Caruso Bavisotto C, Marino Gammazza A, Lo Cascio F, Mocciaro E, Vitale AM, Vergilio G, Pace A, Cappello F, Campanella C, Palumbo Piccionello A.
      The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial-mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.
    Keywords:  HSP60; brain tumors; extracellular HSP60; heat shock proteins; molecular chaperones; post-translational modifications; protein folding
    DOI:  https://doi.org/10.3390/ijms21020661
  1065. J Clin Med. 2020 Jan 21. pii: E302. [Epub ahead of print]9(2):
    VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy.
    Lavoz C, Rodrigues-Diez RR, Plaza A, Carpio D, Egido J, Ruiz-Ortega M, Mezzano S.
      The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.
    Keywords:  GREMLIN; VEGFA; VEGFR2; diabetes; diabetic nephropathy; inflammation; podocytes; tubular cells
    DOI:  https://doi.org/10.3390/jcm9020302
  1066. Sci Rep. 2020 Jan 22. 10(1): 993
    AMPA receptor-mTORC1 signaling activation is required for neuroplastic effects of LY341495 in rat hippocampal neurons.
    Seo MK, Hien LT, Park MK, Choi AJ, Seog DH, Kim SH, Park SW, Lee JG.
      The group II metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 produces antidepressant-like effects by acting on mammalian target of rapamycin complex 1 (mTORC1) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in rodent. We investigated whether LY341495 affects neuroplasticity via these mechanisms in rat primary hippocampal cultures under conditions of dexamethasone (DEX)-induced neurotoxicity. Ketamine was used for comparison. Hippocampal cultures were treated with LY341495 under conditions of DEX-induced toxicity. Changes in mTORC1-mediated proteins were determined by Western blotting analyses. Changes in dendritic outgrowth and spine density were evaluated via immunostaining. LY341495 significantly prevented DEX-induced decreases in the levels of mTORC1, 4E-BP1, and p70S6K phosphorylation as well as the levels of the synaptic proteins. These effects were blocked by pretreatment with the AMPA receptor inhibitor 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo(f)quinoxaline (NBQX) and the mTORC1 inhibitor rapamycin. LY341495 significantly attenuated DEX-induced decreases in dendritic outgrowth and spine density. Pretreatment with rapamycin and NBQX blocked these effects of LY341495. Further analyses indicted that induction of BDNF expression produced by LY341495 was blocked by pretreatment with NBQX and rapamycin. LY341495 has neuroplastic effects by acting on AMPA receptor-mTORC1 signaling under neurotoxic conditions. Therefore, activation of AMPA receptor and mTORC1 signaling, which enhance neuroplasticity, may be novel targets for new antidepressants.
    DOI:  https://doi.org/10.1038/s41598-020-58017-3
  1067. Bioconjug Chem. 2020 Jan 21.
    Antibody targeted PET Imaging of 64Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA positive tumors.
    Wong P, Li L, Chea J, Hu W, Poku E, Ebner T, Bowles N, Wong JYC, Yazaki PJ, Sligar SG, Shively JE.
      Lipid nanodiscs (LNDs), comprising a phospholipid bilayer encircled by two molecules of a recombinant membrane scaffold protein, can be targeted to tumors with covalently attached antibodies (Abs) or their fragments. Antibody attachment to click chemistry based PEGylated lipids on LNDs including DOTA allowed PET imaging with the positron emitter 64Cu. Carcinoembryonic antigen (CEA) positive tumors in CEA transgenic mice were chosen as a tumor target. Fab' fragments, that otherwise are rapidly cleared by the kidney due to their small size, were retained in circulation when conjugated to LNDs. Untargeted PET imaging of 64Cu-DOTA-LNDs revealed low tumor uptake (4-5 %ID/g) in the range expected for the enhanced permeability retention (EPR) effect with high liver uptake (17-21 %ID/g) indicating gut clearance. Fab'-targeted LNDs showed little improvement over untargeted LNDs, but intact IgG targeted LNDs gave high tumor uptake (40 %ID/g) with low liver (8 %ID/g), demonstrating that tumor targeting with antibody conjugated LNDs is feasible.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.9b00854
  1068. J Genet Genomics. 2019 Dec 28. pii: S1673-8527(19)30207-3. [Epub ahead of print]
    MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses.
    Li Y, Li W, Xie Z, Xu H, He ZG.
      Mycobacterium tuberculosis possesses unique cellular envelope components that contribute to bacterial escape from host immune surveillance. Phosphatidylinositol mannosides (PIMs) and their higher derivatives are important molecules implicated in host-pathogen interactions in the course of tuberculosis. However, the biosynthetic regulation of these specific lipids and its effect on the bacterial fate in the infected host remain unclear. Here, we show that a hypothetical M. tuberculosis transcriptional factor designated as MpbR negatively regulates two transporter genes and affects mycobacterial PIM biosynthesis and biofilm formation. MpbR inhibits the accumulation of acylated PIM lipids and triggers the mycobacterium to reduce the production of reactive oxygen species and NO during infection, which enhances the survival of M. tuberculosis in macrophages. MpbR deletion reduces M. tuberculosis lung burdens and inflammation of infected mice. These findings provide new insights into the regulation of mycobacterial lipid metabolism and its correlation with pathogenesis of M. tuberculosis.
    Keywords:  Lipid metabolism; Mycobacterium tuberculosis; Transcriptional factor
    DOI:  https://doi.org/10.1016/j.jgg.2019.12.002
  1069. Sci Rep. 2020 Jan 22. 10(1): 958
    Offsetting anthropogenic carbon emissions from biomass waste and mineralised carbon dioxide.
    Tripathi N, Hills CD, Singh RS, Singh JS.
      The present work investigates biomass wastes and their ashes for re-use in combination with mineralised CO2 in cement-bound construction products. A range of biomass residues (e.g., wood-derived, nut shells, fibres, and fruit peels) sourced in India, Africa and the UK were ashed and exposed to CO2 gas. These CO2-reactive ashes could mineralise CO2 gas and be used to cement 'raw' biomass in solid carbonated monolithic composites. The CO2 sequestered in ashes (125-414 g CO2/kg) and that emitted after incineration (400-500 g CO2/kg) was within the same range (w/w). The CO2-reactive ashes embodied significant amounts of CO2 (147-424 g equivalent CO2/kg ash). Selected ashes were combined with raw biomass and Portland Cement, CEM 1 and exposed to CO2. The use of CEM 1 in the carbonated products was offset by the CO2 mineralised (i.e. samples were 'carbon negative', even when 10% w/w CEM 1 was used); furthermore, biomass ashes were a suitable substitute for CEM 1 up to 50% w/w. The approach is conceptually simple, scalable, and can be applicable to a wide range of biomass ashes in a closed 'emission-capture' process 'loop'. An extrapolation of potential for CO2 offset in Europe provides an estimate of CO2 sequestration potential to 2030.
    DOI:  https://doi.org/10.1038/s41598-020-57801-5
  1070. Eur Respir J. 2020 Jan 24. pii: 1901952. [Epub ahead of print]
    Prolidase deficiency: a new genetic cause of combined pulmonary fibrosis and emphysema syndrome in the adult.
    Cottin V, Nasser M, Traclet J, Chalabreysse L, Lèbre AS, Si-Mohamed S, Philit F, Thivolet-Béjui F.
      
    DOI:  https://doi.org/10.1183/13993003.01952-2019
  1071. Curr Opin Biotechnol. 2020 Jan 19. pii: S0958-1669(19)30161-2. [Epub ahead of print]61 160-167
    Antimicrobials for food and feed; a bacteriocin perspective.
    O'Connor PM, Kuniyoshi TM, Oliveira RP, Hill C, Ross RP, Cotter PD.
      Bacteriocins are natural antimicrobials that have been consumed via fermented foods for millennia and have been the focus of renewed efforts to identify novel bacteriocins, and their producing microorganisms, for use as food biopreservatives and other applications. Bioengineering bacteriocins or combining bacteriocins with multiple modes of action (hurdle approach) can enhance their preservative effect and reduces the incidence of antimicrobial resistance. In addition to their role as food biopreservatives, bacteriocins are gaining credibility as health modulators, due to their ability to regulate the gut microbiota, which is strongly associated with human wellbeing. Indeed the strengthening link between the gut microbiota and obesity make bacteriocins ideal alternatives to Animal Growth Promoters (AGP) in animal feed also. Here we review recent advances in bacteriocin research that will contribute to the development of functional foods and feeds as a consequence of roles in food biopreservation and human/animal health.
    DOI:  https://doi.org/10.1016/j.copbio.2019.12.023
  1072. J Biol Regul Homeost Agents. 2019 Nov-Dec;33(6):33(6): 1675-1683
    Expression of SIRT5 protein in gastric cancer cells.
    Wu ZP, Fang HX.
      The purpose of this paper was to investigate the dynamic trend of SIRT5 (Sirtuins 5) protein expression in gastric cancer cells, for which a hypoxic gastric cancer cell line was established. Afterward, the parental gastric cancer cell group and hypo group were designed, and the levels of related proteins and mRNAs were detected by using Western blot along with real-time quantitative fluorescence PCR (RT-PCR). The results showed that the expression of SIRT5 in hypoxic gastric cancer cells increased significantly, which could increase the phosphorylation level of c-MET (hepatocyte growth factor receptor) and promote the migration of gastric cancer cells. When the expression of SIRT5 protein was observed under hypoxic conditions, SIRT5 silencing significantly reduced the migration ability of MGC803/hypo cells. It could be predicted that SIRT5-mediated protein desuccinylation played an important role in promoting the migration of hypoxic gastric cancer cells. Therefore, the migration rate of gastric cancer cells could be affected by controlling the expression of SIRT5 protein, which provides a novel idea for the treatment of gastric cancer in the future.
    Keywords:  SIRT5 protein; cell migration; gastric neoplasms; hypoxia tolerance
    DOI:  https://doi.org/10.23812/19-184-A
  1073. Transplant Proc. 2020 Jan 17. pii: S0041-1345(19)30205-2. [Epub ahead of print]
    Role of HIF-1α in Cold Ischemia Injury of Rat Donor Heart Via the miR-21/PDCD4 Pathway.
    Zhu L, Mu J, Wu Y, Feng S, Qu C, Cao T, Jing T, Xie Y, Wen L, Fan Z, Jia J, Ma T.
      BACKGROUND: Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that plays a major role under hypoxia conditions. Cold storage during heart transplantation causes the donor heart long-term hypoxia. There is some evidence indicating a conceivable HIF-1α/microRNA-21 (miR-21)/phosphatase and tensin homolog (PTEN)/programmed cell death 4 (PDCD4) pathway. We assessed the hypothesis that HIF-1α has a positive effect during donor heart cold storage by making the miR-21 upregulate to reduce the expression of PDCD4.METHODS: We established the rat heart cold storage model and stratified it into 6-hour groups from 0 to 24 hours. Western blot and quantitative reverse transcription polymerase chain reaction were performed to detect the expression of HIF-1α, miR-21, PDCD4, and PTEN.
    RESULTS: After cold storage the expression of HIF-1α increased from 0 to 6 hours and then gradually decreased, but the expression level was relatively higher compared with the control group. The miR-21 was upregulated from 0 to 12 hours then downregulated. The messenger RNA expression of PDCD4 was upregulated gradually, but the protein expression was significantly downregulated at 12th hour then continued to upregulate. Interestingly, the expression level of miR-21 was highest in the 12th hour, which indicated miR-21 could inhibit the PDCD4. We subsequently detected the messenger RNA of PTEN, which can inhibit HIF-1α and be inhibited by miR-21. The expression of PTEN was also significantly downregulated at the 12th hour.
    CONCLUSION: In conclusion, there is possible interaction between HIF-1α and miR-21, and the conceivable HIF-1α/miR-21/PTEN/PDCD4 pathway plays a protective role in cold storage of the heart.
    DOI:  https://doi.org/10.1016/j.transproceed.2019.11.001
  1074. Thorac Cancer. 2020 Jan 22.
    A prospective study examining the impact of uniportal video-assisted thoracic surgery on the short-term quality of life in patients with lung cancer.
    Xu GW, Xie MR, Wu HR, Xiong R, Li CW, Xu SB, Xu MQ, Li T.
      BACKGROUND: The aim of this study was to evaluate the effect of uniportal and three-portal VATS in lung cancer patients on the postoperative short-term quality of life (QOL).METHODS: A single-center, prospective, nonrandomized study was performed on patients who underwent uniportal or three-portal video-assisted thoracoscopic surgery (VATS) lobectomy and systemic mediastinal lymph node dissection. QOL was measured before surgery at baseline and at one, two, four, and eight weeks after the operation. The measured data of normal distribution were indicated by the mean ± standard deviation, the independent sample t-test was used among the groups, and the χ2 test was used to compare the counting. Non-normal distribution of the measurement data was carried out using the Mann-Whitney test.
    RESULTS: Preoperative functional areas, symptom areas and overall health scores were similar in the two groups. The physical, role, emotional and social functions and overall health status of the uniportal group were significantly higher than those of the three-portal group in postoperative time. The score of symptom field was higher in one week after operation, the score of two, four and eight weeks decreased gradually, but it was still above the preoperative level, and the fatigue and pain of the uniportal group were significantly lower than that of the three-portal group.
    CONCLUSION: The advantages of uniportal VATS include a shorter hospital stay, more rapid recovery and superior cosmetic results compared to three-portal VATS. Additionally, uniportal VATS is superior to three-portal thoracoscopic surgery in terms of the immediate postoperative short-term QOL.
    Keywords:  Lung neoplasms; quality of life; thoracoscopy; uniportal
    DOI:  https://doi.org/10.1111/1759-7714.13305
  1075. Nat Microbiol. 2020 Jan 20.
    Growth effects of N-acylethanolamines on gut bacteria reflect altered bacterial abundances in inflammatory bowel disease.
    Fornelos N, Franzosa EA, Bishai J, Annand JW, Oka A, Lloyd-Price J, Arthur TD, Garner A, Avila-Pacheco J, Haiser HJ, Tolonen AC, Porter JA, Clish CB, Sartor RB, Huttenhower C, Vlamakis H, Xavier RJ.
      Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analysed the influences of metabolites that are differentially abundant in IBD on the growth and physiology of gut bacteria that are also differentially abundant in IBD. We found that N-acylethanolamines (NAEs), a class of endogenously produced signalling lipids elevated in the stool of IBD patients and a T-cell transfer model of colitis, stimulated growth of species over-represented in IBD and inhibited that of species depleted in IBD in vitro. Using metagenomic sequencing, we recapitulated the effects of NAEs in complex microbial communities ex vivo, with Proteobacteria blooming and Bacteroidetes declining in the presence of NAEs. Metatranscriptomic analysis of the same communities identified components of the respiratory chain as important for the metabolism of NAEs, and this was verified using a mutant deficient for respiratory complex I. In this study, we identified NAEs as a class of metabolites that are elevated in IBD and have the potential to shift gut microbiota towards an IBD-like composition.
    DOI:  https://doi.org/10.1038/s41564-019-0655-7
  1076. Nanotechnology. 2020 Jan 24.
    Biomedical Application of Manganese Dioxide Nanomaterials.
    Chen Y, Cong H, Shen Y, Yu B.
      Manganese dioxide nanomaterial is a new type of inorganic nanomaterial, which has lots of advantages, as shown blow：simple preparation, low cost and environmental friendliness. This review summarizes the traditional and novel synthetic methods for manganese dioxide nanomaterials and mainly discusses the potential applications of manganese dioxide nanomaterials in biomedical applications. Manganese dioxide nanomaterials are mainly used as drug carriers in tumor therapy. In recent years, the construction of multifunctional nano-platforms targeting manganese dioxide has gradually improved. The main mechanism is that manganese dioxide nanomaterials can combine with reactive oxygen species in the tumor microenvironment to alleviate tumor hypoxia. In addition, manganese dioxide has also been used as a quencher for quenching fluorescent carbon dots in fluorescent probes. New research shows that manganese dioxide nanomaterials also have great potential in gene therapy and nuclear magnetic imaging.
    Keywords:  Biological sensor; Biomedical application; Drug carrier; Fluorescent quencher; MnO2 nanomaterial; Tumor therapy
    DOI:  https://doi.org/10.1088/1361-6528/ab6fe1
  1077. J Nucl Cardiol. 2020 Jan 23.
    Vascular uptake on 18F-sodium fluoride positron emission tomography: precursor of vascular calcification?
    den Harder AM, Wolterink JM, Bartstra JW, Spiering W, Zwakenberg SR, Beulens JW, Slart RHJA, Luurtsema G, Mali WP, de Jong PA.
      BACKGROUND: Microcalcifications cannot be identified with the present resolution of CT; however, 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) imaging has been proposed for non-invasive identification of microcalcification. The primary objective of this study was to assess whether 18F-NaF activity can assess the presence and predict the progression of CT detectable vascular calcification.METHODS AND RESULTS: The data of two longitudinal studies in which patients received a 18F-NaF PET-CT at baseline and after 6 months or 1-year follow-up were used. The target to background ratio (TBR) was measured on PET at baseline and CT calcification was quantified in the femoral arteries at baseline and follow-up. 128 patients were included. A higher TBR at baseline was associated with higher calcification mass at baseline and calcification progression (β = 1.006 [1.005-1.007] and β = 1.002 [1.002-1.003] in the studies with 6 months and 1-year follow-up, respectively). In areas without calcification at baseline and where calcification developed at follow-up, the TBR was .11-.13 (P < .001) higher compared to areas where no calcification developed.
    CONCLUSION: The activity of 18F-NaF is related to the amount of calcification and calcification progression. In areas where calcification formation occurred, the TBR was slightly but significantly higher.
    Keywords:  Calcification; atherosclerosis; computed tomography; medial artery calcification; positron emission tomography
    DOI:  https://doi.org/10.1007/s12350-020-02031-5
  1078. J Phys Chem B. 2020 Jan 21.
    Structural and Thermophysical Anomalies of Liquid Water: A Tale of Molecules in the Instantaneous Low and High-Density Regions.
    Priyadarsini A, Biswas A, Chakraborty D, Mallik BS.
      Water is believed to be a heterogeneous liquid comprising of multiple density regions that arise due to the presence of interstitial molecules and can be differentiated by their structure as well as the existence of hydrogen-bonded pairs with varying strength. First principles molecular dynamics studies were performed at six different temperatures to investigate the effect of temperature on the thermophysical, structure, dynamics, and vibrational spectral properties of the water molecules using dispersion corrected density functional theory. The variation of properties like density, cohesive energy, and compressibility with a change in temperature produces a trend that matches with experiments and resembles the experimentally observed anomalous behavior. We explore the possibility of explaining the trends in calculated properties by analyzing the structure and dynamics of the water molecules in terms of instantaneous low- and instantaneous high-density regions that are found during the simulation time. The dynamics of these two types of water molecules were studied by calculating the lifetime from the proposed autocorrelation functions. The lifetime of formation of instantaneous low-density water (i-LDW) is found to decrease with an increase in temperature; whereas the lifetime of instantaneous high-density water (i-HDW) is found to be maximum at 298 K among all the considered temperatures. The presence of more interstitial water molecules is observed at this temperature. The signature of these water molecules is found in the RDF, SDF, void distribution, configurational space, orientational dynamics, and spectral diffusion calculations. It is also found that around 298 K, these water molecules are present distinctively that mix up with the first and second solvation shells with the rise of temperature. The outlook of the reported results can be extended to other thermodynamic conditions to explain some of the anomalous properties, which can be related to the presence of the interstitial molecules in water.
    DOI:  https://doi.org/10.1021/acs.jpcb.9b11596
  1079. Sci Rep. 2020 Jan 23. 10(1): 1053
    The Rhinella arenarum transcriptome: de novo assembly, annotation and gene prediction.
    Ceschin DG, Pires NS, Mardirosian MN, Lascano CI, Venturino A.
      The common toad Rhinella arenarum is widely distributed in Argentina, where it is utilised as an autochthonous model in ecotoxicological research and environmental toxicology. However, the lack of a reference genome makes molecular assays and gene expression studies difficult to carry out on this non-model species. To address this issue, we performed a genome-wide transcriptome analysis on R. arenarum larvae through massive RNA sequencing, followed by de novo assembly, annotation, and gene prediction. We obtained 57,407 well-annotated transcripts representing 99.4% of transcriptome completeness (available at http://rhinella.uncoma.edu.ar). We also defined a set of 52,800 high-confidence lncRNA transcripts and demonstrated the reliability of the transcriptome data to perform phylogenetic analysis. Our comprehensive transcriptome analysis of R. arenarum represents a valuable resource to perform functional genomic studies and to identify potential molecular biomarkers in ecotoxicological research.
    DOI:  https://doi.org/10.1038/s41598-020-57961-4
  1080. Thromb Res. 2020 Jan 15. pii: S0049-3848(20)30025-6. [Epub ahead of print]187 88-90
    A recoded view on the F9 p.Cys178Ter pathogenic mechanism.
    Branchini A, Pinotti M.
      
    Keywords:  Factor IX; Hemophilia B; Nonsense mutations; Readthrough
    DOI:  https://doi.org/10.1016/j.thromres.2020.01.016
  1081. Circ J. 2020 Jan 18.
    Should Patients Choose Lung Transplantation or Optimal Drug Therapy?　- The Clinical Situation in the Treatment of Pulmonary Arterial Hypertension in Japan.
    Maki H.
      
    DOI:  https://doi.org/10.1253/circj.CJ-19-1170
  1082. ERJ Open Res. 2020 Jan;pii: 00171-2019. [Epub ahead of print]6(1):
    Volatile organic compound breath signatures of children with cystic fibrosis by real-time SESI-HRMS.
    Weber R, Haas N, Baghdasaryan A, Bruderer T, Inci D, Micic S, Perkins N, Spinas R, Zenobi R, Moeller A.
      Early pulmonary infection and inflammation result in irreversible lung damage and are major contributors to cystic fibrosis (CF)-related morbidity. An easy to apply and noninvasive assessment for the timely detection of disease-associated complications would be of high value. We aimed to detect volatile organic compound (VOC) breath signatures of children with CF by real-time secondary electrospray ionisation high-resolution mass spectrometry (SESI-HRMS). A total of 101 children, aged 4-18 years (CF=52; healthy controls=49) and comparable for sex, body mass index and lung function were included in this prospective cross-sectional study. Exhaled air was analysed by a SESI-source linked to a high-resolution time-of-flight mass spectrometer. Mass spectra ranging from m/z 50 to 500 were recorded. Out of 3468 m/z features, 171 were significantly different in children with CF (false discovery rate adjusted p-value of 0.05). The predictive ability (CF versus healthy) was assessed by using a support-vector machine classifier and showed an average accuracy (repeated cross-validation) of 72.1% (sensitivity of 77.2% and specificity of 67.7%). This is the first study to assess entire breath profiles of children with SESI-HRMS and to extract sets of VOCs that are associated with CF. We have detected a large set of exhaled molecules that are potentially related to CF, indicating that the molecular breath of children with CF is diverse and informative.
    DOI:  https://doi.org/10.1183/23120541.00171-2019
  1083. Toxins (Basel). 2020 Jan 20. pii: E60. [Epub ahead of print]12(1):
    A Structural Study on the Listeria Monocytogenes Internalin A-Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations.
    Dellafiora L, Filipello V, Dall'Asta C, Finazzi G, Galaverna G, Losio MN.
      Listeria monocytogenes is a widespread foodborne pathogen of high concern and internalin A is an important virulence factor that mediates cell invasion upon the interaction with the host protein E-cadherin. Nonsense mutations of internalin A are known to reduce virulence. Although missense mutations are largely overlooked, they need to be investigated in respect to their effects in cell invasion processes. This work presented a computational workflow to early characterize internalin A missense mutations. The method reliably estimated the effects of a set of engineered missense mutations in terms of their effects on internalin A-E-cadherin interaction. Then, the effects of mutations of an internalin A variant from a L. monocytogenes isolate were calculated. Mutations showed impairing effects on complex stability providing a mechanistic explanation of the low cells invasion capacity previously observed. Overall, our results provided a rational approach to explain the effects of internalin A missense mutations. Moreover, our findings highlighted that the strength of interaction may not directly relate to the cell invasion capacity reflecting the non-exclusive role of internalin A in determining the virulence of L. monocytogenes. The workflow could be extended to other virulence factors providing a promising platform to support a better molecular understanding of L. monocytogenes epidemiology.
    Keywords:  E-cadherin; Listeria monocytogenes; cell invasion; in silico modeling; internalin A
    DOI:  https://doi.org/10.3390/toxins12010060
  1084. Crit Rev Oncol Hematol. 2020 Jan;pii: S1040-8428(19)30189-1. [Epub ahead of print]145 102817
    Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis.
    Parmar A, Chaves-Porras J, Saluja R, Perry K, Rahmadian AP, Santos SD, Ko YJ, Berry S, Doherty M, Chan KKW.
      Adjuvant chemotherapy has significantly improved outcomes following surgical resection for pancreatic adenocarcinoma; however, the optimal adjuvant strategy remains unclear. This systematic review and network meta-analysis was conducted to provide indirect comparative evidence across adjuvant chemotherapies. Electronic searches of EMBASE, MEDLINE, Cochrane and ASCO databases were conducted to identify eligible randomized controlled trials (RCT). Direct pairwise meta-analysis was conducted for disease-free survival (DFS), overall-survival (OS) and adverse events (AE). Network meta-analysis of DFS and OS was conducted to evaluate indirect comparisons. Ten publications of eleven RCT met eligibility criteria. Indirect DFS comparison demonstrated superiority of mFOLFIRINOX versus gemcitabine-capecitabine, gemcitabine-erlotinib and gemcitabine-nab-paclitaxel. S-1 demonstrated a DFS benefit versus gemcitabine-capecitabine, gemcitabine-erlotinib, gemcitabine-nab-paclitaxel. OS benefits were demonstrated for mFOLFIRINOX verus gemcitabine-erlotinib and for S-1 versus gemcitabine-based combination with erlotinib, capecitabine and nab-paclitaxel. In conclusion, mFOLFIRINOX is the preferred approach for adjuvant therapy. For mFOLFIRINOX-ineligible patients no additional benefit is seen with gemcitabine-nab-paclitaxel.
    Keywords:  Adjuvant; Chemotherapy; Network meta-analysis; Pancreatic neoplasms; Survival; Systematic review
    DOI:  https://doi.org/10.1016/j.critrevonc.2019.102817
  1085. Int Immunopharmacol. 2020 Jan 20. pii: S1567-5769(19)32816-4. [Epub ahead of print]80 106211
    Anti-tumor immune response varies among individuals: A gene expression profiling of mouse melanoma.
    Yang X, Ma Z, Zhang Y, Wu J, Huang J, Zhao W, Mo F, Lin Z, Xu Y, Zhou Z, Chen S.
      Melanoma is amongst the most aggressive malignant tumors. The purpose of this study is to detect the tumor microenvironment systematically using multi-omics analyses and to propose strategies for precision medicine. Multiple factors of tumor microenvironment contribute to the drug resistance and immune surveillance failure. Here we analyzed genome mutations and characterized the immune state of tumor microenvironments in mouse melanoma by whole exome sequencing (WES) and RNA sequencing (RNA-Seq) approaches. Somatic mutation analysis revealed 35.1% novel mutations in mouse tumors when compared with B16F10 cell line, provided a basis for multi-site sequencing for accurate neoantigen selection. Mutation cluster, gene expression comparison, and gene ontology (GO) analyses by R packages proved DNA repair damage, inflammation, slower cell division, and metabolic change in tumor microenvironment. Further analyses of T-cell receptor (TCR) sequences, immune signaling pathway activation, tumor infiltrated immune cells and chemokine expression revealed extensive difference of antitumor immune response among individuals. Our study revealed the characteristics of tumor microenvironment with mouse melanoma model, suggested the need of comprehensive genome mutations and personal immune state analyses for cancer precision medicine.
    Keywords:  Gene expression comparison; Multi-omics analyses; Neoantigen selection; Precision medicine; TCR sequence; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2020.106211
  1086. Curr Top Microbiol Immunol. 2020 Jan 24.
    Structures of Type III Secretion System Needle Filaments.
    Habenstein B, El Mammeri N, Tolchard J, Lamon G, Tawani A, Berbon M, Loquet A.
      Among the Gram-negative bacterial secretion systems, type III secretion systems (T3SS) possess a unique extracellular molecular apparatus called the needle. This macromolecular protein assembly is a nanometre-size filament formed by the helical arrangement of hundreds of copies of a single, small protein, which is highly conserved between T3SSs from animal to plant bacterial pathogens. The needle filament forms a hollow tube with a channel ~20 Å in diameter that serves as a conduit for proteins secreted into the targeted host cell. In the past ten years, technical breakthroughs in biophysical techniques such as cryo-electron microscopy (cryo-EM) and solid-state NMR (SSNMR) spectroscopy have uncovered atomic resolution details about the T3SS needle assembly. Several high-resolution structures of Salmonella typhimurium and Shigella flexneri T3SS needles have been reported demonstrating a common structural fold. These structural models have been used to explain the active role of the needle in transmitting the host-cell contact signal from the tip to the base of the T3SS through conformational changes as well as during the injection of effector proteins. In this chapter, we summarize the current knowledge about the structure and the role of the T3SS needle during T3SS assembly and effector secretion.
    DOI:  https://doi.org/10.1007/82_2019_192
  1087. Biochem Biophys Res Commun. 2020 Jan 16. pii: S0006-291X(20)30079-6. [Epub ahead of print]
    The metal transporter CrNRAMP1 is involved in zinc and cobalt transports in Chlamydomonas reinhardtii.
    Chang P, Yin H, Imanaka T, Igarashi Y, Li N, Luo F.
      Metal homeostasis is essential cellular progress for cell growth. Metal ion transporters play important roles in the first line of defense to cellular metal homeostasis perturbations. NRAMP transporter family was one of the most important classes in plant cells. However, functions and substrate specificities of the NRAMP family remain unknown in Chlamydomonas reinhardtii, a model unicellular plant. In this study, we identified CrNRAMP1 as an important transporter involved in zinc and cobalt transport. Heterologous and homologous functional analyses of CrNRAMP1 showed that CrNRAMP1 plays important roles in zinc and cobalt homeostasis. The expression of CrNRAMP1 correlated with zinc or cobalt concentrations, but excluding cadmium. These results help to understand the functions and specificities of NRAMP family members in C. reinhardtii.
    Keywords:  Chlamydomonas; Cobalt; Metal homeostasis; NRAMP; Zinc
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.121
  1088. J Theor Biol. 2020 Jan 20. pii: S0022-5193(20)30028-X. [Epub ahead of print] 110172
    Identification of potential therapeutic targets in Neisseria gonorrhoeae by an in-silico approach.
    Tanwer P, Kolora SRR, Babbar A, Saluja D, Chaudhry U.
      Neisseria gonorrhoeae is a gram negative diplococcus bacterium and the causative agent of the sexually transmitted disease Gonorrhea. It has been recently given the status of "superbug" by World Health Organization because of the increasing antibiotic resistance and unavailability of a viable vaccine candidate. Over recent years, there have been increasing reports about the use of subtractive genomics to identify potential drug and vaccine targets. Our study utilizes codon biasing, a tool to identify the essential genes, in N. gonorrhoeae that could be utilized as novel therapeutic targets for drug or vaccine development. Through the screening of 2350 total genes, we present a list of 29 such drug candidate genes based on codon adaptation. Through the data-mining with BLAST2GO and InterProScan databases, we could predict the function of these 29 genes. These genes are involved in pivotal cellular functions like DNA replication, energy synthesis and metabolites production. This study also shortlists the essential genes of N. gonorrhoeae that could be used to target Neisseria. We identified a molecule/drug which can be used to target essential protein DapD (succinyltransferase).
    Keywords:  CAI Values; Codon Usage; Neisseria gonorrhoeae; therapeutic targets
    DOI:  https://doi.org/10.1016/j.jtbi.2020.110172
  1089. Bioorg Med Chem. 2019 Dec 19. pii: S0968-0896(19)31530-5. [Epub ahead of print] 115284
    In situ localization of alkaline phosphatase activity in tumor cells by an aggregation-induced emission fluorophore-based probes.
    Guan Q, Lu X, Su Y, Xu J, Liang X, Li P, Zhu X.
      In situ detection of certain specific enzyme activities in cells is deeply attached to tumor diagnosis. Conventional enzyme-responsive fluorescent probes have difficulty detecting targeted enzymes in situ in cells due to the low detection accuracy caused by the spread of fluorescence probes. In order to solve this problem, we have designed and synthesized an enzyme-responsive, water-soluble fluorescent probe with AIE characteristics, which could aggregate and precipitate to produce in situ fluorescence when reacting with the targeted enzyme in cells. The AIE fluorophore (TPEQH) was utilized to design the enzyme-responsive, fluorescent probe (TPEQHA) by introducing a phosphate group on to it, which could be specifically decomposed by the targeted enzyme, namely alkaline phosphatase (ALP). In tumor cells, TPEQH was highly produced due to the interaction of phosphate on the TPEQHA and the overexpressed ALP. Water-insoluble TPEQH then precipitated and release fluorescence in situ, thereby successfully detecting the ALP. Furthermore, the expression level of ALP could be determined by the fluorescence intensity of TPEQH with higher accuracy due to the inhibition of TPEQH leak, which demonstrated a potential application of in suit ALP detection in both clinical diagnosis and scientific research of tumor.
    Keywords:  AIE probe; ALP; Tumor fluorescence imaging
    DOI:  https://doi.org/10.1016/j.bmc.2019.115284
  1090. J Cell Mol Med. 2020 Jan 22.
    Co-expression of glycosylated aquaporin-1 and transcription factor NFAT5 contributes to aortic stiffness in diabetic and atherosclerosis-prone mice.
    Madonna R, Doria V, Görbe A, Cocco N, Ferdinandy P, Geng YJ, Pierdomenico SD, De Caterina R.
      Increased stiffness characterizes the early change in the arterial wall with subclinical atherosclerosis. Proteins inducing arterial stiffness in diabetes and hypercholesterolaemia are largely unknown. This study aimed at determining the pattern of protein expression in stiffening aorta of diabetic and hypercholesterolaemic mice. Male Ins2+/Akita mice were crossbred with ApoE-/- (Ins2+/Akita : ApoE-/- ) mice. Relative aortic distension (relD) values were determined by ultrasound analysis and arterial stiffness modulators by immunoblotting. Compared with age- and sex-matched C57/BL6 control mice, the aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed increased aortic stiffness. The aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed greater expression of VCAM-1, collagen type III, NADPH oxidase and iNOS, as well as reduced elastin, with increased collagen type III-to-elastin ratio. The aorta of Ins2+/Akita and Ins2+/Akita :ApoE-/- mice showed higher expression of eNOS and cytoskeletal remodelling proteins, such as F-actin and α-smooth muscle actin, in addition to increased glycosylated aquaporin (AQP)-1 and transcription factor NFAT5, which control the expression of genes activated by high glucose-induced hyperosmotic stress. Diabetic and hypercholesterolaemic mice have increased aortic stiffness. The association of AQP1 and NFAT5 co-expression with aortic stiffness in diabetes and hypercholesterolaemia may represent a novel molecular pathway or therapeutic target.
    Keywords:  arterial stiffening; cytoskeletal remodelling; diabetes; hypercholesterolaemia; hyperosmolarity; subclinical atherosclerosis
    DOI:  https://doi.org/10.1111/jcmm.14843
  1091. Sci Total Environ. 2020 Jan 09. pii: S0048-9697(20)30116-9. [Epub ahead of print]713 136606
    The occurrence of polybrominated diphenyl ethers and their metabolites in Portuguese river biota.
    Cruz R, Marmelo I, Monteiro C, Marques A, Casal S, Cunha SC.
      This study focused on the assessment of polybrominated diphenyl ethers (PBDEs) and their methoxylated metabolites (MeO-PBDEs) in estuarine seafood from the main Portuguese river, in order to evaluate their impact in the environment and the safety of consumers' health, thus providing a comparison with other world regions. For the purpose, PBDEs and MeO-PBDEs were determined in several seafood species collected along the Tagus estuary region, Portugal, in two catching seasons of 2019. The analyses were performed by an environmental-friendly method comprising a QuEChERS-based extraction with subsequent gas chromatography (tandem) mass spectrometry detection. Only trace amounts of BDE-47 (up to 2.0 ng·g-1 wet weight) were found in the muscle of lower trophic levels fish species, i.e. mullet and common barbel, collected in the spring. All remaining targeted PBDEs and MeO-PBDEs were below the limits of quantification, which is indicative of a reduced environmental contamination, as well as a low risk of exposure to PBDEs and MeO-PBDEs through the consumption of these species. These amounts are smaller than other regions worldwide and therefore indicative of a low contamination level in Portuguese waters.
    Keywords:  Biota; GC–MS/MS; MeO-PBDEs; PBDEs; River
    DOI:  https://doi.org/10.1016/j.scitotenv.2020.136606
  1092. J Food Biochem. 2020 Jan 21. e13148
    Evaluation of the impact of chlorophyll removal techniques on polyphenols in rosemary and thyme by-products.
    Tzima K, Brunton NP, Rai DK.
      The impact of dechlorophyllization (n-hexane: water partitioning, activated charcoal bleaching, and ChloroFiltr® decolorization) on major polyphenols of two herbal by-products (rosemary and thyme) was assessed. The aim was to produce decolorized extracts for food preservation and improve the quantification of their main phenolics. Activated charcoal bleaching and ChloroFiltr® decolorization effectively removed the chlorophyll a and b, whereas traces were detected after n-hexane: water partitioning. Dechlorophyllized thyme extracts prepared using activated charcoal and ChloroFiltr® had the lowest relative antioxidant capacity index (RACI) values based on 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) antioxidant assays. Conversely, rosemary extracts had positive RACI values following treatment with activated charcoal, whereas n-hexane led to a significant antioxidant loss. Chromatography-mass spectrometry analyses indicated that phenolic diterpenes (carnosol and carnosic acid), as well as rosmarinic acid were in general not significantly decreased (p ˃ .05) after activated charcoal treatment, while n-hexane maintained the flavonoids and phenolic acids with nonsignificant losses. PRACTICAL APPLICATIONS: Commercial exploitation of polyphenol-rich plant based extracts as natural antioxidant agents is impeded by their high chlorophyll content, which when incorporated in food products can result in products that do not meet the consumer expectations for appearance. This study has shown that the activated charcoal bleaching has potentials to remove chlorophyll and retain antioxidant polyphenols in particular diterpenes in fresh herb by-products. Moreover, the commonly used n-hexane was less effective in removing chlorophyll but retained the major flavonoids and phenolic acids. Thus, the choice of chlorophyll removal methods depend on retaining the class of antioxidant polyphenols abundant in the plant matrix.
    Keywords:  antioxidants; chlorophyll; polyphenols; rosemary; thyme
    DOI:  https://doi.org/10.1111/jfbc.13148
  1093. J Assoc Physicians India. 2020 Jan;68(1): 47
    Association between Serum Uric Acid Levels and Metabolic Syndrome.
    Bhardwaj R, Jain R.
      
  1094. Eur J Mass Spectrom (Chichester). 2020 Jan 22. 1469066719894969
    Experimental and computational evidence for C=O π-bonding in [CH2OH]+ and related oxonium ions.
    Bowen RD, Martin WH, Hudson CE, McAdoo DJ.
      
    Keywords:  Oxonium; computational evidence; ion-neutral complex; rotational barriers; thermochemistry; π-bonding
    DOI:  https://doi.org/10.1177/1469066719894969
  1095. Nucl Med Commun. 2020 Jan 21.
    Textural analysis of hybrid DOTATOC-PET/MRI and its association with histological grading in patients with liver metastases from neuroendocrine tumors.
    Weber M, Kessler L, Schaarschmidt B, Fendler WP, Lahner H, Antoch G, Umutlu L, Herrmann K, Rischpler C.
      AIMS: Neuroendocrine tumors (NETs) are known to overexpress somatostatin receptors (SSTR), which can be visualized by DOTATOC-PET. Reduced SSTR expression on the other hand may indicate dedifferentiation. The aim of this retrospective study was to assess, if conventional PET parameters and textural features (TF) derived from simultaneous PET and MRI including apparent diffusion coefficient (ADC) are associated with the proliferative activity of NETs, potentially allowing non-invasive tumor grading.METHODS: Our institutional database was screened for patients with NET and liver metastases >1 cm. We assessed conventional PET parameters, such as maximum and mean standardized uptake value and more elaborate TF parameters from PET and ADC-MRI (including entropy and homogeneity) from up to the five largest liver lesions per patient. The association of proliferative activity as measured by Ki67-/MIB1-index with the aforementioned parameters was analyzed.
    RESULTS: One hundred patients with NET/NECs were eligible with a Ki67-index ranging from <1% to 30%. Overall, 304 liver lesions were analyzed. Conventional PET parameters, entropy, homogeneity of PET and ADC maps differed significantly between G1 and G2 NETs. However, Spearman's test showed a weak association (r = -0.23 to 0.31).
    DISCUSSION: In our study cohort, conventional PET parameters and TF of PET and ADC-MRI showed only a weak correlation with Ki67. This indicates that in patients with a Ki67-index of up to 30% TF analysis of combined PET/MRI may not be reliably used for accurate non-invasive tumor grading. On the other hand, DOTATOC-PET might be a suitable staging tool in some higher grade NET/NECs.
    DOI:  https://doi.org/10.1097/MNM.0000000000001150
  1096. Sci Rep. 2020 Jan 24. 10(1): 1129
    Understanding the Lipid and Protein Corona Formation on Different Sized Polymeric Nanoparticles.
    Lima T, Bernfur K, Vilanova M, Cedervall T.
      When in contact with biological fluids, nanoparticles dynamically absorb biomolecules like proteins and lipids onto their surface, forming a "corona". This biocorona is a dynamic and complex structure that determines how host cells respond to nanoparticles. Despite the common use of mouse models in pre-clinical and toxicological experiments, the impact of corona formed in mouse serum on the biophysical and biological properties of different size NP has not been thoroughly explored. Furthering the knowledge on the corona formed on NP exposed to mouse serum proteins can help in understanding what role it might have in in vivo studies at systemic, tissue, and cellular levels. To investigate biocorona formation, different sized polystyrene NP were exposed to mouse serum. Our data show a size- and time-dependent protein and lipid corona formation. Several proteins were identified and apolipoproteins were by far the most common group on the NPs surfaces. Moreover, we observed that cholesterol and triglycerides effectively bind to NP emphasizing that proteins are not the only biomolecules with high-affinity binding to nanomaterial surfaces. These results highlight that further knowledge on NP interactions with mouse serum is necessary regarding the common use of this model to predict the in vivo efficiency of NP.
    DOI:  https://doi.org/10.1038/s41598-020-57943-6
  1097. Appl Biochem Biotechnol. 2020 Jan 20.
    Low-frequency Ultrasound with Short Application Time Improves Cellulase Activity and Reducing Sugars Release.
    de Carvalho Silvello MA, Martínez J, Goldbeck R.
      In this study, we investigated the effect of ultrasound (US) on the activity of commercial cellulase (Celluclast® 1.5 L) in the absence and in the presence of a cellulosic substrate (Avicel®, 2% w.v-1) using a central composite rotatable design. Sonication time (10 to 330 s), US intensity (120.6 to 263.7 W cm-2), and reaction temperature (25 to 50 °C) were varied using a horn-type ultrasound reactor, and endoglucanase (CMCase) and total cellulase (FPase) activities were determined. US intensity had a positive effect on enzyme activity. Under optimal conditions (170 s, 180.8 W cm-2, and 25 °C), CMCase activity was 13% higher than that of the control. In the presence of substrate, CMCase activity increased by 33.87% and KM reduced by 23% in relation to that of the control. The theoretical yield of cellulose was 42.08%. Cellulase activity can be improved by US treatment to maximize productivity gains and reduce costs in second-generation ethanol production, by the action of a low-frequency ultrasound with a short ultrasonication time of application.
    Keywords:  Cellulases; Kinetic parameters; Substrate-enzyme interaction; US treatment; US Horn-type reactor
    DOI:  https://doi.org/10.1007/s12010-019-03148-1
  1098. Heart Lung Circ. 2019 Dec 27. pii: S1443-9506(19)31554-9. [Epub ahead of print]
    Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation.
    Gladding PA, Legget M, Fatkin D, Larsen P, Doughty R.
      Coronary artery disease (CAD) and atrial fibrillation (AF) are two highly prevalent cardiovascular disorders that are associated with substantial morbidity and mortality. Conventional clinical risk factors for these disorders may not be identified prior to mid-adult life when pathophysiological processes are already established. A better understanding of the genetic underpinnings of disease should facilitate early detection of individuals at risk and preventative intervention. Single rare variants of large effect size that are causative for CAD, AF, or predisposing factors such as hypertension or hyperlipidaemia, may give rise to familial forms of disease. However, in most individuals, CAD and AF are complex traits in which combinations of genetic and acquired factors play a role. Common genetic variants that affect disease susceptibility have been identified by genome-wide association studies, but the predictive value of any single variant is limited. To address this issue, polygenic risk scores (PRS), comprised of suites of disease-associated common variants have been devised. In CAD and AF, incorporation of PRS into risk stratification algorithms has provided incremental prognostic information to clinical factors alone. The long-term health and economic benefits of PRS-guided clinical management remain to be determined however, and further evidence-based data are required.
    Keywords:  Atrial fibrillation; Coronary artery disease; Genetics; Genome-wide association studies (GWAS); Polygenic risk score; Whole Genome Sequencing (WGS); meta-genomic risk score (metaGRS)
    DOI:  https://doi.org/10.1016/j.hlc.2019.12.004
  1099. DNA Cell Biol. 2020 Jan 24.
    Identification of MMP1 as a Potential Prognostic Biomarker and Correlating with Immune Infiltrates in Cervical Squamous Cell Carcinoma.
    Zhao S, Yu M.
      Cervical squamous cell carcinoma (CESC) is a human papillomavirus-driven tumor that the underlying molecular mechanisms are unclear. This study aimed to elucidate the key candidate genes and potential mechanism in CESC by bioinformatics analysis. A total of 132 common differentially expressed genes (DEGs) were identified based on three expression profile data sets. A multivariate Cox proportional regression model was used to develop a four-gene prognostic signature. Mechanistically, the correlationship between MMP1 and tumor-infiltrating lymphocytes was further analyzed. Furthermore, annotations were investigated by Gene Ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, potential drugs for CESC treatment were predicted by Connectivity Map. We profiled four genes (EFNA1, ANLN, MMP1, and ZWINT) with significant prognostic values for CESC. Multiple public available data sets were used for mRNA expression and prognostic characterization. Subsequently, GO and KEGG pathway analyses showed DEGs were mainly enriched in cell cycle, immunity, and metabolic-related pathway. We then conducted an integrated analysis of MMP1, and the expression of MMP1 showed significantly inverse association with the amount of CD8+ T cells, CD4+ T cells, and macrophages infiltration. Our findings suggest the four-gene signature may be associated with prognosis. We further revealed that MMP1 may be a novel biomarker for immunotherapy, and prognostic judgment of patients with cervical cancer.
    Keywords:  cervical squamous cell carcinoma; differently expressed genes; molecular docking and potential drugs; tumor-infiltrating lymphocytes; underlying mechanisms
    DOI:  https://doi.org/10.1089/dna.2019.5129
  1100. J Cell Sci. 2020 Jan 21. pii: jcs.239947. [Epub ahead of print]
    DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis.
    van der Stoel M, Schimmel L, Nawaz K, van Stalborch AM, de Haan A, Klaus-Bergmann A, Valent ET, Koenis DS, van Nieuw Amerongen GP, de Vries CJ, de Waard V, Gloerich M, van Buul JD, Huveneers S.
      Endothelial YAP/TAZ signaling is crucial for sprouting angiogenesis and vascular homeostasis. Yet the underlying molecular mechanisms that explain how YAP/TAZ control the vasculature remain unclear. This study reveals that the focal adhesion protein Deleted-in-Liver-Cancer 1 (DLC1) is a direct transcriptional target of the activated YAP/TAZ-TEAD complex. We find that substrate stiffening and VEGF stimuli promote expression of DLC1 in endothelial cells. In turn, DLC1 expression levels are YAP- and TAZ-dependent, and constitutive activation of YAP is sufficient to drive DLC1 expression. DLC1 is needed to limit F-actin fiber formation, integrin-based focal adhesion lifetime and integrin-mediated traction forces. Depletion of endothelial DLC1 strongly perturbs cell polarization in directed collective migration and inhibits the formation of angiogenic sprouts. Importantly, ectopic expression of DLC1 is sufficient to restore migration and angiogenic sprouting in YAP-depleted cells. Together, these findings point towards a crucial and prominent role for DLC1 in YAP/TAZ-driven endothelial adhesion remodeling and collective migration during angiogenesis.
    Keywords:  Adhesion; Angiogenesis; Endothelium; Integrin; Mechanotransduction; YAP
    DOI:  https://doi.org/10.1242/jcs.239947
  1101. J Recept Signal Transduct Res. 2020 Jan 23. 1-12
    Repurposing of Streptomyces antibiotics as adenosine deaminase inhibitors by pharmacophore modeling, docking, molecular dynamics, and in vitro studies.
    Arun KG, Sharanya CS, Abhithaj J, Sadasivan C.
      Adenosine deaminase (ADA) is an enzyme present in purine metabolic pathway. Its inhibitors are considered to be potent drug lead compounds against inflammatory and malignant diseases. This study aimed to test ADA inhibitory activity of some Streptomyces secondary metabolites by using computational and in vitro methods. The in silico screening of the inhibitory properties has been carried out using pharmacophore modeling, docking, and molecular dynamics studies. The in vitro validation of the selected antibiotics has been carried out by enzyme kinetics and fluorescent spectroscopic studies. The results indicated that novobiocin, an aminocoumarin antibiotic from Streptomyces niveus, has significant inhibition on ADA activity. Hence, the antibiotic can be used as a lead compound for the development of potential ADA inhibitors.
    Keywords:  Adenosine deaminase; antibiotics; fluorescence spectroscopy; inhibition assay; molecular dynamics; pharmacophore modeling
    DOI:  https://doi.org/10.1080/10799893.2020.1715432
  1102. mSystems. 2020 Jan 21. pii: e00847-19. [Epub ahead of print]5(1):
    Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation.
    Khare A, Tavazoie S.
      Antibiotic persistence, the noninherited tolerance of a subpopulation of bacteria to high levels of antibiotics, is a bet-hedging phenomenon with broad clinical implications. Indeed, the isolation of bacteria with substantially increased persistence rates from chronic infections suggests that evolution of hyperpersistence is a significant factor in clinical therapy resistance. However, the pathways that lead to hyperpersistence and the underlying cellular states have yet to be systematically studied. Here, we show that laboratory evolution can lead to increase in persistence rates by orders of magnitude for multiple independently evolved populations of Escherichia coli and that the driving mutations are highly enriched in translation-related genes. Furthermore, two distinct adaptive mutations converge on concordant transcriptional changes, including increased population heterogeneity in the expression of several genes. Cells with extreme expression of these genes showed dramatic differences in persistence rates, enabling isolation of subpopulations in which a substantial fraction of cells are persisters. Expression analysis reveals coherent regulation of specific pathways that may be critical to establishing the hyperpersistence state. Hyperpersister mutants can thus enable the systematic molecular characterization of this unique physiological state, a critical prerequisite for developing antipersistence strategies.IMPORTANCE Bacterial persistence is a fascinating phenomenon in which a small subpopulation of bacteria becomes phenotypically tolerant to lethal antibiotic exposure. There is growing evidence that populations of bacteria in chronic clinical infections develop a hyperpersistent phenotype, enabling a substantially larger subpopulation to survive repeated antibiotic treatment. The mechanisms of persistence and modes of increasing persistence rates remain largely unknown. Here, we utilized experimental evolution to select for Escherichia coli mutants that have more than a thousandfold increase in persistence rates. We discovered that a variety of individual mutations to translation-related processes are causally involved. Furthermore, we found that these mutations lead to population heterogeneity in the expression of specific genes. We show that this can be used to isolate populations in which the majority of bacteria are persisters, thereby enabling systems-level characterization of this fascinating and clinically significant microbial phenomenon.
    Keywords:  Escherichia coli ; antibiotic persistence; gene expression heterogeneity; laboratory evolution; persisters; systems biology; translation
    DOI:  https://doi.org/10.1128/mSystems.00847-19
  1103. J Assoc Physicians India. 2020 Jan;68(1): 59
    Study of Blood Glucose and White Blood Cell Count Combination in Predicting Short Term Outcome of Acute Ischemic Stroke.
    K D, Reddy V.
      
  1104. J Mater Chem B. 2020 Jan 23.
    CuS@PDA-FA nanocomposites: a dual stimuli-responsive DOX delivery vehicle with ultrahigh loading level for synergistic photothermal-chemotherapies on breast cancer.
    Zhang SQ, Liu X, Sun QX, Johnson O, Yang T, Chen ML, Wang JH, Chen W.
      In this study, CuS@PDA nanoparticles were synthesized and used to create a novel tumor-targeting nanocomposite platform composed of copper sulfide@polydopamine-folic acid/doxorubicin (CuS@PDA-FA/DOX) for performing both photothermal and chemotherapeutic cancer treatment. The nanocomposite platform has ultrahigh loading levels (4.2 ± 0.2 mg mg-1) and a greater photothermal conversion efficiency (η = 42.7%) than CuS/PDA alone. The uptake of CuS@PDA-FA/DOX nanocomposites is much higher in MCF-7 cells than in A549 cells because MCF-7 cells have much higher folic acid receptors than A549. Under near infrared (NIR) irradiation, the CuS@PDA-FA/DOX system using a synergistic combination of photothermal therapy and chemotherapy yields a better therapeutic effect than either photothermal therapy or chemotherapy alone. The treatment is very effective with the cell viability is only 5.6 ± 1.4%.
    DOI:  https://doi.org/10.1039/c9tb02440a
  1105. J Assoc Physicians India. 2020 Jan;68(1): 50
    Lower Levels of 25-Hydroxyvitamin D3 are Associated with a Higher Prevalance of Diabetic Retinopathy in Type 2 Diabetes.
    Sekhar MS, Prabhakar .
      
  1106. PLoS One. 2020 ;15(1): e0221851
    Targeting chondroitinase ABC to axons enhances the ability of chondroitinase to promote neurite outgrowth and sprouting.
    Day P, Alves N, Daniell E, Dasgupta D, Ogborne R, Steeper A, Raza M, Ellis C, Fawcett J, Keynes R, Muir E.
      BACKGROUND: There is currently no effective treatment for promoting regeneration of injured nerves in patients who have sustained injury to the central nervous system such as spinal cord injury. Chondroitinase ABC is an enzyme, which promotes neurite outgrowth and regeneration. It has shown considerable promise as a therapy for these conditions. The aim of the study is to determine if targeting chondroitinase ABC expression to the neuronal axon can further enhance its ability to promote axon outgrowth. Long-distance axon regeneration has not yet been achieved, and would be a significant step in attaining functional recovery following spinal cord injury.METHODOLOGY/PRINCIPAL FINDINGS: To investigate this, neuronal cultures were transfected with constructs encoding axon-targeted chondroitinase, non-targeted chondroitinase or GFP, and the effects on neuron outgrowth and sprouting determined on substrates either permissive or inhibitory to neuron regeneration. The mechanisms underlying the observed effects were also explored. Targeting chondroitinase to the neuronal axon markedly enhances its ability to promote neurite outgrowth. The increase in neurite length is associated with an upregulation of β-integrin staining at the axonal cell surface. Staining for phosphofocal adhesion kinase, is also increased, indicating that the β-integrins are in an activated state. Expression of chondroitinase within the neurons also resulted in a decrease in expression of PTEN and RhoA, molecules which present a block to neurite outgrowth, thus identifying two of the pathways by which ChABC promotes neurite outgrowth.
    CONCLUSIONS / SIGNIFICANCE: The novel finding that targeting ChABC to the axon significantly enhances its ability to promote neurite extension, suggests that this may be an effective way of promoting long-distance axon regeneration following spinal cord injury. It could also potentially improve its efficacy in the treatment of other pathologies, where it has been shown to promote recovery, such as myocardial infarction, stroke and Parkinson's disease.
    DOI:  https://doi.org/10.1371/journal.pone.0221851
  1107. J Am Coll Cardiol. 2020 Jan 28. pii: S0735-1097(19)38517-1. [Epub ahead of print]75(3): 289-300
    Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.
    Furtado RHM, Nicolau JC, Guo J, Im K, White JA, Sabatine MS, Newby LK, Giugliano RP.
      BACKGROUND: Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial.OBJECTIVES: This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls.
    METHODS: Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days.
    RESULTS: In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; pinteraction = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; pinteraction = 0.46).
    CONCLUSIONS: When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).
    Keywords:  ADP receptor blocker; clopidogrel; drug interaction; non-ST-segment elevation ACS; opioids
    DOI:  https://doi.org/10.1016/j.jacc.2019.11.035
  1108. IEEE Trans Ultrason Ferroelectr Freq Control. 2020 Jan 20.
    Single-Shot Near-Field Volumetric Imaging System for Optical Ultrasound and Photoacoustics Using Capacitive Micromachined Ultrasonic Transducer Without Transmission Mode.
    Choi WY, Kwon SW, Kim YH, Kang KC, Park KK.
      In this paper, we present a single-shot dual-mode imaging system that uses optical ultrasound (US) as an ultrasonic pulser; thus without transmission circuit. The ultrasonic pulse-echo system comprises an optical US pulser generated by carbon nanotubes (CNTs), which generate a high-power photoacoustic (PA) signal, and a capacitive micromachined ultrasonic transducer (CMUT) receiver. By fabricating a thin CNT-polydimethylsiloxane (PDMS) composite capable of semi-absorption of the laser, a single-shot imaging system was developed. By transmitting semi-penetration light to the object, US and PA imaging were performed in a single shot. A CNT thickness of <1 μm produced a maximum pressure of 154 kPa, and US was received by the CMUT with a 2-MHz center frequency in the PDMS. Additionally, a low-profile and near-depth imaging system was constructed with an intermediate layer of 6-mm PDMS for the dry contact method. We performed a single-shot dual-mode imaging experiment on point and line phantoms, as well as the particle spread in soft tissue. Thus, we examined the feasibility of the near-depth and single-shot dual-mode (US and PA) imaging system capable of dry contact.
    DOI:  https://doi.org/10.1109/TUFFC.2020.2965600
  1109. J Sports Med Phys Fitness. 2020 Jan 23.
    A descriptive analysis of functional impairments and patho-anatomical findings in eight powerlifters.
    Aasa U, Berglund L.
      BACKGROUND: Low back pain (LBP) is a very common pain problem in powerlifters. There is a lack of evidence to guide powerlifters and health-care professionals in understanding the role of powerlifting in the development of LBP and treatment of injuries in powerlifters. This study aimed to describe functional impairments and patho-anatomical findings in eight powerlifters with and without LBP.METHODS: First, four powerlifters with LBP were recruited. Each powerlifter was then matched with a pain-free lifter (Control) by age, Body Mass Index and competition weight class. They all performed physical performance tests and were examined with magnetic resonance imaging. Four weeks prior to the examination the powerlifters also recorded training load. Powerlifters with LBP were also examined by a physiotherapist in order to define their pain and impairments.
    RESULTS: The four male powerlifters with LBP had a nociceptive pain associated with non-ideal squatting technique, higher flexibility in their lumbar spine than in their hips and patho-anatomical findings such as degenerated discs (four), spondylolysis (one) and spinal stenosis (one). However, the controls also showed similar functional impairments and patho- anatomical findings.
    CONCLUSIONS: Powerlifters with and without LBP show similar functional impairments and patho-anatomical findings. However, powerlifters' LBP seems associated with pain during movement and loading of the lumbar spine. The association and causation between specific functional impairments, patho-anatomical findings and LBP in powerlifters has to be further investigated in studies including more participants.
    DOI:  https://doi.org/10.23736/S0022-4707.19.10201-0
  1110. Biol Sex Differ. 2020 Jan 20. 11(1): 5
    Sex-specific association between the gut microbiome and high-fat diet-induced metabolic disorders in mice.
    Peng C, Xu X, Li Y, Li X, Yang X, Chen H, Zhu Y, Lu N, He C.
      BACKGROUND: Accumulating evidence indicates that high-fat diet (HFD)-induced metabolic disorders are associated with dysbiosis of the gut microbiota. However, the sex-specific characteristics of the gut microbiota and its association with a sexually dimorphic response to a HFD remain unclear.METHODS: Male and female mice were randomly assigned to receive a chow diet (CD) or HFD for 12 weeks. A group of HFD mice were pretreated with antibiotic cocktails for 4 weeks. Body weight, insulin sensitivity and the levels of serum metabolic parameters (blood glucose and insulin) were evaluated. 16S rRNA gene sequencing was performed to analyze the composition of the gut microbiota.
    RESULTS: HFD-induced body weight gain (BWG) was higher in male mice than in female mice. While insulin resistance was increased in the HFD group compared to CD group in male mice, there was no difference in insulin resistance among female mice. Antibiotic-pretreatment alleviated HFD-induced insulin resistance in male mice and elevated fasting blood glucose in female mice. The composition of the gut microbiota in male mice was remarkably different from that in female mice independent of diet. A higher abundance of the genera Parabacteroides, Lactobacillus, Bacteroides, and Bifidobacterium was observed in females than inmales. HFD feeding also influenced the structure of the gut microbiota, as it decreased the abundance of short-chain fatty acids-producing bacteria including Roseburia and Lachnospiraceae_NK4A136_group. Alterations in the gut microbiota in response to antibiotics followed by HFD were different between males and females, indicating sex-dependent sensitivity to antibiotics.
    CONCLUSIONS: We identified that sex had a greater impact on the composition of gut microbiota than environmental factors (HFD and antibiotics). The enrichment of beneficial microbes in female mice may be associated with the resistance of female mice to HFD-induced metabolic disorders, which was weakened by antibiotic pretreatment.
    Keywords:  16S rRNA gene sequencing; Antibiotic; Gut microbiota; High fat diet; Metabolic disorders; Sex difference
    DOI:  https://doi.org/10.1186/s13293-020-0281-3
  1111. J Cell Physiol. 2020 Jan 22.
    Anti-inflammatory effect of octyl gallate in alveolar macrophages cells and mice with acute lung injury.
    Haute GV, Luft C, Antunes GL, Silveira JS, de Souza Basso B, da Costa MS, Levorse VGS, Kaiber DB, Donadio MVF, Gracia-Sancho J, de Oliveira JR.
      Acute lung injury (ALI) is an inflammatory process, and has high incidence and mortality. ALI and the acute respiratory distress syndrome are two common complications worldwide that result in acute lung failure, sepsis, and death. Pro-inflammatory substances, such as cytokines and chemokines, are responsible for activating the body's defense mechanisms and usually mediate inflammatory processes. Therefore, the research of substances that decrease the uncontrolled response of organism is seen as potential for patients with ALI. Octyl gallate (OG) is a phenolic compound with therapeutic actions namely antimicrobial, antiviral, and antifungal. In this study, we evaluated its action on lipopolysaccharide (LPS)-activated alveolar macrophages RAW 264.7 cells and ALI in male mice. Our results demonstrated protective effects of OG in alveolar macrophages activated with LPS and mice with ALI. The OG treatment significantly decreased the inflammatory markers in both studies in vitro and in vivo. The data suggested that OG can act as an anti-inflammatory agent for ALI.
    Keywords:  acute lung injury; inflammation; macrophages; octyl gallate
    DOI:  https://doi.org/10.1002/jcp.29536
  1112. Clin Exp Med. 2020 Jan 22.
    BAL biomarkers' panel for differential diagnosis of interstitial lung diseases.
    M D, A C, P C, L B, A P, L V, N L, C V, P S, E B.
      Bronchoalveolar lavage (BAL) is a useful procedure for differential diagnosis of interstitial lung diseases (ILDs) and for identification of granulomatous lung diseases. We investigated a panel of biomarkers from BAL fluid of ILD patients to evaluate their utility in differentiating ILDs. Bronchoscopy with BAL was performed in 100 consecutive patients with suspected ILD (41 sarcoidosis, 11 cHP and 24 other ILDs); the 24 patients negative for ILD diagnosis were included as control group. BAL phenotypes and cell profiles (CD4+/CD8+ ratio, NK and CD103+ cell counts, chitotriosidase and KL-6 levels in BAL) were determined by flow cytometry. A decision-tree statistical algorithm was applied. Sarcoidosis was discriminated by a higher BAL CD4+/CD8+ ratio (p = 5.8E-05), a lower BAL CD103+CD4+ count (p = 5.0E-02) and lower BAL NK percentages (p = 8.8E-03) than the other groups. BAL KL-6 concentrations were higher in sarcoidosis than in other ILDs (p = 1.5E-02) and were directly correlated with CD4+/CD8+ ratio. We used decision-tree statistical analysis to combine our biomarkers into two diagnostic algorithms for differential diagnosis of ILDs. A panel of BAL biomarkers for diagnosis of ILDs is proposed; CD4+/CD8+ ratio, KL-6 concentrations, and NK and CD103+CD4+ cell percentages in BAL could improve the identification and differential diagnosis of sarcoidosis.
    Keywords:  Bronchoalveolar lavage; CD103, NK cells; CD4+/CD8+ ratio; Interstitial lung diseases; KL-6; Sarcoidosis
    DOI:  https://doi.org/10.1007/s10238-020-00608-5
  1113. Cancer Cytopathol. 2020 Jan 24.
    Insulinoma-associated protein 1 (INSM1) is a robust marker for identifying and grading pancreatic neuroendocrine tumors.
    Kim D, Viswanathan K, Goyal A, Rao R.
      BACKGROUND: Pancreatic neuroendocrine tumor (PNET) is a diagnostic challenge with limited samples in not only identification but grading. Prior studies have shown insulinoma-associated protein 1 (INSM1) to be a robust marker in identifying PNETs from other solid pancreatic tumors on resection specimens. In this study, we investigated the utility of INSM1 not only for identifying PNETs but also for grading in cell blocks (CBs) and surgical resections (SRs).METHODS: A search for PNET cases between 2000 and 2019 identified 55 samples (26 CBs and 29 SRs) that were further separated into high (2 CBs, 3 SRs), intermediate (4 CBs, 7 SRs), and low (20 CBs, 19 SRs) grades based on their final pathology report and Ki-67 level. Immunohistochemical (IHC) staining for INSM1 (C-8, Santa Cruz Biotechnology [1:100]) was performed and quantified using an H score of 0 to 300. Non-PNET solid pancreatic tumors were compared and included acinar cell carcinoma, solid pseudopapillary neoplasm, and ductal adenocarcinoma.
    RESULTS: All 55 cases of PNET demonstrated nuclear INSM1 staining. The average H scores for INSM1 staining of PNET were 254 and 252 in CB and SR, respectively. The H scores decreased with increasing tumor grade, with low-grade (G1), intermediate-grade (G2), and high-grade (G3) tumors showing average INSM1 H scores of 229 and 253, 266 and 253, and 30 and 33 in both CB and SR, respectively.
    CONCLUSION: IHC with INSM1 plays a role in identifying and potentially grading PNETs.
    Keywords:  INSM1; grade; immunohistochemistry; neuroendocrine; pancreas
    DOI:  https://doi.org/10.1002/cncy.22242
  1114. Heart Lung Circ. 2019 Dec 17. pii: S1443-9506(19)31528-8. [Epub ahead of print]
    Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation.
    Nguyen MT, Gallagher C, Pitman BM, Emami M, Kadhim K, Hendriks JM, Middeldorp ME, Roberts-Thomson KC, Mahajan R, Lau DH, Sanders P, Wong CX.
      BACKGROUND: Studies have shown that suboptimal anticoagulation quality, as measured by time in therapeutic range (TTR), affects a significant percentage of patients with atrial fibrillation (AF). However, TTR has not been previously characterised in Indigenous Australians who experience a greater burden of AF and stroke.METHOD: Indigenous and non-Indigenous Australians with AF on warfarin anticoagulation therapy were identified from a large tertiary referral centre between 1999 and 2012. Time in therapeutic range was calculated as a proportion of daily international normalised ratio (INR) values between 2 and 3 for non-valvular AF and 2.5 to 3.5 for valvular AF. INR values between tests were imputed using the Rosendaal technique. Linear regression models were employed to characterise predictors of TTR.
    RESULTS: Five hundred and twelve (512) patients with AF on warfarin were included (88 Indigenous and 424 non-Indigenous). Despite younger age (51±13 vs 71±12 years, p<0.001), Indigenous Australians had greater valvular heart disease, diabetes, and alcohol excess compared to non-Indigenous Australians (p<0.05 for all). Time in therapeutic range was significantly lower in Indigenous compared to non-Indigenous Australians (40±29 vs 50±31%, p=0.006). Univariate predictors of poorer TTR included Indigenous ethnicity, younger age, diuretic use, and comorbidities, such as valvular heart disease, heart failure and chronic obstructive pulmonary disease (p<0.05 for all). Valvular heart disease remained a significant predictor of poorer TTR in multivariate analyses (p=0.004).
    CONCLUSION: Indigenous Australians experience particularly poor warfarin anticoagulation quality. Our data also suggest that many non-Indigenous Australians spend suboptimal time in therapeutic range. These findings reinforce the importance of monitoring warfarin anticoagulation quality to minimise stroke risk.
    Keywords:  Anticoagulation; Atrial fibrillation; Indigenous; Stroke; Warfarin
    DOI:  https://doi.org/10.1016/j.hlc.2019.11.006
  1115. Stem Cell Res Ther. 2020 Jan 21. 11(1): 31
    LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway.
    Chen H, Xia W, Hou M.
      AIMS: Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIF-pretreated MSCs in cardiomyocytes and to explore the underlying mechanisms.METHODS AND RESULTS: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF), and delivered to cardiomyocytes subjected to H2O2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. ExosomeMIF protected cardiomyocytes from H2O2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosomeMIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosomeMIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosomeMIF inhibited H2O2-induced apoptosis through modulating oxidative stress.
    CONCLUSIONS: Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosomeMIF in protecting cardiomyocytes from apoptosis.
    Keywords:  Cardiomyocytes apoptosis; Exosome; LncRNA-NEAT1/miR-142-3p/FOXO1 signaling pathway; MIF; Mesenchymal stem cells; Oxidative stress
    DOI:  https://doi.org/10.1186/s13287-020-1556-7
  1116. J Assoc Physicians India. 2020 Jan;68(1): 84
    Quantifi cation and Correlation of Serum Cortisol Levels with Diff erent Parameters of Metabolic Syndrome.
    Gupta S, Chetiwal R, Rastogi P.
      
  1117. J Hazard Mater. 2020 Jan 09. pii: S0304-3894(20)30051-0. [Epub ahead of print]388 122065
    Bioremediation of cadmium polluted soil using a novel cadmium immobilizing plant growth promotion strain Bacillus sp. TZ5 loaded on biochar.
    Ma H, Wei M, Wang Z, Hou S, Li X, Xu H.
      Bioremediation of cadmium polluted soil using biochar (BC) and plant growth promotion bacteria (PGPB) have been widely concerned. In our study, a novel Cd immobilizing PGPB strain TZ5 was isolated based on the Cd immobilizing potential and plant growth promotion (PGP) traits. Further, changes of surface morphology and functional groups of TZ5 cells were observed after exposed to Cd2+ by SEM-EDS and FTIR analyses. Then, the strain TZ5 was successfully loaded on BC as biochemical composites material (BCM). Pot experiment indicated that the percentage of acetic acid-extractable Cd in BCM treatments significantly decreased by 11.34 % than control. Meanwhile, BCM significantly increased the dry weight of ryegrass by 77.78 %, and decreased the Cd concentration of ryegrass by 48.49 %, compared to control. Microbial counts and soil enzyme activities in rhizosphere were both significantly improved by BCM. Furthermore, the proportion of relative abundance of Bacillus genus was enhanced after treated by BCM, which indicated that the strain TZ5 was successfully colonized in the rhizosphere. This study provided a practical strategy for bioremediation of Cd contaminated soil.
    Keywords:  BCM; Cadmium immobilizing; Plant growth promotion; Soil biochemical properties; Strain TZ5
    DOI:  https://doi.org/10.1016/j.jhazmat.2020.122065
  1118. J Bacteriol. 2020 Jan 21. pii: JB.00646-19. [Epub ahead of print]
    Substrate interaction with the EssC coupling protein of the Type VIIb secretion system.
    Mietrach N, Damián-Aparicio D, Süß BM, Lopez D, Geibel S.
      Staphylococcus aureus employs the Type VIIb secretion system (T7SSb) to secrete effector proteins that either have antibacterial activities or promote bacterial persistence in mouse infection models. Here we present the crystal structure of the ATPase domain D3 of the EssC coupling protein from S. aureus USA300_FPR3757, an integral component of the T7SSb complex, resolved at 1.7 Å resolution. EssC-D3 shares structural homology with FtsK/SpoIII like ATPase domains of T7SSa and T7SSb and exhibits a conserved pocket on the surface with differential amino acid composition.In T7SSa, substrate EsxB interacts with the D3 domain through this pocket. Here, we identify amino acids in this pocket that are essential for effector protein secretion in the T7SSb. Our results reveal that the adjacent ATPase domain D2 is a substrate binding site on EssC and that substrates bound to D2 require domain D3 for further transport. Point mutations in the Walker B motif of domain D3 have diametric effects on secretion activity, either abolishing or boosting it pointing to a critical role of domain D3 in the substrate transport. Finally, we identify ATPase domain D3 as a virulence determinant of S. aureus USA300_FPR3757 using an invertebrate in vivo infection model.Importance The emergence of antibiotic resistant bacteria poses a rising problem in antibiotic treatment (1). We have used the multi drug resistant S. aureus USA300_FPR3757 as model organism to study the T7SSb. Effector proteins of this system have been associated with abscess formation and bacterial persistence in mouse models (2, 3). We determined the structure of the essential ATPase domain D3 of the T7SSb at atomic resolution and validated a surface exposed pocket as a potential drug target to block secretion. Furthermore, our study provides new mechanistic insights into the T7SSb substrate transport.
    DOI:  https://doi.org/10.1128/JB.00646-19
  1119. Curr Med Chem. 2020 Jan 21.
    Monoclonal antibodies carried in drug delivery nanosystems as a strategy for cancer treatment.
    Silvestre ALP, Oshiro-Júnior JA, Garcia C, Turco BO, da Silva Leite JM, de Lima Damasceno BPG, Soares JCM, Chorilli M.
      Monoclonal antibodies carried in nanosystems have been extensively studied and reported as a promising tool for the treatment of various types of cancers. Monoclonal antibodies have great advantages for the treatment of cancer because their protein structure can bind to the target tissue; however, it has some challenges such as denaturation following heat exposure and extreme values of pH, temperature and solvents, the ability to undergo hydrolysis, oxidation and deamination and the formation of non-native aggregates, which totally compromises drug stability. In addition to these characteristics, they suffer rapid elimination when in the blood, which results in a short half-life and the production of neutralizing antibodies, rendering the doses ineffective. These challenges are overcome with encapsulation in nanosystems (liposomes, polymer nanoparticles, cyclodextrins, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers and micelles) due to the characteristics of improving solubility, permeability, and selectivity only with tumor tissue; with that, there is a decrease in side effects beyond controlled release, which is critical to improving the therapeutic efficacy of cancer treatment. The article was divided into the different types of nanosystems, with a description of their definitions and applications in various types of cancers. Therefore, this review summarizes the use of monoclonal antibodies encapsulated in nanosystems and the description of clinical studies with biosimilars. Biosimilars are defined as products that are similar to monoclonal antibodies which are produced when the patent for the monoclonal antibodies expires.
    Keywords:  drug delivery nanosystems; biopharmaceuticals; cancer treatment; biosimilars; antibodies; new therapy.
    DOI:  https://doi.org/10.2174/0929867327666200121121409
  1120. Expert Opin Pharmacother. 2020 Feb;21(3): 307-315
    New treatments in spinal muscular atrophy: an overview of currently available data.
    Ramdas S, Servais L.
      Introduction: Spinal muscular atrophy (SMA) is one of the most common inherited neuromuscular disorders. It causes progressive muscle weakness and results in significant disability. Until recently, there were no drugs available for the treatment of SMA. Several phase 1-3 studies, including three double-blind randomized placebo-controlled studies have demonstrated the efficacy of disease-modifying approaches including gene replacement therapy, antisense oligonucleotides, and splicing modifiers.Areas covered: This article covers the publically available data on therapeutic strategies that address the underlying cause of SMA and clinical data available on approved treatments and drugs in the pipeline.Expert opinion: The newer therapeutic options in SMA have a good safety profile and deliver a therapeutic benefit in most patients. It is essential that the recommended standards of care are delivered along with the drugs for the best outcomes. No biomarkers to distinguish responders from non-responders are available; it is important that biomarkers be identified. Early treatment is essential for the maximum efficacy of the newly available treatments.
    Keywords:  Spinal muscular atrophy; antisense oligonucleotide; branaplam; gene therapy; nusinersen; risdiplam; splicing modifiers
    DOI:  https://doi.org/10.1080/14656566.2019.1704732
  1121. Nutrients. 2020 Jan 20. pii: E267. [Epub ahead of print]12(1):
    Maternal Selenium Deficiency in Mice Alters Offspring Glucose Metabolism and Thyroid Status in a Sexually Dimorphic Manner.
    Hofstee P, McKeating DR, Bartho LA, Anderson ST, Perkins AV, Cuffe JSM.
      Selenium is an essential micronutrient commonly deficient in human populations. Selenium deficiency increases the risks of pregnancy complications; however, the long-term impact of selenium deficiency on offspring disease remains unclear. This study investigates the effects of selenium deficiency during pregnancy on offspring metabolic function. Female C57BL/6 mice were allocated to control (>190 μg selenium/kg, n = 8) or low selenium (<50 μg selenium/kg, n = 8) diets prior to mating and throughout gestation. At postnatal day (PN) 170, mice underwent an intraperitoneal glucose tolerance test and were culled at PN180 for biochemical analysis. Mice exposed to selenium deficiency in utero had reduced fasting blood glucose but increased postprandial blood glucose concentrations. Male offspring from selenium-deficient litters had increased plasma insulin levels in conjunction with reduced plasma thyroxine (tetraiodothyronine or T4) concentrations. Conversely, females exposed to selenium deficiency in utero exhibited increased plasma thyroxine levels with no change in plasma insulin. This study demonstrates the importance of adequate selenium intake around pregnancy for offspring metabolic health. Given the increasing prevalence of metabolic disease, this study highlights the need for appropriate micronutrient intake during pregnancy to ensure a healthy start to life.
    Keywords:  DOHaD; endocrine; micronutrients; pregnancy; reproduction; selenoprotein
    DOI:  https://doi.org/10.3390/nu12010267
  1122. Clin Cancer Res. 2020 Jan 21. pii: clincanres.3354.2019. [Epub ahead of print]
    CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies.
    Quayle SN, Girgis N, Thapa DR, Merazga Z, Kemp MM, Histed A, Zhao F, Moreta M, Ruthardt P, Hulot S, Nelson A, Kraemer LD, Beal DR, Witt L, Ryabin J, Soriano J, Haydock M, Spaulding E, Ross JF, Kiener PA, Almo S, Chaparro R, Seidel R, Suri A, Cemerski S, Pienta KJ, Simcox ME.
      PURPOSE: To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E711-20-specific CD8+T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical and anal cancers.EXPERIMENTAL DESIGN: CUE-101 is an Fc fusion protein comprised of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human interleukin-2 (IL-2) molecules, and an effector attenuated human immunoglobulin G (IgG1) Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, while in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Anti-tumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model.
    RESULTS: CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E711-20-specific CD8+T cells from PBMCs relative to non-target cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+T cells in HLA-A2 (AAD) transgenic mice, and anti-cancer efficacy and immunologic memory was demonstrated in TC-1 tumor bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy.
    CONCLUSIONS: Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing Phase 1 trial (NCT03978689).
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-3354
  1123. J Biol Chem. 2020 Jan 20. pii: jbc.RA119.010077. [Epub ahead of print]
    The discovery and maturation of peptide biologics targeting the small G protein Cdc42: a bioblockade for Ras-driven signalling.
    Tetley GJN, Murphy NP, Bonetto S, Ivanova-Berndt G, Revell J, Mott HR, Cooley RN, Owen D.
      Aberrant Ras signalling drives 30% of cancers and inhibition of Rho family small-GTPase signalling has been shown to combat Ras-driven cancers. Here we present the discovery of a 16mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely related small-GTPases. The structure of the tightest binding peptide was solved by NMR and its binding site on Cdc42 determined. Addition of a cell penetrating sequence allowed the peptides to access the cell interior and engage with their target(s), modulating signalling pathways. In Ras-driven cancer cell models, the peptides have an inhibitory effect on proliferation and show suppression of both invasion and motility. As such they represent promising candidates for Rho-family small GTPase inhibitors and therapeutics targeting Ras-driven cancers. Our data adds to the growing literature demonstrating that peptides are establishing their place in the biologics arm of drug discovery.
    Keywords:  CDC42; GTPase Kras (KRAS); biologics; cancer; cancer therapeutics; cell migration; cell proliferation; cell signaling; cyclic peptide; drug discovery; nuclear magnetic resonance (NMR); peptide conformation
    DOI:  https://doi.org/10.1074/jbc.RA119.010077
  1124. Diabetes. 2020 Jan 23. pii: db190388. [Epub ahead of print]
    Liver ChREBP Protects Against Fructose-induced Glycogenic Hepatotoxicity by Regulating L-type Pyruvate Kinase.
    Shi JH, Lu JY, Chen HY, Wei CC, Xu X, Li H, Bai Q, Xia FZ, Lam SM, Zhang H, Shi YN, Cao D, Chen L, Shui G, Yang X, Lu Y, Chen YX, Zhang WJ.
      Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, and this was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G-6-P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.
    DOI:  https://doi.org/10.2337/db19-0388
  1125. Blood. 2020 Jan 21. pii: blood.2019001815. [Epub ahead of print]
    Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions.
    Yoshida N, Shigemori K, Donaldson N, Cordero NA, Stevenson K, Bu X, Arakawa F, Takeuchi M, Ohshima K, Yoda A, Ng SY, Weinstock DM.
      Adult T-cell leukemia/lymphoma (ATLL) in Japan presents at a median age of 70 and only 5% of patients are age <50. We conducted RNA and targeted DNA sequencing of 8 ATLL from Japanese patients <50 and identified 3 (37.5%) with both CTLA4-CD28 and ICOS-CD28 fusions. Mutations of PLCG1, PRKCB and STAT3, which were frequent in other ATLL sequencing studies, were not identified. Differential expression analysis identified the negative checkpoint molecule LAG3 as the most downregulated gene among cases with the fusions. Immunohistochemistry demonstrated expression of CD80 and CD86, the ligands for CTLA4/CD28/ICOS, on ATLL cells and tumor-associated macrophages, respectively. Expression of CTLA4-CD28 in Ba/F3 cells conferred cytokine-independent growth when co-cultured with Raji cells that express CD80 and CD86. Growth was associated with recruitment of the p85 subunit of PI3 kinase to CTLA4-CD28 and phosphorylation of AKT and ERK. A CTLA4-blocking antibody reduced cytokine-independent growth in a dose-dependent manner. Together, these results suggest that young Japanese ATLL cases have a unique biology dependent on cell-nonautonomous interactions that drive CD28 signaling. Assessment for CD28 fusions and treatment with CTLA4 blockade should be considered in younger patients with relapsed/refractory ATLL.
    DOI:  https://doi.org/10.1182/blood.2019001815
  1126. Neurotherapeutics. 2020 Jan 22.
    TSPO PET Identifies Different Anti-inflammatory Minocycline Treatment Response in Two Rodent Models of Epileptogenesis.
    Wolf BJ, Brackhan M, Bascuñana P, Leiter I, Langer BLN, Ross TL, Bankstahl JP, Bankstahl M.
      Epileptogenesis-associated brain inflammation might be a promising target to prevent or attenuate epileptogenesis. Positron emission tomography (PET) imaging targeting the translocator protein (TSPO) was applied here to quantify effects of different dosing regimens of the anti-inflammatory drug minocycline during the latent phase in two rodent models of epileptogenesis. After induction of epileptogenesis by status epilepticus (SE), rats were treated with minocycline for 7 days (25 or 50 mg/kg) and mice for 5 or 10 days (50 or 100 mg/kg). All animals were subjected to scans at 1 and 2 weeks post-SE. Radiotracer distribution was analyzed and statistical parametric mapping (SPM) was performed, as well as histological analysis of astroglial activation and neuronal cell loss. Atlas-based analysis of [18F]GE180 PET in rats revealed a dose-dependent regional decrease of TSPO expression at 2 weeks post-SE. Results of SPM analysis depicted a treatment effect already at 1 week post-SE in rats treated with the higher minocycline dose. In mice, TSPO PET imaging did not reveal any treatment effects whereas histology identified only a treatment-related reduction in dispersion of dentate gyrus neurons. TSPO PET served as an auspicious tool for temporal monitoring and quantification of anti-inflammatory effects during epileptogenesis. Importantly, the findings underline the need to applying more than one animal model to avoid missing treatment effects. For future studies, the setup is ready to be applied in combination with seizure monitoring to investigate the relationship between individual early treatment response and disease outcome.
    Keywords:  Neuroinflammation; PET; epileptogenesis; minocycline; translocator protein
    DOI:  https://doi.org/10.1007/s13311-020-00834-5
  1127. Int J Food Sci Nutr. 2020 Jan 24. 1-9
    Sustained effects of resistant starch on the expression of genes related to carbohydrate digestion/absorption in the small intestine.
    Rosas-Pérez AM, Honma K, Goda T.
      Resistant starch (RS) consumption has beneficial effects on health, such as reduced postprandial blood glucose levels. In this study, we evaluated the effect of a 14-day diet containing RS on α-glucosidase activity and the expression of genes related to carbohydrate digestion/absorption in rats. We examined whether the effects of RS persist when the rats were shifted to a control diet. The results suggest that RS consumption reduces α-glucosidase activity and Mgam, Si and Sglt1 mRNA levels in the proximal jejunum. In addition, RS consumption appeared to influence the serum GIP level, up to 2 days after the animals were shifted to a control diet. To our knowledge, this is the first report that RS has a sustained effect on gut hormone expression and the expression of genes related to carbohydrate digestion/absorption in the proximal jejunum.
    Keywords:  GIP; Resistant starch; small intestine; sustained effect; α-glucosidases
    DOI:  https://doi.org/10.1080/09637486.2019.1711362
  1128. AACE Clin Case Rep. 2019 Mar-Apr;5(2):5(2): e138-e141
    PHOSPHATURIC MESENCHYMAL HEEL TUMOR PRESENTING WITH TUMOR-INDUCED OSTEOMALACIA.
    Kaur T, Rush ET, Bhattacharya RK.
      Objective: To help clinicians identify and treat patients with tumor-induced osteomalacia (TIO) resulting from a phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT).Methods: Describe the history, presentation, laboratory findings, diagnostic studies, treatment, and literature review.
    Results: A 58-year-old female with no significant past medical history presents with ongoing multiple bone pain for years. She had a bone scan showing multiple focal areas of increased uptake involving bilateral ribs, distal right tibia, and left femoral neck, representing previously healed fractures. Her bilateral lower-extremity magnetic resonance imaging showed stress fractures of the anteromedial cortex, right tibia, and the left femoral neck. Phosphorus was noted to be 1.9 mg/dL (normal range, 2.0 to 4.0 mg/dL), and alkaline phosphatase was 179 U/L (normal range, 25 to 110 U/L). Tubular maximum re-absorption of phosphate to glomerular filtration rate ratio was 0.438, which was low. An outside physician initiated patient on teriparatide, which showed bone mineral density improvement after 1 year, and then the teriparatide was stopped. Later, she developed a nontraumatic pubic ramus fracture; teriparatide was resumed. While on teriparatide, she developed several new rib fractures. Due to declining phosphorus levels, further investigation led to an elevated fibroblast growth factor 23 (FGF-23) level of 243 RU/mL (normal, <50 RU/mL). TIO was strongly suspected, and a nuclear medicine positron emission tomography/computed tomography trunk with 68Ga-1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid tyrosine-3-octreotate (i.e., 68Ga-DOTATATE) showed a right heel soft-tissue nodule. Fine-needle aspiration biopsy was performed, confirming PMTMCT, positive for FGF-23 mRNA. After surgery, her symptoms resolved and her phosphorus normalized.
    Conclusion: TIO is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness, and fractures associated with persistent hypophosphatemia. Clinicians now have new imaging tools to help identify and treat patients with PMTMCT.
    DOI:  https://doi.org/10.4158/ACCR-2018-0300
  1129. FEBS J. 2020 Jan 22.
    New regulatory mechanism-based inhibitors of aspartate transcarbamoylase for potential anticancer drug development.
    Lei Z, Wang B, Lu Z, Wang N, Tan H, Jimin Z, Jia Z.
      Aspartate transcarbamoylase (ATCase) is a key enzyme which regulates and catalyzes the second step of de novo pyrimidine synthesis in all organisms. E. coli ATCase is a prototypic enzyme regulated by both product feedback and substrate cooperativity, whereas human ATCase is a potential anticancer target. Through structural and biochemical analyses, we revealed that R167/130's loop region in ATCase serves as a gatekeeper for the active site, playing a new and unappreciated regulatory role in the catalytic cycle of ATCase. Based on virtual compound screening simultaneously targeting the new regulatory region and active site of human ATCase, two compounds were identified to exhibit strong inhibition of ATCase activity, proliferation of multiple cancer cell lines, and growth of xenograft tumors. Our work has not only revealed a previously unknown regulatory region of ATCase that helps uncover the catalytic and regulatory mechanism of ATCase, but also successfully guided the identification of new ATCase inhibitors for anticancer drug development using a dual-targeting strategy.
    Keywords:  Anticancer drug; Aspartate transcarbamoylase; Drug screening; Enzyme mechanism; Molecular dynamics
    DOI:  https://doi.org/10.1111/febs.15220
  1130. J Prev Med Hyg. 2019 Dec;60(4): E354-E360
    Early and current physical activity: cross-sectional associations with overweight among adults.
    Coledam DHC.
      Introduction: The health benefits of physical activity in all ages are widely known, however the effects of early physical activity on future health are not yet fully understood. The aim of this study was to analyze the cross-sectional associations between previous and current physical activity with overweight among adults.Methods: A probabilistic sample of 534 teachers was included in the study. Independent variables were physical activity in childhood, adolescence, and current, and clustering of the variables, all analyzed using a self-report questionnaire. The dependent variable was overweight, estimated by the body mass index, assessed using self-report measures of weight and height. Covariates were sex, age, skin color, income, sedentary behavior, medication use for weight control, and nutritionist counseling. Poisson regression was adopted to estimate Prevalence Ratios (PR) in the multivariate analysis.
    Results: Physical activity at ages 6-10 (PR = 1.03 to 1.13), 12-14 (PR = 0.96 to 0.98), and 15-17 (PR = 0.76 to 0.90) years was not associated with overweight. Participants who do not meet the recommendation of current physical activity have a higher likelihood of being overweight (PR = 1.55 to 2.17) and the magnitude of the association increased when analyzing those who were not physically active through all periods analyzed (PR = 3.69 to 4.69).
    Conclusion: Performing physical activity only in early life does not seem to promote health benefits in the sample analyzed. Although current physical activity is associated with the outcome, the promotion of both early and current physical activity seems to be a better strategy to prevent overweight among adults.
    Keywords:  Adolescence; Body Mass Index; Child; Health; Motor activity
    DOI:  https://doi.org/10.15167/2421-4248/jpmh2019.60.4.1265
  1131. J Clin Endocrinol Metab. 2020 Jan 22. pii: dgaa031. [Epub ahead of print]
    Is Better Sleep Beneficial for Metabolic Outcomes in Obese Female Adolescents with Polycystic Ovarian Syndrome?
    Mehra R, Kashyap SR, Shah V.
      
    DOI:  https://doi.org/10.1210/clinem/dgaa031
  1132. J Public Health Dent. 2020 Jan 21.
    Endodontic therapy and incident cardiovascular disease: The Atherosclerosis Risk in Communities (ARIC) study.
    Cowan LT, Lakshminarayan K, Lutsey PL, Beck J, Offenbacher S, Pankow JS.
      OBJECTIVES: Previous studies on a potential association between endodontic infection (EI) and cardiovascular disease (CVD) produced mixed results. Endodontic treatment (ET) may also be linked to cardiovascular risk, as a marker for prior chronic dental infection and subclinical EI in other teeth. We tested the hypothesis that ET is associated with elevated risk of coronary heart disease (CHD), ischemic stroke (IS), heart failure (HF), or venous thromboembolism (VTE).METHODS: ARIC participants who completed the dental ancillary study exam 4 (1996-1998; n = 6,638) were included in the analyses. Participants were followed through 2013 for CHD, stroke, and HF and 2011 for VTE. Cox-proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CHD, IS, HF, and VTE across ET classifications adjusting for age, sex, race/center, education, income, smoking, alcohol consumption, BMI, statin use, family history of CHD, physical activity, diet quality, insurance status, last dental visit, dental visit frequency, having a current dentist, and tooth loss due to gum disease.
    RESULTS: Among participants, 21.0% reported a single ET, while 28.5% reported multiple ETs. Over a median of 15.8 years of follow-up, there were 506 incident CHD events, 311 IS events, 739 HF events, and 219 VTE events. There were no significant associations between self-reported history of ET and any of our outcomes (HR (95%CI): CHD = 1.16 (0.87,1.44), IS = 0.77 (0.55,1.09), HF = 1.00 (0.81,1.24), VTE = 0.98 (0.67,1.43)) after adjustment.
    CONCLUSIONS: Our results do not support an independent association between ET and development of CHD, IS, HF, or VTE.
    Keywords:  cardiovascular diseases; coronary disease; endodontic; endodontic treatment; heart failure; infection; stroke; venous thromboembolism
    DOI:  https://doi.org/10.1111/jphd.12353
  1133. BMC Neurosci. 2020 Jan 22. 21(1): 4
    Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment.
    Fan R, Schrott LM, Snelling S, Felty J, Graham D, McGauly PL, Arnold T, Korneeva NL.
      BACKGROUND: Opioids are the most effective drugs commonly prescribed to treat pain. Due to their addictive nature, opioid pain relievers are now second to marijuana, ahead of cocaine with respect to dependence. Ours and other studies suggest potential toxic effects of chronic opioid administration leading to neuronal degeneration. It has been suggested that protein carbonylation may represent a sensitive biomarker of cellular degeneration. To evaluate whether prolonged oxycodone administration is associated with accumulation of protein aggregates that may contribute to neuronal degeneration we measured protein carbonylation levels in brain and also in blood plasma of rats after 30-days of 15 mg/kg daily oxycodone administration.RESULTS: We observed a significant increase in the level of carbonylated proteins in rat brain cortex after 30-days of oxycodone treatment compare to that in water treated animals. Also, oxycodone treated rats demonstrated accumulation of insoluble carbonyl-protein aggregates in blood plasma.
    CONCLUSIONS: Our data suggests that tests detecting insoluble carbonyl-protein aggregates in blood may serve as an inexpensive and minimally invasive method to monitor neuronal degeneration in patients with a history of chronic opioid use. Such methods could be used to detect toxic side effects of other medications and monitor progression of aging and neurodegenerative diseases.
    Keywords:  Carbonyl-protein; Carbonylation; Cortex; Integrated stress response; Opioid; Oxidative stress; Oxycodone; Protein aggregates
    DOI:  https://doi.org/10.1186/s12868-020-0552-2
  1134. J Hazard Mater. 2020 Jan 21. pii: S0304-3894(20)30106-0. [Epub ahead of print]389 122118
    Corrigendum: Competitive sorption of Pb(II), Cu(II) and Ni(II) on carbonaceous nanofibers: A spectroscopic and modeling approach.
    Ding C, Cheng W, Wang X, Wu ZY, Sun Y, Chen C, Wang X, Yu SH.
      
    DOI:  https://doi.org/10.1016/j.jhazmat.2020.122118
  1135. Support Care Cancer. 2020 Jan 23.
    Predictive clinical factors of chronic peripheral neuropathy induced by oxaliplatin.
    Yildirim N, Cengiz M.
      PURPOSE: We aimed to identify potential clinical parameters that can be easily obtained by a pre-treatment clinicopathological evaluation and whole blood test to estimate the development of oxaliplatin-induced peripheral neuropathy (OIPN).METHODS: This study was conducted retrospectively. For the FOLFOX regimen, patients received oxaliplatin, 85 mg/m2, every 2 weeks for 12 courses, and with the XELOX regimen, oxaliplatin was 130 mg/m2, every 3 weeks for 6-8 courses. The incidence and degree of neuropathy (NCI-CTCAE v.3) were recorded.
    RESULTS: A total of 186 patients were included in the study. There were 108 (58%) patients in the grade 0-1 (G0-G1) neuropathy group (mean age 50.5 ± 11.5; 63% men), and 78 (42%) patients in the grade 2-3 (G2-G3) neuropathy group (mean age 58.0 ± 10.8; 46.2% men). The relationship between G2-G3 OIPN development and age (p < 0.001), gender (p = 0.02), and ECOG performance status (p = 0.007) was statistically significant. In the G2-G3 neuropathy group, serum gamma-glutamyl transferase (GGT) (p < 0.001) and glucose (p = 0.007) levels were higher, whereas vitamin D (p < 0.001), hemoglobin (Hgb) (p < 0.001), serum albumin (p = 0.001), and serum magnesium (p = 0.035) levels were lower compared with the G0-G1 neuropathy group. G2-G3 neuropathy was observed in 88% of patients with mucinous carcinoma pathologic type (p < 0.001).
    CONCLUSION: This study demonstrated that age, histopathologic type, albumin, GGT, glucose, vitamin D, and Hgb levels were the effective factors in prediction of the development of OIPN. In addition, GGT, vitamin D, and Hgb levels were the most effective factor to predict development of OIPN.
    Keywords:  Gastrointestinal system cancers; Oxaliplatin; Peripheral neuropathy; Toxicity; Treatment
    DOI:  https://doi.org/10.1007/s00520-020-05319-x
  1136. ACS Appl Mater Interfaces. 2020 Jan 21.
    A Core-Shell Layered Oxide Cathode for High-Performance Sodium-Ion Batteries.
    Chen C, Han Z, Chen S, Qi S, Lan X, Zhang C, Chen L, Wang P, Wei W.
      Sodium layered oxides are considered as one of the most potential cathode candidates for large-scale energy storage due to their high reversible capacity and wide availability of sodium resources. A significant hurdle to wide application of these layered oxides lies in simultaneously satisfying high-energy density and long cycle life because of the intrinsic problems associated with their structural irreversibility. Herein, a O3/O'3-P2 core-shell composite that integrates a high specific capacity from O-type Ni-based core and good structural stability from P2-type Mn-rich shell is presented. Multiscale electron microscopy and affiliated spectroscopy analyses reveal that in addition to the microscale O3/O'3-P2 core-shell structure, nanoscale coherent P2/O3 intergrown structure can also be identified in the composite. Such well-tailored structures not only constrain the structural damages (microscale cracks) induced by repeated volumetric changes upon desodiation and re-sodiation, but also facilitate fast Na ions diffusion through the exterior P2-type layered structure. This work may provide new clues into the design of high-performance cathode materials for sodium-ion batteries (SIBs).
    DOI:  https://doi.org/10.1021/acsami.9b19260
  1137. J Bacteriol. 2020 Jan 21. pii: JB.00692-19. [Epub ahead of print]
    Genomic differences between Listeria monocytogenes EGDe isolates reveals crucial roles for SigB and wall rhamnosylation in biofilm formation.
    Hsu CY, Cairns L, Hobley L, Abbott J, O'Byrne C, Stanley-Wall NR.
      Listeria monocytogenes is a Gram-positive Firmicute that causes food-borne infections, in part due to its ability to use multiple strategies, including biofilm formation, to survive adverse growth conditions. As a potential way to screen for genes required for biofilm formation we harnessed the ability of bacteria to accumulate mutations in the genome over time, diverging the properties of seemingly identical strains. By sequencing the genomes of four laboratory reference strains of the commonly used L. monocytogenes EGDe, we showed that each isolate contains SNPs compared with the reference genome. We discovered that two SNPs, contained in two independent genes within one of the isolates, impacted biofilm formation. Using bacterial genetics and phenotypic assays, we confirmed that rsbU and rmlA influence biofilm formation. RsbU is the upstream regulator of the alternative sigma factor, SigB and mutation of either rsbU or sigB increased biofilm formation. In contrast, deletion of rmlA, which encodes the first enzyme for TDP-L-rhamnose biosynthesis, resulted in a reduction in the amount of biofilm formed. Further analysis of biofilm formation in a strain that still produces TDP-L-rhamnose, but which cannot decorate the wall teichoic acid with rhamnose (rmlT mutant), showed that it is the decorated wall teichoic acid that is required for adhesion of the cells to surfaces. Together these data uncover novel routes by which biofilm formation by L. monocytogenes can be impacted.Importance Biofilms are an important mode of growth in many settings. Here we have looked at small differences in the genomes of the bacteria Listeria monocytogenes isolate EGDe and used them to find out how biofilms form. This is important fundamental information may help new treatments to be developed and also highlights the fact that isolates of the same identity often diverge.
    DOI:  https://doi.org/10.1128/JB.00692-19
  1138. AACE Clin Case Rep. 2019 Sep-Oct;5(5):5(5): e271-e275
    INTRAMEDULLARY SPINAL CORD METASTASIS AS THE PRESENTING FEATURE OF PAPILLARY THYROID CARCINOMA.
    Yoel U, Joshua BZ, Shoukrun R, Dyomin V, Levin D, Sufaro YZ, Fraenkel M.
      Objective: The objective of this report is to present an unusual case of intramedullary spinal cord metastasis (ISCM) as the presenting feature of papillary thyroid carcinoma (PTC).Methods: The presented case includes clinical, biochemical, and imaging findings as well as surgical and pathology reports. Treatment with radioactive iodine (RAI) and the response to this treatment are presented.
    Results: A 71-year-old woman was evaluated for debilitating low back pain and walking disability. Magnetic resonance imaging demonstrated an oval, lumbar, intramedullary mass with benign features and surgery was scheduled. On preoperative evaluation for the lumbar mass, a multinodular thyroid goiter (unfortunately overlooked previously) was noticed, causing severe narrowing of the trachea. Total thyroidectomy was performed with a pathology diagnosis of PTC. In a second operation, the lumbar lesion was removed and proved to represent metastatic PTC. External beam radiation was subsequently administered to the thyroid bed, lumbar spine, and other skeletal metastases, followed by 150 milliCurie of RAI. A post-treatment scan showed high uptake over the lumbar spine, and skeletal and lung lesions. Clinically, the patient restored her walking ability and back pain improved.
    Conclusion: ISCM rarely is the presenting feature of PTC. Our patient presented with back pain which is the typical, though non-specific symptom, of ISCM. She showed good clinical response to multimodal treatment which is in line with the few other differentiated thyroid cancer patients with ISCM reported in the literature. Prompt surgical resection, followed by external beam radiation and RAI, may improve neurological signs, alleviate pain, and improve quality of life.
    DOI:  https://doi.org/10.4158/ACCR-2019-0072
  1139. J Invest Dermatol. 2020 Jan 20. pii: S0022-202X(20)30019-1. [Epub ahead of print]
    Activated Hgf-Met signaling cooperates with oncogenic Braf to drive primary cutaneous melanomas and angiotropic lung metastases in mice.
    Braun AD, Mengoni M, Bonifatius S, Tüting T, Gaffal E.
      Oncogenic mutations in the Braf-kinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenic Braf to promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenic Braf mutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood. Here we show in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenic Braf to drive tumor development and metastatic spread. Activation of oncogenic Braf in mice with transgenic Hgf overexpression and an oncogenic Cdk4 germline mutation accelerated and increased the development of primary cutaneous melanomas. Primary melanomas showed considerable phenotypic heterogeneity with frequent signs of dedifferentiation. Braf activation in Hgf-Cdk4 mice also increased the number of lung metastases. Intriguingly, melanoma cells showed a pronounced angiotropic growth pattern both at the invasive front in primary tumors and in metastatic lesions of the lung. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenic Braf can cooperate in melanoma pathogenesis.
    DOI:  https://doi.org/10.1016/j.jid.2019.12.020
  1140. Phys Med Biol. 2020 Jan 24.
    A novel radiomic nomogram for predicting epidermal growth factor receptor mutation in peripheral lung adenocarcinoma.
    Lu X, Li M, Zhang HM, Hua S, Meng F, Yang H, Li X, Cao D.
      OBJECTIVE: To predict the epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma using quantitative radiomic biomarkers and semantic features.METHOD: We analyzed the computed tomography (CT) images and medical record data of 104 patients with lung adenocarcinoma who underwent surgical excision and EGFR mutation detection from 2016 to 2018 at our center. CT radiomic and semantic features that reflect the tumors' heterogeneity and phenotype were extracted from preoperative non-enhanced CT scans. The least absolute shrinkage and selection operator method was applied to select the most distinguishable features. Three logistic regression models were built to predict the EGFR mutation status by combining the CT semantic with clinicopathological characteristics, using the radiomic features alone, and by combining the radiomic and clinicopathological features. Receiver operating characteristic curve analysis was performed using five-fold cross-validation and the mean area under the curve (AUC) values were calculated and compared between the models to obtain the optimal model for predicting EGFR mutation. Furthermore, radiomic nomograms were constructed to demonstrate the performance of the model.
    RESULTS: In total, 1,025 radiomic features were extracted and reduced to 13 features as the most important predictors to build the radiomic signature. The combined radiomic and clinicopathological features model was developed based on the radiomic signature, sex, smoking, vascular infiltration, and pathohistological type. The AUC was 0.90±0.02 for the training, 0.88±0.11 for the verification, and 0.894 for the test dataset. This model was superior to the other prediction models that used the combined CT semantic and clinicopathological features (AUC for the test dataset: 0.768) and radiomic features alone (AUC for the test dataset: 0.837).
    CONCLUSION: The prediction model built by radiomic biomarkers and clinicopathological features, including the radiomic signature, sex, smoking, vascular infiltration, and pathological type, outperformed the other two models and could effectively predict the EGFR mutation status in patients with peripheral lung adenocarcinoma. The radiomic nomogram of this model is expected to become an effective biomarker for patients with lung adenocarcinoma requiring adjuvant targeted treatment.
    Keywords:  Computed tomography (CT); Epidermal growth factor receptor (EGFR); Lung adenocarcinoma; Radiomics
    DOI:  https://doi.org/10.1088/1361-6560/ab6f98
  1141. Asia Pac J Public Health. 2020 Jan 19. 1010539519899777
    Association Between Electronic Cigarette Use and Levels of High-Sensitivity C-Reactive Protein and Uric Acid.
    Moon J, Lee H, Kong M, Kim H, Oh Y.
      The present study investigated whether electronic cigarette use, which is becoming increasingly common, was related to systemic inflammation that may lead to cardiovascular disease, similar to conventional cigarette smoking. The study included 1208 men (19-65 years old) who participated in the 7th Korean National Health and Nutrition Examination Survey (2016). The participants were categorized as electronic cigarette users, conventional cigarette users, and nonsmokers. Serum high-sensitivity C-reactive protein was used as an inflammatory index, and uric acid level was used as a metabolic indicator. After adjusting for confounding factors, electronic cigarette use was significantly associated with elevated serum high-sensitivity C-reactive protein levels (β = 1.326, P = .002), uric acid levels (β = 0.400, P = .042), and hyperuricemia (uric acid level of >7 mg/mL; odds ratio = 2.67, 95% confidence interval = 1.27-5.58). These findings suggest that electronic cigarette use may be associated with systemic inflammation markers, similar to conventional cigarette use.
    Keywords:  KNHANES; electronic cigarette; hs-CRP; inflammatory marker; uric acid
    DOI:  https://doi.org/10.1177/1010539519899777
  1142. Nat Rev Clin Oncol. 2020 Jan 21.
    NGS reveals relevant resistance mutations.
    Romero D.
      
    DOI:  https://doi.org/10.1038/s41571-020-0330-1
  1143. Free Radic Biol Med. 2020 Jan 20. pii: S0891-5849(19)32473-6. [Epub ahead of print]
    Butyrate alleviates oxidative stress by regulating NRF2 nuclear accumulation and H3K9/14 acetylation via GPR109A in bovine mammary epithelial cells and mammary glands.
    Guo W, Liu J, Sun J, Gong Q, Ma H, Kan X, Cao Y, Wang J, Fu S.
      Oxidative stress consistently affects lactation length and quality in dairy cows. Oxidative stress in the mammary gland of high-yielding dairy cows is a serious problem. Therefore, we studied the role of butyrate in dairy cow oxidative stress and further elucidated the mechanism of the antioxidative action of mammary epithelial cells in dairy cows. Oxidative stress and activated GPR109A were present in high-yielding dairy cows. Then, bovine mammary epithelial cells (BMECs) were isolated, and oxidative stress-related protein expression was measured, confirming that sodium butyrate (NaB) exerted antioxidant effects through GPR109A, NRF2 and H3K9/14 acetylation. To further study the antioxidative mechanism of butyrate in dairy cows, we also confirmed that butyrate promoted NRF2 nuclear accumulation and H3K9/14 acetylation through the AMPK signaling pathway by western blotting. Additionally, we preliminarily clarified the interaction between NRF2 and H3K9/14 acetylation by Co-IP and ChIP. Butyrate activated the AMPK signaling pathway through GPR109A to promote NRF2 nuclear accumulation and H3K9/14 acetylation, subsequently exerting antioxidant effects through the synergistic functions of these two processes. Then, we studied the effect of butyrate on oxidative stress in dairy cows in vivo, and the results were consistent with those in vitro. Therefore, butyrate played an antioxidant and antiapoptotic role through the GPR109A/AMPK/NRF2 signaling pathway, while H3K9/14 acetylation could promote NRF2 transcription and enhance the antioxidant capacity of BMECs.
    Keywords:  BMECs; Butyrate; GPR109A; H3K9/14 acetylation; NRF2; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.01.016
  1144. Curr Obes Rep. 2020 Jan 22.
    Sleep Apnea, Obesity, and Disturbed Glucose Homeostasis: Epidemiologic Evidence, Biologic Insights, and Therapeutic Strategies.
    Pugliese G, Barrea L, Laudisio D, Salzano C, Aprano S, Colao A, Savastano S, Muscogiuri G.
      PURPOSE OF REVIEW: Obstructive sleep apnea (OSA), obesity, and disturbed glucose homeostasis are usually considered distinct clinical condition, although they are tightly related to each other. The aim of our manuscript is to provide an overview of the current evidence on OSA, obesity, and disturbed glucose homeostasis providing epidemiologic evidence, biological insights, and therapeutic strategies.RECENT FINDINGS: The mechanisms hypothesized to be involved in this complex interplay are the following: (1) "direct weight-dependent" mechanisms, according to which fat excess compromises respiratory mechanics, and (2) "indirect weight-dependent" mechanisms such as hyperglycemia, insulin resistance and secondary hyperinsulinemia, leptin resistance and other hormonal dysregulations frequently found in subjects with obesity, type 2 diabetes, and/or sleep disorders. Moreover, the treatment of each of these clinical conditions, through weight loss induced by diet or bariatric surgery, the use of anti-obesity or antidiabetic drugs, and continuous positive airway pressure (CPAP), seems to positively influence the others. These recent data suggest not only that there are multiple connections among these diseases but also that treating one of them may result in an improvement of the others.
    Keywords:  Metabolic syndrome; Obesity; Obstructive sleep apnea; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1007/s13679-020-00369-y
  1145. Evid Based Complement Alternat Med. 2020 ;2020 6212907
    Effects of Huang-Lian-Jie-Du Decoction on Oxidative Stress and AMPK-SIRT1 Pathway in Alzheimer's Disease Rat.
    Gu X, Zhao H, Zhou J, Zhou Y, Wei X, Wang H, Bian B, Yang J, Ren W, Si N.
      Huang-Lian-Jie-Du Decoction (HLJDD), traditional Chinese medicine (TCM), is proven to have ameliorative effects on learning and memory deficits of Alzheimer's disease (AD). The current study aims to reveal the underlying mechanism of HLJDD in the treatment of AD by simultaneous determination on the regulation of HLJDD on oxidative stress, neurotransmitters, and AMPK-SIRT1 pathway in AD. AD model rat was successfully established by injection of D-galactose and Aβ 25-35-ibotenic acid. Morris Water Maze (MWM) test was used to evaluate the success of AD modelling. On this basis, an advanced technique with UPLC-QqQ MS/MS was built up and applied to determine the levels of 8 neurotransmitters in rat plasma. Significant alternation in methionine, glutamine, and tryptophan was observed in AD rats' plasma after the administration of HLJDD, relative to the model group. Meanwhile, HLJDD could upregulate the levels of SOD, GSH-Px, AMPK, and SIRT1 and downregulate the content of MDA in the peripheral system of the AD rats. The underlying therapeutic mechanism of HLJDD for the treatment of AD was associated with alleviating oxidation stress, inflammation, neurotransmitters, and energy metabolism. These data provide solid foundation for the potential use of HLJDD to treat AD.
    DOI:  https://doi.org/10.1155/2020/6212907
  1146. Int J Biometeorol. 2020 Jan 18.
    Radon-222: environmental behavior and impact to (human and non-human) biota.
    Ćujić M, Janković Mandić L, Petrović J, Dragović R, Đorđević M, Đokić M, Dragović S.
      As an inert radioactive gas, 222Rn could be easily transported to the atmosphere via emanation, migration, or exhalation. Research measurements pointed out that 222Rn activity concentration changes during the winter and summer months, as well as during wet and dry season periods. Changes in radon concentration can affect the atmospheric electric field. At the boundary layer near the ground, short-lived daughters of 222Rn can be used as natural tracers in the atmosphere. In this work, factors controlling 222Rn pathways in the environment and its levels in soil gas and outdoor air are summarized. 222Rn has a short half-life of 3.82 days, but the dose rate due to radon and its radioactive progeny could be significant to the living beings. Epidemiological studies on humans pointed out that up to 14% of lung cancers are induced by exposure to low and moderate concentrations of radon. Animals that breed in ground holes have been exposed to the higher doses due to radiation present in soil air. During the years, different dose-effect models are developed for risk assessment on human and non-human biota. In this work are reviewed research results of 222Rn exposure of human and non-human biota.
    Keywords:  Air; Biota; Dose rate; Outdoor radon concentration; Soil
    DOI:  https://doi.org/10.1007/s00484-020-01860-w
  1147. Cell. 2020 Jan 23. pii: S0092-8674(19)31396-0. [Epub ahead of print]180(2): 218-220
    Bacteriophage Prevents Alcoholic Liver Disease.
    Çolakoğlu M, Xue J, Trajkovski M.
      Alcoholic hepatitis is a severe alcohol-associated liver disease with minimal treatment options. A recent study by Duan et al. uncovers that the exotoxin-secreting gut bacterium Enterococcus faecalis is a critical contributor to alcoholic hepatitis. This bacterium can now be eliminated with a bacteriophage, suggesting a new way to treat this life-threatening disease.
    DOI:  https://doi.org/10.1016/j.cell.2019.12.034
  1148. Mol Biol Cell. 2020 Jan 22. mbcE19010027
    Mechanical stress triggers nuclear remodeling and the formation of Transmembrane Actin Nuclear lines with associated Nuclear Pore Complexes.
    Hoffman LM, Smith MA, Jensen CC, Yoshigi M, Blankman E, Ullman K, Beckerle MC.
      Mechanical stimulation of fibroblasts induces changes in the actin cytoskeleton including stress fiber reinforcement and realignment. Here we characterize the nuclear response to mechanical stimulation (uniaxial cyclic stretch). Using fluorescence microscopy and quantitative image analysis we find that stretch-induced nuclear elongation and alignment perpendicular to the stretch vector are dependent on formin-regulated actin polymerization. The mechanosensitive transcription factors YAP/TAZ and MRTF-A (also known as MKL1 and MAL1) accumulate in the nucleus and activate their target genes in response to uniaxial cyclic stretch. We show that Transmembrane Actin Nuclear (TAN) lines are induced by stretch stimulation and nuclear envelope (NE) proteins including nesprins, SUN2, and lamins form Linkers of the Nucleoskeleton and Cytoskeleton (LINCs) aligned with actin stress fibers. These NE structures are altered by pharmacological treatments (Cytochalasin D and Jasplakinolide) or genetic disruption (zyxin gene deletion) that alter actin, and their persistence requires maintenance of stretch stimulation. Nuclear Pore Complexes (NPCs) accumulate at TAN lines providing a potential mechanism for linking mechanical cues to NPC function. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E19-01-0027
  1149. Toxicology. 2020 Jan 18. pii: S0300-483X(20)30018-4. [Epub ahead of print] 152379
    Multifunctional compounds Lithium Chloride and Methylene Blue attenuate the negative effects of diisopropylfluorophosphate on axonal transport in rat cortical neurons.
    Naughton SX, Beck WD, Wei Z, Wu G, Terry AV.
      Organophosphates (OPs) are valuable as pesticides in agriculture and for controlling deadly vector-borne illnesses; however, they are highly toxic and associated with many deleterious health effects in humans including long-term neurological impairments. Antidotal treatment regimens are available to combat the symptoms of acute OP toxicity, which result from the irreversible inhibition of acetylcholinesterase (AChE). However, there are no established treatments for the long-term neurological consequences of OP exposure. In addition to AChE, OPs can negatively affect multiple protein targets as well as biological processes such as axonal transport. Given the fundamental nature of axonal transport to neuronal health, we rationalized that this process might serve as a general focus area for novel therapeutic strategies against OP toxicity. In the studies described here, we employed a multi-target, phenotypic screening, and drug repurposing strategy for the evaluations of potential novel OP-treatments using a primary neuronal culture model and time-lapse live imaging microscopy. Two multi-target compounds, lithium chloride (LiCl) and methylene blue (MB), which are FDA-approved for other indications, were evaluated for their ability to prevent the negative effects of the OP, diisopropylfluorophosphate (DFP) on axonal transport. The results indicated that both LiCl and MB prevented DFP-induced impairments in anterograde and retrograde axonal transport velocities in a concentration dependent manner. While in vivo studies will be required to confirm our in vitro findings, these experiments support the potential of LiCl and MB as repurposed drugs for the treatment of the long-term neurological deficits associated with OP exposure (currently an unmet medical need).
    Keywords:  Drug Repurposing; Gulf War Illness; Nerve Agent; Organophosphate; Pesticide; Phenotypic; Screening
    DOI:  https://doi.org/10.1016/j.tox.2020.152379
  1150. BMJ Open Diabetes Res Care. 2020 01;pii: e000807. [Epub ahead of print]8(1):
    Therapeutic efficacy and safety of initial triple combination of metformin, sitagliptin, and lobeglitazone in drug-naïve patients with type 2 diabetes: initial triple study.
    Lim S, Ku EJ, Lee SY, Lee JH, Lee JE, Kim KM, Davies MJ.
      OBJECTIVE: To compare the efficacy and safety of an initial triple therapy using metformin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and thiazolidinedione with a stepwise approach using sulfonylurea and metformin in new-onset, drug-naïve patients with type 2 diabetes.RESEARCH DESIGN AND METHODS: Among drug-naïve patients with 9.0%-12.0% glycated hemoglobin (HbA1c) but no hyperglycemic symptoms, 100 subjects who started triple medications (metformin 1000 mg/day, sitagliptin 100 mg/day, and lobeglitazone 0.5 mg/day) were selected as an initial triple therapy group. Age and body mass index-matched subjects (n=100) who started glimepiride (≥2 mg/day with uptitration) and metformin (≥1000 mg/day with uptitration) were selected as a conventional therapy group. We investigated changes in HbA1c level, dynamic indexes for insulin sensitivity and β-cell function, and hypoglycemia.
    RESULTS: After 12 months of treatment, HbA1c levels decreased significantly in both groups: from 10.7%±1.0% to 6.7%±1.3% in the triple group, and from 10.5%±1.0% to 7.3%±1.2% in the conventional therapy group. At 12 months, achievement of the HbA1c target (<7.0%) was higher in the triple group than in the conventional group (70% vs 52%, p<0.01). Dynamic indexes related to β-cell function and insulin sensitivity improved, and albuminuria reduced significantly only in the triple group. Hypoglycemia was more common in the conventional group.
    CONCLUSIONS: Initial triple combination therapy with the DPP4 inhibitor, metformin, and thiazolidinedione showed a higher achievement of the target HbA1c goal with a lower risk of hypoglycemia, better restoration of β-cell function, and multiple metabolic benefits, implying durable glycemic control. This strategy may be useful for patients presenting with type 2 diabetes and high HbA1c levels.
    Keywords:  combination therapy; conventional programme; dipeptidyl peptidase IV; thiazolidinediones
    DOI:  https://doi.org/10.1136/bmjdrc-2019-000807
  1151. Diabetes Ther. 2020 Jan 18.
    Metformin Delays the Development of Atherosclerosis in Type 1 Diabetes Mellitus Via the Methylglyoxal Pathway.
    Liu A, Li K, Xu L, Si M, Teng G, Li G, Xue J, Liang S, Song W.
      INTRODUCTION: The aim of our study was to determine the effect of metformin administration on juvenile type 1 diabetes mellitus and atherosclerosis in apolipoprotein E null (ApoE-/-) mice and to explore the mechanism involved.METHODS: Eighteen male ApoE-/- mice were injected with streptozotocin to induce diabetes (diabetic group) and 18 mice who received no streptozotocin injection were assigned to the control (non-diabetic) group. Six mice in each group were then orally administered metformin, simvastatin, or vehicle, respectively, following which the mice were euthanized and tissue samples collected.
    RESULTS: Fasting plasma glucose, low-density lipoprotein-cholesterol, and triglyceride concentrations were significantly higher in the three diabetic groups than in the three non-diabetic groups. Plasma N∈-(carboxymethyl)lysine and N∈-(carboxyethyl)lysine concentrations were higher in the diabetic mice than in the non-diabetic mice, but metformin treatment reduced these concentrations more effectively than simvastatin. All three diabetic groups demonstrated obvious arterial plaques, but these were largest in the vehicle-treated diabetic group. The expression of extracellular nitric oxide synthase was highest in the simvastatin-treated non-diabetic group, and in diabetic mice it was higher in the simvastatin-treated group than in the other two groups. No significant expression of AMP-activated protein kinase (AMPK) was measured in the three diabetic groups, but a low level of AMPK expression was detected in the non-diabetic groups.
    CONCLUSIONS: Metformin can limit the development of atherosclerosis secondary to diabetes in young diabetic mice. A possible mechanism is the removal of methylglyoxal, thereby reducing the formation of advanced glycation endproducts, rather than by lowering the blood glucose level.
    FUNDING: This work was supported by the National Natural Science Foundation of China (81901106) and Jinan clinical medical science and technology innovation plan (201907002).
    Keywords:  Atherosclerosis; Metformin; Methylglyoxal; Type 1 diabetes mellitus
    DOI:  https://doi.org/10.1007/s13300-020-00761-w
  1152. Curr Biol. 2020 Jan 08. pii: S0960-9822(19)31580-5. [Epub ahead of print]
    Cell Death in Cells Overlying Lateral Root Primordia Facilitates Organ Growth in Arabidopsis.
    Escamez S, André D, Sztojka B, Bollhöner B, Hall H, Berthet B, Voß U, Lers A, Maizel A, Andersson M, Bennett M, Tuominen H.
      Plant organ growth is widely accepted to be determined by cell division and cell expansion, but, unlike that in animals, the contribution of cell elimination has rarely been recognized. We investigated this paradigm during Arabidopsis lateral root formation, when the lateral root primordia (LRP) must traverse three overlying cell layers within the parent root. A subset of LRP-overlying cells displayed the induction of marker genes for cell types undergoing developmental cell death, and their cell death was detected by electron, confocal, and light sheet microscopy techniques. LRP growth was delayed in cell-death-deficient mutants lacking the positive cell death regulator ORESARA1/ANAC092 (ORE1). LRP growth was restored in ore1-2 knockout plants by genetically inducing cell elimination in cells overlying the LRP or by physically killing LRP-overlying cells by ablation with optical tweezers. Our results support that, in addition to previously discovered mechanisms, cell elimination contributes to regulating lateral root emergence.
    Keywords:  Arabidopsis; cell death; endodermis; lateral root emergence; lateral root primordia; organ growth; plant development; programmed cell death
    DOI:  https://doi.org/10.1016/j.cub.2019.11.078
  1153. Neuropharmacology. 2020 Jan 13. pii: S0028-3908(20)30031-9. [Epub ahead of print]166 107965
    Endocannabinoid modulating drugs improve anxiety but not the expression of conditioned fear in a rodent model of post-traumatic stress disorder.
    Vimalanathan A, Gidyk DC, Diwan M, Gouveia FV, Lipsman N, Giacobbe P, Nobrega JN, Hamani C.
      The endocannabinoid (eCB) system is a potential target for the treatment of symptoms of post-traumatic stress disorder (PTSD). Similar to clinical PTSD, approximately 25-30% of rats that undergo cued fear conditioning exhibit impaired extinction learning. In addition to extinction-resistant fear, these "weak extinction" (WE) rats show persistent anxiety-like behaviors. The goal of the present study was to test the hypothesis that behavioural differences between WE animals and those presenting normal extinction patterns (strong extinction; SE) could be mediated by the eCB system. Rats undergoing fear conditioning/extinction and fear recall sessions were initially segregated in weak and strong-extinction groups. Two weeks later, animals underwent a fear recall session followed by a novelty-suppressed feeding (NSF) test. In acute experiments, WE rats were injected with either the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the CB1 agonist WIN55,212-2 1 h prior to long-term recall and NSF testing. SE animals were injected with the inverse CB1 receptor agonist AM251. In chronic experiments, WE and SE rats were given daily injections of URB597 or AM251 between short and long-term recall sessions. We found that acute administration of WIN55,212-2 but not URB597 reduced anxiety-like behaviour in WE rats. In contrast, AM251 was anxiogenic in SE animals. Neither treatment was effective in altering freezing expression during fear recall. The chronic administration of AM251 to SE or URB597 to WE did not alter fear or anxiety-like behaviour or changed the expression of FAAH and CB1. Together, these results suggest that systemic manipulations of the eCB system may alter anxiety-like behaviour but not the behavioural expression of an extinction-resistant associative fear memory.
    Keywords:  Animal models; Anxiety; Endocannabinoids; Fear extinction; PTSD
    DOI:  https://doi.org/10.1016/j.neuropharm.2020.107965
  1154. Chem Commun (Camb). 2020 Jan 20.
    Conformationally rigid pyrazoloquinazoline α-amino acids: one- and two-photon induced fluorescence.
    Bell JD, Harkiss AH, Nobis D, Malcolm E, Knuhtsen A, Wellaway CR, Jamieson AG, Magennis SW, Sutherland A.
      The synthesis and photophysical properties of a new class of α-amino acid bearing a rigid pyrazoloquinazoline chromophore are described. Confromational constraint of the amino acid side-chains resulted in high emission quantum yields, while the demonstration of two-photon-induced fluorescence via near-IR excitation signifies their potential for sensitive bioimaging applications.
    DOI:  https://doi.org/10.1039/c9cc09064a
  1155. Neuroimage. 2020 Jan 20. pii: S1053-8119(20)30043-4. [Epub ahead of print] 116556
    Comparing MEG and high-density EEG for intrinsic functional connectivity mapping.
    Coquelet N, De Tiège X, Destoky F, Roshchupkina L, Bourguignon M, Goldman S, Peigneux P, Wens V.
      Magnetoencephalography (MEG) has been used in conjunction with resting-state functional connectivity (rsFC) based on band-limited power envelope correlation to study the intrinsic human brain network organization into resting-state networks (RSNs). However, the limited availability of current MEG systems hampers the clinical applications of electrophysiological rsFC. Here, we directly compared well-known RSNs as well as the whole-brain rsFC connectome together with its state dynamics, obtained from simultaneously-recorded MEG and high-density scalp electroencephalography (EEG) resting-state data. We also examined the impact of head model precision on EEG rsFC estimation, by comparing results obtained with boundary and finite element head models. Results showed that most RSN topographies obtained with MEG and EEG are similar, except for the fronto-parietal network. At the connectome level, sensitivity was lower to frontal rsFC and higher to parieto-occipital rsFC with MEG compared to EEG. This was mostly due to inhomogeneity of MEG sensor locations relative to the scalp and significant MEG-EEG differences disappeared when taking relative MEG-EEG sensor locations into account. The default-mode network was the only RSN requiring advanced head modeling in EEG, in which gray and white matter are distinguished. Importantly, comparison of rsFC state dynamics evidenced a poor correspondence between MEG and scalp EEG, suggesting sensitivity to different components of transient neural functional integration. This study therefore shows that the investigation of static rsFC based on the human brain connectome can be performed with scalp EEG in a similar way than with MEG, opening the avenue to widespread clinical applications of rsFC analyses.
    Keywords:  Connectome; Electroencephalography; Envelope correlation; Magnetoencephalography; Resting-state networks; State dynamics
    DOI:  https://doi.org/10.1016/j.neuroimage.2020.116556
  1156. Gastroenterology. 2020 Jan 20. pii: S0016-5085(20)30114-1. [Epub ahead of print]
    Precision therapy in RAS mutant colorectal cancer.
    Dienstmann R, Connor K, Byrne AT, , Fridman WH, Lambrechts D, Sadanandam A, Trusolino L, Prehn JHM, Tabernero J, Kolch W.
      
    DOI:  https://doi.org/10.1053/j.gastro.2019.12.051
  1157. Sci Total Environ. 2020 Jan 11. pii: S0048-9697(20)30169-8. [Epub ahead of print]713 136659
    Do microplastics affect the zoanthid Zoanthus sociatus?
    Rocha RJM, Rodrigues ACM, Campos D, Cícero LH, Costa APL, Silva DAM, Oliveira M, Soares AMVM, Patrício Silva AL.
      Microplastics (1 μm-5 mm), a ubiquitous and persistent marine pollutant, pose a severe threat to coral reefs when recently associated with physiological distress and increased diseases on corals. Studies conducted so far have only reported effects on scleractinian species. Knowledge about its effects on other corals (e.g. Order Zoantharia) remains uncovered, and responses at biochemical levels remain poorly documented. This study aimed to assess the potential effects induced by the presence of microplastics (1 and 10 mg L-1 low-density polyethylene, LDPE MP, or polyvinyl chloride, PVC MP) in the tropical and subtropical cosmopolitan species Zoanthus sociatus (order Zoantharia. Anthozoa: Hexacorallia), at organism level (survival and behaviour), endosymbionts (photosynthetic efficiency) and the cellular level (oxidative stress, detoxification capacity and energy metabolism). In a short-term exposure (96 h), this species was more sensitive to PVC MP. The presence of this polymer at a concentration of 10 mg L-1 caused a ten-fold higher adhesion to the coral epidermis, increased photosynthetic efficiency, lipid peroxidation, and antioxidant defences; without, however, inducing energetic costs. Although the observed physiological and biochemical effects did not compromise Z. sociatus survival in the short term, it does not rule out potential long-term (cumulative) effects that could endanger this and other physiologically similar species that underlie coral reefs.
    Keywords:  Corals; Low-density polyethylene; Oxidative stress; Photobiology; Polyvinyl chloride
    DOI:  https://doi.org/10.1016/j.scitotenv.2020.136659
  1158. Semin Ultrasound CT MR. 2020 Feb;pii: S0887-2171(19)30068-X. [Epub ahead of print]41(1): 10-19
    Role of Nuclear Medicine in Imaging.
    Sureshkumar A, Hansen B, Ersahin D.
      Nuclear medicine (NM) plays a unique role in the detection of infection and inflammation. This review looks at different methods that are used for detection of infections and explains how they differ from cross-sectional imaging such as computed tomography and magnetic resonance imaging. Images are provided to aid understanding and interpretation of NM scans. There is also a brief discussion of future techniques that can alter the use of NM for infection work up.
    DOI:  https://doi.org/10.1053/j.sult.2019.10.005
  1159. Cell Death Differ. 2020 Jan 20.
    Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH.
    Tan M, Mosaoa R, Graham GT, Kasprzyk-Pawelec A, Gadre S, Parasido E, Catalina-Rodriguez O, Foley P, Giaccone G, Cheema A, Kallakury B, Albanese C, Yi C, Avantaggiati ML.
      Nonalcoholic fatty liver disease (NAFLD) and its evolution to inflammatory steatohepatitis (NASH) are the most common causes of chronic liver damage and transplantation that are reaching epidemic proportions due to the upraising incidence of metabolic syndrome, obesity, and diabetes. Currently, there is no approved treatment for NASH. The mitochondrial citrate carrier, Slc25a1, has been proposed to play an important role in lipid metabolism, suggesting a potential role for this protein in the pathogenesis of this disease. Here, we show that Slc25a1 inhibition with a specific inhibitor compound, CTPI-2, halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, while starkly mitigating obesity induced by a high-fat diet. These effects are differentially recapitulated by a global ablation of one copy of the Slc25a1 gene or by a liver-targeted Slc25a1 knockout, which unravel dose-dependent and tissue-specific functions of this protein. Mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts signaling from peroxisome proliferator-activated receptor gamma, a key regulator of glucose and lipid metabolism, and inhibits the expression of gluconeogenic genes. The combination of these activities leads not only to inhibition of lipid anabolic processes, but also to a normalization of hyperglycemia and glucose intolerance as well. In summary, our data show for the first time that Slc25a1 serves as an important player in the pathogenesis of fatty liver disease and thus, provides a potentially exploitable and novel therapeutic target.
    DOI:  https://doi.org/10.1038/s41418-020-0491-6
  1160. Int J Mol Sci. 2020 Jan 17. pii: E631. [Epub ahead of print]21(2):
    Relaxin Positively Influences Ischemia-Reperfusion Injury in Solid Organ Transplantation: A Comprehensive Review.
    Jakubauskiene L, Jakubauskas M, Leber B, Strupas K, Stiegler P, Schemmer P.
      In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT.
    Keywords:  heart transplantation; kidney transplantation; liver transplantation; lung transplantation; relaxin; review; serelaxin
    DOI:  https://doi.org/10.3390/ijms21020631
  1161. J Agric Food Chem. 2020 Jan 21.
    Electrical-driven Release and Migration of Herbicide Using a Gel-based Nanocomposite.
    Zhang L, Chen C, Zhang G, Liu B, Wu Z, Cai D.
      In this work, an electrical-driven release and migration glyphosate (EDRMG) was fabricated by using a nanocomposite made up of attapulgite (ATP), glyphosate (Gly), and calcium alginate (CA). Therein, ATP-CA acted as a nanonetwork structured carrier to efficiently load plenty of Gly to form porous ATP-Gly-CA hydrogel spheres (actually EDRMG-0.5) via cross-linking reaction. The pores in EDRMG-0.5 hydrogel spheres were enlarged under electric field because of the coulomb force of anionic CA polymer and the release of negatively-charged Gly from the spheres could be driven by electric field force. Thus EDRMG-0.5 exhibited a great electro-responsively controlled release property, which was confirmed by a pot experiment. Importantly, the EDRMG-0.5 hydrogel spheres owned a fine biocompatibility on fish and mice, displaying a good biosafety. This work provides a low cost and promising approach to control Gly release, deliver Gly precisely, and improve utilization efficiency, which might have a high application value.
    DOI:  https://doi.org/10.1021/acs.jafc.9b07166
  1162. J Mater Chem B. 2020 Jan 22.
    Probing two PESIN-indocyanine-dye-conjugates: significance of the used fluorophore.
    Hübner R, Benkert V, Cheng X, Wängler B, Krämer R, Wängler C.
      Peptide-dye-conjugates hold a great promise in application for biological and medical imaging of cellular processes and in delineation and characterization of human tumors. In particular, indocyanine dyes are of great interest due to their reported superior properties such as absorption and emission in the near-infrared (NIR) spectral range, favorable Stokes shifts and their well-studied safety profile in humans. In this study, we investigated and describe the influence of indocyanine dyes on different properties of the final peptide-dye-conjugates. As a target peptide, PESIN, a bombesin derivative, was used as a model peptide which addresses GRP receptors overexpressed on different malignancies. Here, we map similarities and differences of the fluorescent conjugates and by this elucidate the influence of the dyes on different properties of the formed conjugates. We performed the dye syntheses, subsequent bioconjugation reactions and in the following investigated the optical properties, water/octanol distribution coefficients and target receptor affinities by in vitro competitive binding studies on PC-3 cells. The obtained results give a handrail to medical and biological researchers planning studies involving indocyanine dye biomolecule conjugates.
    DOI:  https://doi.org/10.1039/c9tb01794a
  1163. J Clin Med. 2020 Jan 21. pii: E293. [Epub ahead of print]9(2):
    Female Specific Association of Low Insulin-Like Growth Factor 1 (IGF1) Levels with Increased Risk of Premature Mortality in Renal Transplant Recipients.
    Klont F, Kieneker LM, Gomes-Neto AW, Stam SP, Ten Hacken NHT, Kema IP, van Beek AP, van den Berg E, Horvatovich P, Bischoff R, Bakker SJL.
      Associations between insulin-like growth factor 1 (IGF1) and mortality have been reported to be female specific in mice and in human nonagenarians. Intervention in the growth hormone (GH)-IGF1 axis may particularly benefit patients with high risk of losing muscle mass, including renal transplant recipients (RTR). We investigated whether a potential association of circulating IGF1 with all-cause mortality in stable RTR could be female specific and mediated by variation in muscle mass. To this end, plasma IGF1 levels were measured in 277 female and 343 male RTR by mass spectrometry, and their association with mortality was assessed by Cox regression. During a median follow-up time of 5.4 years, 56 female and 77 male RTR died. In females, IGF1 was inversely associated with risk (hazard ratio (HR) per 1-unit increment in log2-transformed (doubling of) IGF1 levels, 95% confidence interval (CI)) of mortality (0.40, 0.24-0.65; p < 0.001), independent of age and the estimated Glomerular filtration rate (eGFR). In equivalent analyses, no significant association was observed for males (0.85, 0.56-1.29; p = 0.44), for which it should be noted that in males, age was negatively and strongly associated with IGF1 levels. The association for females remained materially unchanged upon adjustment for potential confounders and was furthermore found to be mediated for 39% by 24 h urinary creatinine excretion. In conclusion, low IGF1 levels associate with an increased risk of all-cause mortality in female RTR, which may link to conditions of low muscle mass that are known to be associated with poor outcomes in transplantation patients. For males, the strongly negative association of age with IGF1 levels may explain why low IGF1 levels were not found to be associated with an increased risk of all-cause mortality.
    Keywords:  growth hormone; insulin-like growth factor 1; muscle mass; patient survival; physical activity; renal transplant recipients
    DOI:  https://doi.org/10.3390/jcm9020293
  1164. Cancer Sci. 2020 Jan 22.
    Modulation of Nqo1 Activity Intercepts Anoikis Resistance and Reduces Metastatic Potential of Hepatocellular Carcinoma.
    Shimokawa M, Yoshizumi T, Itoh S, Iseda N, Sakata K, Yugawa K, Toshima T, Harada N, Ikegami T, Mori M.
      The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid-derived 2-like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage-independent culture, HCC cells showed increased ROS, leading to the up-regulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β-lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability; which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Nrf2/Nqo1 overexpression in primary HCC was associated with tumor size, high alpha-fetoprotein and des-gamma-carboxy-prothrombin levels. Nrf2/Nqo1 overexpression was associated with multiple intrahepatic recurrences (P = 0.0073) and was an independent risk factor for poor prognosis (P = 0.0031). Nqo1 plays an important role in anchorage-independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggesting that targeting Nqo1 activity may be a potential strategy for HCC adjuvant therapy.
    Keywords:  Nqo1; Nrf2; hepatocellular carcinoma; metastasis; oxidative stress
    DOI:  https://doi.org/10.1111/cas.14320
  1165. J Clin Hypertens (Greenwich). 2020 Jan 19.
    Pathophysiological mechanisms underlying the beneficial effects of physical activity in hypertension.
    Gambardella J, Morelli MB, Wang XJ, Santulli G.
      
    DOI:  https://doi.org/10.1111/jch.13804
  1166. Curr Med Imaging Rev. 2019 ;15(1): 39-51
    Neuroimaging methods in Epilepsy of Temporal Origin.
    Tsougos I, Kousi E, Georgoulias P, Kapsalaki E, Fountas KN.
      BACKGROUND: Temporal Lobe Epilepsy (TLE) comprises the most common form of symptomatic refractory focal epilepsy in adults. Accurate lateralization and localization of the epileptogenic focus are a significant prerequisite for determining surgical candidacy once the patient has been deemed medically intractable. Structural MR imaging, clinical, electrophysiological, and neurophysiological data have an established role in the localization of the epileptogenic foci. Nevertheless, hippocampal sclerosis cannot be detected on MR images in more than 30% of patients with TLE, and the presurgical assessment remains controversial.DISCUSSION: In the last years, advanced MR imaging techniques, such as 1H-MRS, DWI, DTI, DSCI, and fMRI, may provide valuable additional information regarding the physiological and metabolic characterization of brain tissue. MR imaging has shifted towards functional and molecular imaging, thus, promising to improve the accuracy regarding the lateralization and the localization of the epileptogenic focus. Additionally, nuclear medicine studies, such as SPECT and PET imaging modalities, have become an asset for the decoding of brain function and activity, and can be diagnostically helpful as well, since they provide valuable data regarding the altered metabolic activity of the seizure foci.
    CONCLUSION: Overall, advanced MRI, SPECT, and PET imaging techniques are increasingly becoming an essential part of TLE diagnostics, when the epileptogenic area is not identified on structural MRI or when structural MRI, clinical, and electrophysiological findings are not in concordance.
    Keywords:  Diffusion tensor imaging; MR spectroscopy; PET; SPECT; epilepsy; functional MRI; temporal
    DOI:  https://doi.org/10.2174/1573405613666170622114920
  1167. J Nucl Cardiol. 2020 Jan 23.
    Normal imaging findings after aortic valve implantation on 18F-Fluorodeoxyglucose positron emission tomography with computed tomography.
    Wahadat AR, Tanis W, Scholtens AM, Bekker M, Graven LH, Swart LE, den Harder AM, Lam MGEH, de Heer LM, Roos-Hesselink JW, Budde RPJ.
      BACKGROUND: To determine the normal perivalvular 18F-Fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography (PET) with computed tomography (CT) within one year after aortic prosthetic heart valve (PHV) implantation.METHODS: Patients with uncomplicated aortic PHV implantation were prospectively included and underwent 18F-FDG PET/CT at either 5 (± 1) weeks (group 1), 12 (± 2) weeks (group 2) or 52 (± 8) weeks (group 3) after implantation. 18F-FDG uptake around the PHV was scored qualitatively (none/low/intermediate/high) and quantitatively by measuring the maximum Standardized Uptake Value (SUVmax) and target to background ratio (SUVratio).
    RESULTS: In total, 37 patients (group 1: n = 12, group 2: n = 12, group 3: n = 13) (mean age 66 ± 8 years) were prospectively included. Perivalvular 18F-FDG uptake was low (8/12 (67%)) and intermediate (4/12 (33%)) in group 1, low (7/12 (58%)) and intermediate (5/12 (42%)) in group 2, and low (8/13 (62%)) and intermediate (5/13 (38%)) in group 3 (P = 0.91). SUVmax was 4.1 ± 0.7, 4.6 ± 0.9 and 3.8 ± 0.7 (mean ± SD, P = 0.08), and SUVratio was 2.0 [1.9 to 2.2], 2.0 [1.8 to 2.6], and 1.9 [1.7 to 2.0] (median [IQR], P = 0.81) for groups 1, 2, and 3, respectively.
    CONCLUSION: Non-infected aortic PHV have similar low to intermediate perivalvular 18F-FDG uptake with similar SUVmax and SUVratio at 5, 12, and 52 weeks after implantation.
    Keywords:  Image interpretation; Infection; Inflammation; PET; Valvular heart disease
    DOI:  https://doi.org/10.1007/s12350-019-02025-y
  1168. Int J Vitam Nutr Res. 2020 Jan 23. 1-10
    In silico, in-vitro and in vivo screening of biological activities of citral.
    Habib S, Gupta P, Bhat SS, Gupta J.
       Citral, one of the main components of lemongrass oil (65-85%), is known to possess various medicinal properties like enhancing skin health and vision-improvement. It also acts as flavoring agent, used in perfumes and skin care products. The objective of this work was to elucidate the biological properties of citral at molecular level using an integrated in silico, in vitro and in vivo approaches. To elucidate this in silico molecular docking studies were performed with in vitro validation by DPPH scavenging activity, MTT assays, enzymatic assays and Chorio Allantoic Membrane (CAM) assay. The in silico analysis demonstrated the potential binding of citral with PPARγ ligand binding domain and vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2). Citral is already a proven anti-oxidant which is further confirmed by increased DPPH inhibition with increased citral concentration (IC50: 6.9 ± 1.68 μg/ml, p < 0.05). The results demonstrated that citral protect yeast cells from cytotoxic effects of hydrogen peroxide and also increase the activities of antioxidant enzymes like GST, SOD and LPO. It was also demonstrated to be cytotoxic to cancerous HeLa cells (IC50: 3.9 ± 0.38 μM, p < 0.01) and was found anti-angiogenic by CAM assay. This study highlights many important pharmaceutical properties of citral which can be explored further to increase its industrial applications.
    Keywords:  Citral; PPARγ agonist; molecular docking; similarity searching; vascular endothelial growth factor receptors
    DOI:  https://doi.org/10.1024/0300-9831/a000625
  1169. Nurs Res. 2020 Jan 15.
    Health Literacy and Outcomes of a Community-Based Self-Help Intervention: A Case of Korean Americans with Type 2 Diabetes.
    Kim MT, Kim KB, Ko J, Murry N, Xie B, Radhakrishnan K, Han HR.
      BACKGROUND: Although scientific reports increasingly document the negative impact of inadequate health literacy on health-seeking behaviors, health literacy's effect on health outcomes in patients with diabetes is not entirely clear, owing to insufficient empirical studies, mixed findings, and insufficient longitudinal research.OBJECTIVE: To empirically examine underlying mechanisms of health literacy's role in diabetes management among a group of Korean Americans with type 2 diabetes mellitus.
    METHODS: Data from a randomized clinical trial of an health literacy-focused type 2 diabetes self-management intervention conducted during 2012-2016 in the Korean American community were collected at baseline, 3, 6, 9, and 12 months. A total of 250 Korean Americans with type 2 diabetes participated (intervention, 120; control, 130). Participants were first-generation Korean American immigrants. Health literacy knowledge was measured with the original Rapid Estimate of Adult Literacy in Medicine and the diabetes mellitus-specific Rapid Estimate of Adult Literacy in Medicine. Functional health literacy was measured with the numeracy subscale of the Test of Functional Health Literacy in Adults and the Newest Vital Sign screening instrument, which also uses numeracy. Primary outcomes included glucose control and diabetes quality of life. Multivariate analyses included latent variable modeling.
    RESULTS: A series of path analyses identified self-efficacy and self-care skills as significant mediators between health literacy and glucose control and quality of life. Education and acculturation were the most significant correlates of health literacy.
    DISCUSSION: Despite inconsistent findings in the literature, this study indicates that health literacy may indirectly influence health outcomes through mediators such as self-care skills and self-efficacy. The study highlights the importance of health literacy, as well as underlying mechanisms with which health literacy influences processes and outcomes of diabetes self-management.
    DOI:  https://doi.org/10.1097/NNR.0000000000000409
  1170. Biology (Basel). 2020 Jan 18. pii: E20. [Epub ahead of print]9(1):
    Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer.
    Cotzomi-Ortega I, Rosas-Cruz A, Ramírez-Ramírez D, Reyes-Leyva J, Rodriguez-Sosa M, Aguilar-Alonso P, Maycotte P.
      Breast cancer is the main cause of cancer-related death in women in the world. Because autophagy is a known survival pathway for cancer cells, its inhibition is currently being explored in clinical trials for treating several types of malignancies. In breast cancer, autophagy has been shown to be necessary for the survival of cancer cells from the triple negative subtype (TNBC), which has the worst prognosis among breast cancers and currently has limited therapeutic options. Autophagy has also been involved in the regulation of protein secretion and, of importance for this work, the inhibition of autophagy is known to promote the secretion of proinflammatory cytokines from distinct cell types. We found that the inhibition of autophagy in TNBC cell lines induced the secretion of the macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine involved in breast cancer invasion and immunomodulation. MIF secretion was dependent on an increase in reactive oxygen species (ROS) induced by the inhibition of autophagy. Importantly, MIF secreted from autophagy-deficient cells increased the migration of cells not treated with autophagy inhibitors, indicating that autophagy inhibition in cancer cells promoted malignancy in neighboring cells through the release of secreted factors, and that a combinatorial approach should be evaluated for cancer therapy.
    Keywords:  MIF; ROS; autophagy; breast cancer; chloroquine; p115; reactive oxygen species; secretion
    DOI:  https://doi.org/10.3390/biology9010020
  1171. Langmuir. 2020 Jan 19.
    Nano Hydroxyapatite Particle Brushes via Direct Initiator Tethering and Surface Initiated ATRP for Dual Responsive Pickering Emulsion.
    Wang M, Wang X, Zhang K, Wu M, Wu Q, Liu J, Yang J, Zhang J.
      Well defined polymer grafted solid inorganic nanoparticles (NPs) are imperative for the practical applications in various fields based on the prerequisite of facile initiator immobilization. Direct ATRP initiator tethered solid NPs is described by using 2-bromo-2-methylpropionic acid as tetherable initiator. To illustrate the versatility of the proposed strategy, nano hydroxyapatite (n-HAP) nanocrystals (NCs) were selected to demonstrate the morphology controlled synthesis of 2-bromo-2-methylpropionate (2-BrMP) groups immobilized n-HAP (n-HAP-Br) NCs. When water was employed as the sole solvent, the continually introduced 2-BrMP groups altered the surface hydrophobic capacity of n-HAP-Br NC and thus led to unavoidable aggregation of n-HAP-Br NCs. The synthesis of individually dispersed n-HAP-Br NCs was achieved by rational adjusting polarity of aqueous medium through the adding portion of water miscible organic solvents. The type and concentration of added water miscible organic solvents had critical effects on the morphology and particle size of n-HAP-Br NCs. To verify the efficiency of tethered initiator, n-HAP-g-poly2-(dimethylamino) ethyl methacrylate (n-HAP-g-PDMAEMA), n-HAP-g-polyacrylonitrile (n-HAP-g-PAN), and n-HAP-g-polymethyl methacrylate (n-HAP-g-PMMA) were fabricated by surface-initiated ATRP (SI-ATRP), respectively. Acting as solid particle emulsifier, the designed n-HAP-g-PDMAEMA stabilized Pickering emulsion displayed dual pH and temperature response with reversible behaviors. This work presents a versatile and simple way for fabrication of initiator immobilized solid NPs (e.g. n-HAP NCs, gibbsite nanoplatelets, γ-FeOOH nanofibers) ready for polymer grafting and thus enables promising performance in wide applications.
    DOI:  https://doi.org/10.1021/acs.langmuir.9b02790
  1172. Metabolomics. 2020 Jan 21. 16(2): 17
    Migrating from partial least squares discriminant analysis to artificial neural networks: a comparison of functionally equivalent visualisation and feature contribution tools using jupyter notebooks.
    Mendez KM, Broadhurst DI, Reinke SN.
      INTRODUCTION: Metabolomics data is commonly modelled multivariately using partial least squares discriminant analysis (PLS-DA). Its success is primarily due to ease of interpretation, through projection to latent structures, and transparent assessment of feature importance using regression coefficients and Variable Importance in Projection scores. In recent years several non-linear machine learning (ML) methods have grown in popularity but with limited uptake essentially due to convoluted optimisation and interpretation. Artificial neural networks (ANNs) are a non-linear projection-based ML method that share a structural equivalence with PLS, and as such should be amenable to equivalent optimisation and interpretation methods.OBJECTIVES: We hypothesise that standardised optimisation, visualisation, evaluation and statistical inference techniques commonly used by metabolomics researchers for PLS-DA can be migrated to a non-linear, single hidden layer, ANN.
    METHODS: We compared a standardised optimisation, visualisation, evaluation and statistical inference techniques workflow for PLS with the proposed ANN workflow. Both workflows were implemented in the Python programming language. All code and results have been made publicly available as Jupyter notebooks on GitHub.
    RESULTS: The migration of the PLS workflow to a non-linear, single hidden layer, ANN was successful. There was a similarity in significant metabolites determined using PLS model coefficients and ANN Connection Weight Approach.
    CONCLUSION: We have shown that it is possible to migrate the standardised PLS-DA workflow to simple non-linear ANNs. This result opens the door for more widespread use and to the investigation of transparent interpretation of more complex ANN architectures.
    Keywords:  Artificial neural networks; Jupyter; Machine learning; Metabolomics; Partial least squares; Variable importance in projection
    DOI:  https://doi.org/10.1007/s11306-020-1640-0
  1173. Curr Opin Clin Nutr Metab Care. 2020 Jan 16.
    Do micronutrient deficiencies contribute to mitochondrial failure in critical illness?
    Berger MM.
      PURPOSE OF REVIEW: Mitochondrial dysfunction seems to be the common denominator of several critical care conditions and particularly of sepsis. Faced with relative failure, and limited progress of sepsis therapies aiming at blocking some oxidative and/or inflammatory pathways, the question of antioxidants micronutrient therapy, particularly of selenium, ascorbic acid and thiamine remains open.RECENT FINDINGS: The rationale for the essentiality of numerous micronutrients within the mitochondria is well established. Many studies have tested single micronutrients in animal and in-vitro models and provide positive evidences in favor of reduction of organ failure (cardiac and renal mainly). In clinical settings, high-dose selenium administration in sepsis has been disappointing. The most recent high dose, short-term ascorbic acid trial in sepsis is promising though, with an associated reduction of mortality, but analysis of the impact of this intervention on the various organs remains to be conducted.
    SUMMARY: Results from animal and human studies indicate that there are indeed intervention options at the level of the mitochondria, but neither the optimal dose nor the optimal combination of micronutrients is yet identified.
    DOI:  https://doi.org/10.1097/MCO.0000000000000635
  1174. Int J Mol Sci. 2020 Jan 21. pii: E706. [Epub ahead of print]21(3):
    The Effect of Transcription Factor MYB14 on Defense Mechanisms in Vitis quinquangularis-Pingyi.
    Luo Y, Wang Q, Bai R, Li R, Chen L, Xu Y, Zhang M, Duan D.
      In the current study, we identified a transcription factor, MYB14, from Chinese wild grape, Vitis quinquangularis-Pingyi (V. quinquangularis-PY), which could enhance the main stilbene contents and expression of stilbene biosynthesis genes (StSy/RS) by overexpression of VqMYB14. The promoter of VqMYB14 (pVqMYB14) was shown to be induced as part of both basal immunity (also called pathogen-associated molecular pattern (PAMP)-triggered immunity, PTI) and effector-triggered immunity (ETI), triggered by the elicitors flg22 and harpin, respectively. This was demonstrated by expression of pVqMYB14 in Nicotiana benthamiana and Vitis. We identified sequence differences, notably an 11 bp segment in pVqMYB14 that is important for the PTI/ETI, and particularly for the harpin-induced ETI response. In addition, we showed that activation of the MYB14 promoter correlates with differences in the expression of MYB14 and stilbene pattern induced by flg22 and harpin. An experimental model of upstream signaling in V. quinquangularis-PY is presented, where early defense responses triggered by flg22 and harpin partially overlap, but where the timing and levels differ. This translates into a qualitative difference with respect to patterns of stilbene accumulation.
    Keywords:  Chinese wild Vitis; ETI; MYB14; PTI; defense; stilbene
    DOI:  https://doi.org/10.3390/ijms21030706
  1175. Cancer Sci. 2020 Jan 21.
    Drug resistance mechanisms in Japanese ALK positive NSCLC and the clinical responses based on the resistant mechanisms.
    Yanagitani N, Uchibori K, Koike S, Tsukahara M, Kitazono S, Yoshizawa T, Horiike A, Ohyanagi F, Tambo Y, Nishikawa S, Fujita N, Katayama R, Nishio M.
      The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer is rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKIs) are available in clinical practice. But the acquired resistance to these drugs has become an important issue. In this study, we collected and a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatment to unveil the resistance mechanisms to ALK-TKI. Among 32 patients, twenty-four patients received more than two ALK-TKIs. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y, and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in three of seven samples after ceritinib treatment. L1196M+G1202R, a compound mutation, was detected in one specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs. 1.2 months). In conclusion, resistance to ALK-TKIs based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. The appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.
    Keywords:  ALK; PFS; mutation; resistance mechanism; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1111/cas.14314
  1176. ACS Appl Mater Interfaces. 2020 Jan 23.
    Steric Effects Control Dry Friction of H- and F-Terminated Carbon Surfaces.
    Reichenbach T, Mayrhofer L, Kuwahara T, Moseler M, Moras G.
      A stable passivation of surface dangling bonds underlies the outstanding friction properties of diamond and diamond-like carbon (DLC) coatings in boundary lubrication. While hydrogen is the simplest termination of a carbon dangling bond, fluorine can also be used as a monoatomic termination, providing an even higher chemical stability. However, whether and under which conditions a substitution of hydrogen with fluorine can be beneficial to friction is still an open question. Moreover, which of the chemical differences between C-H and C-F bonds are responsible for the change in friction has not been unequivocally understood yet. In order to shed light on this problem, we develop a density-functional-theory-based, non-reactive force field that describes the relevant properties of hydrogen- and fluorine-terminated diamond and DLC tribological interfaces. Molecular dynamics and nudged-elastic band simulations reveal that the frictional stress at such interfaces correlates with the corrugation of the contact potential energy, thus ruling out a significant role of the mass of the terminating species on friction. Furthermore, the corrugation of the contact potential energy is almost exclusively determined by steric factors, while electrostatic interactions only play a minor role. In particular, friction between atomically flat diamond surfaces is controlled by the density of terminations, by the C-H and C-F bond lengths and by the H and F atomic radii. For sliding DLC/DLC interfaces, the intrinsic atomic-scale surface roughness plays an additional role. While surface fluorination decreases friction of incommensurate diamond contacts, it can negatively affect the friction performance of carbon surfaces that are disordered and not atomically flat. This work provides a general framework to understand the impact of chemical structure of surfaces on friction and to generate design rules for optimally terminated low-friction systems.
    DOI:  https://doi.org/10.1021/acsami.9b18019
  1177. Clin Cancer Res. 2020 Jan 22. pii: clincanres.2503.2019. [Epub ahead of print]
    Shortened Leukocyte Telomere Length Associates with an Increased Prevalence of Chronic Health Conditions among Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort.
    Song N, Li Z, Qin N, Howell CR, Wilson CL, Easton J, Mulder HL, Edmonson MN, Rusch M, Zhang J, Hudson MM, Yasui Y, Robison LL, Ness KK, Wang Z.
      PURPOSE: We aimed to analyze and compare leukocyte telomere length (LTL) and age-dependent LTL attrition between childhood cancer survivors and non-cancer controls, and to evaluate the associations of LTL with treatment exposures, chronic health conditions (CHCs), and health behaviors among survivors.EXPERIMENTAL DESIGN: We included 2,427 survivors and 293 non-cancer controls of European ancestry, drawn from the participants in St. Jude Lifetime Cohort Study (SJLIFE), a retrospective hospital-based study with prospective follow-up (2007-2016). Common non-neoplastic CHCs (59 types) and subsequent malignant neoplasms (5 types) were clinically assessed. LTL was measured with whole-genome sequencing data.
    RESULTS: After adjusting for age at DNA sampling, gender, genetic risk score based on 9 SNPs known to be associated with telomere length, and eigenvectors, LTL among survivors was significantly shorter both overall (adjusted mean [AM]=6.20kb; SE=0.03kb) and across diagnoses than controls (AM=6.69kb; SE=0.07kb). Among survivors, specific treatment exposures associated with shorter LTL included chest or abdominal irradiation, glucocorticoid, and vincristine chemotherapies. Significant negative associations of LTL with 14 different CHCs, and a positive association with subsequent thyroid cancer occurring out of irradiation field were identified. Health behaviors were significantly associated with LTL among survivors aged 18-35 years (p trend=0.03).
    CONCLUSIONS: LTL is significantly shorter among childhood cancer survivors than non-cancer controls, and is associated with CHCs and health behaviors, suggesting LTL as an aging biomarker may be a potential mechanistic target for future intervention studies designed to prevent or delay onset of CHCs in childhood cancer survivors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-2503
  1178. Molecules. 2020 Jan 18. pii: E400. [Epub ahead of print]25(2):
    Biodegradability of Dental Care Antimicrobial Agents Chlorhexidine and Octenidine by Ligninolytic Fungi.
    Linhartová L, Michalíková K, Šrédlová K, Cajthaml T.
      Chlorhexidine (CHX) and octenidine (OCT), antimicrobial compounds used in oral care products (toothpastes and mouthwashes), were recently revealed to interfere with human sex hormone receptor pathways. Experiments employing model organisms-white-rot fungi Irpex lacteus and Pleurotus ostreatus-were carried out in order to investigate the biodegradability of these endocrine-disrupting compounds and the capability of the fungi and their extracellular enzyme apparatuses to biodegrade CHX and OCT. Up to 70% ± 6% of CHX was eliminated in comparison with a heat-killed control after 21 days of in vivo incubation. An additional in vitro experiment confirmed manganese-dependent peroxidase and laccase are partially responsible for the removal of CHX. Up to 48% ± 7% of OCT was removed in the same in vivo experiment, but the strong sorption of OCT on fungal biomass prevented a clear evaluation of the involvement of the fungi or extracellular enzymes. On the other hand, metabolites indicating the enzymatic transformation of both CHX and OCT were detected and their chemical structures were proposed by means of liquid chromatography-mass spectrometry. Complete biodegradation by the ligninolytic fungi was not achieved for any of the studied analytes, which emphasizes their recalcitrant character with low possibility to be removed from the environment.
    Keywords:  chlorhexidine; dental hygiene; laccase; ligninolytic fungi; manganese-dependent peroxidase; octenidine; personal care products; quaternary ammonium compounds; recalcitrant pollutant
    DOI:  https://doi.org/10.3390/molecules25020400
  1179. Infect Immun. 2020 Jan 21. pii: IAI.00943-19. [Epub ahead of print]
    Inhibition of tRNA Synthetases Induces Persistence in Chlamydia.
    Hatch ND, Ouellette SP.
      Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections, and C. pneumoniae causes community-acquired respiratory infections. In vivo, the host immune system will release interferon-gamma (IFNγ) to combat infection. IFNγ activates human cells to produce the tryptophan (trp) catabolizing enzyme, IDO. Consequently, there is a reduction in cytosolic trp in IFNγ-activated host cells. In evolving to obligate intracellular dependence, Chlamydia has significantly reduced its genome size and content as it relies on the host cell for various nutrients. Importantly, C. trachomatis and C. pneumoniae are trp auxotrophs and are starved for this essential nutrient when the human host cell is exposed to IFNγ. To survive this, chlamydiae enter an alternative developmental state referred to as persistence. Chlamydial persistence is characterized by a halt in the division cycle, aberrant morphology, and, in the case of IFNγ-induced persistence, trp codon-dependent changes in transcription. We hypothesize that these changes in transcription are dependent on the particular amino acid starvation state. To investigate the chlamydial response mechanisms acting when other amino acids become limiting, we tested the efficacy of prokaryotic specific tRNA synthetase inhibitors, indolmycin and AN3365, to mimic starvation of trp and leucine, respectively. We show that these drugs block chlamydial growth and induce changes in morphology and transcription consistent with persistence. Importantly, growth inhibition was reversed when the compounds were removed from the medium. With these data, we find that indolmycin and AN3365 are valid tools that can be used to mimic the persistent state independently of IFNγ.
    DOI:  https://doi.org/10.1128/IAI.00943-19
  1180. Fa Yi Xue Za Zhi. 2019 Dec;35(6): 706-709
    Application of Quantitative Analysis of Diatoms in Lung Tissue for the Diagnosis of Drowning of Experimental Animals.
    Zhao J, Luo YZ, Wang YZ, Xiao C, Shi H, Hu SL, Kang XD, Xu QY, Cheng JD, Liu C.
      Abstract: Objective To discuss the application value of diatom examination in lung tissue for the forensic diagnosis of drowning. Methods The experimental animals were divided randomly into drowning, postmortem submergence and dying on land group. Diatoms in lung tissue and drowning fluid were analyzed quantitatively by microwave digestion-vacuum filtration-automated scanning electron microscopy diatom examination method. The ratios of content of diatoms in lung tissue and drowning fluid （CL/CD ratio） were recorded. Results The CL/CD ratios of experimental rabbits in the drowning group （5.82±3.50） were much higher than that of postmortem submergence group （0.47±0.35）; the CL/CD ratios of different parts of the lung lobes of experimental pigs in the drowning group were higher than that of postmortem submergence group （P<0.05）; in seawater, brackish water, river fresh water and lake fresh water, the CL/CD ratios of experimental pigs in the drowning group were higher than that of postmortem submergence group （P<0.05）. In animal experiments, all the cases with CL/CD ratio >1.6 were from drowning group. Conclusion CL/CD ratio is an indicator with good application prospects in the diagnosis of drowning.
    Keywords:  forensic pathology; drowning; diatoms; animals, laboratory; rabbits; swine; lung
    DOI:  https://doi.org/10.12116/j.issn.1004-5619.2019.06.011
  1181. Am J Clin Oncol. 2020 Feb;43(2): 146-147
    Competing Mortality in Patients With Neuroendocrine Tumors: Erratum.
      
    DOI:  https://doi.org/10.1097/COC.0000000000000664
  1182. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(19)32387-3. [Epub ahead of print]
    The role of bone-derived PDGF-AA in age-related pancreatic β cell proliferation and function.
    Liu X, Zhang F, Chai Y, Wang L, Yu B.
      The occurrence of type 2 diabetes(T2D) increases with age. The platelet-derived growth factor (PDGF) is one of the key factors regulating β cell proliferation and function, but the contribution of PDGF signaling in β cells aging and senescence remains unexplored. Here, we showed that the level of both serum and tissue PDGF-AA decreased with age, and the serum PDGF-AA level was positively correlated with β cell proliferation and function in aging. The decline of PDGF-AA level in aging was partly due to decreased number as well as secretion of osteoblast lineage cells in bone tissue. Conditioned medium from osteoblast lineage cells induced insulinoma β cells proliferation and insulin secretion in vitro, while addition of PDGF-AA neutralizing antibody attenuated this effect. Transplantation of juvenile osteoblast lineage cells increased serum PDGF-AA level and promoted β cell proliferation and function in aging mice, which eventually resulted in better glucose tolerance. Taken together, these findings revealed the role of decreased bone-derived PDGF-AA in mediating the disrupted proliferation and function of β cells in aging.
    Keywords:  Aging; Osteoblast; Pancreatic β cell; Platelet-derived growth factor; Senescence; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.bbrc.2019.12.057
  1183. Microbiome. 2020 Jan 23. 8(1): 5
    Single-cell genomics of uncultured bacteria reveals dietary fiber responders in the mouse gut microbiota.
    Chijiiwa R, Hosokawa M, Kogawa M, Nishikawa Y, Ide K, Sakanashi C, Takahashi K, Takeyama H.
      BACKGROUND: The gut microbiota can have dramatic effects on host metabolism; however, current genomic strategies for uncultured bacteria have several limitations that hinder their ability to identify responders to metabolic changes in the microbiota. In this study, we describe a novel single-cell genomic sequencing technique that can identify metabolic responders at the species level without the need for reference genomes, and apply this method to identify bacterial responders to an inulin-based diet in the mouse gut microbiota.RESULTS: Inulin-feeding changed the mouse fecal microbiome composition to increase Bacteroides spp., resulting in the production of abundant succinate in the mouse intestine. Using our massively parallel single-cell genome sequencing technique, named SAG-gel platform, we obtained 346 single-amplified genomes (SAGs) from mouse gut microbes before and after dietary inulin supplementation. After quality control, the SAGs were classified as 267 bacteria, spanning 2 phyla, 4 classes, 7 orders, and 14 families, and 31 different strains of SAGs were graded as high- and medium-quality draft genomes. From these, we have successfully obtained the genomes of the dominant inulin-responders, Bacteroides spp., and identified their polysaccharide utilization loci and their specific metabolic pathways for succinate production.
    CONCLUSIONS: Our single-cell genomics approach generated a massive amount of SAGs, enabling a functional analysis of uncultured bacteria in the intestinal microbiome. This enabled us to estimate metabolic lineages involved in the bacterial fermentation of dietary fiber and metabolic outcomes such as short-chain fatty acid production in the intestinal environment based on the fibers ingested. The technique allows the in-depth isolation and characterization of uncultured bacteria with specific functions in the microbiota and could be exploited to improve human and animal health. Video abstract.
    Keywords:  Bacteroides; Gut microbiome; Inulin; Mouse; Single-cell genomics; Uncultured bacteria
    DOI:  https://doi.org/10.1186/s40168-019-0779-2
  1184. Cell. 2020 Jan 23. pii: S0092-8674(19)31375-3. [Epub ahead of print]180(2): 359-372.e16
    Identification of a Master Regulator of Differentiation in Toxoplasma.
    Waldman BS, Schwarz D, Wadsworth MH, Saeij JP, Shalek AK, Lourido S.
      Toxoplasma gondii chronically infects a quarter of the world's population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections.
    Keywords:  Toxoplasma gondii; bradyzoite; chronic infection; differentiation; master regulator; single-cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.cell.2019.12.013
  1185. Atherosclerosis. 2020 Jan 12. pii: S0021-9150(20)30020-4. [Epub ahead of print]295 8-17
    Myeloid atg5 deletion impairs n-3 PUFA-mediated atheroprotection.
    Wang Z, Sequeira RC, Zabalawi M, Madenspacher J, Boudyguina E, Ou T, Nelson JM, Nie Y, Zhao Q, Fessler MB, Zhu X.
      BACKGROUND AND AIMS: Dietary long-chain (≥20 carbons) n-3 polyunsaturated fatty acids (PUFAs) reduce atherosclerosis and enhance macrophage autophagy activation. How macrophage autophagy impacts atherosclerotic progression, particularly when comparing dietary n-3 PUFA supplementation vs. saturated fat feeding, is unknown.METHODS: We generated myeloid-specific autophagy-deficient and control mice in the Ldlr-/- background by transplanting bone marrow from myeloid-specific autophagy-related (atg) 5 knockout mice and wild type controls into irradiated Ldlr-/- recipients. After 7 weeks for recovery from radiation, mice were fed an atherogenic diet containing 0.2% cholesterol and 20% calories as palm oil (PO diet), or 10% calories as PO plus 10% calories as fish oil (FO diet) for 16 weeks.
    RESULTS: Compared to PO, FO significantly reduced plasma cholesterol, triglyceride, hepatic neutral lipid, and aortic caspase-1 cleavage, but increased aortic efferocytosis, leading to attenuated atherosclerosis in Ldlr-/- mice receiving wild type bone marrow. Myeloid atg5 deletion had little impact on plasma lipid concentrations and hepatic neutral lipid content, regardless of diet. Myeloid atg5 deletion increased aortic caspase-1 cleavage, decreased aortic efferocytosis and worsened atherosclerosis only in the FO-fed Ldlr-/- mice.
    CONCLUSIONS: Deficient myeloid autophagy significantly attenuated FO-induced atheroprotection, suggesting that dietary n-3 PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy.
    Keywords:  Apoptosis; Atherosclerosis; Autophagy; Fish oil; Inflammation; Macrophage
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2020.01.004
  1186. Biochem Biophys Res Commun. 2020 Jan 18. pii: S0006-291X(20)30080-2. [Epub ahead of print]
    Inhibition of miR-200b-3p alleviates hypoxia-ischemic brain damage via targeting Slit2 in neonatal rats.
    Zhang N, Yang L, Meng L, Cui H.
      BACKGROUND: Brain damage in premature infants often occurs in very low birth weight infants (VLBW) as a result of hypoxia-ischemia and can lead to cognitive impairment and movement disorders. Many miRNAs have been demonstrated to participate in hypoxia-ischemic brain damage (HIBD). This study was designed to investigate the roles of miR-200b-3p in brain damage of neonatal rats induced by hypoxia-ischemia.METHODS AND RESULTS: Three-day-old SD rats were used to establish the model of hypoxia-ischemic brain injury mimicking premature infants. RT-qPCR showed that miR-200b-3p was up-regulated in rat brains at the early stage following hypoxia-ischemic treatment. Bioinformatics analysis identified that Slit2 is a target gene of miR-200b-3p and luciferase reporter gene assay confirmed that miR-200b-3p can interact with and target Slit2 mRNA. Inhibition of miR-200b-3p by antagomir increased Slit2 expression at both the mRNA and protein levels in rat brains. TUNEL assay and transmission electron microscopy (TEM) analysis showed decreased numbers of apoptotic neurons in the hypoxia-ischemia-treated animals as a result of administration of miR-200b-3p antagomir. Administration of miR-200b-3p antagomir attenuated spatial and learning memory loss in the animals induced by hypoxia-ischemia as compared to controls.
    CONCLUSION: Our study has demonstrated that Slit2 is a target gene of miR-200b-3p and that the hypoxia-ischemic brain damage in neonatal rats was alleviated by inhibiting miR-200b-3p via Slit2. miR-200b-3p may be a potential therapeutic target of HIBD for further investigation.
    Keywords:  Brain damage; Hypoxia-ischemia; Premature infants; Slit2; miR-200b-3p
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.029
  1187. Medicine (Baltimore). 2020 Jan;99(4): e18735
    Multi-center, randomized, double-blind, placebo-controlled, exploratory study to evaluate the efficacy and safety of HAD-B1 for dose-finding in EGFR positive and locally advanced or metastatic NSCLC subjects who need Afatinib therapy: Study protocol clinical trial (SPIRIT Compliant).
    Park SJ, Kang HJ, Jun HJ, Shin SH, Yoo HS.
      BACKGROUND: In recent studies, afatinib, a second-generation inhibitor, showed superior outcomes, when compared to the first-generation of EGFR-tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, in patients with advanced non-small cell lung cancer (NSCLC) harboring mutations of epidermal growth factor receptor (EGFR). Patients who receive TKIs with a significant initial efficacy, inevitably experience an acquired resistance (AR) within 9 to 13 months. Traditional Korean medicine may have synergistic effects when combined with chemotherapy or radiotherapy. The purpose of this trial is to assess whether afatinib plus HAD-B1 improves disease control rates (DCRs) compared with afatinib alone and to evaluate the efficacy and safety of HAD-B1 for finding the proper dose.METHODS: This is a randomized, double-blind, placebo-controlled, multi-center, therapeutic, exploratory clinical trial. This trial is designed to determine whether HAD-B1 combined with afatinib results in better DCRs with less toxicity than afatinib alone. A total of 66 NSCLC patients with EGFR mutations will be randomly assigned to treatment group 1 (afatinib 40 mg/day plus HAD-B1 972 mg), treatment group 2 (afatinib 40 mg/day plus HAD-B1 1944 mg) and a control group (afatinib 40 mg/day). Afatinib combined with HAD-B1 or with a placebo will be administered to the participants for 12 weeks. The primary endpoint is a comparison of the DCRs among groups. Secondary endpoints are comparisons of the complete response (CR) and the partial response (PR) to the treatment, the stability of the disease (SD), progression free survival (PFS), time to progression (TTP), and tumor marker (CEA, NSE) and WBC differential count (LMR, NLR) and natural killer cell activity and quality of life (QOL) among groups.
    DISCUSSION: The results from this clinical trial will provide evidence of efficacy and safety of HAD-B1 in EGFR positive and locally advanced or metastatic NSCLC patients who need afatinib therapy.
    DOI:  https://doi.org/10.1097/MD.0000000000018735
  1188. J Med Case Rep. 2020 Jan 20. 14(1): 15
    Multiple electrolyte imbalances and mixed acid-base disorder posing a diagnostic dilemma: a case report.
    Alabi FO, Alabi CO, Basso RG, Lakhdar N, Oderinde AO.
      BACKGROUND: In clinical practice, both the history and laboratory testing are paramount to making an accurate diagnosis. Situations in which laboratory findings and patient history are not congruent pose a diagnostic dilemma. We report a case of a young woman presenting with a myriad of electrolyte and acid-base disorders. Difficulty in reaching a unifying diagnosis persisted due to discordant patient history. We believe this case shows that lab findings will clearly portray the problems a patient has and should be given more credence in a case where the history is discordant with lab findings.CASE PRESENTATION: A 28-year-old Hispanic American woman presented to the emergency room of our institution with a complaint of painless and sudden onset of stiffness in her upper and lower limbs. Associated weakness worse in the distal limbs was also reported. She experienced shortness of breath with minimal exertion, diaphoresis, and anxiety. Her vital signs revealed tachycardia without corresponding fever. She was conscious, oriented, and alert. Her physical exam revealed dry mucous membranes and warm extremities. She denied recent consumption of a large carbohydrate meal, diarrhea, vomiting, use of laxatives, and use of alcohol or recreational drugs. She vaguely described two previous similar episodes in the last 7 months that spontaneously resolved. Her medical history was significant only for hypothyroidism treated with daily levothyroxine tablets. Laboratory analysis revealed the following abnormalities: an elevated anion gap with significant lactate, hypokalemia, hypomagnesemia, elevated mean corpuscular volume, elevated mean cell hemoglobin, and elevated liver enzymes with aspartate aminotransferase/alanine aminotransferase ratio > 2. She was hydrated with balanced crystalloids, and her electrolyte deficiencies corrected. The etiology of her multiple electrolyte abnormalities was unclear because alcohol use was vehemently denied. Extensive evaluation for causes of electrolyte disorder was undertaken, which was unrevealing. On further interrogation, she admitted to recent alcohol intoxication and several episodes of vomiting before presentation. She was advised to refrain from alcohol use and discharged afterward.
    CONCLUSION: Both patient history and laboratory analysis have a role in identifying and confirming a diagnosis. In cases in which laboratory tests are incongruous with reported history, making a unifying diagnosis can be challenging or delayed. The importance of taking a comprehensive history cannot be overemphasized, but history provided by patients may be prone to intentional or unintentional distortion, whereas laboratory findings are more objective. The case presented underscores why the lab findings should be given credence in cases in which there is discordance between lab results and the provided patient history.
    Keywords:  Alcohol intoxication; Electrolyte imbalance; History; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia; Lab; Lactic acidosis; Mixed acid-base disorder
    DOI:  https://doi.org/10.1186/s13256-019-2330-2
  1189. J Assoc Physicians India. 2020 Jan;68(1): 104
    A new perspective of enzyme inhibition by organophosphates.
    Tamilmathy S, Sureshkanna S, Rajkumar V.
      
  1190. Obesity (Silver Spring). 2020 Feb;28(2): 223
    New Concerns About Military Recruits with Metabolic Obesity but Normal Weight ("Skinny Fat").
    Foulis SA, Hughes JM, Friedl KE.
      
    DOI:  https://doi.org/10.1002/oby.22724
  1191. Mar Drugs. 2020 Jan 20. pii: E69. [Epub ahead of print]18(1):
    Chitooligosaccharides Modulate Glucose-Lipid Metabolism by Suppressing SMYD3 Pathways and Regulating Gut Microflora.
    Wang Q, Jiang Y, Luo X, Wang C, Wang N, He H, Zhang T, Chen L.
      Chitooligosaccharides (COS) have a variety of biological activities due to their positively charged amino groups. Studies have shown that COS have antidiabetic effects, but their molecular mechanism has not been fully elucidated. The present study confirmed that COS can reduce hyperglycemia and hyperlipidemia, prevent obesity, and enhance histological changes in the livers of mice with type 2 diabetes mellitus (T2DM). Additionally, treatment with COS can modulate the composition of the gut microbiota in the colon by altering the abundance of Firmicutes, Bacteroidetes, and Proteobacteria. Furthermore, in T2DM mice, treatment with COS can upregulate the cholesterol-degrading enzymes cholesterol 7-alpha-hydroxylase (CYP7A1) and incretin glucagon-like peptide 1 (GLP-1) while specifically inhibiting the transcription and expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the key enzyme in cholesterol synthesis. Furthermore, using an oleic acid-induced hepatocyte steatosis model, we found that HMGCR can be directly transactivated by SET and MYND domain containing 3 (SMYD3), a transcriptional regulator, via 5'-CCCTCC-3' element in the promoter. Overexpression of SMYD3 can suppress the inhibitory effect of COS on HMGCR, and COS might regulate HMGCR by inhibiting SMYD3, thereby exerting hypolipidemic functions. To the best of our knowledge, this study is the first to illustrate that COS mediate glucose and lipid metabolism disorders by regulating gut microbiota and SMYD3-mediated signaling pathways.
    Keywords:  HMGCR; SMYD3; chitooligosaccharides; glycolipid metabolism disorder; intestinal microflora
    DOI:  https://doi.org/10.3390/md18010069
  1192. Eur Ann Otorhinolaryngol Head Neck Dis. 2020 Jan 20. pii: S1879-7296(20)30007-7. [Epub ahead of print]
    HPV vaccination: Strong messages from a meta-analysis, a report and a press-release.
    Laccourreye O.
      
    DOI:  https://doi.org/10.1016/j.anorl.2020.01.006
  1193. Behav Anal Pract. 2019 Sep;12(3): 734-740
    Utilizing Peers to Support Academic Learning for Children With Autism Spectrum Disorder.
    Haas A, Vannest K, Smith SD.
      The inclusion of students with autism spectrum disorder in academic settings is becoming more common. However, most practices focus on increasing social skills even though students also struggle in academic areas. There is a need for strategies that address both social and academic skill deficits, are evidence based, and are easy to implement in the classroom. Peer-mediated interventions have evidence supporting their use in promoting social and academic behavior change and are socially valid and cost-effective. The purpose of this paper is to present examples of how to implement 2 common peer-tutoring strategies: Classwide Peer Tutoring and Peer-Assisted Learning Strategies. Examples for implementing both strategies are provided using a hypothetical student in a general education setting, followed by a brief summary of evidence supporting the peer-mediated academic instruction.
    Keywords:  Academic skills; Autism; Evidence-based practice; Peer instruction
    DOI:  https://doi.org/10.1007/s40617-019-00363-4
  1194. Annu Rev Immunol. 2020 Jan 21.
    Hypoxia and Innate Immunity: Keeping Up with the HIFsters.
    Colgan SP, Furuta GT, Taylor CT.
      Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF. Expected final online publication date for the Annual Review of Immunology, Volume 38 is April 26, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-immunol-100819-121537
  1195. Clin Nucl Med. 2020 Jan 17.
    Re: Cutaneous Manifestation of Sarcoidosis in Lower-Back Tattoo With Increased Uptake of 18F-FDG.
    Kluger N.
      
    DOI:  https://doi.org/10.1097/RLU.0000000000002918
  1196. Curr Opin Clin Nutr Metab Care. 2020 Jan 20.
    Nutrition intake in the post-ICU hospitalization period.
    Ridley EJ, Chapple LS, Chapman MJ.
      PURPOSE OF REVIEW: The care of critically ill patients has evolved over recent years, resulting in significant reductions in mortality in developed countries; sometimes with prolonged issues with recovery. Nutrition research has focused on the early, acute period of critical illness, until more recently, where the post-ICU hospitalization period in critical care survivors has become a focus for nutrition rehabilitation. In this period, nutrition rehabilitation may be a vital component of recovery.RECENT FINDINGS: Overall, oral nutrition is the most common mode of nutrition provision in the post-ICU period. Compared with oral intake alone, calorie and protein requirements can be better met with the addition of oral supplements and/or enteral nutrition to oral intake. However, calorie and protein intake remains below predicted targets in the post-ICU hospitalization period. Achieving nutrition targets are complex and multifactorial, but can primarily be grouped into three main areas: patient factors; clinician factors; and system factors.
    SUMMARY: A nutrition intervention in the post-ICU hospitalization period may provide an opportunity to improve survival and functional recovery. However, there are multiple barriers to the delivery of calculated nutrition requirements in this period, a limited understanding of how this can be improved and how this translates into clinical benefit.
    DOI:  https://doi.org/10.1097/MCO.0000000000000637
  1197. Pestic Biochem Physiol. 2020 Feb;pii: S0048-3575(19)30471-7. [Epub ahead of print]163 84-93
    Ivermectin-induced programmed cell death and disruption of mitochondrial membrane potential in bovine mammary gland epithelial cells.
    Park H, Song G, Lim W.
      Ivermectin (IVM) is a commercially well-known antiparasitic agent derived from the natural fermentation product avermectin. Originally used as a veterinary drug, IVM has been studied for its pharmacokinetic advantages, such as anticancer, antimigration, and antiproliferative effects, using several cell types. In the present study, we verified that IVM suppressed bovine mammary gland epithelial cell proliferation and induced the arrest of the cell cycle from the sub-G1 to the G2/M phase in these cells. Due to IVM treatment, the homeostasis of calcium ions, which play a crucial role in intracellular metabolism, deteriorated, leading to the loss of the mitochondrial membrane potential (MMP). To underpin these results, further studies using inhibitors of Ca2+ signaling were performed; combination treatment with IVM and these factors, including 2-APB, BAPTA-AM, or ruthenium red, inhibited the IVM-induced MMP disruption. Furthermore, following IVM treatment, the relationships among various cell signaling mediators were altered, and the balance between diverse cellular processes associated with cell survival or death was disturbed. In conclusion, we assessed the anti-survival effects of IVM on mammary gland epithelial cells; IVM may impede normal lactation in dairy cows.
    Keywords:  Ca(2+) chelation; Cell signaling pathway; Ivermectin; MMP; Programmed cell death
    DOI:  https://doi.org/10.1016/j.pestbp.2019.10.011
  1198. J Sci Food Agric. 2020 Jan 21.
    Inhibitory mechanism of lactoferrin on antibacterial activity of oenothein B: isothermal titration calorimetry and computational docking simulation.
    Zhao L, Zhou A, Liu Z, Xiao J, Wang Y, Cao Y, Wang L.
      BACKGROUND: Many foods contain proteins and polyphenols, but there is a poor understanding of the nature of the inhibitory effect of protein on the biologic activity of polyphenols. The inhibitory mechanism of the food protein lactoferrin on the antibacterial activity of oligomeric ellagitannin oenothein B (OeB) was investigated using fluorescence quenching, isothermal titration calorimetry (ITC), circular dichroism (CD) measurement and molecular docking.RESULTS: The antibacterial activity of OeB against S. aureus was inhibited by lactoferrin, which was retained at about 60%. An interaction study revealed that an interaction occurred between OeB and lactoferrin. Thermodynamic analyses indicate that the binding process was spontaneous, and the main driving forces were based on electrostatic interactions that contributed to a high interaction affinity between OeB and lactoferrin. Furthermore, circular dichroism spectra provided insights into conformational changes of lactoferrin. Finally, molecular docking analysis provided a visual representation of a single binding site where OeB interacted with specific amino acid residues located at the active site of lactoferrin. In particular, due to the unique macrocyclic structure and rigid ring structure of OeB, a small number of hydroxyl groups in the rigid structure of OeB interacted with the amino acid of lactoferrin while most of the phenolic hydroxyl groups were not associated with lactoferrin.
    CONCLUSION: Our study provides a theoretical basis for the use of OeB as an antibacterial substance that can be used in nutraceuticals and pharmaceutical products. This article is protected by copyright. All rights reserved.
    Keywords:  antibacterial activity; interaction mechanism; lactoferrin; molecular docking; oenothein B
    DOI:  https://doi.org/10.1002/jsfa.10271
  1199. J Dairy Sci. 2020 Jan 21. pii: S0022-0302(20)30051-5. [Epub ahead of print]
    Short communication: Milk microbiota profiling on water buffalo with full-length 16S rRNA using nanopore sequencing.
    Catozzi C, Ceciliani F, Lecchi C, Talenti A, Vecchio D, De Carlo E, Grassi C, Sánchez A, Francino O, Cuscó A.
      The identification of milk microbial communities in ruminants is relevant for understanding the association between milk microbiota and health status. The most common approach for studying the microbiota is amplifying and sequencing specific hypervariable regions of the 16S rRNA gene using massive sequencing techniques. However, the taxonomic resolution is limited to family and, in some cases, genus level. We aimed to improve taxonomic classification of the water buffalo milk microbiota by amplifying and sequencing the full-length 16S rRNA gene (1,500 bp) using Nanopore sequencing (single-molecule sequencing). When comparing with short-read results, we improved the taxonomic classification, reaching species level. We identified the main microbial agents of subclinical mastitis at the species level that were in accordance with the microbiological culture results. These results confirm the potential of single-molecule sequencing for in-depth analysis of microbial populations in dairy animals.
    Keywords:  milk microbiota; nanopore sequencing; water buffalo
    DOI:  https://doi.org/10.3168/jds.2019-17359
  1200. Mar Drugs. 2020 Jan 18. pii: E64. [Epub ahead of print]18(1):
    Crab vs. Mushroom: A Review of Crustacean and Fungal Chitin in Wound Treatment.
    Jones M, Kujundzic M, John S, Bismarck A.
      Chitin and its derivative chitosan are popular constituents in wound-treatment technologies due to their nanoscale fibrous morphology and attractive biomedical properties that accelerate healing and reduce scarring. These abundant natural polymers found in arthropod exoskeletons and fungal cell walls affect almost every phase of the healing process, acting as hemostatic and antibacterial agents that also support cell proliferation and attachment. However, key differences exist in the structure, properties, processing, and associated polymers of fungal and arthropod chitin, affecting their respective application to wound treatment. High purity crustacean-derived chitin and chitosan have been widely investigated for wound-treatment applications, with research incorporating chemically modified chitosan derivatives and advanced nanocomposite dressings utilizing biocompatible additives, such as natural polysaccharides, mineral clays, and metal nanoparticles used to achieve excellent mechanical and biomedical properties. Conversely, fungi-derived chitin is covalently decorated with -glucan and has received less research interest despite its mass production potential, simple extraction process, variations in chitin and associated polymer content, and the established healing properties of fungal exopolysaccharides. This review investigates the proven biomedical properties of both fungal- and crustacean-derived chitin and chitosan, their healing mechanisms, and their potential to advance modern wound-treatment methods through further research and practical application.
    Keywords:  chitin; chitosan; derivatization; nanocomposites; wound treatment
    DOI:  https://doi.org/10.3390/md18010064
  1201. Plant Physiol Biochem. 2020 Jan 08. pii: S0981-9428(20)30008-5. [Epub ahead of print]148 114-121
    Negative regulation by transcription factor VvWRKY13 in drought stress of Vitis vinifera L.
    Hou L, Fan X, Hao J, Liu G, Zhang Z, Liu X.
      Drought is a major environmental factor limiting crop growth and development worldwide. WRKY transcription factor, a unique transcription factor in plants, has been shown to play important roles in plant response to abiotic stress. Previously, we have cloned the VvWRKY13 gene from resistant grape varieties and found that its expression was obviously induced by drought. Here we further explored the mechanism of VvWRKY13 in response to drought stress. After drought treatment, the expression of VvWRKY13 in the sensitive grape varieties was significantly higher than resistant grape varieties. Moreover, phenotypic changes of VvWRKY13 transgenic Arabidopsis were observed and drought-related indexes were detected under drought treatment. The results showed that VvWRKY13 transgenic Arabidopsis exhibited more sensitive phenotype to drought stress compared with wild type. The water loss rate of leaves in the transgenic Arabidopsis was significantly higher than wild type. The content of proline, soluble sugar and the expression of related genes decreased in transgenic Arabidopsis leaves under drought stress. The level of endogenous hydrogen peroxide and oxygen free radicals was increased, while the activity of catalase (CAT) and superoxide dismutase enzyme (SOD) were decreased. In addition, the expression of stress response gene was significantly decreased in transgenic Arabidopsis. Taken together, our results suggest that VvWRKY13 negatively modulates plant drought tolerance through regulating the metabolism of intracellular osmotic substances (proline, soluble sugar), the level of ROS, and the expression of stress-related genes.
    Keywords:  Drought; Negative regulation; Osmotic regulator substance; ROS; Vitis vinifera L; VvWRKY13
    DOI:  https://doi.org/10.1016/j.plaphy.2020.01.008
  1202. Br J Radiol. 2020 Jan 24. 20190556
    Anatomical analysis of the pelvis to identify any predisposing anatomical factors for ischiofemoral space pathology: a retrospective study.
    López-Royo MP, Valero-Tena E, Roca M.
      OBJECTIVES: Anatomical analysis of the hips and pelvis was performed using MRI to evaluate morphological characteristics and associations between them. We identified correlations between the ischiofemoral space (IFS), quadratus femoris space (QFS), femoral version angle (FVA) and cervicodiaphyseal angle (CDA).METHODS: This study involved a retrospective search of a database of consecutive reports of adult hip MRI examinations carried out between January and September 2016. Patients with a medical history likely to affect pelvic and hip morphometry were excluded.
    RESULTS: A total of 137 adult patients were enrolled in the study (45.3% males and 54.7% females), with a mean age of 50.16 ± 13.87 years. The mean IFS was 20.88 ± 5.96 mm, mean QFS was 15.2 ± 6.18 mm, mean FVA was 12.43 ± 6.98, and mean CDA was 121.27 ± 4.6°. The IFS measurements were significantly correlated with femoral measurements (p = 0.025). These visible differences showed a slight negative relationship (-0.191), and females had a smaller distance between these anatomical structures than males (p < 0.001). Females had a significantly smaller QFS than males (12.42 ± 5.94 vs 18.73 ± 4.48 mm, p = 0.000). There was a small but significant positive relationship between CDA and FVA (p = 0.022), with a correlation coefficient of 0.195.
    CONCLUSIONS: A higher FVA was correlated with a smaller IFS. Furthermore, an increase in the CDA appeared in tandem with an increase in the FVA.
    ADVANCES IN KNOWLEDGE: A single conventional MRI sequence can alert us to how anatomical factors could predispose individuals to a decrease in IFS.
    DOI:  https://doi.org/10.1259/bjr.20190556
  1203. Sci Rep. 2020 Jan 23. 10(1): 1017
    Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination.
    Roy S, Liu HY, Jaeson MI, Deimel LP, Ranasinghe C.
      This study demonstrates that 24 h following viral vector-based vaccination IL-13Rα2 functions as a master sensor on conventional dendritic cells (cDCs), abetted by high protein stability coupled with minimal mRNA expression, to rapidly regulate DC mediated IL-13 responses at the lung mucosae, unlike IL-13Rα1. Under low IL-13, IL-13Rα2 performs as a primary signalling receptor, whilst under high IL-13, acts to sequester IL-13 to maintain homeostasis, both in a STAT3-dependent manner. Likewise, we show that viral vector-derived IL-13 levels at the vaccination site can induce differential STAT3/STAT6 paradigms in lung cDC, that can get regulated collaboratively or independently by TGF-β1 and IFN-γ. Specifically, low IL-13 responses associated with recombinant Fowlpox virus (rFPV) is regulated by early IL-13Rα2, correlated with STAT3/TGF-β1 expression. Whilst, high IL-13 responses, associated with recombinant Modified Vaccinia Ankara (rMVA) is regulated in an IL-13Rα1/STAT6 dependent manner associated with IFN-γR expression bias. Different viral vaccine vectors have previously been shown to induce unique adaptive immune outcomes. Taken together current observations suggest that IL-13Rα2-driven STAT3/STAT6 equilibrium at the cDC level may play an important role in governing the efficacy of vector-based vaccines. These new insights have high potential to be exploited to improve recombinant viral vector-based vaccine design, according to the pathogen of interest and/or therapies against IL-13 associated disease conditions.
    DOI:  https://doi.org/10.1038/s41598-020-57815-z
  1204. Cancer Sci. 2020 Jan 20.
    ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer.
    Kawakami R, Mashima T, Kawata N, Kumagai K, Migita T, Sano T, Mizunuma N, Yamaguchi K, Seimiya H.
      Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug-resistant properties called "persister" cells. While this early-phase drug tolerance is considered to be related to the stem cell-like characteristic of persister cells, how the stem cell-related pathways contribute to drug resistance has remained elusive. Here, we conducted a single cell analysis based on the stem cell- and gastric cell lineage-related gene expression in patient-derived gastric cancer cell models. These analyses revealed that 5-fluorouracil (5-FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell-related genes were enriched in the residual cancer cells after 5-FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5-FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment, and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mTOR cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU-tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3-mTOR axis could be a novel therapeutic target to eradicate drug-tolerant gastric cancer cells.
    Keywords:  ALDH1A3; drug tolerance; gastric cancer; persister cells; tumor heterogeneity
    DOI:  https://doi.org/10.1111/cas.14316
  1205. Br J Pharmacol. 2020 Jan 22.
    Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma-like lung disease in mice.
    Goldblatt DL, Flores JR, Valverde Ha G, Jaramillo AM, Tkachman S, Kirkpatrick CT, Wali S, Hernandez B, Ost DE, Scott BL, Chen J, Evans SE, Tuvim MJ, Dickey BF.
      BACKGROUND AND PURPOSE: Respiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll-like receptor (TLR) agonists could attenuate the severity of chronic asthma-like lung disease.EXPERIMENTAL APPROACH: Mice were treated by aerosol with 1 μM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4 μM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge.
    KEY RESULTS: Treatment with ODN/Pam2 caused ~75% reduction in lung Sendai virus burden five days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion, and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL-33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by downregulating Type 2 (allergic) inflammation.
    CONCLUSION AND IMPLICATIONS: These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce initiation, exacerbation, and progression of asthma.
    DOI:  https://doi.org/10.1111/bph.14977
  1206. J Physiol. 2020 Jan 20.
    A high-fat high-calorie diet induces fibre-specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle.
    Whytock KL, Parry SA, Turner MC, Woods RM, James LJ, Ferguson RA, Ståhlman M, Borén J, Strauss JA, Cocks M, Wagenmakers AJM, Hulston CJ, Shepherd SO.
      KEY POINTS: We have recently shown that a high-fat high-calorie (HFHC) diet decreases whole body glucose clearance without impairing skeletal muscle insulin signalling, in healthy lean individuals. These diets are also known to increase skeletal muscle IMTG stores, but the effect on lipid metabolites leading to skeletal muscle insulin resistance has not been investigated. This study measured the effect of 7 days HFHC diet on: 1) skeletal muscle concentration of lipid metabolites, and 2) potential changes in the perilipin (PLIN) content of the lipid droplets (LD) storing IMTG. The HFHC diet increased PLIN3 protein expression and redistributed PLIN2 to LD stores in type I fibres. The HFHC diet increased IMTG content in type I fibres, while lipid metabolite concentrations remained the same. The data suggest that the increases in IMTG stores assists reducing the accumulation of lipid metabolites known to contribute to skeletal muscle insulin resistance.ABSTRACT: A HFHC diet reduces whole body glucose clearance without impairing skeletal muscle insulin signalling in healthy lean individuals. HFHC diets also increase skeletal muscle lipid stores. However, unlike certain lipid metabolites, intramuscular triglyceride (IMTG) stored within lipid droplets (LD) does not directly contribute to skeletal muscle insulin resistance. Increased expression of perilipin (PLIN) proteins and colocalisation to LD has been shown to assist in IMTG storage. We aimed to test the hypothesis that 7 days on a HFHC diet increases IMTG content while minimising accumulation of lipid metabolites known to disrupt skeletal muscle insulin signalling in sedentary and obese individuals. We also aimed to identify changes in expression and subcellular distribution of proteins involved in IMTG storage. Muscle biopsies were obtained from the m. vastus lateralis of 13 (n = 11 males, n = 2 females) healthy lean individuals (age: 23 ± 2.5 y, BMI: 24.5 ± 2.4 kg m-2 ), following an overnight fast, before and after consuming a high-fat (64% energy) high-calorie (+47% kcal) diet for 7 days. After the HFHC diet, IMTG content increased in type I fibres only (+10%; P < 0.001), whereas there was no change in the concentration of either total diacylglycerol (P = 0.123) or total ceramides (P = 0.150). Of the PLINs investigated, only PLIN3 content increased (+50%; P < 0.01) solely in type I fibres. LDs labelled with PLIN2 increased (80%; P < 0.01), also in type I fibres only. We propose that these adaptations to LD support IMTG storage and minimise accumulation of lipid metabolites to protect skeletal muscle insulin signalling following 7 days HFHC diet. This article is protected by copyright. All rights reserved.
    Keywords:  confocal immunohistochemistry; high-fat; intramuscular triglyceride; perilipin
    DOI:  https://doi.org/10.1113/JP279129
  1207. Regul Toxicol Pharmacol. 2020 Jan 21. pii: S0273-2300(20)30003-9. [Epub ahead of print] 104577
    The value of avian gross pathology in identifying endocrine disrupting properties.
    Temple D, Springer T, Gallagher S, du Hoffmann G, Wheeler JR.
      The European Chemical Agency and European Food Safety Authority recommend that gross pathology findings, from avian reproduction studies, be used to support assessment of potential endocrine disrupting properties of active pesticidal and biocidal substances. In open literature, little information is available on the utility of gross pathology data for informing endocrine evaluations. Here the gross pathology data from historical control groups of 51 northern bobwhite and 51 mallard reproduction tests is analyzed to evaluate the utility of such information. Incidence of gross morphology findings in untreated birds may aid the interpretation of some gross abnormalities, potentially indicative of an endocrine interaction (e.g. reproductive condition). Statistical analysis of the historical control data indicates that gross pathology is not likely to be useful for detecting endocrine effects as abnormalities with relatively high increases in prevalence (more than 20-30%, depending on prevalence in controls) are reliably interpreted as a treatment response. Gross pathology changes are only indicative and not diagnostic of endocrine interactions making it difficult to distinguish gross pathology abnormalities, due to endocrine-mediated effects, from systemic toxicity. This work demonstrates the utility of using historical control analyses to establish the value and properties of selected endpoints for regulatory applications.
    Keywords:  Avian reproduction test; Endocrine disruption; Gross pathology; Necropsy; Regulatory toxicology
    DOI:  https://doi.org/10.1016/j.yrtph.2020.104577
  1208. GE Port J Gastroenterol. 2020 Jan;27(1): 68-70
    Massive Hematemesis: An Uncommon Presentation of an Unusual Diagnosis.
    Mendo R, Félix C, Figueiredo PC.
      
    Keywords:  Dieulafoy's lesion; Gastrointestinal bleeding; Small-bowel diverticulosis
    DOI:  https://doi.org/10.1159/000501402
  1209. Nature. 2020 Jan;577(7791): 460-461
    Stress, anxiety, harassment: huge survey reveals pressures of scientists' working lives.
    Abbott A.
      
    Keywords:  Culture; Institutions
    DOI:  https://doi.org/10.1038/d41586-020-00101-9
  1210. J Clin Med. 2020 Jan 23. pii: E321. [Epub ahead of print]9(2):
    Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index.
    Garcia E, Shalaurova I, Matyus SP, Oskardmay DN, Otvos JD, Dullaart RPF, Connelly MA.
      BACKGROUND: Quantifying mildly elevated ketone bodies is clinically and pathophysiologically relevant, especially in the context of disease states as well as for monitoring of various diets and exercise regimens. As an alternative assay for measuring ketone bodies in the clinical laboratory, a nuclear magnetic resonance (NMR) spectroscopy-based test was developed for quantification of β-hydroxybutyrate (β-HB), acetoacetate (AcAc) and acetone.METHODS: The ketone body assay was evaluated for precision, linearity and stability and method comparisons were performed. In addition, plasma ketone bodies were measured in the Insulin Resistance Atherosclerosis Study (IRAS, n = 1198; 373 type 2 diabetes mellitus (T2DM) subjects).
    RESULTS: β-HB and AcAc quantified using NMR and mass spectrometry and acetone quantified using NMR and gas chromatography/mass spectrometry were highly correlated (R2 = 0.996, 0.994, and 0.994 for β-HB, AcAc, acetone, respectively). Coefficients of variation (%CVs) for intra- and inter-assay precision ranged from 1.3% to 9.3%, 3.1% to 7.7%, and 3.8% to 9.1%, for β-HB, AcAc and acetone, respectively. In the IRAS, ketone bodies were elevated in subjects with T2DM versus non-diabetic individuals (p = 0.011 to ≤0.001). Age- and sex-adjusted multivariable linear regression analysis revealed that total ketone bodies and β-HB were associated directly with free fatty acids (FFAs) and T2DM and inversely with triglycerides and insulin resistance as measured by the Lipoprotein Insulin Resistance Index.
    CONCLUSIONS: Concentrations of the three main ketone bodies can be determined by NMR with good clinical performance, are elevated in T2DM and are inversely associated with triglycerides and insulin resistance.
    Keywords:  insulin resistance; ketone bodies; nuclear magnetic resonance spectroscopy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/jcm9020321
  1211. Sci Total Environ. 2020 Feb 25. pii: S0048-9697(19)35795-X. [Epub ahead of print]705 135800
    Impacts of polystyrene microplastics on Daphnia magna: A laboratory and a mesocosm study.
    Aljaibachi R, Laird WB, Stevens F, Callaghan A.
      Most research into microplastics (MPs) in freshwaters has concentrated on measurements under controlled conditions without any link to the natural environment. Here we studied the effects of a 15 μm polystyrene MP on Daphnia magna survival, growth, and reproduction in the laboratory. We also exposed fifteen 25 L freshwater mesocosms to a high concentration of the same MPs. Five were controls seeded with five species found in all ponds (mosquito, water flea, midge, spire shell and water mite), five identical but treated with 15 μm polystyrene MPs and five seeded with only mosquitoes and water fleas. The laboratory chronic toxicity test for both adults and neonate Daphnia magna revealed that effects were more related to the availability of food rather than the toxicity of MPs. In the mesocosms most of the MPs settled in the sediment after the first week of exposure. After four weeks the D. magna population decreased significantly in the MP mesocosms compared to the control mesocosms, although it subsequently recovered. There was no impact on other organisms added to the mesocosms, other than a difference in timing of lesser water boatman (Corixa punctata) colonisation, which colonised the control mesocosms in week 4 and the treated 4 weeks later. The detrivorous, sediment sifting, mayfly Leptophlebia marginata appeared in mesocosms in the fourth week of sampling and with significantly higher numbers in the MP treated mesocosm. Their activity had no significant impact on MPs in the water column, although numbers did increase above zero. The significant decline of D. magna suggests that their effect in a natural situation is unpredictable where environmental conditions and invertebrate communities may add additional stresses.
    Keywords:  Biodiversity; Daphnia magna; Ecotoxicology; Mesocosms; Microplastics
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.135800
  1212. J Thorac Cardiovasc Surg. 2019 Dec 20. pii: S0022-5223(19)39876-9. [Epub ahead of print]
    Commentary: Tis the season to filter your perfusate.
    Guo Y, Krupnick AS.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.12.012
  1213. Endocr Metab Immune Disord Drug Targets. 2020 Jan 20.
    Characterization of the active components of the multimerized sTNFRII-adiponectin fusion protein showing both TNFα-antagonizing and glucose uptake-promoting activities.
    Wang Y, Lian H, Wang X, Zheng T, Yu X, Chen R, Huang Z, Lv Y, Zhao A, Gao J.
      Background：The sTNFRII-adiponectin fusion protein had been previously shown to have strong TNFα antagonistic activity. However, the protein exists as a mixture of different multimers. The aim of the present study was to characterize its active components. Methods：In this study, the protein was isolated and purified by Ni-NTA affinity and gel exclusion chromatography, and further identified by Coomassie staining and western blotting. The TNFα antagonistic and hypoglycemic activities were determined in vitro, and glucose detection kit and 2-NBDG （2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose）were used to measure their effects on glucose metabolism (including glucose consumption and glucose uptake in HepG2 and H9C2 cells). Effect of the protein on glucose uptake was also examined in a free fatty acid (FFA)-induced insulin resistance cell model. Results: The sTNFRII-adiponectin fusion protein was found to exist in three forms: 250 kDa (hexamer), 130 kDa (trimer), and 60 kDa (monomer), with the final purity of 90.2%, 60.1%, and 81.6%, respectively. The fusion protein could effectively antagonize the killing effect of TNFα in L929 cells, and the multimer was found to be superior to the monomer. In addition, the fusion protein could increase glucose consumption without impacting the number of cells (HepG2, H9C2 cells) in a dose-dependent manner. Mechanistically, glucose uptake was found to be enhanced by the translocation of GLUT4. However, it could not improve glucose uptake in the cell model of insulin resistance. Conclusion：In summary, the hexamer and trimer of sTNFRII-adiponectin fusion protein had both TNFα-antagonizing and glucose uptake-promoting activities, although neither could improve glucose uptake in the cell model of insulin resistance.
    Keywords:  Adiponectin; Fusion protein; Insulin resistance; Multimer; Soluble TNFRII; TNFα antagonist
    DOI:  https://doi.org/10.2174/1871530320666200121100449
  1214. Cancer Cell. 2020 Jan 23. pii: S1535-6108(20)30041-6. [Epub ahead of print]
    Science that Inspires.
    .
      
    DOI:  https://doi.org/10.1016/j.ccell.2020.01.002
  1215. J Am Chem Soc. 2020 Jan 21.
    Gas-Phase Formation of Fulvenallene (C7H6) via the Jahn-Teller Distorted Tropyl (C7H7) Radical Intermediate under Single-Collision Conditions.
    He C, Thomas AM, Galimova GR, Morozov AN, Mebel AM, Kaiser RI.
      The fulvenallene molecule (C7H6) has been synthesized via the elementary gas-phase reaction of the methylidyne radical (CH) with the benzene molecule (C6H6) on the doublet C7H7 surface under single collision conditions. The barrier-less route to the cyclic fulvenallene molecule involves the addition of the methylidyne radical to the π-electron density of benzene leading eventually to a Jahn-Teller distorted tropyl (C7H7) radical intermediate and exotic ring opening - ring contraction sequences terminated by atomic hydrogen elimination. The methylidyne-benzene system represents a benchmark to probe the outcome of the elementary reaction of the simplest hydrocarbon radical - methylidyne - with the prototype of a closed-shell aromatic molecule - benzene - yielding non-benzenoid fulvenallene. Combined with electronic structure and statistical calculations, this bimolecular reaction sheds light on the unusual reaction dynamics of Hückel aromatic systems and remarkable (polycyclic) reaction intermediates, which cannot be studied via classical organic, synthetic methods thus opening up a versatile path to access this previously largely obscure class of fulvenallenes.
    DOI:  https://doi.org/10.1021/jacs.9b13269
  1216. Antioxidants (Basel). 2020 Jan 23. pii: E98. [Epub ahead of print]9(2):
    Improved Tetanic Force and Mitochondrial Calcium Homeostasis by Astaxanthin Treatment in Mouse Skeletal Muscle.
    Sztretye M, Singlár Z, Szabó L, Angyal Á, Balogh N, Vakilzadeh F, Szentesi P, Dienes B, Csernoch L.
      BACKGROUND: Astaxanthin (AX) a marine carotenoid is a powerful natural antioxidant which protects against oxidative stress and improves muscle performance. Retinol and its derivatives were described to affect lipid and energy metabolism. Up to date, the effects of AX and retinol on excitation-contraction coupling (ECC) in skeletal muscle are poorly described.METHODS: 18 C57Bl6 mice were divided into two groups: Control and AX supplemented in rodent chow for 4 weeks (AstaReal A1010). In vivo and in vitro force and intracellular calcium homeostasis was studied. In some experiments acute treatment with retinol was employed.
    RESULTS: The voltage activation of calcium transients (V50) were investigated in single flexor digitorum brevis isolated fibers under patch clamp and no significant changes were found following AX supplementation. Retinol shifted V50 towards more positive values and decreased the peak F/F0 of the calcium transients. The amplitude of tetani in the extensor digitorum longus was significantly higher in AX than in control group. Lastly, the mitochondrial calcium uptake was found to be less prominent in AX.
    CONCLUSION: AX supplementation increases in vitro tetanic force without affecting ECC and exerts a protecting effect on the mitochondria. Retinol treatment has an inhibitory effect on ECC in skeletal muscle.
    Keywords:  astaxanthin; excitation contraction coupling; force; intracellular calcium; mitochondrial calcium; retinol; skeletal muscle
    DOI:  https://doi.org/10.3390/antiox9020098
  1217. Br J Radiol. 2020 Jan 20. 20190976
    The choice and definition of summary measure for meta-analysis of clinical studies with binary outcomes: Effect on clinical interpretation.
    Plumb A, Halligan S, Mallett S.
      Many systematic reviews and meta-analyses concern the effect of a healthcare intervention on a binary outcome i.e. occurrence (or not) of a particular event. Usually, the overall effect, pooled across all studies included in the meta-analysis, is summarised using the odds ratio (OR) or the relative risk (RR). Under most circumstances, it is obvious how to identify what should be considered as the event of interest - for example, death or a clinically-important side-effect. However, on occasion it may not be clear in which "direction" the event should be specified - such as attendance ( vs non-attendance) at cancer screening. Usually, this choice is not critical to the overall conclusion of the meta-analysis, but occasionally it can lead to differences in how the included studies are pooled, ultimately affecting the overall meta-analytic result, particularly when using relative risks rather than odds ratios. In this commentary, we will explain this phenomenon in more detail using examples from the literature, and explore how analysts and readers can avoid some potential pitfalls.
    DOI:  https://doi.org/10.1259/bjr.20190976
  1218. J Clin Med. 2020 Jan 22. pii: E317. [Epub ahead of print]9(2):
    Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity.
    Atawia RT, Bunch KL, Fouda AY, Lemtalsi T, Eldahshan W, Xu Z, Saul A, Elmasry K, Al-Shabrawey M, Caldwell RB, Caldwell RW.
      Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation. A2 deletion also has been shown to be protective against retinal inflammation in models of ischemic retinopathy and multiple sclerosis. We investigated the effect of A2 deletion on western diet-induced retinopathy. Wild-type mice fed a high-fat, high-sucrose western diet for 16 weeks exhibited elevated retinal expression of A2, markers of the inflammasome pathway, oxidative stress, and activation of microglia/macrophages. Western diet feeding induced exaggerated retinal light responses without affecting visual acuity or retinal morphology. These effects were reduced or absent in mice with global A2 deletion. Exposure of retinal endothelial cells to palmitate and high glucose, a mimic of the obese state, increased expression of A2 and inflammatory mediators and induced cell death. These effects, except for A2, were prevented by pretreatment with an arginase inhibitor. Collectively, our study demonstrated a substantial role of A2 in early manifestations of diabetic retinopathy.
    Keywords:  arginase 2; inflammasome; obesity/diabetes-induced retinopathy; oxidative stress
    DOI:  https://doi.org/10.3390/jcm9020317
  1219. J Pharmacol Toxicol Methods. 2019 Sep - Oct;99:pii: S1056-8719(19)30202-3. [Epub ahead of print]99 106595
    Inhibition of C-Fos protein and mRNA expression in the brain of adjuvant-induced arthritic rats following treatment with N-(2-hydroxy phenyl) acetamide.
    Simjee SU, Jawed H, Ali SUS.
      
    DOI:  https://doi.org/10.1016/j.vascn.2019.05.089
  1220. Behav Processes. 2020 Jan 16. pii: S0376-6357(19)30383-3. [Epub ahead of print] 104058
    Effect of a magnetic pulse on orientation behavior in rainbow trout (Oncorhynchus mykiss).
    Fitak RR, Wheeler BR, Johnsen S.
      Magnetoreception remains one of the most enigmatic of animal senses. Rainbow trout (Oncorhynchus mykiss) represent an ideal species to study this sense, as magnetoreception based upon microscopic particles of magnetite is suspected to play an important role in their orientation and navigation. Here we found that compared with controls, a magnetic pulse (a treatment commonly used to demonstrate magnetite-based magnetoreception) can induce orientation behavior in juvenile rainbow trout on a specific experimental day. Multiple circular-linear regression also indicated that this effect could at least be partially explained by daily variation in solar electromagnetic activity (i.e., sunspot count and disturbance storm time index). These results are consistent with magnetite-based magnetoreception in rainbow trout and suggest that 1) solar activity may impact magnetic orientation and 2) researchers should be cognizant of its potential consequences on studies of magnetoreception.
    Keywords:  circular-linear regression; geomagnetic field; magnetic pulse; orientation; solar activity
    DOI:  https://doi.org/10.1016/j.beproc.2020.104058
  1221. Int J Biol Macromol. 2020 Jan 16. pii: S0141-8130(20)30079-9. [Epub ahead of print]
    Functional and physicochemical properties of flours and starches from different tuber crops.
    Wang H, Yang Q, Gao L, Gong X, Qu Y, Feng B.
      Flours and isolated starches from different potato and sweet potato varieties were evaluated for their physical, functional, pasting, and thermal properties. The flours had higher protein and amylose contents than starches. The L values of the starches ranged from 91.92 (S-2) to 96.42 (S-1); thus, the whiteness of the starch samples was satisfactory. X-ray diffraction mode showed that potato starch could be a special material for crystalline nanomaterials with potential industrial applications. The starches had higher viscosity than flours. Therefore, starches can be used as thickeners in different food products. The flours exhibited high gelatinization temperatures but low enthalpy, which can be attributed to the effects of non-starch components in the flours, such as proteins and lipids. Potato flours and starches exhibited higher amylose contents and pasting characteristics and wider applications in the food industry than sweet potato flours and starches. The purple-fleshed varieties had high antioxidant activity. Therefore, the colorful flours of potatoes and sweet potatoes can be combined with other cereals for the development of functional flours with nutritional applications.
    Keywords:  Amylose; Flours; Structural properties
    DOI:  https://doi.org/10.1016/j.ijbiomac.2020.01.146
  1222. Cancers (Basel). 2020 Jan 17. pii: E226. [Epub ahead of print]12(1):
    Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype.
    Casciati A, Tanori M, Manczak R, Saada S, Tanno B, Giardullo P, Porcù E, Rampazzo E, Persano L, Viola G, Dalmay C, Lalloué F, Pothier A, Merla C, Mancuso M.
      Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains significant and the long-term adverse effects in survivors are substantial. The fraction of cancer stem-like cells (CSCs) because of their self-renewal ability and multi-lineage differentiation potential is critical for tumor initiation, growth, and resistance to therapies. For the development of new CSC-targeted therapies, further in-depth studies are needed using enriched and stable MB-CSCs populations. This work, aimed at identifying the amount of CSCs in three available human cell lines (DAOY, D341, and D283), describes different approaches based on the expression of stemness markers. First, we explored potential differences in gene and protein expression patterns of specific stem cell markers. Then, in order to identify and discriminate undifferentiated from differentiated cells, MB cells were characterized using a physical characterization method based on a high-frequency dielectrophoresis approach. Finally, we compared their tumorigenic potential in vivo, through engrafting in nude mice. Concordantly, our findings identified the D283 human cell line as an ideal model of CSCs, providing important evidence on the use of a commercial human MB cell line for the development of new strategic CSC-targeting therapies.
    Keywords:  CD133; D283Med; cancer stem cell; cross-over frequency; dielectrophoresis; stemness biomarkers
    DOI:  https://doi.org/10.3390/cancers12010226
  1223. Anal Chem. 2020 Jan 23.
    Fluorescence Signal Amplification by Using β-Galactosidase for Flow Cytometry; Advantages of an Endogenous Activity-free Enzyme.
    Nobori T, Kawamura M, Yoshida R, Joichi T, Kamino K, Kishimura A, Baba E, Mori T, Katayama Y.
      We previously proposed using a hydrolysis enzyme for fluorescent signal amplification in flow cytometric detection of antigen proteins, which was named the catalyzed reporter penetration (CARP) method. In this method, antigen proteins are labeled with enzyme-modified antibodies, and then fluorophore-modified substrates stain cells by penetrating the cell membrane upon hydrolysis of the substrate. We proved the concept by using alkaline phosphatase (AP) as the hydrolysis enzyme. However, a required prior inactivation process of endogenous AP activity on the cell surface risked disrupting recognition of antigen proteins by antibodies. In this report, the CARP method was extended to β-galactosidase (β-gal) as an amplification enzyme, which circumvented the requirement of an initial inactivation process because endogenous β-gal activity on the surface of examined cells was found to be negligible. The substrate structure for β-gal was optimized and used for the CARP method. The CARP method showed significantly higher fluorescent signals than a conventional method using fluorophore-modified antibodies. Moreover, the degree of amplification of the fluorescence signal was higher for antigens with low expression levels, showing that the CARP method is a suitable signal amplification method over current conventional approaches.
    DOI:  https://doi.org/10.1021/acs.analchem.9b04471
  1224. Sensors (Basel). 2020 Jan 19. pii: E541. [Epub ahead of print]20(2):
    A Lever-Type Method of Strain Exposure for Disk F-Shaped Torque Sensor Design.
    Shu R, Chu Z, Shu H.
      Disk-shaped torque sensors are widely used in robotic joints and wheel driving. However, in terms of conventional spoke-type geometries, there is always a trade-off between sensitivity and stiffness, because their strain exposure depends upon a bending deformation mode which causes strain nonuniformity. This paper presents a lever-type method of strain exposure that performs a uniaxial tension and compression deformation mode to optimize the strain uniformity and improve the trade-off. Moreover, on the basis of this approach, the proposed disk F-shaped torque sensor enjoys has axial thinness, easy installation of strain gauges and flexible customization. The simulation and experimental results have validated the basic design idea.
    Keywords:  disk F-shaped; lever-type; strain exposure; torque sensor
    DOI:  https://doi.org/10.3390/s20020541
  1225. Am J Physiol Regul Integr Comp Physiol. 2020 Jan 22.
    Astrocytic glutamate transporters reduce the neuronal and physiological influence of metabotropic glutamate receptors in nucleus tractus solitarii.
    Martinez D, Rogers RC, Hermann GE, Hasser EM, Kline DD.
      Astrocytic excitatory amino acid transporters (EAATs) are critical to restraining synaptic and neuronal activity in the nucleus tractus solitarii (nTS). Relief of nTS EAAT restraint generates two opposing effects, an increase in neuronal excitability that reduces blood pressure and breathing, and an attenuation in afferent (TS)-driven EPSC amplitude. While the former is due, in part, to activation of ionotropic glutamate receptors, there remains a substantial contribution from another unidentified glutamate receptor. In addition, the mechanism(s) by which EAAT inhibition reduced TS-EPSC amplitude is unknown. Metabotropic glutamate receptors (mGluRs) differentially modulate nTS excitability. Activation of Group I mGluRs on nTS neuron somas leads to depolarization, whereas Group II/III mGluRs on sensory afferents decrease TS-EPSC amplitude. Thus, we hypothesize EAATs control postsynaptic excitability and TS-EPSC amplitude via restraint of mGluR activation. To test this hypothesis, we used in vivo recording, brain slice electrophysiology, and imaging of glutamate release and TS-afferent Ca2+. Results show EAAT blockade in the nTS with TFB-TBOA induces Group I mGluR-mediated depressor, bradycardic, and apneic responses that were accompanied by neuronal depolarization, elevated discharge and increased spontaneous synaptic activity. Conversely, upon TS stimulation TFB-TBOA elevated extracellular glutamate to decrease presynaptic Ca2+ and TS-EPSC amplitude via activation of Group II/III mGluRs. Together, these data suggest an important role of EAATs in restraining mGluR activation and overall cardiorespiratory function.
    Keywords:  astroglia; autonomic function,; glutamate signaling; respiration
    DOI:  https://doi.org/10.1152/ajpregu.00319.2019
  1226. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19936. [Epub ahead of print]24(1): 376-384
    Expression of lncRNA-ANRIL in patients with coronary heart disease before and after treatment and its short-term prognosis predictive value.
    Liu ZF, Hu WW, Li R, Gao Y, Yan LL, Su N.
      OBJECTIVE: This study was designed to explore the expression of LncRNA-ANRIL in patients with coronary heart disease before and after treatment and its short-term survival prediction value.PATIENTS AND METHODS: Eighty-three patients with coronary heart disease who came to our hospital undergoing interventional therapy were selected as a research group, 81 healthy volunteers who came to our hospital for normal physical examination during the same period were selected as a control group, and LncRNA-ANRIL of subjects in the two groups before and after treatment were detected by RT-PCR. Levels of Gensini score, lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), creatine kinase (CK), and BNP of patients in research group before treatment were evaluated and detected, and the correlation between those and LncRNA-ANRIL was analyzed. Then, the effective treatment of LncRNA-ANRIL for patients with coronary heart disease and the predictive value of poor prognosis were analyzed.
    RESULTS: The expression of LncRNA-ANRIL in patients with coronary heart disease was lower than that of normal subjects (p<0.05), and the expression levels of Gensini score, LDH, CK-MB, CK, and BNP gradually increased with the increased number of their diseased vessels (p<0.05). The expression of LncRNA-ANRIL was negatively correlated with expressions of Gensini score, LDH, CK-MB, CK, and BNP (p<0.05); ROC of LncRNA-ANRIL in predicting effective treatment, and poor prognosis of patients with coronary heart disease was over 0.9, as well as smoking; LncRNA-ANRIL, Gensini score, LDH, CK-MB, CK, and BNP were independent risk factors for the occurrence of MACE.
    CONCLUSIONS: LncRNA-ANRIL expresses low in the serum of patients with coronary heart disease, and it has high predictive value both for effective treatment and poor prognosis of them. Also, lncRNA-ANRIL is also an independent risk factor for their poor prognosis.
    DOI:  https://doi.org/10.26355/eurrev_202001_19936
  1227. ISA Trans. 2020 Jan 16. pii: S0019-0578(20)30025-2. [Epub ahead of print]
    Multirate control strategies for avoiding sample losses. Application to UGV path tracking.
    Salt J, Alcaina J, Cuenca Á, Baños A.
      When in a digital control strategy there are samples lost due to limitations, different multirate (MR) control options can be used for solving the problem: Dual-rate inferential control (IC) and model-based dual-rate control (MBDR). The objective of this contribution is to analyze, compare, and to assess their behavior under different perspectives. Is a dual-rate inferential control better than a model-based dual-rate control? Both options lead to a periodically time-varying discrete-time system and for this reason a lifted modeling is considered. An efficient algorithm is used for computing a MR system's frequency response for these control structures. The robust performance and disturbance effects are studied in detail under sample losses and process uncertainty, and some considerations are reported. A new QFT (quantitative feedback theory) procedure for dual-rate systems analysis is also described. Analysis and simulation examples and experimental results for UGV path tracking are introduced in this work, revealing that MBDR outperforms IC when the model contains important uncertainties.
    Keywords:  Dual-rate systems; Frequency response; Inferential control; Model-based control; Quantitative feedback theory; Stability; UGV
    DOI:  https://doi.org/10.1016/j.isatra.2020.01.025
  1228. Cell Mol Neurobiol. 2020 Jan 23.
    Caveolin: A New Link Between Diabetes and AD.
    Surguchov A.
      Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Patients with T2D have an increased risk to develop AD, while glucose metabolism abnormalities are frequent among AD patients. Epidemiological studies and the results of basic science point to possible shared pathophysiology between T2D and AD. Co-occurrence of diabetes mellitus and AD was noticed long time ago. However, more recent data reveal that comorbidity of AD and T2D occurs significantly more frequently than is expected by chance alone. In spite of the high importance of this association, the inter-relational mechanisms are unclear. The results of recent investigations indicate that caveolin-1 (CAV-1)-a small membrane protein involved in signaling pathways-may play an important role in this association. Preliminary results pointing to this role of CAV-1 were collected after examination of patients with AD. Subsequent investigation in an animal model confirmed these initial observations. The involvement of CAV-1 in T2D and AD may be mediated by cellular organelles, including mitochondria and endoplasmic reticulum.
    Keywords:  Alzheimer’s disease; Amyloid precursor protein; Beta-amyloid; Caveolins; Diabetes mellitus; Tau
    DOI:  https://doi.org/10.1007/s10571-020-00796-4
  1229. J Assoc Physicians India. 2020 Jan;68(1): 102
    Clinical & Lab Marker Predicting Early Molecular Response Inpatient of CML Chronic Phase Treated With Imatinib.
    Choudhary S, Singh J, Malhotra H, Sharma R.
      
  1230. Drug Alcohol Depend. 2020 Jan 13. pii: S0376-8716(20)30021-1. [Epub ahead of print]208 107856
    Role of the treatment environment in the effects of aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice.
    Libarino-Santos M, de Santana Santos ACG, Cata-Preta EG, Barros-Santos T, Nunes Brandão NR, Borges ALN, Santos-Baldaia R, Hollais AW, Baldaia MA, Berro LF, Marinho EAV, Frussa-Filho R, Oliveira-Lima AJ.
      BACKGROUND: Evidence suggests that aripiprazole, a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist, show significant efficacy in reducing alcohol use. We have previously demonstrated that treatment with aripiprazole blocked the reinstatement of cocaine-induced behavioral sensitization in a context-dependent manner, suggesting that the treatment environment may modulate the therapeutic effects of aripiprazole. The present study aimed to evaluate the effects of treatment with aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice, and the role of the treatment environment in those effects.METHODS: Adult female mice were either sensitized with ethanol injections in the open-field apparatus, or conditioned with ethanol in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle or 0.1 mg/kg aripiprazole paired to the test environment (open-field or CPP apparatus) or not (home-cage treatments) for 4 alternate days, and the subsequent expression of behavioral sensitization or CPP to ethanol was evaluated during or following an ethanol re-exposure, respectively.
    RESULTS: Repeated treatment with aripiprazole attenuated the expression of ethanol-induced behavioral sensitization regardless of the treatment environment. Treatment with aripiprazole was only effective at preventing the reinstatement of ethanol-induced CPP when paired with the ethanol-associated environment, but not when administered in the home-cage.
    CONCLUSIONS: The present findings corroborate previous studies suggesting the effectiveness of aripiprazole for the treatment of alcohol use disorder. Our results also point to an important role of the treatment environment in the therapeutic effects of aripiprazole in rodent models of ethanol abuse.
    Keywords:  Aripiprazole; Behavioral sensitization; Conditioned place preference; Ethanol; Mice
    DOI:  https://doi.org/10.1016/j.drugalcdep.2020.107856
  1231. Nature. 2020 Jan;577(7791): 459-460
    Research on embryo-like structures struggles to win US government funding.
    Subbaraman N.
      
    Keywords:  Developmental biology; Medical research
    DOI:  https://doi.org/10.1038/d41586-020-00127-z
  1232. Proc Natl Acad Sci U S A. 2020 Jan 23. pii: 201906369. [Epub ahead of print]
    GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons.
    Bryson A, Hatch RJ, Zandt BJ, Rossert C, Berkovic SF, Reid CA, Grayden DB, Hill SL, Petrou S.
      The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential-a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.
    Keywords:  GABA; interneuron subtypes; neuromodulation; neuronal excitability; tonic inhibition
    DOI:  https://doi.org/10.1073/pnas.1906369117
  1233. Oral Oncol. 2020 Jan 21. pii: S1368-8375(19)30414-2. [Epub ahead of print] 104503
    Prioritisation of research topics for head and neck cancer in Africa - Report of the International Collaboration On Improving Cancer outcomes in low and middle income countries - ICOnIC Africa.
    , Sharma N, Fagan J, Wallace M, Joubert E, Greef L, Konney A, Simonds H, Vanderpuye V, Sewram V, Young T, Mehanna H.
      
    DOI:  https://doi.org/10.1016/j.oraloncology.2019.104503
  1234. Curr Opin Struct Biol. 2020 Jan 15. pii: S0959-440X(19)30154-X. [Epub ahead of print]61 132-138
    Advances in molecular simulations of protein mechanical properties and function.
    Franz F, Daday C, Gräter F.
      Single-molecule force spectroscopy and classical molecular dynamics are natural allies. Recent advances in both experiments and simulations have increasingly facilitated a direct comparison of SMFS and MD data, most importantly by closing the gap between time scales, which has been traditionally at least 5 orders of magnitudes wide. In this review, we will explore these advances chiefly on the computational side. We focus on protein dynamics under force and highlight recent studies that showcase how lower loading rates and more statistics help to better interpret previous experiments and to also motivate new ones. At the same time, steadily increasing system sizes are used to mimic more closely the mechanical environment in the biological context. We showcase some of these advances on atomistic and coarse-grained scale, from asymmetric membrane tension to larger (multidomain/multimeric) protein assemblies under force.
    DOI:  https://doi.org/10.1016/j.sbi.2019.12.015
  1235. Front Pharmacol. 2019 ;10 1504
    Microarray Expression Profiling and Raman Spectroscopy Reveal Anti-Fatty Liver Action of Berberine in a Diet-Induced Larval Zebrafish Model.
    Chen B, Zheng YM, Zhang MQ, Han Y, Zhang JP, Hu CQ.
      Background: The prevalence of non-alcohol fatty liver disease (NAFLD) is increasing in children and adolescents who are mostly resulted from overfeeding. Previous studies demonstrate that berberine (BBR), a compound derived from plant, has beneficial effects on NAFLD in adults but poorly understood in the pediatric population. This study employed a larval zebrafish model to mimic the therapeutic effects of BBR in the pediatric population and the mechanisms underlying its hepatoprotection. Methods: High-cholesterol diet (HCD)-fed zebrafish exposed to BBR at doses of 0, 1, 5, and 25 μM. After the larvae were treated with BBR for 10 days, its effect on hepatic steatosis was evaluated. We introduced Raman imaging and three-dimensional (3D) molecular imaging to detect changes in the biochemical composition and reactive oxygen species (ROS) levels of zebrafish liver. Gene expression microarray was performed to identify differentially expressed genes (DEGs) followed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and functional category analysis. Results: BBR (5 and 25 μM) administration prevented HCD-induced liver lipid accumulation in larval zebrafish. The result was further confirmed by the pathological observation. Raman mapping indicated that the biochemical composition in the liver of BBR-treated group shifted to the control. The quantitative analysis of 3D imaging showed that the ROS level was significantly decreased in the liver of BBR-treated larvae. In the livers of the BBR group, we found 468 DEGs, including 172 genes with upregulated expression and 296 genes with downregulated expression. Besides, GO enrichment, KEGG pathway, and functional category analysis showed that various processes related to glucolipid metabolism, immune response, DNA damage and repair, and iron were significantly enriched with DEGs. The expression levels of the crucial genes from the functional analysis were also confirmed by quantitative PCR (qPCR). Conclusion: BBR can significantly improve hepatic steatosis in HCD-fed zebrafish larvae. Its mechanisms might be associated with the regulation of lipid metabolism, oxidative stress, and iron homeostasis. Raman imaging in larval zebrafish might become a useful tool for drug evaluation. Mainly, the gene expression profiles provide molecular information for BBR on the prevention and treatment of pediatric NAFLD.
    Keywords:  Raman mapping; berberine; larval zebrafish; non-alcohol fatty liver disease; transcriptomics
    DOI:  https://doi.org/10.3389/fphar.2019.01504
  1236. Ann Oncol. 2020 Feb;pii: S0923-7534(19)39083-0. [Epub ahead of print]31(2): 266-273
    Supporting clinical decision making in advanced melanoma by preclinical testing in personalized immune-humanized xenograft mouse models.
    Ny L, Rizzo LY, Belgrano V, Karlsson J, Jespersen H, Carstam L, Bagge RO, Nilsson LM, Nilsson JA.
      BACKGROUND: The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients.PATIENTS AND METHODS: Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools.
    RESULTS: Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice.
    CONCLUSIONS: Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.
    Keywords:  NOG mice; immunotherapy; melanoma; mouse models; patient-derived xenografts
    DOI:  https://doi.org/10.1016/j.annonc.2019.11.002
  1237. iScience. 2020 Jan 24. pii: S2589-0042(19)30530-9. [Epub ahead of print]23(1): 100785
    Defining lncRNAs Correlated with CHO Cell Growth and IgG Productivity by RNA-Seq.
    Vito D, Eriksen JC, Skjødt C, Weilguny D, Rasmussen SK, Smales CM.
      How the long non-coding RNA (lncRNA) genome in recombinant protein producing Chinese hamster ovary (CHO) cell lines relates to phenotype is not well described. We therefore defined the CHO cell lncRNA transcriptome from cells grown in controlled miniature bioreactors under fed-batch conditions using RNA-Seq to identify lncRNAs and how the expression of these changes throughout growth and between IgG producers. We identify lncRNAs including Adapt15, linked to ER stress, GAS5, linked to mTOR signaling/growth arrest, and PVT1, linked to Myc expression, which are differentially regulated during fed-batch culture and whose expression correlates to productivity and growth. Changes in (non)-coding RNA expression between the seed train and the equivalent day of fed-batch culture are also reported and compared with existing datasets. Collectively, we present a comprehensive lncRNA CHO cell profiling and identify targets for engineering growth and productivity characteristics of CHO cells.
    Keywords:  Biological Sciences; Biotechnology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2019.100785
  1238. Trends Cell Biol. 2020 Jan 21. pii: S0962-8924(19)30220-X. [Epub ahead of print]
    Relevance and Regulation of Cell Density.
    Neurohr GE, Amon A.
      Cell density shows very little variation within a given cell type. For example, in humans variability in cell density among cells of a given cell type is 100 times smaller than variation in cell mass. This tight control indicates that maintenance of a cell type-specific cell density is important for cell function. Indeed, pathological conditions such as cellular senescence are accompanied by changes in cell density. Despite the apparent importance of cell-type-specific density, we know little about how cell density affects cell function, how it is controlled, and how it sometimes changes as part of a developmental process or in response to changes in the environment. The recent development of new technologies to accurately measure the cell density of single cells in suspension and in tissues is likely to provide answers to these important questions.
    Keywords:  cell density; cell growth; cell volume; molecular crowding
    DOI:  https://doi.org/10.1016/j.tcb.2019.12.006
  1239. J Phys Chem Lett. 2020 Jan 24.
    Helix Shape Power-Dependent Properties of Single Upconversion Nanoparticles.
    Liao J, Jin D, Chen C, Li Y, Zhou J.
      Non-blinking, non-bleaching and super-bright single upconversion nanoparticles have been recently discovered with non-linear power-dependent properties and can be switchable under dual beam excitations, which are ideal for super-resolution microscopy, single-molecule tracking, and digital assays. Here, we report that the brightness of Nd3+-Yb3+-Er3+ doped nanoparticles displays a pair of unusual double helix shapes as the function of power densities of 976 nm and 808 nm excitations. We systemically analyse the power-dependent emission spectra, lifetimes, and power-intensity double-log slopes of single upconversion nanoparticles, which reveal that the dynamic roles of Nd3+ ions in the tri-doped nanosystem with underlining electron population pathways are power dependent. That is, at high power 808 nm excitation, Nd3+ ions can directly emit upconverted luminescence, with their conventional role of sensitization saturated in the Nd3→Yb3+→Er3+ energy transfer systems. Moreover, we confirm that the universal helix shape phenomena commonly exist in a set of eight batches of core-shell nanoparticles regardless of the doping concentrations of Nd3+, Yb3+ and Er3+ ions in the sensitization shell, migration shell, and active core, though the crossing nodes occur at different excitation power ranges. This study emphasizes the important role of power-dependent properties in both improving the upconversion emission efficiency and the design of non-linear responsive probes for imaging and sensing.
    DOI:  https://doi.org/10.1021/acs.jpclett.9b03838
  1240. J Cell Mol Med. 2020 Jan 22.
    Circulating adiposity-related microRNAs as predictors of the response to a low-fat diet in subjects with obesity.
    Assmann TS, Riezu-Boj JI, Milagro FI, Martínez JA.
      Recent studies have revealed the critical role of several microRNAs (miRNAs) in energy homeostasis and metabolic processes and suggest that circulating miRNAs can be used as early predictors of weight loss in the design of precision nutrition. Thus, the aim of this study was to investigate circulating adiposity-related miRNAs as biomarkers of the response to two specific weight loss dietary treatments. The expression of 86 miRNAs was investigated in plasma of 78 subjects with obesity randomized to two different diets [moderately high-protein diet (n = 38) and low-fat diet (n = 40)] and in 25 eutrophic controls (BMI ≤ 25 kg/m2 ). Bioinformatic analyses were performed to explore the target genes and biological pathways regulated by the dysregulated miRNAs. As results, 26 miRNAs were found differently expressed in eutrophic and volunteers with obesity. Moreover, 7 miRNAs (miR-130a-3p, miR-142-5p, miR-144-5p, miR-15a-5p, miR-22-3p, miR-221-3p and miR-29c-3p) were differentially expressed between responders and non-responders to a low-fat diet. Furthermore, after adjustment for basal glucose levels, 1-SD increase in miR-22-3p expression was associated with reduction in the risk of non-response to low-fat diet [OR = 0.181, 95% CI (0.084-0.947), P = .043]. Bioinformatic analyses evidenced that these 7 miRNAs regulate the expression of genes participating in important metabolic pathways. Conclusively, 7 circulating miRNAs related to adiposity could be used for predicting the response to a low-fat diet intervention prescribed to lose weight.
    Keywords:  biomarkers; dietary intervention; microRNAs; obesity; weight loss
    DOI:  https://doi.org/10.1111/jcmm.14920
  1241. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30084-2. [Epub ahead of print]49(1): 69-77
    Integration of Diabetes Technology in Clinical Practice.
    Peters AL.
      This article attempts to aid clinicians in using diabetes devices in their clinical practice. It reviews device selection, initiation, and follow-up. It discusses work flow in an office and provides tips on billing. It stresses the need for patient choice, education, and on-going support through downloading and interpretation of data to optimize care.
    Keywords:  Continuous glucose monitoring; Insulin pump therapy; Outpatient clinic
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.002
  1242. Life Sci. 2020 Jan 20. pii: S0024-3205(20)30087-4. [Epub ahead of print] 117340
    Curcumin reduces LPS-induced septic acute kidney injury through suppression of lncRNA PVT1 in mice.
    Huang W, Li X, Wang D, Sun Y, Wang Q, Bu Y, Niu F.
      OBJECTIVE: To investigate the protective effects of curcumin on LPS-induced septic acute kidney injury and to explore its underlying molecular mechanisms.METHODS: A mouse model of septic acute kidney injury (AKI) was given an intraperitoneal injection of lipopolysaccharide (LPS), followed by administration of variable levels of curcumin (intragastric). And NRK cells were used as the kidney cell model for all in vitro studies.
    RESULTS: Curcumin significantly decreased the levels of serum Scr, BUN, and Cyc c and reduced kidney injury in LPS-induced AKI mice. Kidney tissues of LPS-induced AKI mice showed an increase in PVT1, ED-1, TNF-α, IL-1β, IL-6, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN expression levels; however, treatment with curcumin significantly reduced this effect. Curcumin increased the survival rate NRK cells exposed to LPS-induced inflammation in vitro. Moreover, NRK cells that overexpressed PVT1 had lower survival rates than WT NRK cells obtained from mice that received curcumin treatment after treating with LPS. Additionally, curcumin reduced the LPS-induced increase in Bax, cleaved-caspase3/caspase 3, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN protein expression, and increased Bcl2 protein expression in NRK cells. However, the extent of these changes was low in NRK cells that overexpressed PVT1.
    CONCLUSION: Curcumin decreased PVT1 expression in LPS-induced septic acute kidney tissues and reduced LPS-induced septic acute kidney injury in mice. This might be related to the inhibition of the JNK/NF-κB pathway by curcumin through suppression of lncRNA PVT1.
    Keywords:  Acute kidney injury; Curcumin; JNK/NF-κB pathway; PVT1
    DOI:  https://doi.org/10.1016/j.lfs.2020.117340
  1243. Cell. 2020 Jan 02. pii: S0092-8674(19)31380-7. [Epub ahead of print]
    Cerebellar Neurodynamics Predict Decision Timing and Outcome on the Single-Trial Level.
    Lin Q, Manley J, Helmreich M, Schlumm F, Li JM, Robson DN, Engert F, Schier A, Nöbauer T, Vaziri A.
      Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (>10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.
    Keywords:  Cerebellum; Light field microscopy; action selection; decision making; demixed principal component analysis; motor planning; operant learning; population ramping activity; whole-brain calcium imaging; zebrafish
    DOI:  https://doi.org/10.1016/j.cell.2019.12.018
  1244. New Phytol. 2020 Jan 21.
    Synthetic biology of hypoxia.
    Licausi F, Giuntoli B.
      Synthetic biology can greatly aid the investigation of fundamental regulatory mechanisms and enable their direct deployment in the host organisms of choice. In the field of plant hypoxia physiology, a synthetic biology approach has been recently exploited to infer general properties of the plant oxygen sensing mechanism, by expression of plant-specific components in yeast. Moreover, genetic sensors have been devised to report cellular oxygen levels or physiological parameters associated to hypoxia, and orthogonal switches have been introduced in plants to trigger oxygen-specific responses. Upcoming applications are expected, such as genetic tailoring of oxygen-responsive traits, engineering of plant hypoxic metabolism and oxygen delivery to hypoxic tissues, and expansion of the repertoire of genetically encoded oxygen sensors.
    Keywords:  flooding; genetically encoded sensors; hypoxia; metabolic engineering; plants; synthetic biology
    DOI:  https://doi.org/10.1111/nph.16441
  1245. Chemosphere. 2020 Jan 16. pii: S0045-6535(20)30128-4. [Epub ahead of print]247 125936
    Surface charge-dependent bioaccumulation dynamics of silver nanoparticles in freshwater algae.
    Zhang J, Xiang Q, Shen L, Ling J, Zhou C, Hu J, Chen L.
      Silver nanoparticles (AgNPs) can gradually accumulate in algae to exert their toxicity; however, there is little knowledge about their bioaccumulation dynamics. For the first time, this study reports the effect of surface charge of AgNPs on their bioaccumulation dynamics in freshwater algae (Chlorella vulgaris) using biodynamic modeling. Polyethylene-coated AgNPs (PEI-AgNPs) and citrate-coated AgNPs (Cit-AgNPs) were selected as positively and negatively charged AgNPs, i.e., P-AgNPs and N-AgNPs, respectively. Their uptake and elimination dynamics were investigated at a concentration of 50% inhibition of growth rate values (EC50) and 10% inhibition of growth rate values (EC10). The one-component model can generally well simulate the algal uptake and elimination kinetics of N-AgNPs but not of P-AgNPs. At both concentrations, the uptake rate constants (ku) for P-AgNPs were ∼20 times higher than that for N-AgNPs. The parameters of biphasic elimination kinetics revealed that P-AgNPs were eliminated faster than N-AgNPs during depuration compared to in subsequent processes. Compared with N-AgNPs, extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory and dark-field imaging revealed that P-AgNPs can be rapidly absorbed on the algal cell surface membrane owing to their remarkably lower energy barrier between algal cells, resulting in a faster adsorption/uptake process and aggregation of algal cells. Our results clearly demonstrate that the AgNPs exhibited surface charge-dependent bioaccumulation dynamics in algal cells. Thus, AgNP surface charge primarily influences the AgNP accumulation dynamics in algal cells.
    Keywords:  Bioaccumulation dynamics; Biodynamic modeling; Chlorella vulgaris; Silver nanoparticles; Surface charge
    DOI:  https://doi.org/10.1016/j.chemosphere.2020.125936
  1246. Genes (Basel). 2020 Jan 16. pii: E103. [Epub ahead of print]11(1):
    The velvet Regulator VosA Governs Survival and Secondary Metabolism of Sexual Spores in Aspergillus nidulans.
    Kim MJ, Lee MK, Pham HQ, Gu MJ, Zhu B, Son SH, Hahn D, Shin JH, Yu JH, Park HS, Han KH.
      The velvet regulator VosA plays a pivotal role in asexual sporulation in the model filamentous fungus Aspergillus nidulans. In the present study, we characterize the roles of VosA in sexual spores (ascospores) in A. nidulans. During ascospore maturation, the deletion of vosA causes a rapid decrease in spore viability. The absence of vosA also results in a lack of trehalose biogenesis and decreased tolerance of ascospores to thermal and oxidative stresses. RNA-seq-based genome-wide expression analysis demonstrated that the loss of vosA leads to elevated expression of sterigmatocystin (ST) biosynthetic genes and a slight increase in ST production in ascospores. Moreover, the deletion of vosA causes upregulation of additional gene clusters associated with the biosynthesis of other secondary metabolites, including asperthecin, microperfuranone, and monodictyphenone. On the other hand, the lack of vosA results in the downregulation of various genes involved in primary metabolism. In addition, vosA deletion alters mRNA levels of genes associated with the cell wall integrity and trehalose biosynthesis. Overall, these results demonstrate that the velvet regulator VosA plays a key role in the maturation and the cellular and metabolic integrity of sexual spores in A. nidulans.
    Keywords:  Aspergillus nidulans; VosA; ascospores; sexual development
    DOI:  https://doi.org/10.3390/genes11010103
  1247. J Phys Chem B. 2020 Jan 20.
    Controlling the Rotational Barrier of Single Porphyrin Rotors on Surfaces.
    Zhang Q, Pang R, Luo T, Van Hove MA.
      Artificial molecular machines have played an indispensable role in many chemical and biological processes in recent decades. Among all kinds of molecular machines, molecular rotor systems have attracted increasing attention. In this work, we used density functional theory (DFT) calculations to investigate the rotational behaviors of on-surface molecular rotors based on porphyrin, which is a species of molecule with wide biological and chemical compatibilities. Moreover, our comparative studies demonstrate that macrocycle metalation, replacing the supporting substrate and substituting functional groups can effectively modify the rotational barrier of porphyrin rotors. We believe that these modification methods can further guide the path to achieve highly controllable on-surface molecular rotor systems in future applications.
    DOI:  https://doi.org/10.1021/acs.jpcb.9b09986
  1248. Clin Nucl Med. 2020 Jan 17.
    Presacral Anastomotic Sinus After Low Anterior Resection Mimicking Recurrent Rectal Cancer.
    Kim C, Kim DY, Hong IK.
      Presacral anastomotic sinus is recognized as a complication of anastomotic leakage in patients with rectal cancer. Active inflammation in the anastomotic sinus can masquerade as pelvic recurrence of rectal cancer. We present a case of progressive inflammation in anastomotic sinus demonstrated by serial FDG PET/CT scans. Despite its benign nature, increased FDG uptake in this nonnegligible condition, which could lead to further detrimental complications including secondary cancer, may have clinical implications.
    DOI:  https://doi.org/10.1097/RLU.0000000000002934
  1249. Pharmacol Res. 2020 Jan 18. pii: S1043-6618(19)32302-3. [Epub ahead of print] 104656
    Probing Biological Mechanisms with Chemical Tools.
    Kang C, Keller TH.
      Traditionally small molecules have mainly been used to inhibit biochemical activities of proteins, however such compounds can also be used to change the conformational energy landscape of proteins. Tool compounds that allosterically modulate protein conformations often reveal unexpected biological mechanisms, which have therapeutic potential. We discuss two examples where screening hits were found to bind to unexpected binding pockets on well know proteins, establishing new routes for the inhibition of proteins that were thought to be undruggable.
    Keywords:  (E)-3-fluoro-N'-((5-(pyrimidin-2-ylthio)furan-2-yl)methylene) benzohydrazide (PubChem CID: 76554134); 2-chloro-1-[2-[3-(trifluoromethyl)anilino]phenyl]ethanone (PubChem CID: 137796964); Flufenamic acid (PubChem CID: 3371); Iodoacetamide (PubChem CID: 3727); allosteric inhibitors; chemical biology; drug discovery; structural biology
    DOI:  https://doi.org/10.1016/j.phrs.2020.104656
  1250. Med Sci Monit. 2020 Jan 20. 26 e918174
    Expression of MiR-140 and MiR-199 in Synovia and its Correlation with the Progression of Knee Osteoarthritis.
    Chao Y, Zhang L, Zhang X, Ma C, Chen Z.
      BACKGROUND The aim of this study was to explore the expression of miR-140 and miR-199 in synovia of patients with knee osteoarthritis (KOA) and its correlation with the progression of this disease. We used the Kellgren and Lawrence grading (KLG) system. MATERIAL AND METHODS There were 110 patients with early (KLG <2), middle (KLG=2) and late (KLG >2) stage KOA and 60 healthy individuals (control) included in this study. RESULTS The relative expression levels of miR-140 (1.07±0.091) and miR-199 (1.03±0.110) in synovia of the control group were higher than those of KOA groups (0.511±0.130, 0.298±0.168) and the difference exhibited statistical significance (P<0.01). Expression of miR-140 in the middle and the late stage KOA groups (0.322±0.118 and 0.110±0.088 respectively) were 58.80% and 81.29% lower, respectively, compared to the early stage KOA group (0.588±0.172), which was significant (P<0.05). Expression of miR-199 in the middle and the late stage KOA groups (0.210±0.124 and 0.056±0.068 respectively) were 39.41% (P<0.05) and 83.72% (P<0.01) respectively lower than that in the early KOA group (0.344±0.147). The severity of OA was significantly negatively correlated with the expressions of miR-140 and miR-199 (r=-0.859, P<0.05; r=-0.724, P<0.001 respectively). Matrix metalloproteinase (MMP)-3 levels of the early stage, middle stage and late stage KOA groups were 1.320±0.118, 1.488±0.210, and 1.955±0.023 respectively; and IL-1ß mRNA was 1.401±0.204, 1.522±0.210, and 1.889±0.217 respectively, which were obviously higher than those in the control group (1.020±0.085), (P<0.05). CONCLUSIONS Expression levels of miR-140 and miR-199 in synovia might act as an early diagnostic marker for KOA. These expression levels might also act as indicators of OA progression to some extent.
    DOI:  https://doi.org/10.12659/MSM.918174
  1251. Am J Nucl Med Mol Imaging. 2019 ;9(6): 321-334
    Dynamic monitoring of STAT3 activation in live cells using a novel STAT3 Phospho-BRET sensor.
    Dimri S, Arora R, Jasani A, De A.
      Phosphorylation (pY705) mediated homodimerization is a rate-limiting step controlling STAT3 key oncogenic functions making it an attractive target for drug discovery. Hence, this study reports development of a sensitive and versatile STAT3 Phospho-BRET biosensor platform technology to monitor activation dynamics of STAT3 signalling directly from live cells. Categorically, we first demonstrate that NanoLuc donor and TurboFP635 acceptor serves as an excellent BRET system over other tested fluorophores like mOrange and TagRFP, both for live cells as well as in vivo optical imaging of protein-protein interactions. Based on initial multi-parametric optimizations, our Phospho-BRET sensor developed by fusing STAT3 with NanoLuc and TurboFP at the C-terminus, successfully captured the activation kinetics of STAT3 in response to different ligands (e.g. IL6 & EGF) and across multiple cancer cell types either with or without the endogenous STAT3 pool. Perturbation in EGF-mediated STAT3 BRET activation signal upon blocking with EGFR neutralizing antibody further confirms the specificity of the sensor to judge ligand-receptor pathway dependent STAT3 activation. Finally, we determine the high-throughput compatibility of the developed biosensor by testing a few known/unknown STAT3 inhibitors in a 96- and 384-well plate format. The results from this screen revealed that drug molecules such as curcumin and niclosamide are more efficient inhibitors over known molecule like Stattic. Thus, the STAT3 Phospho-BRET sensor is a first of its kind live cell platform technology developed for its use to study STAT3 pathway dynamics and screen potential drug molecules in vivo.
    Keywords:  Bioluminescence resonance energy transfer (BRET); STAT3; Stattic; TurboFP635; cancer; high-throughput screening; nanoluciferase; niclosamide; phosphorylation; protein-protein interactions
  1252. Nat Rev Immunol. 2020 Jan 20.
    A new life for self-reactive T cell precursors.
    Bosselut R.
      
    DOI:  https://doi.org/10.1038/s41577-020-0277-6
  1253. Lung Cancer. 2020 Jan 10. pii: S0169-5002(20)30018-0. [Epub ahead of print]141 72-77
    Micropapillary pattern is associated with the development of brain metastases and the reduction of survival time in EGFR-mutation lung adenocarcinoma patients with surgery.
    Li C, Shen Y, Hu F, Chu T, Yang X, Shao J, Zheng X, Xu J, Zhang H, Han B, Zhong H, Zhang X.
      OBJECTIVE: The role of micropapillary pattern (MIP) in EGFR-mutated NSCLC patients with brain metastases (BM) after complete surgical resection still remains unclear. Therefore, a retrospective study was conducted to evaluate the role of MIP in those patients.METHODS: This study included 332 stage I-III patients with EGFR-mutant lung adenocarcinoma and complete resection. Patients were classified in four groups: the MIP-positive patients without BM development, the MIP-negative patients without BM development, the MIP-positive patients with BM development and the MIP-negative patients with BM development. Intracranial disease-free survival (iDFS), systemic disease-free survival (DFS) and overall survival (OS) were evaluated.
    RESULTS: The median OS in the whole group was 70 months. The patients with MIP show inferior DFS (13 months vs. 22 months; P < 0.001) and OS (56 months vs. 74 months; P < 0.001). Furthermore, BM development was more likely to be found in patients with MIP (P = 0.001). In addition, the MIP-positive patients showed a significantly shorter iDFS compared with MIP-negative patients (14.5 months vs. 26 months; P < 0.001). Furthermore, the MIP-positive patients had significantly inferior iDFS in both BM as first line development groups (13 months vs. 19 months; P < 0.001) and BM as non-first line development groups (18 months vs. 33 months; P = 0.007).
    CONCLUSIONS: MIP was related to the earlier recurrence and shortened survival time. In addition, MIP was an independent poor prognostic factor for the increase of BM rate and the shortened time of BM development after surgery.
    Keywords:  Brain metastases; EGFR; Lung adenocarcinoma; Micropapillary; Surgical resection
    DOI:  https://doi.org/10.1016/j.lungcan.2020.01.007
  1254. Plant Biotechnol J. 2020 Jan 25.
    Natural variation and CRISPR/Cas9-mediated mutation in GmPRR37 affect photoperiodic flowering and contribute to regional adaptation of soybean.
    Wang L, Sun S, Wu T, Liu L, Sun X, Cai Y, Li J, Jia H, Yuan S, Chen L, Jiang B, Wu C, Hou W, Han T.
      Flowering time is a critical determinant of the geographic distribution and regional adaptability of soybean (Glycine max), and is strongly regulated by photoperiod and temperature. In this study, quantitative trait locus (QTL) mapping and subsequent candidate gene analysis revealed that GmPRR37, encoding a pseudo-response regulator protein, is responsible for the major QTL qFT12-2, which was identified from a population of 308 recombinant inbred lines (RILs) derived from a cross between a very late-flowering soybean cultivar, 'Zigongdongdou (ZGDD)', and an extremely early-flowering cultivar, 'Heihe27 (HH27)', in multiple environments. Comparative analysis of parental sequencing data confirmed that HH27 contains a nonsense mutation that causes the loss of the CCT domain in the GmPRR37 protein. CRISPR/Cas9-induced Gmprr37-ZGDD mutants in soybean exhibited early flowering under natural long-day (NLD) conditions. Overexpression of GmPRR37 significantly delayed the flowering of transgenic soybean plants compared with wild type under long photoperiod conditions. In addition, both the knockout and overexpression of GmPRR37 in soybean showed no significant phenotypic alterations in flowering time under short-day (SD) conditions. Furthermore, GmPRR37 downregulated the expression of the flowering-promoting FT homologs GmFT2a and GmFT5a, and upregulated flowering-inhibiting FT homolog GmFT1a expression under long-day (LD) conditions. We analyzed haplotypes of GmPRR37 among 180 cultivars collected across China, and found natural Gmprr37 mutants flower earlier and enable soybean to be cultivated at higher latitudes. This study demonstrates that GmPRR37 controls soybean photoperiodic flowering and provides opportunities to breed optimized cultivars with adaptation to specific regions and farming systems.
    Keywords:   GmPRR37 ; CRISPR/Cas9; QTL; adaptation; flowering time; soybean (Glycine max (L.) Merr.)
    DOI:  https://doi.org/10.1111/pbi.13346
  1255. Plants (Basel). 2020 Jan 18. pii: E125. [Epub ahead of print]9(1):
    Fast Track to Discover Novel Promoters in Rice.
    Yoo YH, Kim YJ, Moon S, Gho YS, Hong WJ, Kim EJ, Jiang X, Jung KH.
      Promoters are key components for the application of biotechnological techniques in crop plants. Reporter genes such as GUS or GFP have been used to test the activity of promoters for diverse applications. A huge number of T-DNAs carrying promoterless GUS near their right borders have been inserted into the rice genome, and 105,739 flanking sequence tags from rice lines with this T-DNA insertion have been identified, establishing potential promoter trap lines for 20,899 out of 55,986 genes in the rice genome. Anatomical meta-expression data and information on abiotic stress related to these promoter trap lines enable us to quickly identify new promoters associated with various expression patterns. In the present report, we introduce a strategy to identify new promoters in a very short period of time using a combination of meta-expression analysis and promoter trap lines.
    Keywords:  GUS; meta-expression analysis; promoter trap; rice
    DOI:  https://doi.org/10.3390/plants9010125
  1256. Magn Reson Imaging. 2020 Jan 21. pii: S0730-725X(19)30527-2. [Epub ahead of print]
    Measuring the link between cardiac mechanical function and metabolism during hyperpolarized 13C-pyruvate magnetic resonance experiments.
    Barton GP, Macdonald EB, Goss KN, Eldridge MW, Fain SB.
      PURPOSE: The goal of this study was to develop a methodology to investigate the relationship between contractile function and hyperpolarized (HP) [1-13C]pyruvate metabolism in a small animal model. To achieve sufficient signal from HP 13C compounds, HP 13C MRS/MRSI has required relatively large infusion volumes relative to the total blood volume in small animal models, which may affect cardiac function.METHODS: Eight female Sprague Dawley rats were imaged on a 4.7T scanner with a dual tuned 1H/13C volume coil. ECG and respiratory gated k-t spiral MRSI and an IDEAL based reconstruction to determine [1-13C]pyruvate metabolism in the myocardium. This was coupled with 1H cine MRI to determine ventricular volumes and mechanical function pre- and post-infusion of [1-13C]pyruvate. For comparison to the [1-13C]pyruvate experiments, three female Sprague Dawley rats were imaged with 1H cine MRI to determine myocardial function pre- and post-saline infusion.
    RESULTS: We demonstrated significant changes in cardiac contractile function between pre- and post-infusion of [1-13C]pyruvate. Specifically, there was an increase in end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF). Additionally, the ventricular vascular coupling ratio (VVCR) showed an improvement after [1-13C]pyruvate infusion, indicating increased systolic performance due to an increased arterial load. There was a moderate to strong relationship between the downstream metabolic conversion of pyruvate to bicarbonate and a strong relationship between the conversion of pyruvate to lactate and the cardiac mechanical function response.
    CONCLUSION: The infusion of [1-13C]pyruvate resulted in demonstrable increases in contractile function which was related to pyruvate conversion to bicarbonate and lactate. The combined effects of the infusion volume and inotropic effects of pyruvate metabolism likely explains the augmentation in myocardial mechanical function seen in these experiments. Given the relationship between pyruvate metabolism and contractile function observed in this study, this methodological approach may be utilized to better understand cardiac metabolic and functional remodeling in heart disease.
    Keywords:  Carbon-13; Contractile function; Hyperpolarized; K-t spiral; MRSI; Metabolism
    DOI:  https://doi.org/10.1016/j.mri.2020.01.009
  1257. Eur J Nucl Med Mol Imaging. 2020 Jan 24.
    Slice-selective learning for Alzheimer's disease classification using a generative adversarial network: a feasibility study of external validation.
    Kim HW, Lee HE, Lee S, Oh KT, Yun M, Yoo SK.
      PURPOSE: The aim of this feasibility study was to use slice selective learning using a Generative Adversarial Network for external validation. We aimed to build a model less sensitive to PET imaging acquisition environment, since differences in environments negatively influence network performance. To investigate the slice performance, each slice evaluation was performed.METHODS: We trained our model using a 18F-fluorodeoxyglucose ([18F]FDG) PET/CT dataset obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and tested the model with a Severance Hospital dataset. We applied slice selective learning to reduce computational cost and to extract unbiased features. We extracted features of Alzheimer's disease (AD) and normal cognitive (NC) condition using a Boundary Equilibrium Generative Adversarial Network (BEGAN) for stable convergence. Then, we utilized these features to train a support vector machine (SVM) classifier to distinguish AD from NC.
    RESULTS: The slice range that covered the posterior cingulate cortex (PCC) using double slices showed the best performance. The accuracy, sensitivity, and specificity of our proposed network was 94.33%, 91.78%, and 97.06% using the Severance dataset and 94.82%, 92.11%, and 97.45% using the ADNI dataset. The performance on the two independent datasets showed no statistical difference (p > 0.05). Moreover, there was a statistical difference in the performance between using two slices and one slice as input (p < 0.05).
    CONCLUSIONS: Our model learned the generalized features of AD and NC for external validation when appropriate slices were selected. This study showed the feasibility of this model with consistent performance when tested using datasets acquired from a variety of image-acquisition environments.
    Keywords:  Alzheimer’s disease; External validation; Feasibility study; Generative Adversarial Network; [18F] FDG PET/CT
    DOI:  https://doi.org/10.1007/s00259-019-04676-y
  1258. J Adolesc. 2020 Jan 15. pii: S0140-1971(20)30006-3. [Epub ahead of print]79 122-127
    Mental-health disparities between heterosexual and sexual-minority adolescents: Examining the role of informant discrepancies.
    Perales F, Campbell A, Johnson S.
      INTRODUCTION: An emerging literature documents substantial mental-health disparities by sexual orientation amongst adolescents, with sexual-minority youth exhibiting poorer mental health than heterosexual youth. This brief report provides the first empirical account of how the association between sexual-minority status and adolescent mental health differs depending on who assesses adolescents' mental health (child/mother/father/teacher), and how informant discrepancies in assessments of adolescent mental health differ by adolescents' sexual orientation.METHODS: Data come from an Australian national sample of 14-/15-year-old adolescents (Longitudinal Study of Australian Children; n~3,000). Adolescent mental health is measured using multiple measures from the Strengths and Difficulties Questionnaire, and modelled using multivariable linear regression models.
    RESULTS: Mental-health disparities between sexual-minority and heterosexual adolescents emerged irrespective of who assessed the child's mental health. However, their magnitude varied substantially by informant, being largest when mental-health was reported by adolescents (~0.7 standard deviations) and smallest when reported by teachers (~0.2 standard deviations). Discrepancies between mental-health scores collected from the child and other informants were largest for internalising than externalising behaviours, and in child-father than child-mother comparisons.
    CONCLUSIONS: Understanding informant discrepancies and their meaning is pivotal to designing surveys that generate robust insights into the health of sexual-minority adolescents, as well as appropriate policy interventions.
    Keywords:  LGBTIQ+; Mental health; Multiple informants; Sexual orientation; Socio-emotional functioning
    DOI:  https://doi.org/10.1016/j.adolescence.2020.01.006
  1259. Ther Adv Respir Dis. 2020 Jan-Dec;14:14 1753466619898598
    Airway wall thickness and airflow limitations in asthma assessed in quantitative computed tomography.
    Patyk M, Obojski A, Sokołowska-Dąbek D, Parkitna-Patyk M, Zaleska-Dorobisz U.
      BACKGROUND: Asthma is a frequent chronic disease of the airways. In spite of the fact that symptoms of asthma are well known, the pathogenesis has not yet been fully understood. Quantitative computed tomography (qCT) of the lung allows for the measurment of a set of parameters. The aim of this study was to evaluate the usefulness of quantitative computed tomography in the assessment of airway wall thickness in asthma.METHODS: The prospective study was performed on a group of 83 patients with well-defined, long-term asthma between 2016 and 2018. The control group was composed of 30 healthy volunteers. All examined subjects were non-smokers. All computed tomography (CT) studies were performed using a 128 multi-slice CT scanner with no contrast, following a chest scanning protocol in the supine position, at full inspiration and breath-holds.
    RESULTS: Quantitative bronchial tree measurements were obtained from the third up to the ninth generation of the posterior basal bronchi (B10) of the right lung in a blinded fashion. The value of the wall thickness in patients with asthma was significantly higher in all measured generations of the bronchial tree (third to ninth generation). The lumen area and the inner diameter significantly correlated with the lung function tests and were substantially smaller in the examined group from the seventh to the ninth generation of the bronchi (p < 0.05).
    CONCLUSIONS: We conclude that airway remodelling occurs in most patients with long-term asthma and is associated mainly with the medium and small airways. Imaging techniques, especially qCT can be useful in the diagnosis and management of asthma. The reviews of this paper are available via the supplemental material section.
    Keywords:  airway remodelling; asthma; quantitative computed tomography
    DOI:  https://doi.org/10.1177/1753466619898598
  1260. J Inherit Metab Dis. 2020 Jan;43(1): 1
    "Old Roads-New Connections" SSIEM 2018 Annual Symposium in Athens.
    Michelakakis H.
      
    DOI:  https://doi.org/10.1002/jimd.12212
  1261. Int Immunopharmacol. 2020 Jan 20. pii: S1567-5769(19)31954-X. [Epub ahead of print]80 106201
    A network pharmacology approach to explore the potential targets underlying the effect of sinomenine on rheumatoid arthritis.
    Guo X, Ji J, Feng Z, Hou X, Luo Y, Mei Z.
      OBJECTIVE: To explore the potential targets underlying the effect of sinomenine (SIN) on rheumatoid arthritis (RA) by utilizing a network pharmacology approach.METHODS: SIN and its drug targets were identified using network analysis followed by experimental validation. First, the Pharmmapper, UniProt and GeneCards databases were mined for information relevant to the prediction of SIN targets and RA-related targets. Second, the SIN-target gene and SIN-RA target gene networks were created in Cytoscape software followed by the collection of the candidate targets of each component by R software. Eventually, the key targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.
    RESULTS: Sixty-seven potential targets of SIN and 3797 related targets involved in RA were subjected to network analysis, and the 20 intersection targets indicated the principal pathways linked to RA. Additionally, 16 key targets, which were linked to more than three genes, were determined to be crucial genes. GO analysis showed that 14 biological processes, 5 cellular components and 2 molecular functions were identified, when corrected by a P value ≤ 0.01. Seven related signaling pathways were identified by KEGG analysis, when corrected according to a Bonferroni P value ≤ 0.05.
    CONCLUSION: The present study explored the potential targets and signaling pathways of SIN during the treatment of RA, which may help to illustrate the mechanism (s) involved in the action of SIN and may provide a better understanding of its anti-rheumatoid arthritis effects in terms of inhibiting angiogenesis, synovial hyperplasia, and bone destruction.
    Keywords:  Enrichment analysis; Network pharmacology; Rheumatoid arthritis; Sinomenine
    DOI:  https://doi.org/10.1016/j.intimp.2020.106201
  1262. J Pharm Biomed Anal. 2019 Dec 19. pii: S0731-7085(19)31908-9. [Epub ahead of print]181 113051
    Lifecycle management in pharmaceutical analysis: How to establish an efficient and relevant continued performance monitoring program.
    Ermer J, Aguiar D, Boden A, Ding B, Obeng D, Rose M, Vokrot J.
      It is the objective of a systematic and holistic Quality-by-Design approach to demonstrate and ensure that an analytical procedure is fit for its intended purpose over its entire lifecycle. Such a lifecycle approach, as proposed for a new USP General Information Chapter includes the three stages Procedure Design and Development, Procedure Performance Qualification, and Continued Procedure Performance Verification, in alignment to manufacturing process validation. A decisive component of this approach is the Analytical Target Profile, which defines the performance requirements for the measurement of a Quality Attribute as the target for selection, development and optimization of the respective analytical procedures. Although the most benefit can be gained by a comprehensive Quality-by-Design approach establishing the Analytical Target Profile in the very beginning of a drug development project, it may also be established retrospectively for analytical procedures long in routine use, in order to facilitate future lifecycle activities such as continual improvements, transfers, monitoring and periodic performance evaluations. In contrast to the first two stages of the analytical lifecycle with usually limited amount of data, the Continued Procedure Performance Verification stage offers the possibility to utilize a much more reliable data base to collect, analyze, and evaluate data that relate to analytical procedure performance. This monitoring program should be aligned as far as possible with other quality systems already in place and may include performance indicators such as Conformity (i.e. out-of specification test results with analytical root-cause), Validity (i.e. failure to meet method acceptance criteria, e.g. system suitability tests), and (numerical) analytical performance parameters (e.g. ranges for replicate determinations, control sample results, etc). In addition to the monitoring of analytical control parameters by means of control charts, average (pooled) performance parameters can be calculated. Over time, a large number of data can be included and thus the reliability of these estimates is increased tremendously. Such reliable estimates for the true performance parameters, e.g. repeatability or intermediate precision are essential to identify systematic effects (also called special cause variation) with good confidence. The intent of the analytical procedure performance evaluation is to identify substandard performance, identify root cause through investigations, and determine when additional activities are required to improve it. Examples are provided for the monitoring and evaluation of performance parameters for the compendial drug substance Furosemide and for biopharmaceutical applications.
    Keywords:  Analytical lifecycle management; Analytical monitoring; Analytical target profile; Control chart; Quality-by-design; Target measurement uncertainty
    DOI:  https://doi.org/10.1016/j.jpba.2019.113051
  1263. Mol Pharm. 2020 Jan 21.
    Relative Activity Factor (RAF)-Based Scaling of Uptake Clearance Mediated by Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3 in Human Hepatocytes.
    Izumi S, Nozaki Y, Kusuhara H, Hotta K, Mochizuki T, Komori T, Maeda K, Sugiyama Y.
      
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.0c00025
  1264. Br J Pharmacol. 2020 Jan 23.
    Roflupram exerts neuroprotection via activation of CREB/PGC-1α signaling in experimental models of Parkinson's disease.
    Zhong J, Dong W, Qin Y, Xie J, Xiao J, Xu J, Wang H.
      BACKGROUND AND PURPOSE: Roflupram (ROF) improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of ROF in ameliorating Parkinson's disease (PD) remain unknown. Therefore, we aimed to elucidate the pharmacological effects and mechanisms of action of ROF in experimental models of PD.EXPERIMENTAL APPROACH: We utilized SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium iodide (MPP+ ) as an in vitro PD model. Cell viability and apoptosis were analyzed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity and ROS were measured by a mitochondrial tracker, a Seahorse analyzer and a MitoSOX-Red dye. For in vivo PD model, behavioral tests, Nissl staining and immunohistochemistry were used to evaluate the protection of ROF. The levels of tyrosine hydroxylase (TH), cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were analyzed by Western blotting.
    KEY RESULTS: ROF decreased MPP+ -induced apoptosis in SH-SY5Y cells and human dopaminergic neurons. ROF also increased mitochondrial respiratory capacity, decreased ROS production and restored mitochondrial morphology. ROF reversed the MPP+ -induced reductions of phosphorylated CREB, PGC-1α, and TH, while the protective effects were blocked by the PKA inhibitor H-89 and via PGC-1α siRNA. In mice treated with MPTP, ROF significantly improved motor functions. Importantly, ROF prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC-1α in the substantia nigra and striatum.
    CONCLUSION AND IMPLICATIONS: ROF protects dopaminergic neurons from apoptosis via the CREB/PGC-1α pathway in PD models. Hence, ROF has potential as a protective drug for the treatment of PD.
    Keywords:  Parkinson's disease; Phosphodiesterase 4; Roflupram; mitochondria
    DOI:  https://doi.org/10.1111/bph.14983
  1265. Medicine (Baltimore). 2020 Jan;99(4): e18961
    Depressed sympathovagal modulation indicates sepsis in patients with suspected infection.
    Hsu CT, Tai HC, Chung JY, Chen JH, Chen WL.
      This study explored whether sympathovagal modulation assessed through frequency domains of heart rate variability (HRV) can indicate sepsis in patients with suspected infection.In total, 370 consecutive adult patients with suspected infection admitted to the emergency department were enrolled in this single-center cohort study. A continuous 10-minute electrocardiography for HRV analysis was recorded immediately for these patients after inclusion. Patients were stratified into non-sepsis and sepsis groups based on a sepsis-related organ failure assessment score of ≥2 that met the Third International Consensus Definitions for Sepsis. Seven frequency domains of HRV were compared between these 2 groups.Compared with the non-sepsis group (n = 98), the sepsis group (n = 272) had a significantly lower incidence of respiratory tract infection, higher total power, higher very-low-frequency component, higher high-frequency (HF) component, higher normalized HF component, lower normalized low-frequency (LF) component, and lower LF component/HF component ratio (LF/HF). Multiple logistic regression model identified HF component (odds ratio [OR] = 0.994; 95% confidence interval [CI], 0.990-0.999) and LF/HF (OR = 0.494; 95% CI, 0.423-0.578) as significant variables associated with sepsis. The area under receiver operating characteristic curves of HF component and LF/HF was 0.741 (95% CI, 0.685-0.797) and 0.930 (95% CI, 0.900-0.960), respectively, in identifying sepsis in patients with suspected infection.Tilted sympathovagal balance toward increased vagal activity and depressed sympathetic modulation, assessed by the HF component and LF/HF, may indicate sepsis in patients with suspected infection.
    DOI:  https://doi.org/10.1097/MD.0000000000018961
  1266. Sci Rep. 2020 Jan 24. 10(1): 1100
    The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model.
    Tourolle Né Betts DC, Wehrle E, Paul GR, Kuhn GA, Christen P, Hofmann S, Müller R.
      An improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury. Recent preclinical studies of bone defect in animal models have used cross-sectional data to examine this phenomenon indirectly. In this study, a direct time-lapsed imaging approach was used to investigate the local mechanical strains that precede the formation of mineralised tissue at the tissue scale. The goal was to test two hypotheses: 1) the local mechanical signal that precedes the onset of tissue mineralisation is higher in areas which mineralise, and 2) this local mechanical signal is independent of the magnitude of global mechanical loading of the tissue in the defect. Two groups of mice with femoral defects of length 0.85 mm (n = 10) and 1.45 mm (n = 9) were studied, allowing for distinct distributions of tissue scale strains in the defects. The regeneration and (re)modelling of mineralised tissue was observed weekly using in vivo micro-computed tomography (micro-CT), which served as a ground truth for resolving areas of mineralised tissue formation. The mechanical environment was determined using micro-finite element analysis (micro-FE) on baseline images. The formation of mineralised tissue showed strong association with areas of higher mechanical strain (area-under-the-curve: 0.91 ± 0.04, true positive rate: 0.85 ± 0.05) while surface based strains could correctly classify 43% of remodelling events. These findings support our hypotheses by showing a direct association between the local mechanical strains and the formation of mineralised tissue.
    DOI:  https://doi.org/10.1038/s41598-020-57461-5
  1267. Domest Anim Endocrinol. 2019 Nov 22. pii: S0739-7240(19)30098-0. [Epub ahead of print]72 106419
    Plasma steroid profiles before and after ACTH stimulation test in healthy horses.
    Kirchmeier A, van Herwaarden AE, van der Kolk JH, Sauer FJ, Gerber V.
      This study describes steroid profiles in equine plasma before and after ACTH stimulation. In human medicine, other steroids have been shown to have a more pronounced reaction to an ACTH stimulation test than cortisol. This study aimed to determine if the same was true for the horse. A total of 11 clinically healthy horses were selected for this study. Ethylenediaminetetraacetic acid plasma samples were taken before and 60 min after stimulation with 1 μg/kg BW of synthetic ACTH administered intravenously. The samples were analyzed for cortisol, 11-deoxycortisol, 21-deoxycortisol, cortisone, corticosterone, 11-deoxycorticosterone, androstenedione, 17-OH-progesterone, progesterone, and testosterone with a liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cortisol, 11-deoxycortisol, cortisone, corticosterone, and 11-deoxycorticosterone showed a significant increase after ACTH stimulation. In conclusion, the LC-MS/MS represents a viable method to measure glucocorticoids and related precursors or metabolites in equine plasma samples. In addition, we were able to show a more pronounced increase of 11-deoxycorticosterone, 11-deoxycortisol, and corticosterone compared with cortisol. These 3 metabolites could potentially serve as more sensitive biomarkers for stress in horses than cortisol.
    Keywords:  ACTH stimulation test; Equine steroid profiles; Equine stress marker; Liquid chromatography–tandem mass spectrometry (LC-MS/MS)
    DOI:  https://doi.org/10.1016/j.domaniend.2019.106419
  1268. ACS Omega. 2020 Jan 14. 5(1): 897-903
    Hydrostatic Pressure-Induced Spectral Variation of Reichardt's Dye: A Polarity/Pressure Dual Indicator.
    Miyagawa A, Eng J, Okada T, Inoue Y, Penfold TJ, Fukuhara G.
      The famous solvatochromic Reichardt's dye was applied to quantify hydrostatic pressure in media. The UV/vis spectra of the dye in various organic solvents are shifted bathochromically or hypsochromically at the shorter- or longer-wavelength band, respectively, upon hydrostatic pressurization. The E T value, determined by an absorption maximum, in ethyl acetate increases from 38.5 kcal mol-1 at 0.1 MPa to 39.2 kcal mol-1 at 300 MPa, which is mostly equal to the one in chloroform at 0.1 MPa. These spectroscopic origins were supported by the time-dependent density functional theory (TD-DFT) calculations. The concept and approach proposed in this paper, i.e., a dual indicator, should attract the attention of a broad spectrum in multidisciplinary science.
    DOI:  https://doi.org/10.1021/acsomega.9b03880
  1269. Int J Mol Sci. 2020 Jan 23. pii: E747. [Epub ahead of print]21(3):
    The Endocannabinoid System: A Target for Cancer Treatment.
    Laezza C, Pagano C, Navarra G, Pastorino O, Proto MC, Fiore D, Piscopo C, Gazzerro P, Bifulco M.
      In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions. Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis. However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation. In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.
    Keywords:  Cannabinoids; angiogenesis; cancer stem cell; metastasis
    DOI:  https://doi.org/10.3390/ijms21030747
  1270. Br J Radiol. 2020 Jan 23. 20190574
    Building confidence in digital health through metrology.
    Smith NAS, Sinden D, Thomas SA, Romanchikova M, Talbott JE, Adeogun M.
      Healthcare is increasingly and routinely generating large volumes of data from different sources, which are difficult to handle and integrate. Confidence in data can be established through the knowledge that the data are validated, well-curated and with minimal bias or errors. As the National Measurement Institute of the UK, the National Physical Laboratory (NPL) is running an interdisciplinary project on digital health data curation. The project addresses one of the key challenges of the UK's Measurement Strategy, to provide confidence in the intelligent and effective use of data. A workshop was organised by NPL in which important stakeholders from NHS, industry and academia outlined the current and future challenges in healthcare data curation. This paper summarises the findings of the workshop and outlines NPL's views on how a metrological approach to the curation of healthcare data sets could help solve some of the important and emerging challenges of utilising healthcare data.
    DOI:  https://doi.org/10.1259/bjr.20190574
  1271. Cancer Discov. 2020 Jan 22.
    Q&A: Christina Curtis on Computational and Systems Biology.
      Computational and systems biologist Christina Curtis, PhD, discusses the use of novel technologies and modeling approaches to quantify the biology of tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-ND2020-001
  1272. Bioorg Med Chem. 2020 Jan 07. pii: S0968-0896(19)31353-7. [Epub ahead of print] 115304
    Mangiferin: A promising natural xanthone from Mangifera indica for the control of acyclovir - resistant herpes simplex virus 1 infection.
    Rechenchoski DZ, Agostinho KF, Faccin-Galhardi LC, Lonni AASG, da Silva JVH, de Andrade FG, Cunha AP, Ricardo NMPS, Nozawa C, Linhares REC.
      Mangiferin is found in many plant species as the mango tree (Mangifera indica) with ethnopharmacological applications and scientific evidence. The emergence of resistant herpes simplex virus (HSV) strains to Acyclovir (ACV) has encouraged the search for new drugs. We investigated the in vitro and in vivo activity of mangiferin obtained from M. indica against ACV-resistant HSV-1 (AR-29) and sensitive (KOS) strains. The in vitro activity was performed under varying treatment protocols. The substance showed a CC50 > 500 μg/mL and IC50 of 2.9 μg/mL and 3.5 μg/mL, respectively, for the AR-29 and KOS strains. The in vivo activity was performed in Balb/c mice treated with 0.7% topical mangiferin formulation. This formulation inhibited most effectively the AR-29 strain, attenuated the lesions, postponed their appearance or enhanced healing, in comparison to control group. We demonstrated the potentiality of mangiferin from M. indica to control HSV replication with emphasis to ACV-resistant infection.
    Keywords:  Acyclovir-Resistance; Antiviral; HSV; Mangifera indica; Mangiferin
    DOI:  https://doi.org/10.1016/j.bmc.2020.115304
  1273. J Med Microbiol. 2020 Jan 20.
    Narrative of a versatile and adept species Pseudomonas putida.
    Kivisaar M.
      Pseudomonas putida is a fast-growing bacterium found mostly in temperate soil and water habitats. The metabolic versatility of P. putida makes this organism attractive for biotechnological applications such as biodegradation of environmental pollutants and synthesis of added-value chemicals (biocatalysis). This organism has been extensively studied in respect to various stress responses, mechanisms of genetic plasticity and transcriptional regulation of catabolic genes. P. putida is able to colonize the surface of living organisms, but is generally considered to be of low virulence. A number of P. putida strains are able to promote plant growth. The aim of this review is to give historical overview of the discovery of the species P. putida and isolation and characterization of P. putida strains displaying potential for biotechnological applications. This review also discusses some major findings in P. putida research encompassing regulation of catabolic operons, stress-tolerance mechanisms and mechanisms affecting evolvability of bacteria under conditions of environmental stress.
    Keywords:  biodegradation; biotechnology; evolution; interactions with eukaryotic hosts; species Pseudomonas putida; stress tolerance
    DOI:  https://doi.org/10.1099/jmm.0.001137
  1274. Br Dent J. 2020 Jan;228(2): 61
    A work of FiCTION.
    Sellars S.
      
    DOI:  https://doi.org/10.1038/s41415-020-1205-7
  1275. Biophys J. 2019 Dec 18. pii: S0006-3495(19)34392-9. [Epub ahead of print]
    Spontaneous Curvature, Differential Stress, and Bending Modulus of Asymmetric Lipid Membranes.
    Hossein A, Deserno M.
      Lipid bilayers can exhibit asymmetric states, in which the physical characteristics of one leaflet differ from those of the other. This most visibly manifests in a different lipid composition, but it can also involve opposing lateral stresses in each leaflet that combine to an overall vanishing membrane tension. Here, we use theoretical modeling and coarse-grained simulation to explore the interplay between a compositional asymmetry and a nonvanishing differential stress. Minimizing the total elastic energy leads to a preferred spontaneous curvature that balances torques due to both bending moments and differential stress, with sometimes unexpected consequences. For instance, asymmetric flat bilayers, whose specific areas in each leaflet are matched to those of corresponding tensionless symmetric flat membranes, still exhibit a residual differential stress because the conditions of vanishing area strain and vanishing bending moment differ. We also measure the curvature rigidity of asymmetric bilayers and find that a sufficiently strong differential stress, but not compositional asymmetry alone, can increase the bending modulus. The likely cause is a stiffening of the compressed leaflet, which appears to be related to its gel transition but not identical with it. We finally show that the impact of cholesterol on differential stress depends on the relative strength of elastic and thermodynamic driving forces: if cholesterol solvates equally well in both leaflets, it will redistribute to cancel both leaflet tensions almost completely, but if its partitioning free energy prefers one leaflet over the other, the resulting distribution bias may even create differential stress. Because cells keep most of their lipid bilayers in an asymmetric nonequilibrium steady state, our findings suggest that biomembranes are elastically more complex than previously thought: besides a spontaneous curvature, they might also exhibit significant differential stress, which could strongly affect their curvature energetics.
    DOI:  https://doi.org/10.1016/j.bpj.2019.11.3398
  1276. Oncogene. 2020 Jan 20.
    GRK2 enforces androgen receptor dependence in the prostate and prostate tumors.
    Adler AJ, Mittal P, Hagymasi AT, Menoret A, Shen C, Agliano F, Wright KT, Grady JJ, Kuo CL, Ballesteros E, Claffey KP, Vella AT.
      Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces AR-dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression toward the deadliest stage.
    DOI:  https://doi.org/10.1038/s41388-020-1159-x
  1277. Nucleic Acids Res. 2020 Jan 22. pii: gkaa007. [Epub ahead of print]
    AON-induced splice-switching and DMPK pre-mRNA degradation as potential therapeutic approaches for Myotonic Dystrophy type 1.
    Stepniak-Konieczna E, Konieczny P, Cywoniuk P, Dluzewska J, Sobczak K.
      Expansion of an unstable CTG repeat in the 3'UTR of the DMPK gene causes Myotonic Dystrophy type 1 (DM1). CUG-expanded DMPK transcripts (CUGexp) sequester Muscleblind-like (MBNL) alternative splicing regulators in ribonuclear inclusions (foci), leading to abnormalities in RNA processing and splicing. To alleviate the burden of CUGexp, we tested therapeutic approach utilizing antisense oligonucleotides (AONs)-mediated DMPK splice-switching and degradation of mutated pre-mRNA. Experimental design involved: (i) skipping of selected constitutive exons to induce frameshifting and decay of toxic mRNAs by an RNA surveillance mechanism, and (ii) exclusion of the alternative exon 15 (e15) carrying CUGexp from DMPK mRNA. While first strategy failed to stimulate DMPK mRNA decay, exclusion of e15 enhanced DMPK nuclear export but triggered accumulation of potentially harmful spliced out pre-mRNA fragment containing CUGexp. Neutralization of this fragment with antisense gapmers complementary to intronic sequences preceding e15 failed to diminish DM1-specific spliceopathy due to AONs' chemistry-related toxicity. However, intronic gapmers alone reduced the level of DMPK mRNA and mitigated DM1-related cellular phenotypes including spliceopathy and nuclear foci. Thus, a combination of the correct chemistry and experimental approach should be carefully considered to design a safe AON-based therapeutic strategy for DM1.
    DOI:  https://doi.org/10.1093/nar/gkaa007
  1278. Theriogenology. 2020 Jan 09. pii: S0093-691X(20)30020-0. [Epub ahead of print]144 194-203
    Effect of scrotal insulation on sperm quality and seminal plasma proteome of Brangus bulls.
    Pereira GR, de Lazari FL, Dalberto PF, Bizarro CV, Sontag ER, Koetz Junior C, Menegassi SRO, Barcellos JOJ, Bustamante-Filho IC.
      Seminal plasma (SP) contributes to sperm physiology and metabolism, prevents premature capacitation, and protects sperm against oxidative stress. In order to evaluate the impact of heat stress in the semen of tropically adapted Brangus breed and in their seminal plasma proteome, we studied the effects of scrotal insulation for 72 h. Semen samples from six bulls, between 7 and 8 years of age, were collected prior to scrotal insulation (pre-insulation), and at 4 and 11 wk after insulation. Seminal plasma samples were analyzed by 2D SDS-PAGE and liquid chromatography coupled with mass spectrometry (LC-MS/MS). Insulation caused decrease in vigour, gross and total motility after 4 wk of scrotal insult (P < 0.001). Total defects in sperm were higher after 4 wk compared to pre-insulation and 11 wk after scrotal insulation (P < 0.001). The analysis of the 2D protein profile of the SP resulted in the identification 183 unique protein spots in all gels evaluated. There was no difference in mean number of protein spots amongst time points. Eight protein spots were more abundant in SP after scrotal insulation, returning to the same expression level at 11 wk post-insulation. One spot had higher abundance at 11 wk post-insulation, and one spot had decreased abundance 4 wk after insulation. The ten protein spots with differential abundance amongst time points were identified as Seminal plasma protein PDC-109, Seminal plasma protein A3, Seminal plasma protein BSP-30 kDa, Spermadhesin-1 and Metalloproteinase inhibitor 2. The validation of these five proteins as biomarkers for thermal testicular stress in Brangus breed would allow the development of new biotechnologies that could improve bovine semen analysis in breeding systems in tropical and subtropical conditions. A close association between the identified BSP and Spermadhesin-1 was evidenced in protein-protein interaction analysis. Based on gene ontology analysis, variation in sperm function after insulation could be explained by variation in the expressed proteins in the SP. Further studies are required to verify if these proteins could be used as biomarkers for the identification of bulls with increased seminal resistance to heat stress in Brangus breed.
    Keywords:  Bulls; Heat stress; Mass spectrometry; Proteomics; Scrotal insulation
    DOI:  https://doi.org/10.1016/j.theriogenology.2020.01.014
  1279. Bioresour Technol. 2020 Jan 07. pii: S0960-8524(20)30010-9. [Epub ahead of print] 122741
    Emerging prospects of mixotrophic microalgae: Way forward to sustainable bioprocess for environmental remediation and cost-effective biofuels.
    Patel AK, Choi YY, Sim SJ.
      Algal bioremediation becoming most fascinating to produce biomass as biofuels feedstock while remediating wastes, also improving carbon-footprint through carbon capturing and utilization (CCU) technology. Non-algae process however offers effective treatment but metabolic CO2 emission is major drawback towards sustainable bioprocess. Mixotrophic cultivation strategy (MCS) enables to treat organic and inorganic wastes which broadly extend microalgae application towards cleaner and sustainable bioeconomy. Latest focus of global think-tanks to encourage bioprocess holding promise of sustainability via CCU ability as important trait. Several high CO2 emitting industries forced to improve their carbon-footprints. MCS driven microalgae treatment could be best solution for those industries. This review covers recent updates on MCS applications for waste-to-value (biofuels) and environment remediation. Moreover, recommendations to fill knowledge gaps, and commercial algal biofuel could be cost-effectiveness and sustainable technology for biocircular economy if fuelled by waste streams from other industries.
    Keywords:  Environmental; Microalgae; Mixotrophic; Organic; Pollutant; Remediation
    DOI:  https://doi.org/10.1016/j.biortech.2020.122741
  1280. Plants (Basel). 2020 Jan 18. pii: E123. [Epub ahead of print]9(1):
    Biostimulant Effect and Biochemical Response in Lettuce Seedlings Treated with A Scenedesmus quadricauda Extract.
    Puglisi I, La Bella E, Rovetto EI, Lo Piero AR, Baglieri A.
      The use of natural biostimulants is becoming an attractive option in order to reduce the use of fertilizer and increase the yield of crops. In particular, algal extracts are suitable candidates as they positively affect plant physiology. Among crops, lettuce often requires the use of biostimulants to improve both the quality and quantity of production. The aim of this work is to investigate the potential use of a Scenedesmus quadricauda extract as a biostimulant in order to obtain sustainable cultivation and a reduction in the cost of chemical fertilizers in lettuce cultivation. Therefore, the effect of S. quadricauda extract on lettuce seedlings was explored by evaluating the physiological parameters, chlorophyll, carotenoid, and total protein contents as well as several plant enzymatic activities involved in primary and secondary metabolisms. The experiment was performed by growing plants on inert substrate (pumice) with a 16-h photoperiod, by carrying out two consecutive radical treatments, one week apart, using a concentration of the extract corresponding to 1 mg Corg L-1. Lettuce plants were sampled at 1, 4, and 7 days from the first treatment and 7 days from the second treatment. The results showed that the S. quadricauda extract positively affected the growth of lettuce seedlings, mainly acting at the shoot level, determining an increase in dry matter, chlorophylls, carotenoids, proteins, and influencing the activities of several enzymes involved in the primary metabolism.
    Keywords:  GOGAT; PAL; chlorophylls; citrate sintase; glutamine synthetase; malate dehydrogenase
    DOI:  https://doi.org/10.3390/plants9010123
  1281. Int J Soc Psychiatry. 2020 Jan 20. 20764019899975
    Dual diagnosis: A systematic review of the organization of community health services.
    Fantuzzi C, Mezzina R.
      BACKGROUND: Dual diagnosis (DD), as the co-occurrence of a substance use disorder and a psychiatric disorder, is underestimated, under-diagnosed and often poorly treated throughout the world, although it is highly prevalent in people suffering from a mental disorder.AIMS AND METHODS: This review analyzed 48 studies from a PubMed and PsycINFO databases search, in order to verify the state of the art regarding the organization of community health services for DD treatment.
    RESULTS: Four macro-themes have been identified: service organization, critical issues, assessment tools and evidence-based interventions. An effective service recognizes the complexity of DD, promotes a common staff culture, and tailors the organization to local needs. The main critical issues in its implementation include the lack of specific staff training, the poor management of resources and the need for greater personalization of care plans, with attention to psychosocial interventions. Integrated service assessment tools can be used as a benchmark measure at the program level for implementation planning and at the national level to affect policy change. The integrated treatment model for DD should also aim to improve access to care and offer treatments based on scientific evidence. It is also evident that the integration of services can improve outcomes but it is not a guarantee for it.
    CONCLUSION: There is an urgent need to improve networking between mental health and addiction services in order to deal with DD and create new integrated intervention models, paying attention to an approach to the whole person, seen in his/her absolute uniqueness.
    Keywords:  Dual diagnosis; community health services; evidence-based interventions; integrated health care delivery; service organization
    DOI:  https://doi.org/10.1177/0020764019899975
  1282. Fitoterapia. 2020 Jan 15. pii: S0367-326X(20)30063-0. [Epub ahead of print]141 104481
    Steroidal glycoalkaloids from Solanum lyratum inhibit the pro-angiogenic activity of A549-derived exosomes.
    Du X, Wang JN, Sun J, Wu T, Cao XQ, Liu LY, Yang YK.
      In this study, seven previously undescribed steroidal glycoalkaloids, compounds 1-7, were isolated from Solanum lyratum, along with two known ones (8 and 9). Comprehensive spectroscopy techniques were used to determine their structures. Although 1-8 only showed a weak inhibitory effect on the proliferation of the tumor-derived vascular endothelial cells, however, in a former study we found both total steroidal glycoalkaloids from Solanum lyratum (TSGS) and 9 significantly inhibited tumor angiogenesis and its mechanism was linked to its ability to interfere with cell membrane lipid rafts. Lipid rafts are closely related to the functions of tumor-derived exosomes, a vital factor in cancer progression. Thus, we investigated the impacts of TSGS and 9 on the functions of A549-derived exosomes. Our results indicated that A549-derived exosomes can significantly enhance the angiogenesis abilities of human umbilical vein endothelial cells, whereas the intervention of TSGS or 9 significantly inhibited this activity of A549-derived exosomes. These findings suggest that TSGS and 9 exert anti-tumor angiogenesis by inhibiting the pro-angiogenic activity of A549-derived exosomes.
    Keywords:  Angiogenesis; Exosome; Lipid raft; Solanum lyratum; Steroidal glycoalkaloid
    DOI:  https://doi.org/10.1016/j.fitote.2020.104481
  1283. Life Sci Alliance. 2020 Feb;pii: e201900499. [Epub ahead of print]3(2):
    Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition.
    Schukken KM, Lin YC, Bakker PL, Schubert M, Preuss SF, Simon JE, van den Bos H, Storchova Z, Colomé-Tatché M, Bastians H, Spierings DC, Foijer F.
      Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.
    DOI:  https://doi.org/10.26508/lsa.201900499
  1284. Endoscopy. 2020 Jan 22.
    Whole-fornix endoscopic submucosal dissection for gastric mucosal adenocarcinoma.
    Shichijo S, Takeuchi Y, Fukuda H, Maekawa A, Kanesaka T, Uedo N, Ishihara R.
      
    DOI:  https://doi.org/10.1055/a-1085-9472
  1285. Microb Pathog. 2020 Jan 18. pii: S0882-4010(19)31687-0. [Epub ahead of print] 103987
    Proteomic analysis of Sporothrix schenckii cell wall reveals proteins involved in oxidative stress response induced by menadione.
    Félix-Contreras C, Alba-Fierro CA, Ríos-Castro E, Luna-Martínez F, Cuéllar-Cruz M, Ruiz-Baca E.
      Sporotrichosis is an emergent subcutaneous mycosis that is a threat to both humans and other animals. Sporotrichosis is acquired by the traumatic implantation of species of the Sporothrix genus. Added to the detoxification systems, pathogenic fungi possess different mechanisms that allow them to survive within the phagocytic cells of their human host during the oxidative burst. These mechanisms greatly depend from the cell wall (CW) since phagocytic cells recognize pathogens through specific receptors associated to the structure. To date, there are no studies addressing the modulation of the expression of S. schenckii CW proteins (CWP) in response to reactive oxygen species (ROS). Therefore, in this work, a proteomic analysis of the CW of S. schenckii in response to the oxidative agent menadione (O2•-) was performed. Proteins that modulate their expression were identified which can be related to the fungal survival mechanisms within the phagocyte. Among the up-regulated CWP in response to the oxidative agent, 13 proteins that could be involved in the mechanisms of oxidative stress response in S. schenckii were identified. The proteins identified were thioredoxin1 (Trx1), superoxide dismutase (Sod), GPI-anchored cell wall protein, β-1,3-endoglucanase EglC, glycoside hydrolase (Gh), chitinase, CFEM domain protein, glycosidase crf1, covalently-linked cell wall protein (Ccw), 30 kDa heat shock protein (Hsp30), lipase, trehalase (Treh), fructose-bisphosphate aldolase (Fba1) and citrate synthase (Cs). The identification of CWP that modulates their expression in response to superoxide ion (O2•-) in S. schenckii is a useful approach to understand how the fungus defends itself against ROS, in order to evade the phagocytic cells from the host and cause the infection.
    Keywords:  Cell wall; Menadione; Oxidative stress; Sporothrix schenckii
    DOI:  https://doi.org/10.1016/j.micpath.2020.103987
  1286. Pediatr Blood Cancer. 2020 Jan 21. e28176
    Autologous stem cell transplantation following high-dose chemotherapy in children with high-risk neuroblastoma: Practicality in resource-limited countries.
    Lau SCD, Unni MNM, Teh KH, Aziz MA, Muda Z, Thomas SA, Quah SW, Ibrahim H, Othman IS.
      
    DOI:  https://doi.org/10.1002/pbc.28176
  1287. BMJ Case Rep. 2020 Jan 23. pii: e232308. [Epub ahead of print]13(1):
    Pulmonary haemorrhage following thrombolysis with streptokinase in myocardial infarction.
    Prasad K, Singh P, Kanabar K, Vijayvergiya R.
      Pulmonary haemorrhage is a rare but a life-threatening complication of thrombolytic therapy in patients with acute ST-elevation myocardial infarction (MI). It usually presents with anaemia, massive haemoptysis, acute-onset respiratory distress and diffuse bilateral lung infiltrates on imaging. We hereby describe two patients, who had pulmonary haemorrhage following streptokinase therapy for acute MI. The first patient improved with conservative treatment, while the second patient died due to respiratory failure. Streptokinase, a fibrin non-specific agent, is a widely used thrombolytic in low-income and middle-income countries. Pulmonary haemorrhage should be suspected in patients who develop sudden respiratory compromise after receiving thrombolytics, especially streptokinase. The management issues related to this uncommon life-threatening complication have been discussed in this article.
    Keywords:  adult intensive care; interventional cardiology; mechanical ventilation
    DOI:  https://doi.org/10.1136/bcr-2019-232308
  1288. J Clin Pathol. 2020 Jan 24. pii: jclinpath-2020-206431. [Epub ahead of print]
    Gene of the month: GLI-1.
    Chetty R.
      The Glioma-associated homologue-1 (GLI-1) gene was first discovered to be amplified in glioblastoma multiforme. It encodes for a zinc-finger transcription factor in the Kruppel family of proteins and is important in the sonic hedgehog signalling pathway. GLI-1 also plays a role in several other pathways and is important for proliferation, migration, invasion, growth and angioinvasion, and cancer stem cell self-renewal in a variety of malignancies. GLI-1 is amplified in several malignancies, including an epithelioid, pericytomatous soft tissue neoplasm that can exhibit malignant behaviour. More recently, GLI-1 fusions with other partner genes have been found in three rare tumours: a pericytomatous tumour with a t(7;12) translocation, where it partners with Actin beta 1, and gastroblastoma and plexiform fibromyxoma, where the partner gene is metastasis-associated lung adenocarcinoma transcript 1, respectively.
    Keywords:  cancer genetics; gene amplification; molecular pathology
    DOI:  https://doi.org/10.1136/jclinpath-2020-206431
  1289. Spine Deform. 2019 Mar;7(2): 331-337
    Ability of the Global Alignment and Proportion Score to Predict Mechanical Failure Following Adult Spinal Deformity Surgery-Validation in 149 Patients With Two-Year Follow-up.
    Bari TJ, Ohrt-Nissen S, Hansen LV, Dahl B, Gehrchen M.
      STUDY DESIGN: Retrospective analysis of prospectively collected data.OBJECTIVES: To validate the Global Alignment and Proportion (GAP) score in a single-center cohort of adult spinal deformity (ASD) patients. Surgical treatment for ASD is associated with a high risk of mechanical failure and consequent revision surgery. To improve prediction of mechanical complications, the GAP score was developed with promising results. Development was based on the assumption that not all patients would benefit from the same fixed radiographic targets as pelvic incidence is an individual, morphological parameter that greatly influences the sagittal curves of the spine.
    METHODS: In a validation study of the GAP score, patients undergoing ASD surgery with four or more levels of instrumentation were consecutively included at a tertiary spine unit. Patients were followed for a minimum of two years. Pre- and postoperative GAP score and categories were calculated for all patients, and the association with mechanical failure and revision surgery was analyzed.
    RESULTS: A total of 149 patients with a mean age of 57.4 years were included. Overall, the rates of mechanical failure and revision surgery were 51% and 35% respectively. The area under the curve (AUC) using receiver operating characteristic was classified as "no or low discriminatory power" for the GAP score in predicting either outcome (AUC = 0.50 and 0.49, respectively). Similarly, there were no significant associations between GAP categories and the occurrence of mechanical failure or revision surgery when using Cochran-Armitage test of trend (p = .28 for mechanical failure and p = .58 for revision surgery).
    CONCLUSIONS: In a consecutive series of surgically treated ASD patients, we found no significant association between postoperative GAP score and mechanical failure or revision surgery. Despite minor limitations in similarities to the original study cohort, further validation studies or adjustments to the original scoring system are proposed.
    LEVEL OF EVIDENCE: Level II.
    Keywords:  Adult spinal deformity; Classification; Postoperative complications; Radiography; Reproducibility of results; Sagittal alignment; Spinal fusion; Validation studies
    DOI:  https://doi.org/10.1016/j.jspd.2018.08.002
  1290. Pharmacogenomics. 2020 Feb;21(3): 157-161
    Gene signatures of breast cancer development and the potential for novel targeted treatments.
    Kothari C, Diorio C, Durocher F.
      
    Keywords:  TNBC; breast cancer progression; epigenetics; gene signature; hereditary breast cancer; target therapy
    DOI:  https://doi.org/10.2217/pgs-2019-0158
  1291. J Mater Chem B. 2020 Jan 22.
    A self-assembled pH/enzyme dual-responsive prodrug with PEG deshielding for multidrug-resistant tumor therapy.
    Ni R, Zhu J, Xu Z, Chen Y.
      Multidrug resistance (MDR) is one of the major obstacles for tumor therapy. Intake by receptor-mediated endocytosis enables molecules to bypass ABC transporter efflux, which is the primary mechanism of MDR. Here, we developed a novel pH/enzyme dual-responsive polypeptide prodrug to reverse multidrug resistance. This drug is composed of pH/MMP2-sensitive nanoparticles (MSNPs) self-assembled from mPEG-peptide-DOX. MSNPs can overcome sequential physiological barriers of multidrug resistance by prolonging the circulation time through PEGylation, enhancing tumor accumulation through passive targeting, increasing tumor penetration by enzyme-sensitive PEG deshielding, bypassing ABC transporter efflux by undergoing receptor-mediated endocytosis, and inducing sufficient DOX release from nanoparticles triggered by lysosomal pH. The reversal of MDR by MSNPs was evaluated in MCF-7/ADR cells and nude mice bearing tumors consisting of MCF-7/ADR cells. Both in vitro and in vivo studies showed that the MSNPs can effectively reverse MDR. Thus, MSNPs may constitute a potentially promising strategy for overcoming MDR in clinical applications.
    DOI:  https://doi.org/10.1039/c9tb02264c
  1292. Epilepsy Res. 2020 Jan 15. pii: S0920-1211(19)30536-4. [Epub ahead of print]160 106276
    Prenatal betamethasone exposure increases corticotropin-releasing hormone expression along with increased hippocampal slice excitability in the developing hippocampus.
    Benson MJ, Lauková M, Borges K, Velíšková J, Velíšek L.
      BACKGROUND: The objective of this study was to determine whether prenatal exposure to betamethasone alters hippocampal expression of corticotropin-releasing hormone (CRH) and resultant hippocampal circuit excitability.METHODS: Real time (RT)-PCR and western blots were used to determine CRH mRNA and protein expression levels, respectively, in hippocampal extracts of two-week old rat pups prenatally primed with betamethasone or saline on gestational day 15. The data were compared to changes in epileptiform activity induced by kainic acid (KA) or depletion of [Mg2+]0 in combined hippocampus-entorhinal cortex slices.
    RESULTS: RT-PCR analysis showed 3-fold increased levels of CRH mRNA in hippocampal extracts from prenatally betamethasone-primed pups compared to saline controls (p < 0.05), but no changes in mRNA expression of CRH receptors (1 and 2). Changes in CRH protein isoform ratio in hippocampal extracts suggest 30 % increase in mature CRH levels in betamethasone-primed hippocampi (p < 0.05). No changes in mRNA expression in CRH feedback loop associated genes, GR and FKBP51, were found. Compared to saline-exposed pups, slices from betamethasone-primed pups had faster onset of epileptiform-like activity (inter-ictal discharges and seizure-like-events) after bath application of 4 μM KA (p < 0.05) suggesting a "more hyperexcitable" state. The epileptiform-like activity after KA application was significantly reduced following bath application of a CRH R2 antagonist (p < 0.05) but CRH R1 antagonist had no effect (p > 0.05). Also in the low-Mg2+-induced epileptiform activity, there was increased excitability, in the form of enhanced inter-ictal discharges, in slices from betamethasone primed compared to saline exposed rat pups (p < 0.05).
    CONCLUSIONS: Our study suggests a possible mechanistic link to prenatal betamethasone priming-induced increase in postnatal hippocampal excitability that involves enhanced expression of CRH acting at CRH R2. This is important in regards to the links between prenatal stress/corticosteroid-exposure and syndromes, such as epilepsy, autism spectrum disorders and other psychiatric disorders associated with neuronal hyperexcitability.
    Keywords:  Corticotrophin; Epilepsy; Excitability; Hippocampus; Hormone; Kainic acid; Low magnesium; N-Methyl-d-Aspartate; Releasing
    DOI:  https://doi.org/10.1016/j.eplepsyres.2020.106276
  1293. Clin Exp Allergy. 2020 Jan 19.
    Relationship between immune parameters during a severe exacerbation in allergic asthmatic children and asthma outcomes in the following year.
    Lejeune S, Mordacq C, Drumez E, Brisset S, Pouessel G, Pichavant M, Engelmann I, Béghin L, Decleyre-Badiu I, Neve V, Thumerelle C, Gosset P, Deschildre A.
      Despite improvement in asthma maintenance treatment, exacerbations remain important issues. They are markers of severe asthma but can also occur in mild asthma (1). Viruses, and mainly Rhinoviruses (RVs), are the main triggers, and they may interact with aeroallergen-specific immunoinflammatory pathways in atopic patients (2,3). Some studies have suggested that these episodes could be related to an alteration of innate immune defenses and particularly a defective production of type I and III interferons (IFN) (4).
    Keywords:  asthma; exacerbation; innate immunity; outcomes; virus
    DOI:  https://doi.org/10.1111/cea.13570
  1294. Methods Mol Biol. 2020 ;2117 179-205
    Interactive Alternative Splicing Analysis of Human Stem Cells Using psichomics.
    Saraiva-Agostinho N, Barbosa-Morais NL.
      Alternative splicing (AS) generates functionally distinct transcripts and is involved in multiple cellular processes, including stem cell differentiation. Several epithelial-to-mesenchymal transition-related splicing factors have also been associated with pluripotency. Concomitantly with the interest in studying AS in stem cell biology, the advent of next-generation sequencing of RNA (RNA-seq) has increased the public availability of transcriptomic data and enabled genome-wide AS studies. To facilitate performing such analyses in large publicly available or user-provided transcriptomics datasets, the psichomics R package provides an easy-to-use interface and efficient data visualization tools for AS quantification and integrative analyses of AS and gene expression data.psichomics is employed herein to study AS changes between human stem cells and fibroblasts, based on dimensionality reduction, and median- and variance-based differential AS and gene expression analyses. Putative RNA-binding protein regulators involved in those alterations are then identified based on correlation analyses in large cohorts of human tissue transcriptomes. We identified several alterations, both novel and previously reported, in alternative splicing events and in the expression of their candidate regulators that are associated with stem cell differentiation into fibroblasts.
    Keywords:  Differential gene expression analysis; Differential splicing analysis; Integrative analyses; RNA-seq; Stemness; psichomics
    DOI:  https://doi.org/10.1007/978-1-0716-0301-7_10
  1295. Sensors (Basel). 2020 Jan 16. pii: E509. [Epub ahead of print]20(2):
    Effect of Cultivar on Chlorophyll Meter and Canopy Reflectance Measurements in Cucumber.
    de Souza R, Grasso R, Peña-Fleitas MT, Gallardo M, Thompson RB, Padilla FM.
      Optical sensors can be used to assess crop N status to assist with N fertilizer management. Differences between cultivars may affect optical sensor measurement. Cultivar effects on measurements made with the SPAD-502 (Soil Plant Analysis Development) meter and the MC-100 (Chlorophyll Concentration Meter), and of several vegetation indices measured with the Crop Circle ACS470 canopy reflectance sensor, were assessed. A cucumber (Cucumis sativus L.) crop was grown in a greenhouse, with three cultivars. Each cultivar received three N treatments, of increasing N concentration, being deficient (N1), sufficient (N2) and excessive (N3). There were significant differences between cultivars in the measurements made with both chlorophyll meters, particularly when N supply was sufficient and excessive (N2 and N3 treatments, respectively). There were no consistent differences between cultivars in vegetation indices. Optical sensor measurements were strongly linearly related to leaf N content in each of the three cultivars. The lack of a consistent effect of cultivar on the relationship with leaf N content suggests that a unique equation to estimate leaf N content from vegetation indices can be applied to all three cultivars. Results of chlorophyll meter measurements suggest that care should be taken when using sufficiency values, determined for a particular cultivar.
    Keywords:  genotype; greenhouse; leaf nitrogen; proximal optical sensors; vegetation index
    DOI:  https://doi.org/10.3390/s20020509
  1296. Curr Med Chem. 2020 Jan 21.
    New aspects of monoamine oxidase B inhibitors: the key role of halogens to open the golden door.
    Mathew B, Carradori S, Guglielmi P, Sahab Uddin M, Kim H.
      A large plethora of drugs and promising lead compounds contain halogens in their structures. The introduction of such moieties strongly modulates their physical-chemical features as well as pharmacokinetic and pharmacodynamic profile. The most important outcome was shown to be the ability of these halogens to favourably influence the drug-target interaction and energetic stability within the active site by the establishment of halogen bonds. This review attempted to demonstrate the key role exerted by these versatile moieties when correctly located in an organic scaffold to display monoamine oxidase (MAO) inhibition and selectivity toward the B isoform of this important enzyme. Human MAOs are well-recognized as therapeutic targets for mood disorders and neurodegenerative diseases and medicinal chemists were prompted to discover the structural requirements crucial to discriminate the slight differences between the active sits of the two isoforms (MAO-A and MAO-B). The analysis of the structure-activity relationships of the most important scaffolds (hydrazothiazoles, coumarins, chromones, chalcones, pyrazolines) and the impact of halogen (F, Cl, Br and I) insertion on this biological activity and isozyme selectivity have been reported being a source of inspiration for the medicinal chemists.
    Keywords:  chalcone.; chromone; coumarin; halogen; inhibitors; monoamine oxidase B; thiazole
    DOI:  https://doi.org/10.2174/0929867327666200121165931
  1297. Allergy. 2020 Jan 22.
    Cord Blood Hemopoietic Cell Receptor Expression is Associated with Early Life Atopic Risk and Lung Function.
    Akhabir L, Rosenberg E, Tworek D, Heroux D, Balhara J, McNagny KM, Sears MR, Lefebvre DL, Becker AB, Turvey SE, Mandhane PJ, Moraes TJ, Subbarao P, Paré G, Denburg JA.
      
    Keywords:  CHILD Study; allergic disease; atopy; cord blood; dendritic cell; hemopoietic progenitor cell
    DOI:  https://doi.org/10.1111/all.14190
  1298. Anal Chem. 2020 Jan 22.
    Microfluidics-based Single-Cell Protrusion Analysis for Rapid Screening Drugs Targeting Subcellular Mitochondrial Trafficking in Cancer Progression.
    Zhang P, Yao J, Wang B, Qin L.
      Cancer cell migration is often guided by cell protrusions, whose formation and activity involve subcellular localization of mitochondria. However, the role of subcellular mitochondrial trafficking during cell protrusion generation is not well understood amidst a lack of quantitative data. Here, we present a high-throughput microfluidic platform that enables the quantitative, single-cell precision analysis of cell protrusion formation during cell migration that is regulated by subcellular mitochondrial trafficking. Gene expression profiling of the isolated cell protrusions suggested that mitochondria were found in high numbers within cell protrusions, a finding validated by mitochondrial staining. Quantitative analysis revealed that the formation of cell protrusions could be effectively suppressed by inhibiting subcellular mitochondrial trafficking. We further demonstrated that rapid screening of mitochondria-specific therapeutic drugs to evaluate their effects on cell protrusion formation with single-cell precision could be achieved in the microfluidic platform, which could have clinical utility in the development of new anti-cancer agents.
    DOI:  https://doi.org/10.1021/acs.analchem.9b04702
  1299. Sci Rep. 2020 Jan 21. 10(1): 1187
    Publisher Correction: The glycogen synthase kinase MoGsk1, regulated by Mps1 MAP kinase, is required for fungal development and pathogenicity in Magnaporthe oryzae.
    Zhou T, Dagdas YF, Zhu X, Zheng S, Chen L, Cartwright Z, Talbot NJ, Wang Z.
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    DOI:  https://doi.org/10.1038/s41598-020-58148-7
  1300. Am J Physiol Endocrinol Metab. 2020 Jan 21.
    Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss.
    Lawenius L, Scheffler JM, Gustafsson KL, Henning P, Nilsson KH, Colldén H, Islander U, Plovier H, Cani PD, de Vos WM, Ohlsson C, Sjögren K.
      Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 weeks, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.
    Keywords:  Akkermansia; bone mass; gut microbiota; osteoporosis; probiotic
    DOI:  https://doi.org/10.1152/ajpendo.00425.2019
  1301. ACS Appl Mater Interfaces. 2020 Jan 20.
    High-Efficiency Flexible Perovskite Solar Cells Enabled by Ultrafast Room-Temperature Reactive Ion Etching Process.
    Kim BJ, Kwon SL, Kim MC, Jin YU, Lee DG, Jeon JB, Yun Y, Choi M, Boschloo G, Lee S, Jung HS.
      Perovskite solar cells (PSCs), which have surprisingly emerged in recent years, are now aiming at commercialization. Rapid, low-temperature, and continuous fabrication processes that can produce high-efficiency PSCs with a reduced fabrication cost and shortened energy payback time are important challenges on the way to commercialization. Herein, we report a reactive ion etching (RIE) method, which is an ultrafast room-temperature technique, to fabricate mesoporous TiO2 (mp-TiO2) as an electron transport layer for high-efficiency PSCs. Replacing the conventional high-temperature annealing process by RIE, reduces the total processing time for fabricating 20 PSCs by 40%. Additionally, the RIE-processed mp-TiO2 exhibits enhanced electron extraction, whereupon the optimized RIE-mp-TiO2-based PSC exhibits a power conversion efficiency (PCE) of 19.60% without J-V hysteresis, when the devices were optimized with a TiCl4 surface treatment process. Finally, a flexible PSC employing the RIE-mp-TiO2 is demonstrated with 17.29% PCE. Considering that the RIE process has been actively used in the semiconductor industry, including for the fabrication of silicon photovoltaic modules, the process developed in this work could be easily applied towards faster, simpler, and cheaper manufacturing of PSC modules.
    DOI:  https://doi.org/10.1021/acsami.9b19030
  1302. ACS Appl Mater Interfaces. 2020 Jan 23.
    Redox-Channeling Polydopamine-Ferrocene (PDA-Fc) Coating to Confer Context-Dependent and Photothermal Antimicrobial Activities.
    Song J, Liu H, Lei M, Tan H, Chen Z, Antoshin A, Payne GF, Qu X, Liu C.
      Microbial disinfection associated with medical device surfaces has been an increasing need and surface modification strategies such as antibacterial coatings have gained great interest. Here, we report the development of Polydopamine-Ferrocene (PDA-Fc) functionalized TiO2 nanorods (Ti-Nd-PDA-Fc) as a context-dependent antibacterial system on implant to combat bacterial infection and hinder biofilm formation. In this work, two synergistic antimicrobial mechanisms of the PDA-Fc coating are proposed. First, the PDA-Fc coating is redox-active and can be locally activated to release antibacterial reactive oxygen species (ROS), especially •OH in response to the acidic microenvironment induced by bacteria colonization and host immune responses. The results demonstrate that redox-based antimicrobial activity of Ti-Nd-PDA-Fc offers antibacterial efficacy of over 95% and 92% against MRSA and E. coli, respectively. Second, the photothermal effect of PDA can enhance the antibacterial capability upon NIR irradiation, with over 99% killing efficacy against MRSA and E. coli, and even suppress the formation of biofilm through both localized hyperthermia and enhanced •OH generation. Additionally, Ti-Nd-PDA-Fc is biocompatible when tested with model pre-osteoblast MC-3T3 E1 cells and promotes cell adhesion and spreading presumably due to its nano-topographical features. The MRSA infected wound model also indicates that Ti-Nd-PDA-Fc with NIR irradiation can effectively eliminate bacterial infection and suppress host inflammatory responses. We believe this study demonstrates a simple means to create biocompatible redox-active coatings that confer context-dependent antibacterial activities to implant surfaces.
    DOI:  https://doi.org/10.1021/acsami.9b22339
  1303. J Pak Med Assoc. 2020 Jan;70(1): 80-85
    Association of body mass index, cardiorespiratory fitness, and their correlates among female physiotherapy students in Nawabshah.
    Ali B, Ansari MA, Qambrani MR, Memon AR, Ahmed I, Rehman Memon AU.
      OBJECTIVE: To explore the association of body mass index with cardiorespiratory fitness and other health correlates among physiotherapy students.METHODS: This cross-sectional study was conducted from February to July 2018 at the Peoples University of Medical and Health Sciences for Women, Nawabshah, Pakistan, comprising female undergraduate physiotherapy students aged 17-25 years. All the eligible participants were assessed using a self-report questionnaire, body mass index, and standardised cardiorespiratory fitness criteria. SPSS 20 was used for data analysis.
    RESULTS: There were 228 subjects with a mean age of 20.89±1.66 years. Of the total, 77(33.8%) students were overweight/obese and 52(22.8%) were underweight. Overall, 212(93%) reported good quality of life, and 189(82.9%) were satisfied with their general health. Also, 180(79%) subjects had a post-exercise heart rate below average. There was a significant negative correlation for body mass index and maximum oxygen uptake, body mass index and age, and maximum oxygen uptake and subjective quality of life (p<0.05 each).
    CONCLUSIONS: The frequency of both overweight/obesity and underweight physiotherapy undergraduates was high.
    Keywords:   Aerobic capacity, Cardiorespiratory fitness, Obesity, Physiotherapy students, Quality of life.
    DOI:  https://doi.org/10.5455/JPMA.678
  1304. ACS Chem Biol. 2020 Jan 24.
    Clickable Galactose Analogs for Imaging Glycans in Developing Zebrafish.
    Daughtry JL, Cao W, Ye J, Baskin JM.
      Galactose is one of only nine monosaccharide precursors used to build complex glycans in vertebrates. Defects in galactose metabolism cause galactosemia and lysosomal storage diseases, and the ability to visualize metabolic flux through these pathways would help to understand mechanisms underlying disease pathogenesis. Bioorthogonal metabolic reporters are widely used tools to image glycan biosynthesis, but to date, no galactose analogs have capitalized on this strategy. We demonstrate that the galactose salvage pathway is remarkably intolerant of unnatural galactose and galactose-1-phosphate analogs. Subtle modifications to uridine diphosphate galactose (UDP-Gal), the universal donor for galactosyltransferases, however, yielded effective metabolic probes for labeling glycans in vivo. We applied 6-alkynyl UDP-Gal, followed by click chemistry tagging, to visualize glycosylation during zebrafish development, revealing a striking accumulation into glycan-rich ridges within the organism's enveloping layer. UDP-Gal analogs represent a new class of glycan metabolic probes for revealing physiological and pathological changes in glycosylation in vivo.
    DOI:  https://doi.org/10.1021/acschembio.9b00898
  1305. Plant Physiol Biochem. 2020 Jan 11. pii: S0981-9428(20)30010-3. [Epub ahead of print]148 152-165
    Physiological and transcriptomic analyses of cadmium stress response in Dendrobium officinale seedling.
    Jiang W, Wu Z, Wang T, Mantri N, Huang H, Li H, Tao Z, Guo Q.
      Dendrobium officinale is an economically important Chinese herb with ornamental and medicinal values. However, the mechanisms by which D. officinale adapts to cadmium (Cd) stress is unknown. Here, physiological changes in D. officinale roots and leaves exposed to increasing levels of Cd stress (CdSO4 concentration of 2, 5, 9, 14 mg L-1) were analyzed at 7, 15, 30, and 45 days after treatment. The Cd stress of 14 mg L-1 significantly increased the levels of antioxidants and induced malondialdehyde and proline accumulation (P < 0.05). Cd subcellular distribution showed that Cd sequestration into soluble fraction is the major detoxification mechanism in D. officinale roots. Subsequently, the transcriptome profile of D. officinale roots treated with 14 mg L-1 Cd for 15 and 30 days was analyzed. Compared to control, 2,469 differentially expressed genes (DEGs) were identified, comprising 1,486 up-regulated genes and 983 down-regulated genes. The DEGs associated with metabolic pathways for Cd uptake, transportation and detoxification were analyzed. Several processes such as metal transporter, sulfate glutathione metabolism, cell wall metabolism, phenylpropanoid metabolism were identified to be important for Cd stress adaptation. More genes were expressed at 15 days after treatment compared to 30 days. WRKY, Trihelix, NF-YC, MYB, bZIP and bHLH transcription factors were over-expressed at both time points. Furthermore, candidate genes from the glutathione metabolism pathway were identified, and qRT-PCR analysis of ten DEGs indicated a high coorelation with RNA-seq expression profiles. Our findings provide significant information for further research of Cd stress responsive genes functions in D. officinale, especially the genes from the glutathione metabolism pathway.
    Keywords:  Cadmium stress; Dendrobium officinale; Differential expression genes; Glutathione metabolism; Physiology; Transcriptome
    DOI:  https://doi.org/10.1016/j.plaphy.2020.01.010
  1306. Sci Rep. 2020 Jan 21. 10(1): 815
    Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice.
    Nishikawa T, Nagata N, Shimakami T, Shirakura T, Matsui C, Ni Y, Zhuge F, Xu L, Chen G, Nagashimada M, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S, Ota T.
      Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.
    DOI:  https://doi.org/10.1038/s41598-020-57784-3
  1307. J Nanobiotechnology. 2020 Jan 21. 18(1): 18
    Core-shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts.
    Kovács D, Igaz N, Marton A, Rónavári A, Bélteky P, Bodai L, Spengler G, Tiszlavicz L, Rázga Z, Hegyi P, Vizler C, Boros IM, Kónya Z, Kiricsi M.
      BACKGROUND: Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts.RESULTS: We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis.
    CONCLUSIONS: Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.
    Keywords:  Cancer-associated fibroblasts; Core–shell nanoparticles; Metastasis; RNA sequencing; Tumour stroma
    DOI:  https://doi.org/10.1186/s12951-020-0576-x
  1308. Adv Respir Med. 2019 ;87(6): 268-269
    Cystic lung disease in an adult non-smoker.
    Joshi A, Gupta N, Ish P, Chakrabarti S.
      
    Keywords:  non-smoker; pLCH; pneumothorax
    DOI:  https://doi.org/10.5603/ARM.2019.0066
  1309. J Neurooncol. 2020 Jan 20.
    Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.
    Ferreira MSV, Sørensen MD, Pusch S, Beier D, Bouillon AS, Kristensen BW, Brümmendorf TH, Beier CP, Beier F.
      PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance.METHODS: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1R132H mutation and CS-TL was studied in vitro using an IDH1R132H doxycycline-inducible glioma cell line system.
    RESULTS: Virtually all ALTpositive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALTpositive samples had IDH1R132H mutations, resulting in a significantly longer CS-TL of IDH1R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDHwildtype, ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDHR132H in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT.
    CONCLUSION: ALT is the major telomere maintenance mechanism in IDHR132H mutated astrocytomas, while TERT promoter mutations were associated with IDHwildtype glioma. IDH1R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1R132H mutations, ATRX loss, and ALT.
    Keywords:  ALT; ATRX; D2HG; Isocitrate dehydrogenase; Q-FISH; TERT promoter; Telomerase; Telomere length
    DOI:  https://doi.org/10.1007/s11060-020-03394-y
  1310. Med Hypotheses. 2020 Jan 09. pii: S0306-9877(19)31217-4. [Epub ahead of print]137 109564
    Dysbiosis in Parkinson's disease might be triggered by certain antibiotics.
    Ternák G, Kuti D, Kovács KJ.
      Parkinson's disease (PD) is a neurodegenerative amyloid disorder with debilitating motor symptoms due to the loss of dopamine-synthesizing, basal ganglia-projecting neurons in the substantia nigra. An interesting feature of the disease is that most of PD patients have gastrointestinal problems and bacterial dysbiosis, years before the full expression of motor symptoms. We hypothesized that antibiotic consumption might be a contributing factor of gut microbiome dysbiosis in PD, favoring curli-producing Enterobacteria. Curli is a bacterial α-synuclein (αSyn) which is deposited first in the enteric nervous system and amyloid deposits are propagated in a prion like manner to the central nervous system. In addition, antibiotics result in a low-grade systemic inflammation, which also contributes to damage of neurons in enteric- and central nervous system. To support our hypothesis, by comparing PD prevalence change with antibiotic consumption data in EU countries, we found significant positive correlation between use narrow spectrum penicillin + penicillinase resistant penicillin and increased prevalence of the disease.
    Keywords:  Amyloid-like protein; Antibiotics; Broad spectrum antibiotics; Curli protein; Dysbiosis; Microbiome; Narrow-spectrum penicillin; Parkinson’s disease (PD)
    DOI:  https://doi.org/10.1016/j.mehy.2020.109564
  1311. J Cardiol. 2020 Jan 21. pii: S0914-5087(20)30002-2. [Epub ahead of print]
    Advent of New perioperative care for fluid management after cardiovascular surgery: A review of current evidence.
    Nishi H.
      Fluid management with diuretics is a key factor for postoperative management following cardiovascular surgery, and it is common to administer intermittent doses of diuretics and fluids in the early postoperative stage as primary therapy. Loop diuretics are usually given as the first option, followed by an aldosterone blocker, mannitol, and human atrial natriuretic peptide (hANP) or recombinant human B-type natriuretic peptide infusion. Although the effects of tolvaptan, a new type of diuretic with an aquaretic effect to increase urine volume without increasing electrolyte excretion into urine by blocking the vasopressin V2 receptor, on congestive heart failure are well known, it has not been established whether advantages may also be recognized in the volume overload in early postoperative stage after cardiac surgery. In this review, we clarified the efficacy of tolvaptan as the advent of new fluid management after cardiovascular surgery. Tolvaptan has advantageous effects for immediate body weight reduction in patients with positive postoperative water balance following cardiac surgery. This immediate volume reduction could help recovery of respiratory dysfunction due to lung edema. Also, hypernatremia was rarely seen; therefore, it can be used safely during postoperative period. With regard to the response of tolvaptan, it seemed to have a beneficial effect in patients with decreased renal function, increased body weight, and hypoalbuminemia. Although long-term outcome is still unknown, tolvaptan treatment added to conventional diuretics treatment in patients undergoing cardiovascular surgery provides sufficient amount of fluid removal without affecting renal function and serum sodium concentrations, and reduced the incidence of worsening renal function.
    Keywords:  Cardiovascular surgery; Heart failure; Postoperative fluid management; Renal function; Tolvaptan
    DOI:  https://doi.org/10.1016/j.jjcc.2019.12.010
  1312. Tob Control. 2020 Jan 22. pii: tobaccocontrol-2019-055354. [Epub ahead of print]
    Tobacco manufacturer lobbying to undercut minimum price laws: an analysis of internal industry documents.
    Apollonio DE, Glantz S.
      BACKGROUND: Increasing the price of tobacco products has the potential to reduce tobacco consumption. As other forms of promotion have been increasingly restricted over time, tobacco manufacturers have relied more on trade discounts. Minimum price laws that prevented the use of manufacturer promotions were once common; however in most US jurisdictions these discounts are now legally protected.METHODS: We collected tobacco industry documents, state legislation and court cases between 1987 and 2016 to review tobacco manufacturer strategies to change minimum price laws in the USA.
    RESULTS: Beginning in 2000, tobacco manufacturers lobbied to amend minimum price legislation after state regulators indicated that manufacturer promotions were illegal under existing laws. Companies viewed changing these laws as critical to maintaining tobacco sales, and after the initiation of an industry lobbying campaign, at least 20 states changed the way they calculated tobacco prices.
    CONCLUSIONS: Modifying existing minimum price laws so that manufacturer discounts are no longer protected, and implementing new minimum price policies with comparable scope, would likely increase prices and reduce tobacco use.
    Keywords:  advertising and promotion; advocacy; price; public policy; tobacco industry documents
    DOI:  https://doi.org/10.1136/tobaccocontrol-2019-055354
  1313. AMB Express. 2020 Jan 18. 10(1): 14
    NADPH biosensor-based identification of an alcohol dehydrogenase variant with improved catalytic properties caused by a single charge reversal at the protein surface.
    Spielmann A, Brack Y, van Beek H, Flachbart L, Sundermeyer L, Baumgart M, Bott M.
      Alcohol dehydrogenases (ADHs) are used in reductive biotransformations for the production of valuable chiral alcohols. In this study, we used a high-throughput screening approach based on the NADPH biosensor pSenSox and fluorescence-activated cell sorting (FACS) to search for variants of the NADPH-dependent ADH of Lactobacillus brevis (LbADH) with improved activity for the reduction of 2,5-hexanedione to (2R,5R)-hexanediol. In a library of approx. 1.4 × 106 clones created by random mutagenesis we identified the variant LbADHK71E. Kinetic analysis of the purified enzyme revealed that LbADHK71E had a ~ 16% lowered KM value and a 17% higher Vmax for 2,5-hexanedione compared to the wild-type LbADH. Higher activities were also observed for the alternative substrates acetophenone, acetylpyridine, 2-hexanone, 4-hydroxy-2-butanone, and methyl acetoacetate. K71 is solvent-exposed on the surface of LbADH and not located within or close to the active site. Therefore, K71 is not an obvious target for rational protein engineering. The study demonstrates that high-throughput screening using the NADPH biosensor pSenSox represents a powerful method to find unexpected beneficial mutations in NADPH-dependent alcohol dehydrogenases that can be favorable in industrial biotransformations.
    Keywords:  Enzyme optimization; Fluorescence-activated cell sorting; Lactobacillus brevis; NADPH biosensor; NADPH-dependent alcohol dehydrogenase; Random mutagenesis
    DOI:  https://doi.org/10.1186/s13568-020-0946-7
  1314. J Cell Physiol. 2020 Jan 21.
    E35 ablates acute leukemia stem and progenitor cells in vitro and in vivo.
    Chen Y, Zheng J, Gan D, Chen Y, Zhang N, Chen Y, Lin Z, Wang W, Chen H, Lin D, Hu J.
      Leukemia stem cells (LSCs) have critical functions in acute leukemia (AL) pathogenesis, participating in its initiation and relapse. Thus, identifying new molecules to eradicate LSCs represents a high priority for AL management. This work identified E35, a novel Emodin derivative, which strongly inhibited growth and enhanced apoptosis of AL stem cell lines, and primary stem and progenitor cells from AL cases, while sparing normal hematopoietic cells. Furthermore, functional assays in cultured cells and animals suggested that E35 preferentially ablated primitive leukemia cell populations without impairing their normal counterparts. Moreover, molecular studies showed that E35 remarkably downregulated drug-resistant gene and dramatically inhibited the Akt/mammalian target of rapamycin signaling pathway. Notably, the in vivo anti-LSC activity of E35 was further confirmed in murine xenotransplantation models. Collectively, these findings indicate E35 constitutes a novel therapeutic candidate for AL, potentially targeting leukemia stem and progenitor cells.
    Keywords:  Akt/mTOR; E35; acute leukemia; apoptosis; leukemia stem/progenitor cells; xenograft model
    DOI:  https://doi.org/10.1002/jcp.29457
  1315. Sci Total Environ. 2020 Jan 10. pii: S0048-9697(20)30106-6. [Epub ahead of print]713 136596
    Integrated modelling to assess N pollution swapping in slurry amended soils.
    Cameira MDR, Li R, Fangueiro D.
      
    Keywords:  Mitigation measures; N emission factors; N leaching factors; N(2)O emissions; NO(3)(−) leaching
    DOI:  https://doi.org/10.1016/j.scitotenv.2020.136596
  1316. J Clin Med. 2020 Jan 17. pii: E246. [Epub ahead of print]9(1):
    Association between On-Treatment Haemoglobin A1c and All-Cause Mortality in Individuals with Type 2 Diabetes: Importance of Personalized Goals and Type of Anti-Hyperglycaemic Treatment.
    Orsi E, Bonora E, Solini A, Fondelli C, Trevisan R, Vedovato M, Cavalot F, Zerbini G, Morano S, Nicolucci A, Penno G, Pugliese G.
      The increased mortality reported with intensive glycaemic control has been attributed to an increased risk of treatment-related hypoglycaemia. This study investigated the relationships of haemoglobin (Hb) A1c, anti-hyperglycaemic treatment, and potential risks of adverse effects with all-cause mortality in patients with type 2 diabetes. Patients (n = 15,773) were stratified into four categories according to baseline HbA1c and then assigned to three target categories, based on whether HbA1c was ≤0.5% below or above (on-target), >0.5% below (below-target) or >0.5% above (above-target) their HbA1c goal, personalized according to the number of potential risks among age > 70 years, diabetes duration > 10 years, advanced complication(s), and severe comorbidity (ies). The vital status was retrieved for 15,656 patients (99.26%). Over a 7.4-year follow-up, mortality risk was increased among patients in the highest HbA1c category (≥8.5%) (adjusted hazard ratio, 1.34 (95% confidence interval, 1.22-1.47), p < 0.001) and those above-target (1.42 (1.29-1.57), p < 0.001). Risk was increased among individuals in the lowest HbA1c category (<6.5%) and those below-target only if treated with agents causing hypoglycaemia (1.16 (1.03-1.29), p = 0.01 and 1.10 (1.01-1.22), p = 0.04, respectively). These data suggest the importance of setting both upper and lower personalized HbA1c goals to avoid overtreatment in high-risk individuals with type 2 diabetes treated with agents causing hypoglycaemia.
    Keywords:  HbA1c all-cause mortality; adverse treatment effects; hypoglycaemia; type 2 diabetes
    DOI:  https://doi.org/10.3390/jcm9010246
  1317. Br J Sports Med. 2020 Jan 21. pii: bjsports-2019-101765. [Epub ahead of print]
    Physical activity and mortality: what is the dose response and how big is the effect?
    Ekelund U, Dalene KE, Tarp J, Lee IM.
      
    Keywords:  physical activity
    DOI:  https://doi.org/10.1136/bjsports-2019-101765
  1318. Sci Rep. 2020 Jan 20. 10(1): 688
    Natural drivers of multidecadal Arctic sea ice variability over the last millennium.
    Halloran PR, Hall IR, Menary M, Reynolds DJ, Scourse JD, Screen JA, Bozzo A, Dunstone N, Phipps S, Schurer AP, Sueyoshi T, Zhou T, Garry F.
      The climate varies due to human activity, natural climate cycles, and natural events external to the climate system. Understanding the different roles played by these drivers of variability is fundamental to predicting near-term climate change and changing extremes, and to attributing observed change to anthropogenic or natural factors. Natural drivers such as large explosive volcanic eruptions or multidecadal cycles in ocean circulation occur infrequently and are therefore poorly represented within the observational record. Here we turn to the first high-latitude annually-resolved and absolutely dated marine record spanning the last millennium, and the Paleoclimate Modelling Intercomparison Project (PMIP) Phase 3 Last Millennium climate model ensemble spanning the same time period, to examine the influence of natural climate drivers on Arctic sea ice. We show that bivalve oxygen isotope data are recording multidecadal Arctic sea ice variability and through the climate model ensemble demonstrate that external natural drivers explain up to third of this variability. Natural external forcing causes changes in sea-ice mediated export of freshwater into areas of active deep convection, affecting the strength of the Atlantic Meridional Overturning Circulation (AMOC) and thereby northward heat transport to the Arctic. This in turn leads to sustained anomalies in sea ice extent. The models capture these positive feedbacks, giving us improved confidence in their ability to simulate future sea ice in in a rapidly evolving Arctic.
    DOI:  https://doi.org/10.1038/s41598-020-57472-2
  1319. J Comput Aided Mol Des. 2020 Jan 24.
    The SAMPL6 challenge on predicting octanol-water partition coefficients from EC-RISM theory.
    Tielker N, Tomazic D, Eberlein L, Güssregen S, Kast SM.
      Results are reported for octanol-water partition coefficients (log P) of the neutral states of drug-like molecules provided during the SAMPL6 (Statistical Assessment of Modeling of Proteins and Ligands) blind prediction challenge from applying the "embedded cluster reference interaction site model" (EC-RISM) as a solvation model for quantum-chemical calculations. Following the strategy outlined during earlier SAMPL challenges we first train 1- and 2-parameter water-free ("dry") and water-saturated ("wet") models for n-octanol solvation Gibbs energies with respect to experimental values from the "Minnesota Solvation Database" (MNSOL), yielding a root mean square error (RMSE) of 1.5 kcal mol-1 for the best-performing 2-parameter wet model, while the optimal water model developed for the pKa part of the SAMPL6 challenge is kept unchanged (RMSE 1.6 kcal mol-1 for neutral compounds from a model trained on both neutral and ionic species). Applying these models to the blind prediction set yields a log P RMSE of less than 0.5 for our best model (2-parameters, wet). Further analysis of our results reveals that a single compound is responsible for most of the error, SM15, without which the RMSE drops to 0.2. Since this is the only compound in the challenge dataset with a hydroxyl group we investigate other alcohols for which Gibbs energy of solvation data for both water and n-octanol are available in the MNSOL database to demonstrate a systematic cause of error and to discuss strategies for improvement.
    Keywords:  EC-RISM; Integral equation theory; Quantum chemistry; SAMPL6; Solvation model; log P
    DOI:  https://doi.org/10.1007/s10822-020-00283-4
  1320. Methods Appl Fluoresc. 2020 Jan 23.
    Optimization of FLIM imaging, fitting and analysis for auto-fluorescent NAD(P)H and FAD in cells and tissues.
    Cao R, Wallrabe H, Siller K, Periasamy A.
      Increasingly, the auto-fluorescent coenzymes NAD(P)H and FAD are being tracked by multi-photon fluorescence lifetime microscopy (FLIM) and used as versatile markers for changes in mammalian metabolism. The cellular redox state of different cell model systems, organoids and tissue sections is investigated in a range of pathologies where the metabolism is disrupted or reprogrammed; the latter is particularly relevant in cancer biology. Yet, the actual optimized process of acquiring images by FLIM, execute a correct lifetime fitting procedure and subsequent processing and analysis can be challenging for new users. Questions remain of how to optimize FLIM experiments, whether any potential photo-bleaching affects FLIM results and whether fixed specimens can be used in experiments. We have broken down the multi-step sequence into best-practice application of FLIM for NAD(P)H and FAD imaging, with images generated by a time-correlated-single-photon-counting (TCSPC) system, fitted with Becker & Hickl software and further processed with open-source ImageJ/Fiji and Python software.
    Keywords:  FAD; FLIM; Metabolic Imaging; Multiphoton; NAD(P)H
    DOI:  https://doi.org/10.1088/2050-6120/ab6f25
  1321. Int J Mol Sci. 2020 Jan 19. pii: E655. [Epub ahead of print]21(2):
    Scenarios of Genes-to-Terpenoids Network Led to the Identification of a Novel α/β-Farnesene/β-Ocimene Synthase in Camellia sinensis.
    Jin J, Zhang S, Zhao M, Jing T, Zhang N, Wang J, Wu B, Song C.
      Terpenoids play vital roles in tea aroma quality and plants defense performance determination, whereas the scenarios of genes to metabolites of terpenes pathway remain uninvestigated in tea plants. Here, we report the use of an integrated approach combining metabolites, target gene transcripts and function analyses to reveal a gene-to-terpene network in tea plants. Forty-one terpenes including 26 monoterpenes, 14 sesquiterpenes and one triterpene were detected and 82 terpenes related genes were identified from five tissues of tea plants. Pearson correlation analysis resulted in genes to metabolites network. One terpene synthases whose expression positively correlated with farnesene were selected and its function was confirmed involved in the biosynthesis of α-farnesene, β-ocimene and β-farnesene, a very important and conserved alarm pheromone in response to aphids by both in vitro enzymatic assay in planta function analysis. In summary, we provided the first reliable gene-to-terpene network for novel genes discovery.
    Keywords:  Camellia sinensis; farnesene; gene silencing; gene-to-terpene network; metabolic profiling; terpene synthase; β-ocimene
    DOI:  https://doi.org/10.3390/ijms21020655
  1322. Nihon Hinyokika Gakkai Zasshi. 2019 ;110(1): 36-40
    [DRUG-INDUCED INTERSTITIAL LUNG DISEASE DURING COMBINED ANDROGEN BLOCKADE WITH BICALUTAMIDE AND LEUPRORELIN ACETATE FOR PROSTATE CANCER].
    Maeda K, Osafune T, Masuda Y, Takeda T, Kageyama S, Narita M, Kawauchi A.
      We report a case of drug-induced interstitial lung disease as a result of combined androgen blockade. A 75 year-old male was receiving bicalutamide and reuprorelin acetate treatment for advanced prostate cancer. Two weeks after starting therapy, the patient developed dyspnea due to interstitial lung disease. Based on the clinical diagnosis of drug-induced interstitial lung disease, bicalutamide was withdrawn and steroid therapy was initiated. The patient succumbed 6 days later due to respiratory failure. Drug-induced interstitial lung disease following combined androgen blockade is a rare, but potentially serious adverse effect that requires close attention.
    Keywords:  combined androgen blockade; drug-induced interstitial lung disease; prostate cancer
    DOI:  https://doi.org/10.5980/jpnjurol.110.36
  1323. Acta Myol. 2019 Dec;38(4): 207-214
    Exercise in neuromuscular disorders: a promising intervention.
    Voet NBM.
      Although performing exercise studies in patients with neuromuscular disorders (NMD) is difficult, the number of randomized controlled trials is steadily increasing. There is growing evidence for a positive effect of aerobic exercise in several NMD, on the other hand, the evidence for the effect of strength training is still scarce. Many NMD patients are captured in a vicious circle of physical inactivity, and it is important to let patients adhere to an active lifestyle, in order to prevent further chronic cardiovascular and muscle deconditioning and increased cardiovascular health risks. Exercise has to be prescribed as if it is medicine, in order to increase the adherence of patients and to optimize the efficacy of the intervention. Exercise in NMD is safe, although for some metabolic myopathies there is a contraindication for strenuous exercise. In NMD known to affect cardiac muscle, it is usually safe to exercise, but the consultation of a cardiologist is advised. Based on recent research, an increase in physical activity of moderate intensity and of sufficient duration, i.e. a physically active lifestyle, could be at least as effective and relevant as physical training. Underlying mechanisms of effect of exercise could be the influence of epigenetic mechanisms and the anti-inflammatory effect of exercise, but further studies are needed to confirm these hypotheses.
    Keywords:  exercise; neuromuscular disorders; physical activity
  1324. Nanoscale. 2020 Jan 23.
    Live cell single molecule tracking and localization microscopy of bioorthogonally labeled plasma membrane proteins.
    König AI, Sorkin R, Alon A, Nachmias D, Dhara K, Brand G, Yifrach O, Arbely E, Roichman Y, Elia N.
      Tracking the localization and mobility of individual proteins in live cells is key for understanding how they mediate their function. Such information can be obtained from single molecule imaging techniques including as Single Particle Tracking (SPT) and Single Molecule Localization Microscopy (SMLM). Genetic code expansion (GCE) combined with bioorthogonal chemistry offers an elegant approach for direct labeling of proteins with fluorescent dyes, holding great potential for improving protein labeling in single molecule applications. Here we calibrated conditions for performing SPT and live-SMLM of bioorthogonally labeled plasma membrane proteins in live mammalian cells. Using SPT, the diffusion of bioorthogonally labeled EGF receptor and the prototypical Shaker voltage-activated potassium channel (Kv) was measured and characterized. Applying live-SMLM to bioorthogonally labeled Shaker Kv channels enabled visualizing the plasma membrane distribution of the channel over time with ∼30 nm accuracy. Finally, by competitive labeling with two Fl-dyes, SPT and live-SMLM were performed in a single cell and both the density and dynamics of the EGF receptor were measured at single molecule resolution in subregions of the cell. We conclude that GCE and bioorthogonal chemistry is a highly suitable, flexible approach for protein labeling in quantitative single molecule applications that outperforms current protein live-cell labeling approaches.
    DOI:  https://doi.org/10.1039/c9nr08594g
  1325. ACS Appl Mater Interfaces. 2020 Jan 21.
    Axial alignment of carbon nanotubes on fibers to enable highly conductive fabrics for electromagnetic interference shielding.
    Lan C, Guo M, Li C, Qiu Y, Ma Y, Sun J.
      Conductive coatings show great promise for next-generation electromagnetic interference (EMI) shielding challenges on textile; however, their stringent requirements for electrical conductivity are difficult to meet by conventional approaches of increasing the loading and homogeneity of conductive nanofillers. Here, the axial alignment of carbon nanotubes (CNTs) on fibers that obtained by spontaneous capillary-driven self-assembly is shown on commercial cotton fabrics and its great potential for EMI shielding is demonstrated. The aligned CNTs optimize structurally the conductive network on fabrics and yield an 81-fold increase in electrical conductivity per unit CNT, compared with the disordered CNT microstructure. The high-efficiency electrical conductivity allows a several-micron-thick coating on insulating fabrics to endow an EMI shielding effectiveness of 21.5 dB in the X band and 20.8 dB in the Ku band, respectively, which meets the standard shielding requirement in commercial applications. It is among the minimum reported thicknesses for conductive nanocomposite coatings to date. Moreover, the coated fabrics with aligned CNTs possess a desirable stability upon bending, scratching, stripping and even washing, which is attributed to the dense CNT packing in the aligned microarchitecture. This work presents the anisotropic structure on large areas by self-assembly, offering new opportunities for next-generation portable and wearable electronic devices.
    DOI:  https://doi.org/10.1021/acsami.9b21698
  1326. Ambio. 2020 Jan 20.
    Orchid conservation and research: An analysis of gaps and priorities for globally Red Listed species.
    Wraith J, Norman P, Pickering C.
      Orchids are among the most threatened taxa globally due to increasing anthropogenic threats, inherent rarity and specific conservation needs. But what are the global research and conservation priorities for this charismatic group of plants? Using information for 595 orchids on the IUCN Red List, we reviewed past research and identified key research and conservation priorities. These included understanding threats, monitoring orchid populations and habitats, species management in ex situ conservation, genome resource banks and artificial propagation, land and habitat protection and education and awareness through communication. Based on the available data, we recommend future orchid conservation and research should focus on the current gaps in knowledge and practice including monitoring population trends and distributions, ecology, threats, protection and management of species and their habitats and increasing education and awareness.
    Keywords:  Anthropogenic threats; Conservation; Global biodiversity; IUCN Red List; Threatened species
    DOI:  https://doi.org/10.1007/s13280-019-01306-7
  1327. IEEE Trans Biomed Eng. 2020 Jan 16.
    Extraction of Nonlinear Synergies for Proportional and Simultaneous Estimation of Finger Kinematics.
    Dwivedi SK, Ngeo JG, Shibata T.
      OBJECTIVE: Proportional and simultaneous estimation of finger kinematics from surface EMG based on the assumption that there exists a correlation between muscle activations and finger kinematics in low dimensional space.METHODS: We employ Manifold Relevance Determination (MRD), a multi-view learning model with a nonparametric Bayesian approach, to extract the nonlinear muscle and kinematics synergies and the relationship between them by studying muscle activations (input-space) together with the finger kinematics (output-space).
    RESULTS: This study finds that there exist muscle synergies which are associated with kinematic synergies. The acquired nonlinear synergies and the association between them has further been utilized for the estimation of finger kinematics from muscle activation inputs, and the proposed approach has outperformed other commonly used linear and nonlinear regression approaches with an average correlation coefficient of 0.91±0.03.
    CONCLUSION: There exists an association between muscle and kinematic synergies which can be used for the proportional and simultaneous estimation of finger kinematics from the muscle activation inputs.
    SIGNIFICANCE: The findings of this study not only presents a viable approach for accurate and intuitive myoelectric control but also provides a new perspective on the muscle synergies in the motor control community.
    DOI:  https://doi.org/10.1109/TBME.2020.2967154
  1328. Autophagy. 2020 Jan 20. 1-2
    Targeting selective autophagy by AUTAC degraders.
    Takahashi D, Arimoto H.
      Targeted degradation is a promising new modality in drug discovery that makes it possible to reduce intracellular protein levels with small molecules. It is a complementary approach to the conventional protein knockdown typically used in laboratories and may offer a way to approach the currently undruggable human proteome. Recently, the first autophagy-mediated degraders, called AUTACs, were developed based on observations in a xenophagy study.
    Keywords:  AUTAC; PROTAC; drug discovery; guanylation; mitophagy; targeted degradation
    DOI:  https://doi.org/10.1080/15548627.2020.1718362
  1329. Clin Oncol (R Coll Radiol). 2020 Jan 20. pii: S0936-6555(19)30540-0. [Epub ahead of print]
    Radiotherapy to the Primary Tumour for Patients with Metastatic Prostate Cancer: Practice-Changing Results from STAMPEDE.
    Malik ZI, Fenwick JD.
      
    DOI:  https://doi.org/10.1016/j.clon.2019.12.010
  1330. Anasthesiol Intensivmed Notfallmed Schmerzther. 2020 Jan;55(1): 54-58
    [Anaesthesia in Electrochemotherapy].
    Volberg C, Gschnell M.
      Electrochemotherapy (ECT) is a symptom control method for inoperable or exulcerating cutaneous metastases or skin cancer. With the help of electroporation, an enhancement of the efficacy of the administered chemotherapeutic agent, bleomycin or cisplatin, is achieved, which leads to a local reduction of the metastases and thereby has a low impact on the systemic health.ECT can be performed under local, regional or general anaesthesia, whereby the form of anaesthesia depends on the number and extent of the metastases as well as the affected body site. For general anaesthesia, there are some special aspects to consider. To prevent lung damage from bleomycin, the patient has to be ventilated with a low FiO2 (< 0.3), or preferably with room air. To avoid drug interactions and postoperative pain, general anaesthesia is performed as TIVA in deep relaxation. The anaesthesia team should be aware of the necessary precautions when applying chemotherapeutic agents and should recognize contraindications to performing anaesthesia in ECT in advance.
    DOI:  https://doi.org/10.1055/a-1014-8181
  1331. Nihon Hoshasen Gijutsu Gakkai Zasshi. 2020 ;76(1): 113-118
    [6. Handling of Personal Information].
    Kawamata M.
      
    DOI:  https://doi.org/10.6009/jjrt.2020_JSRT_76.1.113
  1332. Focus (Am Psychiatr Publ). 2019 Apr;17(2): 110-116
    Assessment and Management of Endocarditis Among People Who Inject Drugs in the General Hospital Setting.
    Suzuki J.
      Hospitalizations related to infectious complications from injection drug use are increasing in the context of the opioid crisis. Unfortunately, these hospital encounters are infrequently used to initiate treatment for the underlying opioid use disorder, even though many patients are amenable to treatment initiation. Both buprenorphine and methadone can be utilized with good effect to manage not only opioid use disorder but also acute pain. Controversies exist over the ethics of surgical management for patients who relapse and require reoperation. The appropriate approach may be to ensure that all patients with endocarditis are offered evidence-based treatment for the underlying substance use disorder as soon as possible. In addition, the initiation of medication treatment should be paired with ongoing outpatient treatment, given the high rates of mortality and reinfection due to endocarditis among this population. There is growing evidence that outpatient parenteral antimicrobial therapy may be appropriate even among people who inject drugs.
    Keywords:  Substance use disorder; endocarditis; pain; people who inject drugs
    DOI:  https://doi.org/10.1176/appi.focus.20180040
  1333. J Med Chem. 2020 Jan 23.
    Benzenesulfonamide Derivatives as Calcium/Calmodulin-Dependent Protein Kinase Inhibitors and Antiviral Agents Against Dengue and Zika Virus Infections.
    Chen WC, Simanjuntak Y, Chu LW, Ping YH, Lee YL, Lin YL, Li WS.
      Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socio-economic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barré syndrome. To develop potentially antiviral drugs for combatting these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 µM and displayed EC50 values of 1.52 µM and 1.91 µM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.
    DOI:  https://doi.org/10.1021/acs.jmedchem.9b01779
  1334. Expert Opin Drug Metab Toxicol. 2020 Jan 24.
    Pharmacokinetic and pharmacodynamic considerations in developing a response to the opioid epidemic.
    Balyan R, Hahn D, Huang H, Chidambaran V.
      Introduction: Opioids continue to be used widely for pain management. Widespread availability of prescription opioids has led to opioid abuse and addiction. Besides steps to reduce inappropriate prescribing, exploiting opioid pharmacology to make their use safer is important.Areas covered: This article discusses the pathology and factors underlying opioid abuse. Pharmacokinetic and pharmacodynamic properties affecting abuse liability of commonly abused opioids have been highlighted. These properties inform development of ideal abuse deterrent products. Mechanisms and cost-effectiveness of available abuse deterrent products have been reviewed in addition to the pharmacology of medications used to treat addiction.Expert opinion: The opioid crisis presents unique challenges to managing pain effectively given the limited repertoire of strong analgesics. The 5-point strategy to combat the opioid crisis calls for better preventive, treatment and recovery services, better data, better pain management, better availability of overdose-reversing drugs and better research. There is an urgent need to decrease the cost of abuse deterrent opioids which deters their cost-effectiveness. In addition, discovery of novel analgesics, further insight into central and peripheral pain mechanisms, understanding genomic risk profiles for efficient targeted efforts, and education will be key to winning this fight against the opioid crisis.
    Keywords:  Abuse deterrent product; Opioid crisis; PK-PD; pain pharmacology
    DOI:  https://doi.org/10.1080/17425255.2020.1721458
  1335. Qual Life Res. 2020 Jan 22.
    Health-related quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndrome: an Australian cross-sectional study.
    Eaton-Fitch N, Johnston SC, Zalewski P, Staines D, Marshall-Gradisnik S.
      BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS.METHODS: Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL.
    RESULTS: Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties.
    CONCLUSION: This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.
    Keywords:  Chronic fatigue syndrome; Health-related quality of life; Myalgic encephalomyelitis; SF-36
    DOI:  https://doi.org/10.1007/s11136-019-02411-6
  1336. J Thorac Cardiovasc Surg. 2019 Nov 27. pii: S0022-5223(19)33463-4. [Epub ahead of print]
    Commentary: Age is just an element of the quality of life puzzle following aortic valve replacement.
    Mariscalco G, Juvonen T, Biancari F.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.11.021
  1337. Methods Mol Biol. 2020 ;2117 135-157
    Profiling Cell Type Abundance and Expression in Bulk Tissues with CIBERSORTx.
    Steen CB, Liu CL, Alizadeh AA, Newman AM.
      CIBERSORTx is a suite of machine learning tools for the assessment of cellular abundance and cell type-specific gene expression patterns from bulk tissue transcriptome profiles. With this framework, single-cell or bulk-sorted RNA sequencing data can be used to learn molecular signatures of distinct cell types from a small collection of biospecimens. These signatures can then be repeatedly applied to characterize cellular heterogeneity from bulk tissue transcriptomes without physical cell isolation. In this chapter, we provide a detailed primer on CIBERSORTx and demonstrate its capabilities for high-throughput profiling of cell types and cellular states in normal and neoplastic tissues.
    Keywords:  Cellular heterogeneity; Deconvolution; Digital cytometry; Gene expression; Tumor microenvironment; scRNA-seq
    DOI:  https://doi.org/10.1007/978-1-0716-0301-7_7
  1338. Cell Calcium. 2019 Dec 17. pii: S0143-4160(19)30220-9. [Epub ahead of print]86 102151
    Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure.
    Leenen FHH, Wang HW, Hamlyn JM.
      Accumulating evidence obtained over the last three decades has revealed a neuroendocrine system in the brain that mediates long term increases in blood pressure. The system involves distinct ion transport pathways including the alpha-2 isoform of the Na,K pump and epithelial sodium channels, as well as critical hormone elements such as angiotensin II, aldosterone, mineralocorticoid receptors and endogenous ouabain. Activation of this system either by circulating or central sodium ions and/or angiotensin II leads to a cascading sequence of events that begins in the hypothalamus and involves the participation of several brain nuclei including the subfornical organ, supraoptic and paraventricular nuclei and the rostral ventral medulla. Key events include heightened aldosterone synthesis and mineralocorticoid receptor activation, upregulation of epithelial sodium channels, augmented synthesis and secretion of endogenous ouabain from hypothalamic magnocellular neurons, and sustained increases in sympathetic outflow. The latter step depends upon increased production of angiotensin II and the primary amplification of angiotensin II type I receptor signaling from the paraventricular nucleus to the rostral ventral lateral medulla. The transmission of sympathetic traffic is secondarily amplified in the periphery by increased short- and long-term potentiation in sympathetic ganglia and by sustained actions of endogenous ouabain in the vascular wall that augment expression of sodium calcium exchange, increase cytosolic Ca2+ and heighten myogenic tone and contractility. Upregulation of this multi-amplifier system participates in forms of hypertension where salt, angiotensin and/or aldosterone are elevated and contributes to adverse outcomes in heart failure.
    Keywords:  Brain; Calcium; Hypertension; Ouabain; Sodium potassium pump
    DOI:  https://doi.org/10.1016/j.ceca.2019.102151
  1339. Neuropharmacology. 2020 Jan 16. pii: S0028-3908(20)30030-7. [Epub ahead of print] 107964
    Monoacylglycerol lipase alpha inhibition alters prefrontal cortex excitability and blunts the consequences of traumatic stress in rat.
    Worley NB, Varela JA, Gaillardetz GP, Hill MN, Christianson JP.
      Neural activity within the ventromedial prefrontal cortex (vmPFC) is a critical determinant of stressor-induced anxiety. Pharmacological activation of the vmPFC during stress protects against stress-induced social anxiety suggesting that altering the excitatory/inhibitory (E/I) tone in the vmPFC may promote stress resilience. E/I balance is maintained, in part, by endogenous cannabinoid (eCB) signaling with the calcium dependent retrograde release of 2-arachidonoylglycerol (2-AG) suppressing presynaptic neurotransmitter release. We hypothesized that raising 2-AG levels, via inhibition of its degradation enzyme monoacylglycerol lipase (MAGL) with KML29, would shift vmPFC E/I balance and promote resilience. In acute slice experiments, bath application of KML29 (100 nM) augmented evoked excitatory neurotransmission as evidenced by a left-shift in fEPSP I/O curve, and decreased sIPSC amplitude. In whole-cell recordings, KML29 increased resting membrane potential but reduced the after depolarization, bursting rate, membrane time constant and slow after hyperpolarization. Intra-vmPFC administration of KML29 (200ng/0.5μL/hemisphere) prior to inescapable stress (IS) exposure (25, 5s tail shocks) prevented stress induced anxiety as measured by juvenile social exploration 24 h after stressor exposure. Conversely, systemic administration of KML29 (40 mg/kg, i.p.) 2 h before IS exacerbated stress induced anxiety. MAGL inhibition in the vmPFC may promote resilience by augmenting the output of neurons that project to brainstem and limbic structures that mediate stress responses.
    Keywords:  Endocannabinoids; Monoacylglycerol; Prefrontal cortex; Stress
    DOI:  https://doi.org/10.1016/j.neuropharm.2020.107964
  1340. Genes (Basel). 2020 Jan 23. pii: E126. [Epub ahead of print]11(2):
    Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways.
    Mathew R, Huang J, Iacobas S, Iacobas DA.
      Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), lung histology, and transcriptomes of six-week-old male rats with PH induced by (1) hypoxia (HO), (2) administration of monocrotaline (CM), or (3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations, as well as neointimal lesions and obliteration of the lumen in small arteries. We found that PH increased the expression of caveolin1, matrix metallopeptidase 2, and numerous inflammatory and cell proliferation genes. The cell cycle, vascular smooth muscle contraction, and oxidative phosphorylation pathways, as well as their interplay, were largely perturbed. Our results also suggest that the upregulated Rhoa (Ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed, especially in the HM group, indicate metabolic shift toward aerobic glycolysis.
    Keywords:  RhoA; aerobic glycolysis; caveolin1; hypoxia; monocrotaline; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/genes11020126
  1341. J Phycol. 2020 Jan 23.
    Physiological and metabolic responses of a novel Dunaliella salina strain to Myo-inositol.
    Lv H, Wang QE, Qi B, Liu C, Xiao Y, Jia S.
      Dunaliella salina is well known for its ability to accumulate large amounts of β-carotene. Myo-inositol (MI) enhances the biomass production of D. salina, but the underlying mechanisms were unclear. The present study showed that the concentration of exogenous MI decreased gradually and reached a constant level at the four day of cultivation. MI enhanced the contents of total colored carotenoids and the activity of photosystem II. Metabolic profiles were significantly changed after the addition of exogenous MI, as revealed by multivariate statistical analysis. The metabolites could be categorized into 4 groups based on the relative levels in different samples. Exogenous MI increased the levels of most detected sugars, amino acids, and total saturated and unsaturated fatty acids. Based on the physiological and metabolic analyses, a hypothetical growth-promoting model that MI promotes the growth of D. salina TG by increasing the levels of key metabolites and possibly enhancing photosynthesis, was proposed. This study provides valuable information for understanding the growth-promoting mechanisms of MI in D. salina from the metabolic perspective.
    Keywords:   Dunaliella salina ; Myo-inositol; biomass; metabolomics; photosynthesis
    DOI:  https://doi.org/10.1111/jpy.12973
  1342. J Assoc Physicians India. 2020 Jan;68(1): 49
    Correlation between Mean Platelet Volume and Glycosylated Haemoglobin in Patients with Type 2 Diabetes Mellitus.
    Gulia M, Gupta M, Singla M, Tahlan A, Kaur J.
      
  1343. Sci Rep. 2020 Jan 23. 10(1): 1023
    Effect of cereal soaking and carbohydrase supplementation on growth, nutrient digestibility and intestinal microbiota in liquid-fed grow-finishing pigs.
    Torres-Pitarch A, Gardiner GE, Cormican P, Rea M, Crispie F, O'Doherty JV, Cozannet P, Ryan T, Lawlor PG.
      Soaking the cereal fraction of a liquid diet prior to feeding (Csoak), and/or carbohydrase enzyme supplementation (ENZ) are likely to modulate both feed and intestinal microbial populations and improve feed efficiency (FE) in pigs. To test this hypothesis, a total of 392 grow-finisher pigs (~33.4 kg, 7 pigs/pen) were randomly allocated to 4 treatments in a 2 × 2 factorial arrangement for 70 days as follows: (1) fresh liquid feed (Fresh); (2) Cereal soaked liquid feed (Soak); (3) Fresh + ENZ and (4) Soak + ENZ. An interaction between ENZ and Csoak was found for average daily gain (ADG) during the growing phase (day 0 to 21; P < 0.05) where pigs fed the Soak + ENZ diet had higher ADG than pigs fed the Fresh + ENZ diet. No treatment effect was found for ADG thereafter. Enzyme supplementation increased total tract nutrient digestibility (P < 0.05) and reduced caecal VFA concentrations (P < 0.05) but did not improve pig growth or FE. Both Csoak and ENZ modulated intestinal microbiota composition; increasing abundance of bacterial taxa that were negatively correlated with pig growth and reducing abundance of taxa positively correlated with pig growth and caecal butyrate concentration. In conclusion, both strategies (Csoak and ENZ) improved nutrient digestibility in pigs and modulated intestinal microbiota composition.
    DOI:  https://doi.org/10.1038/s41598-020-57668-6
  1344. J Exp Zool A Ecol Integr Physiol. 2020 Jan 23.
    Evolution of cellular stress response mechanisms.
    Kültz D.
      The cellular stress response (CSR) is pervasive to all domains of life. It has shaped the interaction between organisms and their environment since the origin of the first cell. Although the CSR has been subject to a myriad of nuanced modifications in the various branches of life present today, its core features remain preserved. The scientific literature covering the CSR is enormous and the broad scope of this brief overview was challenging. However, it is critical to conceptually understand how cells respond to stress in a holistic sense and to point out how fundamental aspects of the CSR framework are integrated. It was necessary to be extremely selective and not feasible to even mention many interesting and important developments in this expansive field. The purpose of this overview is to sketch out general and emerging CSR concepts with an emphasis on the initial cellular strain resulting from stress (macromolecular damage) and the evolutionarily most highly conserved elements of the CSR. Examples emphasize fish and aquatic invertebrates to highlight what is known in organisms beyond mammals, yeast, and other common models. Nonetheless, select pioneering studies using canonical models are also considered and the concepts discussed are applicable to all cells. More detail on important aspects of the CSR in aquatic animals is provided in the accompanying articles of this special issue.
    Keywords:  cytoprotective metabolites; fish; macromolecular damage; proteostasis; stress-induced network rewiring; translational preference
    DOI:  https://doi.org/10.1002/jez.2347
  1345. Molecules. 2020 Jan 21. pii: E455. [Epub ahead of print]25(3):
    Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies.
    Chowdhury S, Sripathy S, Webster A, Park A, Lao U, Hsu JH, Loe T, Bedalov A, Simon JA.
      Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD+-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC50 56 and 59 µM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity. Here we describe potent cambinol-based SIRT2 inhibitors, several of which show potency of ~600 nM with >300 to >800-fold selectivity over SIRT1 and 3, respectively. In vitro, these inhibitors are found to be toxic to lymphoma and epithelial cancer cell lines. In particular, compounds 55 (IC50 SIRT2 0.25 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) and 56 (IC50 SIRT2 0.78 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) showed apoptotic as well as strong anti-proliferative properties against B-cell lymphoma cells.
    Keywords:  SIRT2; acetylation; cancer; lymphoma; sirtuin
    DOI:  https://doi.org/10.3390/molecules25030455
  1346. Drug Discov Today. 2020 Jan 16. pii: S1359-6446(20)30001-5. [Epub ahead of print]
    Reporter gene imaging and its role in imaging-based drug development.
    Shaikh FA, Kurtys E, Kubassova O, Roettger D.
      Reporter gene imaging (RGI) is described as the methodology that involves imaging of the encoding proteins that can be used as surrogate markers when fused with regulatory regions of the gene of interest. It provides a means to indirectly monitor molecular processes that are implicated in the pathophysiology of several diseases. The modalities utilized in RGI include MRI, PET, SPECT, as well as optical imaging modalities, such as bioluminescence and fluorescence. RGI provides a highly specific way to qualitatively and quantitatively assess cell targeting, transfection, protein expression and other intracellular processes, which are valuable for pharmacodynamic and pharmacokinetic assessment of cellular, gene and oncolytic viral therapeutics.
    DOI:  https://doi.org/10.1016/j.drudis.2019.12.010
  1347. Curr Neuropharmacol. 2020 Jan 23.
    The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms.
    Guo H, Liu M, Zhang L, Wang L, Hou W, Ma Y, Ma Y.
      17β-Estradiol (estradiol or E2) is a steroid hormone that has been broadly applied as a neuroprotective therapeutic for a variety of neurodegenerative and cerebrovascular disorders such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. Several laboratory and clinical studies have reported that estrogen replacement therapy (ERT) had no effect against these diseases in elderly postmenopausal women, and at worst, increased their risk of onset and mortality. This review focuses on the growing body of data from in vitro and animal models characterizing the potential underlying mechanisms and signaling pathways that govern successful neuroprotection by ERT, including the roles of E2 receptors in mediating neuroprotection, E2 genomic regulation of apoptosis-related pathways, membrane-bound receptor-mediated non-genomic signaling pathways, and the antioxidant mechanisms of E2. Also discussed is current evidence for a critical period of effective treatment with estrogen following natural or surgical menopause and the outcomes of E2 administration within the advantageous time period. The known mechanisms governing the duration of the critical period include depletion of E2 receptors, the switch to a ketogenic metabolic profile by neuronal mitochondria, and a decrease in acetylcholine that accompanies E2 deficiency. Also summarized are the major clinical trials and observational studies concerning postmenopausal hormone therapy (HT), to compare their outcomes with respect to neurological disease and discuss their relevance to the critical period hypothesis. Finally, potential controversies and future directions for this field are discussed throughout the review.
    DOI:  https://doi.org/10.2174/1570159X18666200123165652
  1348. Anal Bioanal Chem. 2020 Jan 22.
    A new analytical workflow using HPLC with drift-tube ion-mobility quadrupole time-of-flight/mass spectrometry for the detection of drug-related metabolites in plants.
    Mlynek F, Himmelsbach M, Buchberger W, Klampfl CW.
      Investigations into the interaction of xenobiotics with plants (and in particular edible plants) have gained substantial interest, as water scarcity due to climate-change-related droughts requires the more frequent use of reclaimed wastewaters for irrigation in agriculture. Non-steroidal anti-inflammatory drugs are common contaminants found in wastewater treatment plant effluents. For this reason, the interaction of nine edible plants with diclofenac (DCF), a widely used representative of this group of drugs, was investigated. For this purpose, plants were hydroponically grown in a medium containing DCF. For the detection of unknown DCF-related metabolites formed in the plant upon uptake of the parent drug' a new workflow based on the use of HPLC coupled to drift-tube ion-mobility quadrupole time-of-flight/mass spectrometry (DTIM QTOF-MS) was developed. Thereby' for chromatographic peaks eluting from the HPLC, drift times were recorded, and analytes were subsequently fragmented in the DTIM QTOF-MS to provide significant fragments. All information available (retention times, drift times, fragment spectra, accurate mass) was finally combined' allowing the suggestion of molecular formulas for 30 DCF-related metabolites formed in the plant, whereby 23 of them were not yet known from the literature.
    Keywords:  Diclofenac; Drift-tube ion-mobility mass spectrometry; Environmental analysis; Pharmaceuticals; Plant metabolism
    DOI:  https://doi.org/10.1007/s00216-020-02429-7
  1349. J Mol Biol. 2020 Jan 15. pii: S0022-2836(20)30020-6. [Epub ahead of print]
    The role of α-cells in islet function and glucose homeostasis in health and type 2 diabetes.
    Gilon P.
      Pancreatic α-cells are the major source of glucagon, a hormone that counteracts the hypoglycemic action of insulin and strongly contributes to the correction of acute hypoglycemia. The mechanisms by which glucose controls glucagon secretion are hotly debated, and it is still unclear to what extent this control results from a direct action of glucose on α-cells or is indirectly mediated by β- and/or δ-cells. Besides its hyperglycemic action, glucagon has many other effects, in particular on lipid and amino acid metabolism. Counterintuitively, glucagon seems also required for an optimal insulin secretion in response to glucose by acting on its cognate receptor and, even more importantly, on GLP-1 receptors. Patients with diabetes mellitus display two main alterations of glucagon secretion: a relative hyperglucagonemia that aggravates hyperglycemia, and an impaired glucagon response to hypoglycemia. Under metabolic stress states, such as diabetes, pancreatic α-cells also secrete GLP-1, a glucose-lowering hormone, whereas the gut can produce glucagon. The contribution of extra-pancreatic glucagon to the abnormal glucose homeostasis is unclear. Here, I review the possible mechanisms of control of glucagon secretion and the role of α-cells on islet function in heathy state. I discuss the possible causes of the abnormal glucagonemia in diabetes, with particular emphasis on type 2 diabetes, and I briefly comment the current anti-diabetic therapies affecting α-cells.
    Keywords:  GLP-1; amino acids; glucagon; insulin; somatostatin
    DOI:  https://doi.org/10.1016/j.jmb.2020.01.004
  1350. J Assoc Physicians India. 2020 Jan;68(1): 45
    A Study of Metabolic Associations with Psoriasis.
    Mandal S, Bajaj S.
      
  1351. Ann Thorac Surg. 2020 Jan 17. pii: S0003-4975(20)30023-0. [Epub ahead of print]
    Lung Volume Reduction Surgery: Re-interpreted With Longitudinal Data Analyses Methodology (Commentary).
    Engelhardt KE.
      
    DOI:  https://doi.org/10.1016/j.athoracsur.2019.11.040
  1352. Diabetologia. 2020 Jan 23.
    Diabetic neuropathy: what does the future hold?
    Callaghan BC, Gallagher G, Fridman V, Feldman EL.
      Frustratingly, disease-modifying treatments for diabetic neuropathy remain elusive. Glycaemic control has a robust effect on preventing neuropathy in individuals with type 1 but not in those with type 2 diabetes, which constitute the vast majority of patients. Encouragingly, recent evidence points to new metabolic risk factors and mechanisms, and thus also at novel disease-modifying strategies, which are desperately needed. Obesity has emerged as the second most important metabolic risk factor for neuropathy (diabetes being the first) from consensus findings of seven observational studies in populations across the world. Moreover, dyslipidaemia and altered sphingolipid metabolism are emergent novel mechanisms of nerve injury that may lead to new targeted therapies. Clinical history and examination remain critical components of an accurate diagnosis of neuropathy. However, skin biopsies and corneal confocal microscopy are promising newer tests that have been used as outcome measures in research studies but have not yet demonstrated clear clinical utility. Given the emergence of obesity as a neuropathy risk factor, exercise and weight loss are potential interventions to treat and/or prevent neuropathy, although evidence supporting exercise currently outweighs data supporting weight loss. Furthermore, a consensus has emerged advocating tricyclic antidepressants, serotonin-noradrenaline (norepinephrine) reuptake inhibitors and gabapentinoids for treating neuropathic pain. Out-of-pocket costs should be considered when prescribing these medications since their efficacy and tolerability are similar. Finally, the downsides of opioid treatment for chronic, non-cancer pain are becoming increasingly evident. Despite these data, current clinical practice frequently initiates and continues opioid prescriptions for patients with neuropathic pain before prescribing guideline-recommended treatments.
    Keywords:  Diabetes; Dyslipidaemia; Exercise; Neuropathy; Obesity; Opioids; Pain; Skin biopsy; Sphingolipids; Weight loss
    DOI:  https://doi.org/10.1007/s00125-020-05085-9
  1353. J Am Med Inform Assoc. 2018 Mar 01. 25(3): 223
    Clinical research informatics: a growing subspecialization of biomedical informatics.
    Ohno-Machado L.
      
    DOI:  https://doi.org/10.1093/jamia/ocy008
  1354. J Assoc Physicians India. 2020 Jan;68(1): 48
    A Study of Correlation between Total Serum Adiponectin and Risk of Peripheral Vascular Disease in patients of Type 2 Diabetes Mellitus.
    C N, Kasal DS.
      
  1355. Sci Rep. 2020 Jan 21. 10(1): 1185
    Publisher Correction: A reference collection of patient-derived cell line and xenograft models of proneural, classical and mesenchymal glioblastoma.
    Stringer BW, Day BW, D'Souza RCJ, Jamieson PR, Ensbey KS, Bruce ZC, Lim YC, Goasdoué K, Offenhäuser C, Akgül S, Allan S, Robertson T, Lucas P, Tollesson G, Campbell S, Winter C, Do H, Dobrovic A, Inglis PL, Jeffree RL, Johns TG, Boyd AW.
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    DOI:  https://doi.org/10.1038/s41598-020-57850-w
  1356. Curr Biol. 2019 Dec 14. pii: S0960-9822(19)31528-3. [Epub ahead of print]
    Salicylic Acid Targets Protein Phosphatase 2A to Attenuate Growth in Plants.
    Tan S, Abas M, Verstraeten I, Glanc M, Molnár G, Hajný J, Lasák P, Petřík I, Russinova E, Petrášek J, Novák O, Pospíšil J, Friml J.
      Plants, like other multicellular organisms, survive through a delicate balance between growth and defense against pathogens. Salicylic acid (SA) is a major defense signal in plants, and the perception mechanism as well as downstream signaling activating the immune response are known. Here, we identify a parallel SA signaling that mediates growth attenuation. SA directly binds to A subunits of protein phosphatase 2A (PP2A), inhibiting activity of this complex. Among PP2A targets, the PIN2 auxin transporter is hyperphosphorylated in response to SA, leading to changed activity of this important growth regulator. Accordingly, auxin transport and auxin-mediated root development, including growth, gravitropic response, and lateral root organogenesis, are inhibited. This study reveals how SA, besides activating immunity, concomitantly attenuates growth through crosstalk with the auxin distribution network. Further analysis of this dual role of SA and characterization of additional SA-regulated PP2A targets will provide further insights into mechanisms maintaining a balance between growth and defense.
    Keywords:  NPR1; PIN; PP2A; auxin; auxin transport; gravitropism; immunity; phosphorylation; protein phosphatase 2A; salicylic acid
    DOI:  https://doi.org/10.1016/j.cub.2019.11.058
  1357. Invest Radiol. 2020 Jan 20.
    Deep Learning Approach for Generating MRA Images From 3D Quantitative Synthetic MRI Without Additional Scans.
    Fujita S, Hagiwara A, Otsuka Y, Hori M, Takei N, Hwang KP, Irie R, Andica C, Kamagata K, Akashi T, Kunishima Kumamaru K, Suzuki M, Wada A, Abe O, Aoki S.
      OBJECTIVES: Quantitative synthetic magnetic resonance imaging (MRI) enables synthesis of various contrast-weighted images as well as simultaneous quantification of T1 and T2 relaxation times and proton density. However, to date, it has been challenging to generate magnetic resonance angiography (MRA) images with synthetic MRI. The purpose of this study was to develop a deep learning algorithm to generate MRA images based on 3D synthetic MRI raw data.MATERIALS AND METHODS: Eleven healthy volunteers and 4 patients with intracranial aneurysms were included in this study. All participants underwent a time-of-flight (TOF) MRA sequence and a 3D-QALAS synthetic MRI sequence. The 3D-QALAS sequence acquires 5 raw images, which were used as the input for a deep learning network. The input was converted to its corresponding MRA images by a combination of a single-convolution and a U-net model with a 5-fold cross-validation, which were then compared with a simple linear combination model. Image quality was evaluated by calculating the peak signal-to-noise ratio (PSNR), structural similarity index measurements (SSIMs), and high frequency error norm (HFEN). These calculations were performed for deep learning MRA (DL-MRA) and linear combination MRA (linear-MR), relative to TOF-MRA, and compared with each other using a nonparametric Wilcoxon signed-rank test. Overall image quality and branch visualization, each scored on a 5-point Likert scale, were blindly and independently rated by 2 board-certified radiologists.
    RESULTS: Deep learning MRA was successfully obtained in all subjects. The mean PSNR, SSIM, and HFEN of the DL-MRA were significantly higher, higher, and lower, respectively, than those of the linear-MRA (PSNR, 35.3 ± 0.5 vs 34.0 ± 0.5, P < 0.001; SSIM, 0.93 ± 0.02 vs 0.82 ± 0.02, P < 0.001; HFEN, 0.61 ± 0.08 vs 0.86 ± 0.05, P < 0.001). The overall image quality of the DL-MRA was comparable to that of TOF-MRA (4.2 ± 0.7 vs 4.4 ± 0.7, P = 0.99), and both types of images were superior to that of linear-MRA (1.5 ± 0.6, for both P < 0.001). No significant differences were identified between DL-MRA and TOF-MRA in the branch visibility of intracranial arteries, except for ophthalmic artery (1.2 ± 0.5 vs 2.3 ± 1.2, P < 0.001).
    CONCLUSIONS: Magnetic resonance angiography generated by deep learning from 3D synthetic MRI data visualized major intracranial arteries as effectively as TOF-MRA, with inherently aligned quantitative maps and multiple contrast-weighted images. Our proposed algorithm may be useful as a screening tool for intracranial aneurysms without requiring additional scanning time.
    DOI:  https://doi.org/10.1097/RLI.0000000000000628
  1358. Lab Chip. 2020 Jan 24.
    A flexible 3-dimensional microelectrode array for in vitro brain models.
    Soscia DA, Lam D, Tooker AC, Enright HA, Triplett M, Karande P, Peters SKG, Sales AP, Wheeler EK, Fischer NO.
      Three-dimensional (3D) in vitro models have become increasingly popular as systems to study cell-cell and cell-ECM interactions dependent on the spatial, mechanical, and chemical cues within the environment of the tissue, which is limited in traditional two-dimensional (2D) models. Although electrophysiological recordings of neuronal action potentials through 2D microelectrode arrays (MEAs) are a common and trusted method of evaluating neuronal function, network communication, and response to chemicals and biologicals, there are currently limited options for measuring electrophysiological activity from many locations simultaneously throughout a 3D network of neurons in vitro. Here, we have developed a thin-film, 3D flexible microelectrode array (3DMEA) that non-invasively interrogates a 3D culture of neurons and can accommodate 256 channels of recording or stimulation. Importantly, the 3DMEA is straightforward to fabricate and integrates with standard commercially available electrophysiology hardware. Polyimide probe arrays were microfabricated on glass substrates and mechanically actuated to collectively lift the arrays into a vertical position, relying solely on plastic deformation of their base hinge regions to maintain vertical alignment. Human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes were entrapped in a collagen-based hydrogel and seeded onto the 3DMEA, enabling growth of suspended cells in the matrix and the formation and maturation of a neural network around the 3DMEA probes. The 3DMEA supported the growth of functional neurons in 3D with action potential spike and burst activity recorded over 45 days in vitro. This platform is an important step in facilitating noninvasive electrophysiological characterization of 3D networks of electroactive cells in vitro.
    DOI:  https://doi.org/10.1039/c9lc01148j
  1359. Heart. 2020 Jan 24. pii: heartjnl-2019-315852. [Epub ahead of print]
    Pericardial diseases in patients with cancer: contemporary prevalence, management and outcomes.
    Imazio M, Colopi M, De Ferrari GM.
      Neoplastic pericardial effusion is a common and serious manifestation of advanced malignancies. Lung and breast carcinoma, haematological malignancies, and gastrointestinal cancer are the most common types of cancer involving the pericardium. Pericardial involvement in neoplasia may arise from several different pathophysiological mechanisms and may be manifested by pericardial effusion with or without tamponade, effusive-constrictive pericarditis and constrictive pericarditis. Management of these patients is a complex multidisciplinary problem, affected by clinical status and prognosis of patients.
    Keywords:  pericardial disease; pericardial effusion; pericardial tamponade
    DOI:  https://doi.org/10.1136/heartjnl-2019-315852
  1360. Sci Rep. 2020 Jan 23. 10(1): 1019
    Linking Small-Scale Flight Manoeuvers and Density Profiles to the Vertical Movement of Insects in the Nocturnal Stable Boundary Layer.
    Wainwright CE, Reynolds DR, Reynolds AM.
      Huge numbers of insects migrate over considerable distances in the stably-stratified night-time atmosphere with great consequences for ecological processes, biodiversity, ecosystem services and pest management. We used a combination of meteorological radar and lidar instrumentation at a site in Oklahoma, USA, to take a new look at the general assistance migrants receive from both vertical and horizontal airstreams during their long-distance flights. Movement in the nocturnal boundary layer (NBL) presents very different challenges for migrants compared to those prevailing in the daytime convective boundary layer, but we found that Lagrangian stochastic modelling is effective at predicting flight manoeuvers in both cases. A key feature for insect transport in the NBL is the frequent formation of a thin layer of fast-moving air - the low-level jet. Modelling suggests that insects can react rapidly to counteract vertical air movements and this mechanism explains how migrants are retained in the jet for long periods (e.g. overnight, and perhaps for several hours early in the morning). This results in movements over much longer distances than are likely in convective conditions, and is particularly significant for the reintroduction of pests to northern regions where they are seasonally absent due to low winter temperatures.
    DOI:  https://doi.org/10.1038/s41598-020-57779-0
  1361. Free Radic Biol Med. 2020 Jan 18. pii: S0891-5849(19)32565-1. [Epub ahead of print]
    Crosstalk between ROS-dependent apoptotic and autophagic signaling pathways in Zn(II) phthalocyanine photodynamic therapy of melanoma.
    Valli F, García Vior MC, Roguin LP, Marino J.
      Melanoma is the most aggressive type of skin cancer, highly resistant to conventional therapies. Photodynamic therapy (PDT) is a minimally invasive treatment modality that combines the use of a photosensitizer, visible light and molecular oxygen, leading to ROS generation in the specific site of irradiation. The cationic zinc(II) phthalocyanine Pc13 has shown to be a potent photosensitizer in different melanoma cell lines. In this study, we explored the intracellular signaling pathways triggered by Pc13 PDT and the role of these cascades in the phototoxic action of Pc13 in human melanoma A375 cells. ROS-dependent activation of MAPKs p38, ERK, JNK and PI3K-I/AKT was observed after treatment. Inhibition of p38 reduced Pc13 phototoxicity, whereas blockage of ERK did not affect this response. Conversely, JNK inhibition potentiated the effect of Pc13 PDT. Results obtained indicate that p38 is involved in the cleavage of PARP-1, an important mediator of apoptosis. On the other hand, Pc13 irradiation induced the activation of an autophagic program, as evidenced by enhanced levels of Beclin-1, LC3-II and GFP-LC3 punctate staining. We also demonstrated that this autophagic response is promoted by JNK and negatively regulated by PI3K-I/AKT pathway. The blockage of autophagy increased Pc13 phototoxicity and enhanced PARP-1 cleavage, revealing a protective role of this mechanism, which tends to prevent apoptotic cell death. Furthermore, reduced susceptibility to treatment and increased activation of autophagy were detected in A375 cells submitted to repeated cycles of Pc13 PDT, indicating that autophagy could represent a mechanism of resistance to PDT. The efficacy of Pc13 PDT and an improved phototoxic action in combination with chloroquine were also demonstrated in tumor spheroids. In conclusion, we showed the interplay between apoptotic and autophagic signaling pathways triggered by Pc13 PDT-induced oxidative stress. Thus, autophagy modulation represents a promising therapeutic strategy to potentiate the efficacy of PDT in melanoma.
    Keywords:  Apoptosis; Autophagy; Cell signaling; Melanoma; Photodynamic therapy; Zinc phthalocyanine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.01.018
  1362. Hepatology. 2020 Jan 22.
    Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz.
    Bisso A, Filipuzzi M, Gamarra Figueroa GP, Brumana G, Biagioni F, Doni M, Ceccotti G, Tanaskovic N, Morelli MJ, Pendino V, Chiacchiera F, Pasini D, Olivero D, Campaner S, Sabò A, Amati B.
      BACKGROUND & AIMS: Activation of MYC and CTNNB1 (encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.APPROACH & RESULTS: We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a "Myc/β-catenin signature", composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/β-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.
    CONCLUSIONS: Myc and β-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
    Keywords:  CTNNB1; WNT; hepatocellular carcinoma; mouse models
    DOI:  https://doi.org/10.1002/hep.31120
  1363. Mol Cell Endocrinol. 2020 Jan 20. pii: S0303-7207(20)30028-9. [Epub ahead of print]504 110728
    Glucocorticoids are active players and therapeutic targets in atherosclerotic cardiovascular disease.
    van der Sluis RJ, Hoekstra M.
      Adrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the development of atherosclerotic cardiovascular disease. Here we review preclinical and clinical findings regarding the relation between changes in plasma glucocorticoid levels and the atherosclerosis extent. It appears that, although the altered glucocorticoid function can in most cases be restored in the different patient groups, current therapies do not necessarily reverse the associated risk for atherosclerotic cardiovascular disease. In our opinion much attention should therefore be given to the development of a Cushing's disease mouse model that can (1) effectively replicate the effect of hypercortisolemia on atherosclerosis outcome observed in humans and (2) be used to investigate, in a preclinical setting, the relative impact on atherosclerosis susceptibility of already available (e.g. metyrapone) and potentially novel (i.e. SR-BI activity modulators) therapeutic agents that target the adrenal glucocorticoid output.
    Keywords:  Atherosclerosis; Cardiovascular disease; Cholesterol; Glucocorticoid; Metabolic disease; Scavenger receptor BI
    DOI:  https://doi.org/10.1016/j.mce.2020.110728
  1364. J Med Chem. 2020 Jan 22.
    Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.
    Wright WC, Chenge J, Wang J, Girvan HM, Yang L, Chai SC, Huber AD, Wu J, Oladimeji PO, Munro AW, Chen T.
      The human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in their structure and substrate preference. Whereas CYP3A4 is predominantly expressed in the liver, CYP3A5 is upregulated in cancer, contributing to drug resistance. Selective inhibitors of CYP3A5 are, therefore, critical to validating it as a therapeutic target. Here we report clobetasol propionate (clobetasol) as a potent and selective CYP3A5 inhibitor identified by high-throughput screening using enzymatic and cell-based assays. Molecular dynamics simulations suggest a close proximity of clobetasol to the heme in CYP3A5 but not in CYP3A4. UV-visible spectroscopy and electron paramagnetic resonance analyses confirmed the formation of an inhibitory type I heme-clobetasol complex in CYP3A5 but not in CYP3A4, thus explaining the CYP3A5 selectivity of clobetasol. Our results provide a structural basis for selective CYP3A5 inhibition, along with mechanistic insights, and highlight clobetasol as an important chemical tool for target validation.
    DOI:  https://doi.org/10.1021/acs.jmedchem.9b02067
  1365. Life (Basel). 2020 Jan 21. pii: E7. [Epub ahead of print]10(2):
    Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces.
    Auboeuf D.
      The current framework of evolutionary theory postulates that evolution relies on random mutations generating a diversity of phenotypes on which natural selection acts. This framework was established using a top-down approach as it originated from Darwinism, which is based on observations made of complex multicellular organisms and, then, modified to fit a DNA-centric view. In this article, it is argued that based on a bottom-up approach starting from the physicochemical properties of nucleic and amino acid polymers, we should reject the facts that (i) natural selection plays a dominant role in evolution and (ii) the probability of mutations is independent of the generated phenotype. It is shown that the adaptation of a phenotype to an environment does not correspond to organism fitness, but rather corresponds to maintaining the genome stability and integrity. In a stable environment, the phenotype maintains the stability of its originating genome and both (genome and phenotype) are reproduced identically. In an unstable environment (i.e., corresponding to variations in physicochemical parameters above a physiological range), the phenotype no longer maintains the stability of its originating genome, but instead influences its variations. Indeed, environment- and cellular-dependent physicochemical parameters define the probability of mutations in terms of frequency, nature, and location in a genome. Evolution is non-deterministic because it relies on probabilistic physicochemical rules, and evolution is driven by a bidirectional interplay between genome and phenotype in which the phenotype ensures the stability of its originating genome in a cellular and environmental physicochemical parameter-depending manner.
    Keywords:  Darwinism; Evolution; Origin of life; RNA; biophysics
    DOI:  https://doi.org/10.3390/life10020007
  1366. J Pharmacokinet Pharmacodyn. 2020 Jan 22.
    Disease progression model of 4T1 metastatic breast cancer.
    Yang L, Yong L, Zhu X, Feng Y, Fu Y, Kong D, Lu W, Zhou TY.
      Cancer metastasis is the main cause of death in various types of cancer. However, in the field of pharmacometrics, cancer disease progression models focus on the growth of primary tumors with tumor volume or weight as target values, while the metastasis process is less mentioned. We propose a series of mathematical models to quantitatively describe and predict the disease progression of 4T1 breast cancer in the aspect of primary breast tumor, lung metastasis and white blood cell. The 4T1 cells were injected into breast fat pad of female BALB/c mice to establish an animal model of breast cancer metastasis. The number and volume of lung metastases at different times were measured. Based on the above data, a disease progression model of breast cancer lung metastasis was established and parameter values were estimated. The white blood cell growth and the primary tumor growth of 4T1 mouse are also modeled. The established models can describe the lung metastasis of 4T1 breast cancer in three aspects: (1) the increase in metastasis number; (2) the growth of metastasis volume; (3) metastasis number-size distribution at different time points. Compared with the prior metastasis models based on von Forester equation, our models distinguished the growth rate of primary tumor and metastasis and got parameter values for 4T1 mouse model. And the current models optimized the metastasis number-size distribution model by utilizing logistic function instead of the prior power function. This study provides a comprehensive description of lung metastasis progression for 4T1 breast cancer model, as well as an alternative disease progression model structure for further pharmacodynamics modeling.
    Keywords:  4T1; Breast cancer; Disease progression model; Lung metastasis; Mathematical model
    DOI:  https://doi.org/10.1007/s10928-020-09673-5
  1367. Environ Pollut. 2020 Feb;pii: S0269-7491(19)36230-X. [Epub ahead of print]257 113491
    Retraction notice to "Trends in bromide wet deposition concentrations in the contiguous United States, 2001-2016" [Environ. Pollut. 233 (2018) 168-179].
    Wetherbee GA, Lehmann CMB, Kerschner BM, Ludtke AS, Green LA, Rhodes MF.
      
    DOI:  https://doi.org/10.1016/j.envpol.2019.113491
  1368. Curr Environ Health Rep. 2020 Jan 20.
    Synthetic Pesticides and Health in Vulnerable Populations: Agricultural Workers.
    Curl CL, Spivak M, Phinney R, Montrose L.
      PURPOSE OF REVIEW: This review aims to summarize epidemiological literature published between May 15, 2018, and May 14, 2019, that examines the relationship between exposure to synthetic pesticides and health of agricultural workers.RECENT FINDINGS: Current research suggests that exposure to synthetic pesticides may be associated with adverse health outcomes. Agricultural workers represent a potentially vulnerable population, due to a combination of unique social and cultural risk factors as well as exposure to hazards inherent in agricultural work. Pesticide exposure among agricultural workers has been linked to certain cancers, DNA damage, oxidative stress, neurological disorders, and respiratory, metabolic, and thyroid effects. This review describes literature suggesting that agricultural workers exposed to synthetic pesticides are at an increased risk of certain cancers and neurological disorders. Recent research on respiratory effects is sparse, and more research is warranted regarding DNA damage, oxidative stress, metabolic outcomes, and thyroid effects.
    Keywords:  Agricultural workers; Cancer; DNA damage; Farmworkers; Pesticide exposure; Synthetic pesticides
    DOI:  https://doi.org/10.1007/s40572-020-00266-5
  1369. Retina. 2020 Feb;40(2): 345-349
    INCREASED SYSTEMIC HEPARANASE IN RETINAL VEIN OCCLUSION IS ASSOCIATED WITH ACTIVATION OF INFLAMMATION AND THROMBOPHILIA.
    Hu Y, Yu Y, Bu Z, Cun B, Gong Y, Li D, Li J, Lu L, Li G, Yuan L.
      PURPOSE: To investigate the levels of systemic heparanase, inflammatory markers, and coagulation factor activities in patients with retinal vein occlusion (RVO).METHODS: This prospective study included 18 patients with central RVO, 22 patients with branch RVO, and 40 patients with age-related cataract as the control group. Serum heparanase protein levels and activities were measured by ELISA and a heparan degrading enzyme assay kit, respectively. Serum levels of MMP-2, MMP-9, TLR-2, and TLR-4 were measured by ELISA kits. The activities of coagulation factors (V, VII, VIII, and IX) were determined with an autoanalyzer. The Mann-Whitney U test was used to compare the above parameters between patients with RVO and control subjects. The relationship between two of the above parameters was analyzed by Spearman's correlation.
    RESULTS: Patients with RVO had higher levels of systemic heparanase protein, heparanase activities, coagulation factors' (V, VIII, and IX) activities, MMP-2, MMP-9, TLR-2, and TLR-4 compared with the control group. Systemic heparanase levels were correlated with serum levels of MMP-2, MMP-9, TLR-2, TLR-4, and activities of coagulation factors VIII and IX.
    CONCLUSION: Increase of systemic heparanase in RVO is associated with activation of systemic inflammation and blood hypercoagulability.
    DOI:  https://doi.org/10.1097/IAE.0000000000002374
  1370. Med Phys. 2020 Jan 19.
    Real-time 4D-MRI-based internal target volume definition for moving lung tumors.
    Rabe M, Thieke C, Düsberg M, Neppl S, Gerum S, Reiner M, Nicolay NH, Schlemmer HP, Debus J, Dinkel J, Landry G, Parodi K, Belka C, Kurz C, Kamp F.
      PURPOSE: In photon radiotherapy, respiratory-induced target motion can be accounted for by internal target volumes (ITV) or mid-ventilation target volumes defined on the basis of four-dimensional computed tomography (4D-CT). Intrinsic limitations of these approaches can result in target volumes that are not representative for the gross tumor volume (GTV) motion over the course of treatment. To address these limitations, we propose a novel patient-specific ITV definition method based on real-time four-dimensional MRI (rt-4DMRI).METHODS: Three lung cancer patients underwent weekly rt-4DMRI scans. A total of 24 datasets were included in this retrospective study. The GTV was contoured on breath-hold MR images and propagated to all rt-4DMRI images by deformable image registration. Different targets were created for the first (reference) imaging sessions: ITVs encompassing all GTV positions over the complete (ITV80 s ) or partial acquisition time (ITV10 s ), ITVs including only voxels with a GTV probability-of-presence (POP) of at least 5% (ITV5%) or 10% (ITV10%), and the mid-ventilation GTV position. Reference planning target volumes (PTVr) were created by adding margins around the ITVs and midV target volumes. The geometrical overlap of the PTVr with ITVn 5% from the six to eight subsequent imaging sessions on days n was quantified in terms of the Dice similarity coefficient (DSC), sensitivity [SE: (PTVr ∩ ITVn 5% )/ITVn 5% ] and precision [PRE: (PTVr ∩ ITVn 5% )/PTVr] as surrogates for target coverage and normal tissue sparing.
    RESULTS: Patient-specific analysis yielded a high variance of the overlap values of PTVr 10 s when different periods within the reference imaging session were sampled. The mid-ventilation-based PTVs were smaller than the ITV-based PTVs. While the SE was high for patients with small breathing pattern variations, changes of the median breathing amplitudes in different imaging sessions led to inferior SE values for the mid-ventilation PTV for one patient. In contrast, PTVr 5% and PTVr 10% showed higher SE values with a higher robustness against interfractional changes, at the cost of larger target volumes.
    CONCLUSIONS: The results indicate that rt-4DMRI could be valuable for the definition of target volumes based on the GTV POP to achieve a higher robustness against interfractional changes than feasible with today's 4D-CT-based target definition concepts.
    Keywords:  4D-MRI; ITV; interfractional changes; lung tumor; mid-ventilation; motion management
    DOI:  https://doi.org/10.1002/mp.14023
  1371. Cardiology. 2020 Jan 22. 1-12
    Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload.
    Mohammadzadeh N, Melleby AO, Palmero S, Sjaastad I, Chakravarti S, Engebretsen KVT, Christensen G, Lunde IG, Tønnessen T.
      INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so-lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM).METHODS AND RESULTS: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/-) hearts compared to wild-type (WT) controls. LUM+/- mice were subjected to AB. There was no difference in survival between LUM+/- and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/- and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/- mice. LUM+/- hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/- compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/- and WT mice post-AB, as assessed by histology and qPCR.
    CONCLUSIONS: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.
    Keywords:  Aortic banding; Cardiac fibrosis; Cardiac remodeling; Lumican
    DOI:  https://doi.org/10.1159/000505318
  1372. Cell Death Dis. 2020 Jan 20. 11(1): 39
    Genome-scale CRISPR screening for potential targets of ginsenoside compound K.
    Yang Y, Liu X, Li S, Chen Y, Zhao Y, Wei Y, Qiu Y, Liu Y, Zhou Z, Han J, Wu G, Ding Q.
      Ginsenosides exhibit a large variety of biological activities in maintaining physical health; however, the molecule underpinnings underlining these biological activities remain to be defined. Here, we took a cellular condition that compound K (CK) induces autophagic cell death in HeLa cells, and setup a high-throughput genetic screening using CRISPR technology. We have identified a number of CK-resistant and CK-sensitive genes, and further validated PMAIP1 as a CK-resistant gene and WASH1 as a CK-sensitive gene. Compound K treatment reduces the expression of WASH1, which further accelerates the autophagic cell death, highlighting WASH1 as an interesting downstream mediator of CK effects. Overall, our study offers an easy-to-adopt platform to study the functional mediators of ginsenosides, and provides a candidate list of genes that are potential targets of CK.
    DOI:  https://doi.org/10.1038/s41419-020-2234-5
  1373. Contrast Media Mol Imaging. 2019 ;2019 8356931
    Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging.
    Bales BC, Grimmond B, Johnson BF, Luttrell MT, Meyer DE, Polyanskaya T, Rishel MJ, Roberts J.
      Contrast-enhanced magnetic resonance imaging is an essential tool for disease diagnosis and management; all marketed clinical magnetic resonance imaging (MRI) contrast agents (CAs) are gadolinium (Gd) chelates and most are extracellular fluid (ECF) agents. After intravenous injection, these agents rapidly distribute to the extracellular space and are also characterized by low serum protein binding and predominant renal clearance. Gd is an abiotic element with no biological recycling processes; low levels of Gd have been detected in the central nervous system and bone long after administration. These observations have prompted interest in the development of new MRI contrast agents based on biotic elements such as iron (Fe); Fe-HBED (HBED = N,N'-bis(2-hydroxyphenyl)ethylenediamine-N,N'-diacetic acid), a coordinatively saturated iron chelate, is an attractive MRI CA platform suitable for modification to adjust relaxivity and biodistribution. Compared to the parent Fe-HBED, the Fe-HBED analogs reported here have lower serum protein binding and higher relaxivity as well as lower relative liver enhancement in mice, comparable to that of a representative gadolinium-based contrast agent (GBCA). Fe-HBED analogs are therefore a promising class of non-Gd ECF MRI CA.
    DOI:  https://doi.org/10.1155/2019/8356931
  1374. Curr Top Dev Biol. 2020 ;pii: S0070-2153(19)30100-0. [Epub ahead of print]136 271-317
    Convergent extension in the amphibian, Xenopus laevis.
    Keller R, Sutherland A.
      This review is a comprehensive analysis of the cell biology and biomechanics of Convergent Extension in Xenopus.
    Keywords:  Convergent extension; Gastrulation; Xenopus
    DOI:  https://doi.org/10.1016/bs.ctdb.2019.11.013
  1375. Eur J Intern Med. 2020 Jan 16. pii: S0953-6205(20)30003-0. [Epub ahead of print]
    Characterisation of patients with acute myocardial infarction complicated by left ventricular thrombus.
    Leow AS, Sia CH, Tan BY, Chan MY, Loh JP.
      
    DOI:  https://doi.org/10.1016/j.ejim.2020.01.003
  1376. Biochem Biophys Res Commun. 2020 Jan 21. pii: S0006-291X(20)30104-2. [Epub ahead of print]
    Arogenate dehydratases can modulate the levels of phenylacetic acid in Arabidopsis.
    Aoi Y, Oikawa A, Sasaki R, Huang J, Hayashi KI, Kasahara H.
      Phenylacetic acid (PAA) is one type of natural auxin and widely exists in plants. Previous biochemical studies demonstrate that PAA in plants is synthesized from phenylalanine (Phe) via phenylpyruvate (PPA), but the PAA biosynthetic genes and its regulation remain unknown. In this article, we show that the AROGENATE DEHYDRATASE (ADT) family, which catalyzes the conversion of arogenate to Phe, can modulate the levels of PAA in Arabidopsis. We found that overexpression of ADT4 or ADT5 remarkably increased the amounts of PAA. Due to an increase in PAA levels, ADT4ox and ADT5ox plants can partially restore the auxin-deficient phenotypes caused by treatments with an inhibitor of the biosynthesis of indole-3-acetic acid (IAA), a main auxin in plants. In contrast, the levels of PAA were significantly reduced in adt multiple knockout mutants. Moreover, the levels of PPA are substantially increased in ADT4 or ADT5 overexpression plants but reduced in adt multiple knockout mutants, suggesting that PPA is a key intermediate of PAA biosynthesis. These results provide an evidence that members of the ADT family of Arabidopsis can modulate PAA level via the PPA-dependent pathway.
    Keywords:  Auxin; Biosynthesis; Phenylacetic acid; Phenylalanine; Phenylpyruvate
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.041
  1377. J Clin Microbiol. 2020 Jan 22. pii: JCM.02082-19. [Epub ahead of print]
    Use of rapid diagnostics to manage pediatric bloodstream infections? You bet your ASP!
    Gonzalez MD, Yarbrough ML.
      Rapid diagnostic testing (RDT) can facilitate earlier optimization of treatment of bloodstream infections, particularly in conjunction with an effective antimicrobial stewardship program (ASP). However, effective implementation and workflow of RDTs is still a matter of debate, particularly in a pediatric setting. In this issue of the Journal of Clinical Microbiology, L.J. Juttukonda et al. (J Clin Microbiol 57:e01400-19, https://doi.org/10.1128/JCM.01400-19) investigate the impact of a multiplex, molecular RDT on changes to antimicrobial therapy in an academic children's hospital. These data reveal several factors that clinical laboratories should consider prior to implementation of RDTs for positive blood cultures.
    DOI:  https://doi.org/10.1128/JCM.02082-19
  1378. AACE Clin Case Rep. 2019 Jul-Aug;5(4):5(4): e255-e258
    USE OF A CONTINUOUS GLUCOSE MONITOR FOR PREOPERATIVE MONITORING AND TREATMENT OF HYPOGLYCEMIA IN A CASE OF PANCREATIC NEUROENDOCRINE TUMOR.
    Lyerla RC, Bajaj A, Shrestha RT.
      Objective: Pancreatic neuroendocrine tumors secreting proinsulin and insulin could lead to life-threatening hypoglycemia. We aim to show this can be avoided by utilizing continuous glucose monitoring.Methods: We describe a case of a 55-year-old female with hypoglycemia unawareness and seizures diagnosed with proinsulinoma. She utilized an intermittently scanned continuous glucose monitor (isCGM) to monitor hypoglycemia preoperatively.
    Results: The patient underwent biochemical and radiographic evaluation to confirm the diagnosis of proinsulinoma. Utilizing isCGM to monitor blood glucose, she was able to prevent hypoglycemia-related seizures prior to definitive surgery.
    Conclusion: In the time leading up to a definitive surgery, patients with proinsulinomas are at risk of hypoglycemic events leading to falls, seizures, and even death. isCGMs can be utilized for preoperative monitoring and treatment of hypoglycemia in these patients.
    DOI:  https://doi.org/10.4158/ACCR-2018-0590
  1379. Cell Discov. 2020 ;6 2
    Biphasic exocytosis of herpesvirus from hippocampal neurons and mechanistic implication to membrane fusion.
    Liu YT, Shivakoti S, Jia F, Tao CL, Zhang B, Xu F, Lau P, Bi GQ, Zhou ZH.
      Exocytosis is a crucial cellular process involved in the release of neural transmitters or signaling hormones, and disposal of waste or toxic materials. The relationship between structural transition and temporal progression of this process is poorly understood, partly due to lack of adequate tools to resolve such dynamic structures at sufficient resolution in 3D. Exocytosis can be hijacked by some viruses, exemplified by the widely used model α-herpesvirus pseudorabies virus (PRV), which relies on exocytosis for trans-synaptic spread across neurons. Here, we have used cryo electron tomography (cryoET) to capture 199 events of PRV exocytosis from cultured hippocampal neurons. We established cumulative frequency analysis to estimate the relative duration of an exocytosis stage based on the frequency of observed viral particles at that stage. This analysis revealed that PRV exocytosis is biphasic, including a fast, "release phase" driven by fusion proteins and fused membranes, and a slow, "recovery phase" driven by flattening of curved membranes. The biphasic property of exocytosis discovered here appears to be conserved for membrane fusion during viral entry, and our approach of cumulative frequency analysis should have general utility for characterizing other membrane fusion events.
    Keywords:  Cryoelectron tomography; Exocytosis; Membrane fusion
    DOI:  https://doi.org/10.1038/s41421-019-0134-6
  1380. Nature. 2020 Jan;577(7791): 453
    Good wolf! Wild canines play ball with people.
      
    Keywords:  Animal behaviour
    DOI:  https://doi.org/10.1038/d41586-020-00083-8
  1381. Sci Rep. 2020 Jan 20. 10(1): 720
    Machine learning with autophagy-related proteins for discriminating renal cell carcinoma subtypes.
    He Z, Liu H, Moch H, Simon HU.
      Machine learning techniques have been previously applied for classification of tumors based largely on morphological features of tumor cells recognized in H&E images. Here, we tested the possibility of using numeric data acquired from software-based quantification of certain marker proteins, i.e. key autophagy proteins (ATGs), obtained from immunohistochemical (IHC) images of renal cell carcinomas (RCC). Using IHC staining and automated image quantification with a tissue microarray (TMA) of RCC, we found ATG1, ATG5 and microtubule-associated proteins 1A/1B light chain 3B (LC3B) were significantly reduced, suggesting a reduction in the basal level of autophagy with RCC. Notably, the levels of the ATG proteins expressed did not correspond to the mRNA levels expressed in these tissues. Applying a supervised machine learning algorithm, the K-Nearest Neighbor (KNN), to our quantified numeric data revealed that LC3B provided a strong measure for discriminating clear cell RCC (ccRCC). ATG5 and sequestosome-1 (SQSTM1/p62) could be used for classification of chromophobe RCC (crRCC). The quantitation of particular combinations of ATG1, ATG16L1, ATG5, LC3B and p62, all of which measure the basal level of autophagy, were able to discriminate among normal tissue, crRCC and ccRCC, suggesting that the basal level of autophagy would be a potentially useful parameter for RCC discrimination. In addition to our observation that the basal level of autophagy is reduced in RCC, our workflow from quantitative IHC analysis to machine learning could be considered as a potential complementary tool for the classification of RCC subtypes and also for other types of tumors for which precision medicine requires a characterization.
    DOI:  https://doi.org/10.1038/s41598-020-57670-y
  1382. Sci Rep. 2020 Jan 23. 10(1): 1025
    Association between non-alcoholic fatty liver disease and coronary calcification depending on sex and obesity.
    Kim SH, Park HY, Lee HS, Jung KS, Lee MH, Jhee JH, Kim TH, Lee JE, Kim HJ, Kim BS, Park HC, Lee BK, Choi HY.
      Non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome and is associated with cardiovascular outcomes. We investigated whether NAFLD was associated with coronary artery calcification (CAC) in participants without a previous history of cardiovascular disease and whether this association differed according to sex and obesity status after adjustment for other atherosclerosis risk factors, alcohol intake, and liver enzyme levels. Among 67,441 participants, data from 8,705 participants who underwent a fatty liver status and CAC assessment during routine health screening were analysed. CAC scores were calculated using computed tomography. NAFLD was diagnosed in patients with evidence of liver steatosis on ultrasonography. Obesity was defined as a body mass index of ≥25 kg/m2. Multivariate analysis showed a significant association between NAFLD and CAC in non-obese participants (odds ratio, 1.24 [95% confidence interval, 1.01-1.53]), whereas NAFLD and CAC were not associated in obese participants. Interaction analysis showed that the association between NAFLD and CAC was influenced by sex and obesity. Subgroup analysis revealed a significant association between NAFLD and CAC in non-obese male participants (odds ratio, 1.36 [1.07-1.75]), but not in female participants. Our study indicates that non-obese men with NAFLD are prone to CAC.
    DOI:  https://doi.org/10.1038/s41598-020-57894-y
  1383. Mol Cancer Ther. 2020 Jan 23. pii: molcanther.0608.2019. [Epub ahead of print]
    Epitope and Fc-mediated Crosslinking, but not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity.
    Ho SK, Xu Z, Thakur A, Fox M, Tan SS, DiGiammarino E, Zhou L, Sho M, Cairns B, Zhao V, Xiong M, Samayoa J, Forsyth CM, Powers DB, Chao DT, Hollenbaugh D, Alvarez HM, Akamatsu Y.
      CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent anti-tumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to non-existent (utomilumab). To exploit the anti-tumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong anti-tumor potency without significant transaminitis in vivo compared to CD137 agonists previously reported. These mAbs are cross-reactive to mouse and cynomolgus monkey and showed crosslinking-dependent T cell costimulation activity in vitro. Anti-tumor efficacy was maintained in Fc gamma receptor (FcγR) III-deficient mice but diminished in FcγRIIB-deficient mice, suggesting the critical role for FcγRIIB to provide cross-linking in vivo. Interestingly, a single dose of an affinity reduced variant was sufficient to control tumor growth, but a higher affinity variant did not improve efficacy. These observations suggest that binding epitope and FcγR interaction, but not necessarily high affinity, are important for anti-tumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-19-0608
  1384. Nat Commun. 2020 Jan 24. 11(1): 495
    A helitron-induced RabGDIα variant causes quantitative recessive resistance to maize rough dwarf disease.
    Liu Q, Deng S, Liu B, Tao Y, Ai H, Liu J, Zhang Y, Zhao Y, Xu M.
      Maize rough dwarf disease (MRDD), caused by various species of the genus Fijivirus, threatens maize production worldwide. We previously identified a quantitative locus qMrdd1 conferring recessive resistance to one causal species, rice black-streaked dwarf virus (RBSDV). Here, we show that Rab GDP dissociation inhibitor alpha (RabGDIα) is the host susceptibility factor for RBSDV. The viral P7-1 protein binds tightly to the exon-10 and C-terminal regions of RabGDIα to recruit it for viral infection. Insertion of a helitron transposon into RabGDIα intron 10 creates alternative splicing to replace the wild-type exon 10 with a helitron-derived exon 10. The resultant splicing variant RabGDIα-hel has difficulty being recruited by P7-1, thus leading to quantitative recessive resistance to MRDD. All naturally occurring resistance alleles may have arisen from a recent single helitron insertion event. These resistance alleles are valuable to improve maize resistance to MRDD and potentially to engineer RBSDV resistance in other crops.
    DOI:  https://doi.org/10.1038/s41467-020-14372-3
  1385. Nat Commun. 2020 Jan 24. 11(1): 483
    Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling.
    Kumar M, Leon Coria A, Cornick S, Petri B, Mayengbam S, Jijon HB, Moreau F, Shearer J, Chadee K.
      Inflammatory bowel disease is associated with changes in the mucosal barrier, increased intestinal permeability, and increased risk of infections and sepsis, but the underlying mechanisms are incompletely understood. Here, we show how continuous translocation of gut microbial components affects iron homeostasis and facilitates susceptibility to inflammation-associated sepsis. A sub-lethal dose of lipopolysaccharide results in higher mortality in Mucin 2 deficient (Muc2-/-) mice, and is associated with elevated circulatory iron load and increased bacterial translocation. Translocation of gut microbial components attenuates hepatic stearoyl CoA desaturase-1 activity, a key enzyme in hepatic de novo lipogenesis. The resulting reduction of hepatic saturated and unsaturated fatty acid levels compromises plasma membrane fluidity of red blood cells, thereby significantly reducing their life span. Inflammation in Muc2-/- mice alters erythrophagocytosis efficiency of splenic macrophages, resulting in an iron-rich milieu that promotes bacterial growth. Our study thus shows that increased intestinal permeability triggers a cascade of events resulting in increased bacterial growth and risk of sepsis.
    DOI:  https://doi.org/10.1038/s41467-019-14182-2
  1386. Nucleic Acids Res. 2020 Jan 22. pii: gkaa013. [Epub ahead of print]
    Correlation between equi-partition of aminoacyl-tRNA synthetases and amino-acid biosynthesis pathways.
    Takénaka A, Moras D.
      The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed to be proportional to the number of reaction steps (NE) involved in the biosynthesis pathway, is one of the parameters that controlled the timescale of aaRSs appearance. Because all pathways are branched at fructose-6-phosphate on the metabolic pathway, this product is defined as the common origin for the NE comparison. For each amino-acid, the NE value, counted from the origin to the final product, provides a timescale for the pathways to be established. An archeological approach based on NE reveals that aaRSs of the two classes are generated in pair along this timescale. The results support the coevolution theory for the origin of the genetic code with an earlier appearance of class II aaRSs.
    DOI:  https://doi.org/10.1093/nar/gkaa013
  1387. J Invest Dermatol. 2020 Jan 16. pii: S0022-202X(20)30018-X. [Epub ahead of print]
    JAK inhibition prevents bleomycin-induced fibrosis in mice and is effective in morphea patients.
    Damsky W, Patel D, Garelli CJ, Garg M, Wang A, Dresser K, Deng A, Harris JE, Richmond J, King B.
      
    DOI:  https://doi.org/10.1016/j.jid.2019.12.019
  1388. Clin J Oncol Nurs. 2020 Feb 01. 24(1): 99-102
    Sepsis: Symptoms, Assessment, Diagnosis, and the Hour-1 Bundle in Patients With Cancer.
    Boucher JE, Carpenter D.
      Sepsis has a higher incidence of hospital stays and poorer morbidity and mortality outcomes in patients with cancer. The development of infection in weakened immune systems and prolonged treatment courses increase the risk for sepsis in patients with cancer. The causes of infection that can lead to sepsis in patients with cancer are further complicated by disease- or therapy-related neutropenia. Early recognition of sepsis is critical for prompt treatment to prevent tissue damage, organ failure, and mortality. The Surviving Sepsis Campaign recommends the Hour-1 bundle as best practice for sepsis management.
    Keywords:  Hour-1 sepsis bundle; cancer-related infection; sepsis; symptom management
    DOI:  https://doi.org/10.1188/20.CJON.99-102
  1389. Heart Lung Circ. 2019 Dec 16. pii: S1443-9506(19)31524-0. [Epub ahead of print]
    The Brain-Heart Connection in Sympathetically Triggered Inherited Arrhythmia Syndromes.
    Winbo A, Paterson DJ.
      Sympathetically triggered inherited arrhythmia syndromes, including the long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), can cause sudden cardiac death in young individuals with structurally normal hearts. With cardiac events typically triggered by physical or emotional stress, not surprisingly, two of the most common treatments are neuromodulators, including mainstay beta blocker pharmacotherapy, and surgical sympathetic cardiac denervation. This review updates the clinician on the relevant anatomy and physiology of the cardiac autonomic nervous system, outlines neurocardiac arrhythmia mechanisms, and discusses the latest rationale for a neurocardiac therapeutic approach to manage sympathetic-induced arrhythmia in patients with inherited cardiac disease.
    Keywords:  Beta blockers; Cardiac sympathetic denervation; Catecholaminergic polymorphic ventricular tachycardia; Long QT syndrome; Neurocardiac; Sympathetic nervous system
    DOI:  https://doi.org/10.1016/j.hlc.2019.11.002
  1390. Monaldi Arch Chest Dis. 2020 Jan 21. 90(1):
    Three's company: A woman with rash, uterine mass and cystic lungs.
    Miranda L, Gilani S, Han L, Epelbaum O.
      Cystic lung disease encompasses a wide variety of clinical entities, the diagnosis of which is sometimes straightforward and other times obscure.  To narrow the list of possibilities, it behooves the physician to consider the context in which the cystic lung disease is uncovered. Clues to the diagnosis might be provided by findings that are not initially obvious and are not located in the thorax. We describe an instructive case of a woman with cystic lungs detected during a search for malignancy prompted by a diagnosis of dermatomyositis. Malignancy was indeed uncovered in the form of endometrial carcinoma, the management of which eventually also established the etiology of cystic lung disease. In the discussion we attempt to connect the patient's autoimmune disease, uterine cancer, and lung cysts. The potential interplay among these three components of her presentation makes for intriguing mechanistic speculation.
    DOI:  https://doi.org/10.4081/monaldi.2020.1162
  1391. Phys Chem Chem Phys. 2020 Jan 21.
    A design rule for two-dimensional van der Waals heterostructures with unconventional band alignments.
    Si Y, Wu HY, Lian JC, Huang WQ, Hu WY, Huang GF.
      The energetic alignment of band edges at the interface plays a central role in determining the properties and applications of two-dimensional (2D) van der Waals (vdW) heterostructures. Generally, three conventional heterojunction types (type-I, type-II, and type-III) have widely been investigated and used in diverse fields. Unconventional band alignments (type-IV, type-V, and type-VI) are, however, hitherto unreported in the vdW heterostructures. We find that 2D binary semiconductors composed of group IV-V elements manifest a similar electronic structure, offering in principle the possibility of designing heterostructures with novel band alignments due to the hybridization of band-edge states. We first show here that a 2D SiAs/GeP heterostructure exhibits a type-VI band alignment, which is induced by the interlayer pz orbital hybridization, and a transition of band alignment from type-VI to type-V occurs when strain or electric field is applied over a critical value. The unconventional band alignments and their transition natures enable broad application of these vdW heterostructures in special opto-electronic devices and energy conversion.
    DOI:  https://doi.org/10.1039/c9cp06465f
  1392. Food Funct. 2020 Jan 22.
    Grape seed proanthocyanidins suppressed macrophage foam cell formation by miRNA-9 via targeting ACAT1 in THP-1 cells.
    Shao D, Di Y, Lian Z, Zhu B, Xu X, Guo D, Huang Q, Jiang C, Kong J, Shi J.
      Abnormal lipid metabolism in macrophages leads to atherosclerosis (AS). Excessive LDL cholesterol uptake by macrophages in the aortic endothelium leads to formation of foam cells. Previous studies suggested that proanthocyanidins effectively suppress this process, while the in-depth mechanism has not been elucidated. In mononuclear THP-1 cells, we found that the oligomeric fraction of proanthocyanidins was more effective in suppressing foam cell formation and 25 μg ml-1 for 48 h were the optimum conditions. Under these model conditions, we investigated gene expression and for the first time reported expression of regulatory microRNA (miRNA). It was found that the proanthocyanidins restrained macrophage foaming mainly by lowering the expression levels of cholesterol influx-related receptors CD36 and SR-A, and promoting the expression of cholesterol efflux-related receptor ABCA1. Further, it was latest revealed that proanthocyanidins could notably inhibit the expression of ACAT1, a key gene for intracellular cholesterol esterification. Further investigation was performed on the expression of regulatory miRNAs (miR-134 for CD36, miR-134, miR-155 for SR-A, miR-155, let-7g for LOX-1, miR-9 for ACAT1, miR-27a, miR-19b, miR-10b and miR-33a for ABCA1). The relative expression of miR-9, a miRNA targeting ACAT1, was decreased after the treatment of proanthocyanidins. It was most likely that proanthocyanidins suppressed the expression of ACAT1 via up-regulating the expression of miR-9, thus lessening the intracellular lipid accumulation and eventually inhibiting macrophage foam cell formation. This assumption was further verified by use of miR-9 mimic and its inhibitor.
    DOI:  https://doi.org/10.1039/c9fo02352f
  1393. J Dairy Sci. 2020 Jan 21. pii: S0022-0302(20)30052-7. [Epub ahead of print]
    Effects of the vat pasteurization process and refrigerated storage on the bovine milk metabolome.
    Zhu D, Kebede B, Chen G, McComb K, Frew R.
      This study is the first to investigate the evolution of cow milk metabolites throughout the vat pasteurization process and storage using untargeted metabolomics based on a multiplatform approach. Nuclear magnetic resonance and ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry were used for fingerprinting water-soluble nutritional compounds, and headspace gas chromatography-mass spectrometry was used to fingerprint the volatile organic compounds. This study demonstrated that vat pasteurization was an efficient and mild means of milk preservation resulting in only minor changes to the metabolites. The pasteurized milk samples exhibited a stable metabolome during the first 8 d of refrigerated storage. However, at the latter stage of storage, the concentrations of pantothenic acid and butyrylcarnitine decreased, whereas some fatty acids, organic acids, α-AA, peptides, and ketones increased. These selected metabolites that changed during milk storage could be used as potential biomarkers to track the storage conditions of pasteurized cow milk.
    Keywords:  pasteurization process; shelf-life study; untargeted metabolomics
    DOI:  https://doi.org/10.3168/jds.2019-17512
  1394. J Cell Physiol. 2020 Jan 20.
    Long noncoding RNA PVT1 acts as an oncogenic driver in human pan-cancer.
    You Z, Xu S, Pang D.
      Increasing evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles during tumorigenesis in multiple types of cancers. However, little is known about the exact role of plasmacytoma variant translocation 1 (PVT1) in human pan-cancer. Here, we report the oncogenic role and function of PVT1 in human pan-cancer, including breast cancer. The expression of PVT1 in human tumor tissues and nontumor tissues, the upstream regulation of PVT1 and the relationship between its expression and prognosis and chemoresistance were examined by using The Cancer Genome Atlas data. PVT1 expression is higher in human cancer tissues compared with adjacent noncancerous tissues, and patients with high levels of PVT1 expression usually have tumors with a higher TNM stage. High PVT1 expression is also associated with worse disease outcomes in patients with cancer. Hypomethylation and transcription factor binding in the PVT1 promoter locus activates its transcriptional expression. Guilt by association analysis revealed that PVT1 may be involved in processes associated with tumorigenesis. Moreover, PVT1 may trigger chemoresistance in human cancer. These results indicated that PVT1 may act as an oncogenic driver and maybe a potential therapeutic target in human cancer.
    Keywords:  PVT1; long noncoding RNA; methylation; pan-cancer; survival
    DOI:  https://doi.org/10.1002/jcp.29447
  1395. Complement Ther Clin Pract. 2020 Jan 07. pii: S1744-3881(19)30364-0. [Epub ahead of print]39 101086
    Vitamin D suppresses proangiogenic factors in patients with ulcerative colitis: A randomized double blind placebo controlled clinical trial.
    Emami MR, Sharifi A, Yaseri M, Derakhshanian H, Hosseinzadeh-Attar MJ.
      BACKGROUND: Angiogenesis and inflammation are involved in the pathogenesis of ulcerative colitis (UC). This study aimed to assess the effect of vitamin D on serum levels of proangiogenic factors, visfatin and vascular endothelial growth factor (VEGF), in patients with UC.MATERIALS AND METHODS: Ninety patients were randomized to receive either a single intramuscular injection of 300,000 IU vitamin D or normal saline. Visfatin, VEGF, and 25-hydroxyvitamin D [25(OH)D] concentrations were assessed before and 90 days after the intervention.
    RESULTS: There were no significant differences in visfatin and VEGF levels between the two groups following supplementation. In patients with vitamin D insufficiency, visfatin increase was significantly lower in the intervention versus placebo group. There was an inverse correlation between serum 25(OH)D and visfatin in the subgroup with vitamin D insufficiency.
    CONCLUSION: Vitamin D might be beneficial in decreasing proangiogenic factors such as visfatin in UC patients with low 25(OH)D levels.
    Keywords:  Ulcerative colitis; Vascular endothelial growth factor; Visfatin; Vitamin D
    DOI:  https://doi.org/10.1016/j.ctcp.2020.101086
  1396. Life Sci. 2020 Jan 21. pii: S0024-3205(20)30090-4. [Epub ahead of print] 117343
    Novel ADAM-17 inhibitor ZLDI-8 inhibits the metastasis of hepatocellular carcinoma by reversing epithelial-mesenchymal transition in vitro and in vivo.
    Lu HY, Chu HX, Tan YX, Qin XC, Liu MY, Li JD, Ren TS, Zhang YS, Zhao QC.
      AIMS: Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo.MAIN METHODS: The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model.
    KEY FINDINGS: In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-β1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo.
    SIGNIFICANCE: ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.
    Keywords:  ADAM-17; EMT; Hepatocellular carcinoma; Metastasis; Notch; ZLDI-8
    DOI:  https://doi.org/10.1016/j.lfs.2020.117343
  1397. ACS Appl Mater Interfaces. 2020 Jan 22.
    High-performance Ag-modified Bi0.5Sb1.5Te3 films for the flexible thermoelectric generator.
    Shang H, Li T, Luo D, Yu L, Zou Q, Huang D, Xiao L, Gu H, Ren Z, Ding F.
      Bi-Sb-Te-based semiconductors possess the best room-temperature thermoelectric performance, but, which are restricted for application in wearable field due to its inherent brittleness, rigidity, and non-scalable manufacturing techniques. Therefore, how to obtain thermoelectric materials with excellent thermoelectric properties and flexibility through the batch production process is a serious challenge. Here we report the fabrication of flexible p-type thermoelectric Ag-modified Bi0.5Sb1.5Te3 films on flexible substrate using a facile approach. Their optimized power factors are ~12.4 and ~14.0 μW cm-1 K-2 at 300 K and 420 K, respectively. These high power factors mainly originate from the optimized carrier transport of the composite system, through which a high level of electrical conductivity is achieved while a remarkably improved Seebeck coefficient is simultaneously obtained. Bending tests demonstrate the excellent flexibility and mechanical durability of the composite films and their power factors decrease by only about 10% after bending for 650 cycles with a bending radius of 5 mm. A flexible thermoelectric module is designed and constructed using the optimized composite films and displays a power density of ~1.4 mW cm-2 at a relatively small ΔT of 60 K. This work demonstrates the potential of inorganic thermoelectric materials to be made on flexible/wearable substrates for energy harvesting and management devices.
    DOI:  https://doi.org/10.1021/acsami.9b21771
  1398. Clin Cancer Res. 2020 Jan 22. pii: clincanres.2485.2019. [Epub ahead of print]
    PI3K inhibitors curtail MYC-dependent mutant p53 gain-of-function in head and neck squamous cell carcinoma.
    Ganci F, Pulito C, Valsoni S, Sacconi A, Turco C, Vahabi M, Manciocco V, Mazza EMC, Meens J, Karamboulas C, Nichols AC, Covello R, Pellini R, Spriano G, Sanguineti G, Muti P, Bicciato S, Ailles L, Strano S, Fontemaggi G, Blandino G.
      BACKGROUND: Mutation of TP53 gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. TP53 mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC.METHODS: mutant p53-associated functions were investigated through Gene Set Enrichment Analysis in the TCGA cohort of HNSCC and in a panel of 22 HNSCC cell lines. mutant p53-dependent transcripts were analyzed in HNSCC cell line Cal27, carrying mutant p53H193L, FaDu, carrying p53R248L and Detroit 562, carrying p53R175H. Drugs impinging on mutant p53-MYC-dependent signature were identified interrogating Connectivity Map (https://clue.io) derived from the Library of Integrated Network-based Cellular Signatures (LINCS) database (http://lincs.hms.harvard.edu/) and analyzed in HNSCC cell lines and PDX models.
    RESULTS: Here, we identified a signature of transcripts directly controlled by gain-of-function mutant p53 protein and prognostic in HNSCC, which is highly enriched of MYC targets. Specifically, both in patient-derived xenografts (PDX) and cell lines of HNSCC treated with the PI3Kalpha-selective inhibitor BYL719 (Alpelisib) the down-regulation of mutant p53/MYC-dependent signature correlates with response to this compound. Mechanistically, mutant p53 favors the binding of MYC to its target promoters and enhances MYC protein stability. Treatment with BYL719 disrupts the interaction of MYC, mutant p53 and YAP proteins with MYC target promoters. Of note, depletion of MYC, mutant p53 or YAP potentiates the effectiveness of BYL719 treatment.
    CONCLUSIONS: Collectively, the blocking of this transcriptional network is an important determinant for the response to BYL719 in HNSCC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-2485
  1399. Sci Rep. 2020 Jan 21. 10(1): 876
    Differential Abundance Analysis with Bayes Shrinkage Estimation of Variance (DASEV) for Zero-Inflated Proteomic and Metabolomic Data.
    Huang Z, Lane AN, Fan TW, Higashi RM, Weiss HL, Yin X, Wang C.
      Mass spectrometry (MS) is frequently used for proteomic and metabolomic profiling of biological samples. Data obtained by MS are often zero-inflated. Those zero values are called point mass values (PMVs). Zero values can be further grouped into biological PMVs and technical PMVs. The former type is caused by true absence of a compound and the later type is caused by a technical detection limit. Methods based on a mixture model have been developed to separate the two types of zeros and to perform differential abundance analysis comparing proteomic/metabolomic profiles between different groups of subjects. However, we notice that those methods may give unstable estimate of the model variance, and thus lead to false positive and false negative results when the number of non-zero values is small. In this paper, we propose a new differential abundance analysis method, DASEV, which uses an empirical Bayes shrinkage method to more robustly estimate the variance and enhance the accuracy of differential abundance analysis. Simulation studies and real data analysis show that DASEV substantially improves parameter estimation of the mixture model and outperforms current methods in identifying differentially abundant features.
    DOI:  https://doi.org/10.1038/s41598-020-57470-4
  1400. Animals (Basel). 2020 Jan 16. pii: E150. [Epub ahead of print]10(1):
    Proteomic Analysis of Beef Tenderloin and Flank Assessed Using an Isobaric Tag for Relative and Absolute Quantitation (iTRAQ).
    Lei Z, Wu J, Zhang D, Liu T, Zhao S, Wang J, Zhang X.
      Herein, we performed a proteomic analysis of tenderloin and flank steaks from Simmental cattle using the isobaric tags for a relative and absolute quantification (iTRAQ) approach. We identified 17 amino acids in both steaks, and Gly, Cys, Ile, Lys, and Pro differed most in abundance between the steak types (p < 0.05). A comparison of the expression patterns in steaks revealed 128 differentially expressed proteins (DEPs), of which 44 were up-regulated and 84 were down-regulated. Furthermore, 27 DEPs (p < 0.05) were subjected to gene ontology (GO) analysis, and many were found to be related to oxidation-reduction, metabolism, hydrogen ion transmembrane transport, transport, the tricarboxylic acid (TCA) cycle, mitochondrial electron transport, and the conversion of nicotinamide adenine dinucleotide (NADH) to ubiquinone. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis also implicated these DEPs in various signalling pathways, including oxidative phosphorylation, cardiac muscle contraction, the TCA cycle, biosynthesis, and the metabolism. These findings provide a new insight into key proteins involved in the determination of amino acid composition in beef.
    Keywords:  GO analysis; KEGG pathway analysis; beef; differential expression; flank steak; iTRAQ; proteomics; tenderloin steak
    DOI:  https://doi.org/10.3390/ani10010150
  1401. Molecules. 2020 Jan 17. pii: E391. [Epub ahead of print]25(2):
    Synthesis of Polyhedral Borane Cluster Fused Heterocycles via Transition Metal Catalyzed B-H Activation.
    Cao K, Zhang CY, Xu TT, Wu J, Wen XY, Jiang WJ, Chen M, Yang J.
      Aromatic heterocycles are ubiquitous building blocks in bioactive natural products, pharmaceutical and agrochemical industries. Accordingly, the carborane-fused heterocycles would be potential candidates in drug discovery, nanomaterials, metallacarboranes, as well as photoluminescent materials. In recent years, the transition metal catalyzed B-H activation has been proved to be an effective protocol for selective functionalization of B-H bond of o-carboranes, which has been further extended for the synthesis of polyhedral borane cluster-fused heterocycles via cascade B-H functionalization/annulation process. This article summarizes the recent progress in construction of polyhedral borane cluster-fused heterocycles via B-H activation.
    Keywords:  B-H activation; carborane; heterocycle; polyhedral borane cluster
    DOI:  https://doi.org/10.3390/molecules25020391
  1402. J Inherit Metab Dis. 2020 Jan;43(1): 156
    ERRATUM.
      
    DOI:  https://doi.org/10.1002/jimd.12170
  1403. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019 Dec 25. 48(6): 674-681
    [Research progress on mechanism in adaptation of hemoglobin to plateau hypoxia].
    Li X, Li W, Feng S, Wang R.
      Low oxygen partial pressure is the main cause of acute mountain sickness.Hemoglobin plays a crucial physiological role in the binding, utilization, transportation and release of oxygen in the body. To increase the capacity of oxygen binding of hemoglobin or the capacity of oxygen supply in tissues can help alleviate altitude sickness. However, increasing hemoglobin content has certain limitations. Using techniques from molecular biology, researchers are looking for endogenous or exogenous substances that can regulate the conformation of hemoglobin to increase oxygen uptake in the alveoli, or the availability of alveolar oxygen in the tissues. At present, the research on allosteric modulators to improve the affinity of hemoglobin has made some progress, and research on applying this mechanism to plateau hypoxia is also underway. This article reviews the relationship between hemoglobin and hypoxia, the structure of hemoglobin and the role of various allosteric modulators in hypoxia, which would provide information for finding new substances regulating the conformation of hemoglobin.
  1404. Thorac Cancer. 2020 Jan 23.
    Human papillomavirus infection maybe not associated with primary lung cancer in the Fujian population of China.
    He F, Xiong W, Yu F, Xiao R, Ye H, Li W, Liu Z, Hu Z, Cai L.
      BACKGROUND: To investigate whether human papillomavirus (HPV) infection is associated with primary lung cancer among the Fujian population.METHODS: HPV infection was detected in 140 pairs of lung cancer tissues and matched paracancerous tissues by examining the 21 clinically relevant HPV types using a combination of viral highly conserved L1 region PCR amplification and specific probe reverse hybridization. Paired χ2 test was used to analyze differences in detection rates of HPV between lung cancer and paracancerous tissues. Differences in detection rates of HPV in lung cancer tissues were analyzed using χ2 test or the exact probability method. The rank sum test was used to analyze differences in the distributions of routine indices of blood and pulmonary function in lung cancer tissues between the HPV negative and positive groups.
    RESULTS: HPV infection was detected in 13 of the 140 tumor specimens and in 16 of the paired normal lung tissues. There was no significant correlation between HPV infection and lung cancer (P > 0.05). The diagnosed HPV infection rates did not differ significantly among lung cancer tissues with different stratification (P > 0.05). However, the platelet count, platelet pressure, residual gas volume, functional residual volume, and residual gas volume/lung total distribution may differ between HPV-negative and HPV-positive lung cancer tissues (0.000625 < P < 0.05).
    CONCLUSIONS: We concluded that HPV infection may not be associated with the risk of primary lung cancer in the Fujian population. However, HPV infection may affect platelet and residual lung function in primary lung cancer patients.
    Keywords:  Clinical index; human papillomavirus; lung function; primary lung cancer
    DOI:  https://doi.org/10.1111/1759-7714.13282
  1405. Neurorehabil Neural Repair. 2020 Jan 24. 1545968319899911
    Hebbian-Type Primary Motor Cortex Stimulation: A Potential Treatment of Impaired Hand Function in Chronic Stroke Patients.
    Revill KP, Haut MW, Belagaje SR, Nahab F, Drake D, Buetefisch CM.
      Background. Stroke often involves primary motor cortex (M1) and its corticospinal (CST) projections. As hand function is critically dependent on these structures, its recovery is often incomplete. Objective. To determine whether impaired hand function in patients with chronic ischemic stroke involving M1 or CST benefits from the enhancing effect of Hebbian-type stimulation (pairing M1 afferent stimulation and M1 activity in a specific temporal relationship) on M1 plasticity and hand function. Methods. In a double-blind, randomized, sham-controlled design, 20 patients with chronic ischemic stroke affecting M1 or CST were randomly assigned to 5 days of hand motor training that was combined with either Hebbian-type (trainingHebb) or sham stimulation (trainingsham) of the lesioned M1. Measures of hand function and task-based M1 functional magnetic resonance imaging (fMRI) activity were collected prior to, immediately following, and 4 weeks after the intervention. Results. Both interventions were effective in improving affected hand function at the completion of training, but only participants in the trainingHebb group maintained functional gains. Changes in hand function and fMRI activity were positively correlated in both ipsilesional and contralesional M1. Compared with trainingsham, participants in the trainingHebb group showed a stronger relationship between improved hand function and changes in M1 functional activity. Conclusions. Only when motor training was combined with Hebbian-type stimulation were functional gains maintained over time and correlated with measures of M1 functional plasticity. As hand dexterity is critically dependent on M1 function, these results suggest that functional reorganization in M1 is facilitated by Hebbian-type stimulation. ClinicalTrials.gov Identifier: NCT01569607.
    Keywords:  chronic stroke; functional magnetic resonance imaging (fMRI); hand function; neurorehabilitation; transcranial magnetic stimulation (TMS)
    DOI:  https://doi.org/10.1177/1545968319899911
  1406. Gastroenterology. 2020 Jan 20. pii: S0016-5085(20)30116-5. [Epub ahead of print]
    Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity but Develop Fewer Tumors Following Chronic Liver Injury.
    Lin YH, Zhang S, Zhu M, Lu T, Chen K, Wen Z, Wang S, Xiao G, Luo D, Jia Y, Li L, MacConmara M, Hoshida Y, Singal A, Yopp A, Wang T, Zhu H.
      BACKGROUND & AIMS: Thirty to ninety percent of hepatocytes contain whole-genome duplications, but little is known about the fates or functions of these polyploid cells or how they affect development of liver disease. We investigated the effects of continuous proliferative pressure, observed in chronically damaged liver tissues, on polyploid cells.METHODS: We studied Rosa-rtTa mice (controls) and Rosa-rtTa;TRE-shRNA mice, which have reversible knockdown of anillin, actin binding protein (ANLN). Transient administration of doxycycline increases the frequency and degree of hepatocyte polyploidy without permanently altering levels of ANLN. Mice were then given diethylnitrosamine and carbon tetrachloride (CCl4) to induce mutations, chronic liver damage, and carcinogenesis. We performed partial hepatectomies to test liver regeneration and then RNA-seq analyses to identify changes in gene expression. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. We imaged dividing hepatocytes to estimate the frequency of mitotic errors during regeneration. We also performed whole-exome sequencing of 54 liver nodules from patients with cirrhosis to quantify aneuploidy-a possible outcome of polyploid cell divisions.
    RESULTS: Liver tissues from control mice given CCl4 had significant increases in ploidy compared with livers from uninjured mice. Mice with knockdown of ANLN had hepatocyte ploidy above physiologic levels and developed significantly fewer liver tumors after administration of diethylnitrosamine and CCl4 compared with control mice. Increased hepatocyte polyploidy was not associated with altered regenerative capacity or tissue fitness, changes in gene expression, or more mitotic errors. Based on lineage-tracing experiments, non-hepatocytes did not contribute to liver regeneration in mice with increased polyploidy. Despite an equivalent rate of mitosis in hepatocytes of differing ploidies, we found no lagging chromosomes or micronuclei in mitotic polyploid cells. In nodules of human cirrhotic liver tissue, there was no evidence of chromosome level copy number variations.
    CONCLUSIONS: Mice with increased polyploid hepatocytes develop fewer liver tumors following chronic liver damage. Remarkably, polyploid hepatocytes maintain the ability to regenerate liver tissues during chronic damage without generating mitotic errors, and aneuploidy is not commonly observed in cirrhotic livers. Strategies to increase numbers of polypoid hepatocytes might be effective in preventing liver cancer.
    Keywords:  DEN; HCC; cell division; mouse model
    DOI:  https://doi.org/10.1053/j.gastro.2020.01.026
  1407. Int J Rheum Dis. 2020 Jan 19.
    Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis.
    Bian F, Ruan G, Xu J, Wang K, Wu J, Ren J, Chang B, Ding C.
      OBJECTIVE: The aim of this study was to investigate cross-sectional associations between serum levels of citrate and knee structural changes and cartilage enzymes in patients with knee osteoarthritis (OA).METHOD: A total of 137 subjects with symptomatic knee OA (mean age 55.0 years, range 34-74, 84% female) were included. Knee radiography was used to assess knee osteophytes, joint space narrowing (JSN) and radiographic OA assessed by Kellgren-Lawrence (K-L) grading system. T2-weighted fat-suppressed fast spin echo magnetic resonance imaging (MRI) was used to determine knee cartilage defects, bone marrow lesions (BMLs) and infrapatellar fat pad (IPFP) signal intensity alternations. Colorimetric fluorescence was used to measure the serum levels of citrate. Enzyme-linked immunosorbent assay was used to measure the serum cartilage enzymes including matrix metalloproteinase (MMP)-3 and MMP-13.
    RESULTS: After adjustment for potential confounders (age, sex, body mass index), serum citrate was negatively associated with knee osteophytes at the femoral site, cartilage defects at medial femoral site, total cartilage defects, and total BMLs (odds ratio [OR] 0.17-0.30, all P < .05). Meanwhile, serum citrate was negatively associated with IPFP signal intensity alteration (OR 0.30, P = .05) in multivariable analyses. Serum citrate was significantly and negatively associated with MMP-13 (β -3106.37, P < .05) after adjustment for potential confounders. However, citrate was not significantly associated with MMP-3 in patients with knee OA.
    CONCLUSION: Serum citrate was negatively associated with knee structural changes including femoral osteophytes, cartilage defects, and BMLs and also serum MMP-13 in patients with knee OA, suggesting that low serum citrate may be a potential indicator for advanced knee OA.
    Keywords:  citrate; enzyme; magnetic resonance imaging; osteoarthritis
    DOI:  https://doi.org/10.1111/1756-185X.13787
  1408. Mol Cell. 2020 Jan 15. pii: S1097-2765(19)30926-8. [Epub ahead of print]
    PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network.
    Reichermeier KM, Straube R, Reitsma JM, Sweredoski MJ, Rose CM, Moradian A, den Besten W, Hinkle T, Verschueren E, Petzold G, Thomä NH, Wertz IE, Deshaies RJ, Kirkpatrick DS.
      Co-opting Cullin4 RING ubiquitin ligases (CRL4s) to inducibly degrade pathogenic proteins is emerging as a promising therapeutic strategy. Despite intense efforts to rationally design degrader molecules that co-opt CRL4s, much about the organization and regulation of these ligases remains elusive. Here, we establish protein interaction kinetics and estimation of stoichiometries (PIKES) analysis, a systematic proteomic profiling platform that integrates cellular engineering, affinity purification, chemical stabilization, and quantitative mass spectrometry to investigate the dynamics of interchangeable multiprotein complexes. Using PIKES, we show that ligase assemblies of Cullin4 with individual substrate receptors differ in abundance by up to 200-fold and that Cand1/2 act as substrate receptor exchange factors. Furthermore, degrader molecules can induce the assembly of their cognate CRL4, and higher expression of the associated substrate receptor enhances degrader potency. Beyond the CRL4 network, we show how PIKES can reveal systems level biochemistry for cellular protein networks important to drug development.
    Keywords:  CRL4; DCAFs; Nedd8; PIKES; QconCAT; cullin-RING ligase; mass spectrometry; quantitative proteomics; targeted protein degradation; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2019.12.013
  1409. Molecules. 2020 Jan 17. pii: E385. [Epub ahead of print]25(2):
    Probabilistic Approach for Virtual Screening Based on Multiple Pharmacophores.
    Madzhidov TI, Rakhimbekova A, Kutlushuna A, Polishchuk P.
      Pharmacophore modeling is usually considered as a special type of virtual screening without probabilistic nature. Correspondence of at least one conformation of a molecule to pharmacophore is considered as evidence of its bioactivity. We show that pharmacophores can be treated as one-class machine learning models, and the probability the reflecting model's confidence can be assigned to a pharmacophore on the basis of their precision of active compounds identification on a calibration set. Two schemes (Max and Mean) of probability calculation for consensus prediction based on individual pharmacophore models were proposed. Both approaches to some extent correspond to commonly used consensus approaches like the common hit approach or the one based on a logical OR operation uniting hit lists of individual models. Unlike some known approaches, the proposed ones can rank compounds retrieved by multiple models. These approaches were benchmarked on multiple ChEMBL datasets used for ligand-based pharmacophore modeling and externally validated on corresponding DUD-E datasets. The influence of complexity of pharmacophores and their performance on a calibration set on results of virtual screening was analyzed. It was shown that Max and Mean approaches have superior early enrichment to the commonly used approaches. Thus, a well-performing, easy-to-implement, and probabilistic alternative to existing approaches for pharmacophore-based virtual screening was proposed.
    Keywords:  ligand-based virtual screening; machine learning; pharmacophores; virtual screening
    DOI:  https://doi.org/10.3390/molecules25020385
  1410. Acta Paediatr. 2020 Jan 22.
    Myalgic Encephalomyelitis - Time to repent.
    Speight N.
      I strongly support Professor Saugstad's plea in your journal for an apology from the western medical profession over our failings with respect to meeting the needs of the community of ME patients (1). I would further endorse his comments about the way in which some innocent families of young people with ME have been subjected to persecution in the form of threats to remove children. These can truly be called examples of "Child Abuse by Professionals".
    DOI:  https://doi.org/10.1111/apa.15181
  1411. Br Dent J. 2020 Jan;228(2): 61
    Sugar levels drop in yoghurts.
      
    DOI:  https://doi.org/10.1038/s41415-020-1217-3
  1412. Sci Rep. 2020 Jan 20. 10(1): 721
    Plasmonic ternary hybrid photocatalyst based on polymeric g-C3N4 towards visible light hydrogen generation.
    Che Y, Liu Q, Lu B, Zhai J, Wang K, Liu Z.
      Surface plasmon resonance (SPR) effect of noble metal nanoparticles (NPs) for photocatalysis has a significant enhancement. In this system, a plasmonic ternary hybrid photocatalyst of Ag/AgBr/g-C3N4 was synthetized and used in water splitting to generation H2 under visible light irradiation. 18%Ag/AgBr/g-C3N4 showed the highest photoactivity, with the efficiency of hydrogen generation as high as 27-fold to that of pristine g-C3N4. Compared to simple mixture of Ag/AgBr and g-C3N4, hetero-composite Ag/AgBr/g-C3N4 showed a higher photoactivity, even though they contained same content of Ag/AgBr. We find that significant factors for enhancing properties were the synergistic effect between Ag/AgBr and g-C3N4, and the light absorption enhancing by SPR effect of Ag NPs. Ag/AgBr NPs firmly anchored on the surface of g-C3N4 and their high dispersion were also responsible for the improved activity and long-term recycling ability. The structure of Ag/AgBr/g-C3N4 hybrid materials and their enhancement to photocatalytic activity were discussed. Meanwhile, the possible reaction mechanism of this system was proposed.
    DOI:  https://doi.org/10.1038/s41598-020-57493-x
  1413. J Comp Eff Res. 2020 Jan 21.
    Crizotinib versus chemotherapy: a real-world cost-effectiveness study in China.
    Huang M, Tian Y, He M, Liu J, Ren L, Gong Y, Peng F, Wang Y, Ding Z, Wang J, Zhu J, Xu Y, Liu Y, Li L, Lu Y.
      Aim: To assess the cost-effectiveness of crizotinib verses platinum-based doublet chemotherapy as the first-line treatment for Anaplastic Lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in the real-world setting. Methods: Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China). They were categorized into two groups as treated with crizotinib (n = 83) or chemotherapy (n = 80) as a first-line therapy. The progression-free survival (PFS) as the primary clinical outcome, and the direct medical costs were collected from hospital information systems. Incremental cost-effectiveness ratio (ICER) was calculated with costs, quality-adjusted life-years, as well as the costs discounted at 3% annually. Additionally, two different kinds of medical insurance (MI) for pharma-economic assessment were considered. Results: Crizotinib improved PFS versus chemotherapy in ALK positive patients (median PFS 19.67 m vs 5.47 m; p < 0.001). Moreover, crizotinib obtained an ICER of US$36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than the willingness to pay threshold (three-times of gross domestic product per capita in mainland China or Sichuan Province). However, ICER was US$7321.16, which is less than willingness to pay, when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anticancer drugs were MI covered. One-way sensitivity analysis for the reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased. Conclusion: Crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC with the MI coverage currently available in Chengdu, Sichuan Province, China.
    Keywords:  cost–effectiveness; crizotinib; real world
    DOI:  https://doi.org/10.2217/cer-2019-0075
  1414. Life Sci. 2020 Jan 20. pii: S0024-3205(20)30083-7. [Epub ahead of print] 117336
    Hederagenin protects mice against ovariectomy-induced bone loss by inhibiting RANKL-induced osteoclastogenesis and bone resorption.
    Tian K, Su Y, Ding J, Wang D, Zhan Y, Li Y, Liang J, Lin X, Song F, Wang Z, Xu J, Liu Q, Zhao J.
      AIMS: Postmenopausal osteoporosis and other osteolytic bone diseases are often caused by the elevation in osteoclastogenesis and/or increased osteoclastic bone resorption, leading to excessive bone loss. Hederagenin (Hed) is a pentacyclic triterpenoid saponin extracted from various natural medicinal plants and exhibits numerous biological activities and may offer benefits against bone-related conditions. We evaluated the effects of Hed on osteoclast formation and bone resorption in vitro and the in vivo therapeutic benefits in the mouse model of ovariectomy (OVX)-induced bone loss.MAIN METHODS: In vitro, osteoclast formation were determined by TRAP staining assessed; bone resorption were examined using Hydroxyapatite resorption assay and Podosomal actin belt formation assay; Related molecular mechanisms were determined by western blot assay. Construction of ovx mice by bilateral oophorectomy to simulate bone loss in vivo.
    KEY FINDINGS: In vitro cellular assays showed that Hed inhibited RANKL-induced osteoclast formation and osteoclast bone (hydroxyapatite) resorption as well as marker gene expression from BMM culture. Mechanistically, Hed attenuated RANKL-induced intracellular reactive oxygen species (ROS) production, and MAPK signaling pathway (ERK and p38) activation which curbed the downstream induction of c-Fos and NFATc1. Consistent with the in vitro findings, Hed administration effectively protected OVX mice from bone loss by reducing osteoclast number and activity on bone surface.
    SIGNIFICANCE: Our data provided promising evidence for the potential use of Hederagenin in the treatment of osteoclast-mediated osteolytic bone diseases such as postmenopausal osteoporosis.
    Keywords:  Bone resorption; Hederagenin; Osteoclast; Osteoclastogenesis; RANKL
    DOI:  https://doi.org/10.1016/j.lfs.2020.117336
  1415. Cells. 2020 Jan 22. pii: E273. [Epub ahead of print]9(2):
    Biological Functions and Analytical Strategies of Sialic Acids in Tumor.
    Zhou X, Yang G, Guan F.
      Sialic acids, a subset of nine carbon acidic sugars, often exist as the terminal sugars of glycans on either glycoproteins or glycolipids on the cell surface. Sialic acids play important roles in many physiological and pathological processes via carbohydrate-protein interactions, including cell-cell communication, bacterial and viral infections. In particular, hypersialylation in tumors, as well as their roles in tumor growth and metastasis, have been widely described. Recent studies have indicated that the aberrant sialylation is a vital way for tumor cells to escape immune surveillance and keep malignance. In this article, we outline the present state of knowledge on the metabolic pathway of human sialic acids, the function of hypersialylation in tumors, as well as the recent labeling and analytical techniques for sialic acids. It is expected to offer a brief introduction of sialic acid metabolism and provide advanced analytical strategies in sialic acid studies.
    Keywords:  sialic acid; sialic acid labeling; sialidase; sialyltransferase; tumor sialylation
    DOI:  https://doi.org/10.3390/cells9020273
  1416. J Pak Med Assoc. 2020 Jan;70(1): 174-177
    Skin pigmentation in a patient with vitamin B12 deficiency presented with subacute combined degeneration of spinal cord.
    Sarwar AK, Zafar MU, Rehman Abid Butt MU.
      Vitamin B12 deficiency results in multisystem manifestations. A 30years-old man presented with progressive weakness of lower limbs along with numbness. Patient had pale colour and noticed progressive pigmentation over dorsal and palmar aspects of both the hands and the feet. Neurological examination revealed absent ankle jerks, sensory impairment until T5 level, loss of joint position sensation and positive Romberg's sign. Workup showed macrocytic anaemia and hypersegmented neutrophils. There was no evidence of hypocortisolism. Magnetic Resonance Imaging of brain and spine was normal; however, Electromyography/Nerve conduction studies were suggestive of demyelinating neuropathy. His clinical and lab findings were suspicious of B12 deficiency, which was found to be very low. Hyperpigmentation is rare in B12 deficiency as presenting symptoms and diagnosis may be overlooked. Therefore, vitamin B12 levels should be checked as any delay in diagnosis and treatment will result in progression of Subacute Combined Degeneration of the spinal cord to the extent that it becomes irreversible.
    Keywords:  Skin pigmentation, vitamin B12 deficiency, sub-acute combined degeneration of spinal cord.
    DOI:  https://doi.org/10.5455/JPMA.23581
  1417. Anal Chem. 2020 Jan 23.
    Thin-Layer Potentiometry for Creatinine Detection in Undiluted Human Urine using Ion-Exchange Membranes as Barriers for Charged Interferences.
    Liu Y, Cánovas R, Crespo GA, Cuartero M.
      Herein, thin-layer potentiometry combined with ion-exchange membranes as barriers for charged interferences is demonstrated for the analytical detection of creatinine (CRE) in undiluted human urine. Briefly, CRE diffuses through an anion-exchange membrane (AEM) from a sample contained in one fluidic compartment to a second reservoir, containing the enzyme CRE deiminase. There, CRE reacts with the enzyme, and the formation of ammonium is dynamically monitored by potentiom-etric ammonium-selective electrodes. This analytical concept is integrated into a lab-on-a-chip microfluidic cell that allows for a high sample throughput and the operation under stop-flow mode, which allows CRE to passively diffuse across the AEM. Conveniently, positively charged species (i.e. potassium, sodium and ammonium, among others) are repelled by the AEM and never reach the ammonium-selective electrodes; thus, possible interference in the response can be avoided. As a result, the dynamic potential response of the electrodes is entirely ascribed to the stoichiometric formation of ammonium. The new CRE biosensor exhibits a Nernstian slope, within a linear range of response from 1 to 50 mM CRE concentration. As expected, the response time (1560 min) primarily depends on the CRE diffusion across the AEM. CRE analysis in urine samples displayed excellent results, without requiring sample pre-treatment (before the introduction of the sample in the microfluidic chip), and with high compatibility with development into a potential point-of-care clinical tool. In an at-tempt to decrease the analysis time, the presented analytical methodology for CRE detection is translated into an all-solid-state platform, in which the enzyme is immobilized on the surface of the ammonium-selective electrode and with the AEM on top. While more work is necessary in this direction, the CRE sensor appears to be promising for CRE analysis in both urine and blood.
    DOI:  https://doi.org/10.1021/acs.analchem.9b05231
  1418. J Nat Prod. 2020 Jan 21.
    Thiopeptide Defense by an Ant's Bacterial Symbiont.
    Chang PT, Rao K, Longo LO, Lawton ES, Scherer G, Van Arnam EB.
      Fungus-growing ants and their microbial symbionts have emerged as a model system for understanding antibiotic deployment in an ecological context. Here we establish that bacterial symbionts of the ant Trachymyrmex septentrionalis antagonize their most likely competitors, other strains of ant-associated bacteria, using the thiopeptide antibiotic GE37468. Genomic analysis suggests that these symbionts acquired the GE37468 gene cluster from soil bacteria. This antibiotic, with known activity against human pathogens, was previously identified in a biochemical screen but had no known ecological role. GE37468's host-associated defense role in this insect niche intriguingly parallels the function of similar thiopeptides in the human microbiome.
    DOI:  https://doi.org/10.1021/acs.jnatprod.9b00897
  1419. Eur J Paediatr Neurol. 2020 Jan 11. pii: S1090-3798(20)30013-1. [Epub ahead of print]
    Disrupted inhibition may give clues in understanding neurodevelopmental disorders.
    Cobb SR.
      
    DOI:  https://doi.org/10.1016/j.ejpn.2020.01.012
  1420. J Assoc Physicians India. 2020 Jan;68(1): 50
    A Study of Association of XBAI GLUT1 Gene Polymorphism in Patients of Type 2 Diabetes Mellitus with Diabetic Nephropathy.
    Singh A, Kalita BC.
      
  1421. J Hazard Mater. 2020 Jan 09. pii: S0304-3894(20)30050-9. [Epub ahead of print]388 122064
    Thermochemical formation of dioxins promoted by chromium chloride: In situ Cr- and Cl-XAFS analysis.
    Zhang M, Fujimori T, Shiota K, Buekens A, Mukai K, Niwa Y, Li X, Takaoka M.
      Chromium is commonly found in the flue gases and ashes of Municipal Solid Waste Incineration. It has been reported as an active catalyst for the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) during de novo tests, yet its specific mode of action has remained unclear. This study aims to identify the effects of chromium chloride on the formation of PCDD/F and other chloro-aromatics and to elucidate the underlying reaction mechanisms. A series of de novo tests, conducted over a wide range of temperature (from 250 to 550 °C) and for four different oxygen contents (0, 5, 10, 20 %), confirmed the promoting effect of CrCl3 on the PCDD/F formation. In situ X-ray Absorption Fine Structure (XAFS) spectroscopy was applied to investigate the behavior of CrCl3 during heating, describing the entire picture of CrCl3-promoted formation pathways of dioxins. The effect of oxygen was studied by measuring XAFS spectra on samples heated at different oxygen concentrations. According to these spectra, chromium compounds play two key roles during dioxins formation: (a) chlorinating carbon, using chlorine derived from conversion of CrCl3 into Cr2O3, and further oxidation to Cr(VI), and (b) facilitating oxidative destruction of the carbon matrix, while reducing Cr(VI) to Cr2O3.
    Keywords:  Chromium chloride; Formation mechanisms; In situ X-ray Absorption Fine Structure (XAFS); Polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDF)
    DOI:  https://doi.org/10.1016/j.jhazmat.2020.122064
  1422. Semin Oncol Nurs. 2020 Jan 18. pii: S0749-2081(19)30165-2. [Epub ahead of print] 150983
    Proactive Rehabilitation for Chemotherapy-Induced Peripheral Neuropathy.
    Knoerl R, Gilchrist L, Kanzawa-Lee GA, Donohoe C, Bridges C, Lavoie Smith EM.
      OBJECTIVE: To review assessment and management approaches for chemotherapy-induced peripheral neuropathy-related physical function deficits.DATA SOURCES: Peer-reviewed articles from PubMed, Ovid MEDLINE, CINAHL PsycINFO, SPORTDiscus, Scopus, and key studies' reference lists.
    CONCLUSION: Brief clinical tests (eg, gait, Timed Up and Go) can screen for neuropathy-related physical function deficits. Exercise and physical therapy may be promising treatments, but the efficacy and optimal dose of such treatments for chemotherapy-induced peripheral neuropathy are unclear.
    IMPLICATIONS FOR NURSING PRACTICE: Screening and assessment of neuropathy-associated physical function deficits should occur throughout neurotoxic chemotherapy treatment. If such deficits are identified, referral for rehabilitation (ie, physical or occupational therapy) and/or exercise interventions is warranted.
    Keywords:  Chemotherapy-induced peripheral Neuropathy; Exercise; Neuropathic pain; Physical therapy modalities; Rehabilitation
    DOI:  https://doi.org/10.1016/j.soncn.2019.150983
  1423. Trends Immunol. 2020 Jan 17. pii: S1471-4906(19)30257-1. [Epub ahead of print]
    Metabolic Adaptations to Infections at the Organismal Level.
    Troha K, Ayres JS.
      Metabolic processes occurring during host-microbiota-pathogen interactions can favorably or negatively influence host survival during infection. Defining the metabolic needs of the three players, the mechanisms through which they acquire nutrients, and whether each participant cooperates or competes with each other to meet their own metabolic demands during infection has the potential to reveal new approaches to treat disease. Here, we review topical findings in organismal metabolism and infection and highlight four emerging lines of investigation: how host-microbiota metabolic partnerships protect against infection; competition for glucose between host and pathogen; significance of infection-induced anorexia; and redefinition of the role of iron during infection. We also discuss how these discoveries shape our understanding of infection biology and their likely therapeutic value.
    Keywords:  anorexia; cooperative defenses; host-microbiota-pathogen interactions; immunometabolism; infection; organismal level
    DOI:  https://doi.org/10.1016/j.it.2019.12.001
  1424. Diabetes. 2020 Jan 23. pii: db190973. [Epub ahead of print]
    A PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD Lipid.
    Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif AA, Gao H, Lovato L, Prudente S, Pandolfi A, Pezzolesi MG, Sigal RJ, Paré G, Marcovina SM, Rotroff DM, Patorno E, Mercuri L, Trischitta V, Chew EY, Kraft P, Buse JB, Wagner MJ, Cresci S, Gerstein HC, Ginsberg HN, Mychaleckyj JC, Doria A.
      The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide-significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported White subjects treated with simvastatin and randomized to fenofibrate or placebo in the Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD) Lipid Trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (HR=0.49; 95%C.I. 0.34-0.72) whereas no benefit was observed for other genotypes (p for interaction=3.7x10-4). The "rs6008845-by-fenofibrate" interaction on MACE was replicated in African-Americans from ACCORD (N=585, p=0.02) and in external cohorts (ACCORD-Blood-Pressure, ORIGIN, and TRIUMPH, total N=3059, p=0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11 - a pro-inflammatory and atherogenic chemokine also known as eotaxin (p for rs6008845-by-fenofibrate interaction=0.003). The Genotype-Tissue Expression (GTEx) dataset revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify T2D patients who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.
    DOI:  https://doi.org/10.2337/db19-0973
  1425. Leukemia. 2020 Jan 23.
    CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition.
    Quijada-Álamo M, Hernández-Sánchez M, Alonso-Pérez V, Rodríguez-Vicente AE, García-Tuñón I, Martín-Izquierdo M, Hernández-Sánchez JM, Herrero AB, Bastida JM, San Segundo L, Gruber M, García JL, Yin S, Ten Hacken E, Benito R, Ordóñez JL, Wu CJ, Hernández-Rivas JM.
      The deletion of 11q (del(11q)) invariably comprises ATM gene in chronic lymphocytic leukemia (CLL). Concomitant mutations in this gene in the remaining allele have been identified in 1/3 of CLL cases harboring del(11q), being the biallelic loss of ATM associated with adverse prognosis. Although the introduction of targeted BCR inhibition has significantly favored the outcomes of del(11q) patients, responses of patients harboring ATM functional loss through biallelic inactivation are unexplored, and the development of resistances to targeted therapies have been increasingly reported, urging the need to explore novel therapeutic approaches. Here, we generated isogenic CLL cell lines harboring del(11q) and ATM mutations through CRISPR/Cas9-based gene-editing. With these models, we uncovered a novel therapeutic vulnerability of del(11q)/ATM-mutated cells to dual BCR and PARP inhibition. Ex vivo studies in the presence of stromal stimulation on 38 CLL primary samples confirmed a synergistic action of the combination of olaparib and ibrutinib in del(11q)/ATM-mutated CLL patients. In addition, we showed that ibrutinib produced a homologous recombination repair impairment through RAD51 dysregulation, finding a synergistic link of both drugs in the DNA damage repair pathway. Our data provide a preclinical rationale for the use of this combination in CLL patients with this high-risk cytogenetic abnormality.
    DOI:  https://doi.org/10.1038/s41375-020-0714-3
  1426. Int J Sports Med. 2020 Jan 22.
    Comparing Maximal Mean and Critical Speed and Metabolic Powers in Elite and Sub-Elite Soccer.
    Lord C, Blazevich A, Abbiss CR, James Drinkwater E, Ma'ayah F.
      The quantification of maximal mean speed (MMS), maximal mean metabolic power (MMPmet), critical speed (CS) and critical metabolic power (CPmet) was conducted over full A-League (elite) and National Premier League (NPL; sub-elite) seasons. Comparisons were made between levels of soccer competition and playing positions (i. e. centre backs, full backs, central midfielders, wide midfielders and strikers). A symmetric moving average algorithm was applied to the GPS raw data using specific time windows (i. e. 1, 5, 10, 60, 300 and 600 s) and maximal values were obtained. Additionally, these maximal values were used to derive estimates of CS and CPmet. Maximal mean values, particularly during smaller time windows (i. e. 1 and 5 s), were greater in A-League match play. Only MMPmet1 was identified as being consistently different between competitions (P=<0.001-0.049) in all playing positions. Significance was only observed in CS (P=0.005) and CPmet (P=0.005) of centre backs between competitions. Centre backs were identified as the least energy demanding playing position. The present findings suggests that both maximal mean and critical analyses are suitable alternatives to common absolute distance and speed assessments of match running performance during competitive matches.
    DOI:  https://doi.org/10.1055/a-1065-2100
  1427. World J Clin Oncol. 2020 Jan 24. 11(1): 11-19
    Predictors of distant metastasis in acinic cell carcinoma of the parotid gland.
    Ali SA, Kovatch KJ, Yousif J, Gupta S, Rosko AJ, Spector ME.
      BACKGROUND: AiCC is a primarily indolent disease process. Our aim with this study is to determine characteristics consistent with rapidly progressive AiCC of the parotid gland.AIM: To report on patients with metastatic lung disease from AiCC and potential correlative factors.
    METHODS: Single-institution retrospective review of patients treated at the University of Michigan between 2000 and 2017. Univariate analyses were performed.
    RESULTS: A total of 55 patients were identified. There were 6 patients (10.9%) with primary AiCC of the parotid gland who developed lung metastases. The mean age at diagnosis for patients with lung metastases was 57.8 years of age, in comparison to 40.2 years for those without metastases (P = 0.064). All 6 of the patients with lung metastases demonstrated gross perineural invasion intraoperatively, in comparison to none of those in the non-lung metastases cohort. Worse disease-free and overall survival were significantly associated with gross perineural invasion, high-grade differentiation, and T4 classification (P < 0.001).
    CONCLUSION: AiCC of the parotid gland is viewed as a low-grade neoplasm with good curative outcomes and low likelihood of metastasis. With metastasis, however, it does exhibit a tendency to spread to the lungs. These patients thereby comprise a unique and understudied patient population. In this retrospective study, factors that have been shown to be statistically significant in association with worse disease-free survival and overall survival include presence of gross facial nerve invasion, higher T-classification, and high-grade disease.
    Keywords:  Acinic cell carcinoma; Distant metastases; Facial nerve; Parotid gland; Perineural invasion
    DOI:  https://doi.org/10.5306/wjco.v11.i1.11
  1428. Am J Pathol. 2020 Jan 20. pii: S0002-9440(20)30015-8. [Epub ahead of print]
    Toll-like receptor 5 signaling ameliorates liver fibrosis by inducing interferon β-modulated interleukin-1 receptor antagonist in mice.
    Zhou Z, Kim JW, Qi J, Eo SK, Lim CW, Kim B.
      Bacterial flagellin, recognized by cell surface of toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin- and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of interleukin-1 receptor antagonist (IL1RN) and interferon (IFNB) markedly increased in fibrotic livers upon flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNB and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/β receptor-1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibro-inflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN showed significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.
    DOI:  https://doi.org/10.1016/j.ajpath.2019.11.012
  1429. Biotechnol Bioeng. 2020 Jan 20.
    Reduced scale model qualification of 5L & 250 mL bioreactors using multivariant visualization & Bayesian inferential methods.
    Banton D, Canova C, Clark K, Naguib S, Schaefer E.
      A novel method for the qualification of reduced scale models (RSMs) was illustrated using data from both a 250 mL Advanced Microscale Bioreactor (ambr) and a 5L bioreactor RSM for a 2000L manufacturing scale process using a CHO cell line to produce a recombinant monoclonal antibody. The example study showed how the method was used to identify process performance attributes (PPAs) and product quality attributes (QAs) that capture important aspects of the RSM qualification process. The method uses two novel statistical approaches: multivariate dimension reduction and data visualization techniques, via Partial Least Squares-Discriminant Analysis (PLS-DA), and Bayesian multivariate linear modeling for inferential analysis. Bayesian multivariate linear modeling allows for individual probability distributions of the differences of the mean of each attribute for each scale, as well as joint probability statements on the differences of the means for multiple attributes. Depending on the results of this inferential procedure, PLS-DA is used to identify the process performance outputs at the different scales which have the greatest negative impact on the multivariate Bayesian joint probabilities. Experience with that particular process can then be leveraged to adjust operating conditions to minimize these differences, and then equivalence can be reassessed using the multivariate linear model. This article is protected by copyright. All rights reserved.
    Keywords:  Bayesian; PLS-DA; Reduced Scale Model; Statistical Qualification
    DOI:  https://doi.org/10.1002/bit.27282
  1430. World J Clin Cases. 2020 Jan 06. 8(1): 97-102
    Pembrolizumab - emerging treatment of pulmonary sarcomatoid carcinoma: A case report.
    Cimpeanu E, Ahmed J, Zafar W, DeMarinis A, Bardarov SS, Salman S, Bloomfield D.
      BACKGROUND: Few studies have addressed the efficacy of pembrolizumab in pulmonary sarcomatoid carcinoma (PSC), a rare, previously rapidly fatal subtype of non-small-cell lung cancer.CASE SUMMARY: We report the case of a 69-year-old man presented with respiratory distress caused by a large left upper lung lobe mass diagnosed as PSC with programmed death-ligand 1 expressed on more than 50 percent of tumor cells. The patient was started on pembrolizumab and, after 5 cycles, there was a more than 80 percent decrease in the size of the tumor mass. Further decrease was seen at the end of 10 cycles. The patient has been tolerating pembrolizumab well, with no limiting side-effects. Fourteen months after first coming into the hospital, he remains asymptomatic.
    CONCLUSION: Pembrolizumab appears as a viable emerging treatment for PSC.
    Keywords:  Case report; Non-small-cell lung cancer; Overall survival; Pembrolizumab; Platinum-based chemotherapy; Programmed death-ligand 1; Pulmonary sarcomatoid carcinoma
    DOI:  https://doi.org/10.12998/wjcc.v8.i1.97
  1431. Drug Metab Pharmacokinet. 2019 Oct 16. pii: S1347-4367(19)30116-8. [Epub ahead of print]
    Numerical analysis of apparent decitabine uptake in HCT116 cells: Incorporation of a bidirectional first-order kinetic parameter for ENT1 transport and Michaelis-Menten parameters for subsequent phosphorylation.
    Ueda K, Nakamura T, Tanaka S, Hosokawa M, Iwakawa S, Ogawara KI.
      Decitabine (DAC), a DNA methylation inhibitor, is transported into cancer cells mainly via equilibrative nucleoside transporter 1 (ENT1) and subsequently phosphorylated by deoxycytidine kinase (dCK). We previously reported that apparent DAC uptake into cells may be described using a simple compartment model with clearance for facilitated diffusion (PS) and subsequent phosphorylation (CLmet). In the present study, time course of apparent intracellular [3H]-DAC uptake was analyzed numerically, and PS and CLmet values were calculated using the compartment model in human colon cancer HCT116 cells. PS at 0.1 μM [3H]-DAC was markedly decreased in the presence of 100 μM irinotecan or etoposide, while CLmet was markedly decreased in the presence of 100 μM cytarabine or gemcitabine. CLmet at 0.1-10 μM [3H]-DAC varied in a concentration-dependent manner and was described by Michaelis-Menten parameters Km,met and Vmax,met. In conclusion, DAC uptake mainly via ENT1 may be described by a bidirectional first-order kinetic parameter, while phosphorylation by dCK may be described by Michaelis-Menten parameters.
    Keywords:  Compartment model; Decitabine; Deoxycytidine kinase; Equilibrative nucleoside transporter 1; Facilitated diffusion; Michaelis-Menten
    DOI:  https://doi.org/10.1016/j.dmpk.2019.10.002
  1432. Colloids Surf B Biointerfaces. 2020 Jan 11. pii: S0927-7765(20)30021-7. [Epub ahead of print]188 110791
    Preparation and characterization of copper and zinc adsorbed cetylpyridinium and N-lauroylsarcosinate intercalated montmorillonites and their antibacterial activity.
    Özdemir G, Yapar S.
      The main objective of the present study was the preparation and characterization of new cationic/anionic surfactants and Cu2+/Zn2+ modified montmorillonites and the evaluation of their potential applicability as antibacterial agents for topical applications. To evaluate the antibacterial activity of Cu2+ and Zn2+ by synergistic effect, as well as to reduce the well-known toxicity of these metal cations; cetylpyridinium (CP) and N-lauroylsarcosinate (SR) intercalated montmorillonite (Mt-CP-SR) was used as the host material. In addition to their role to capture the metal cations and inhibit their release in any contact medium, these surfactants also increase the efficacy of the material due to their antibacterial properties. The effect of surfactant loading on the adsorption behavior of the metal cations onto the Mt-CP was investigated using SR in two different concentrations, namely 0.7 and 1.0 CEC of sodium montmorillonite (Mt-Na). The samples prepared were characterized using SEM, ATR-FTIR, zeta potential, and XRD analyses and they were subjected to antibacterial tests using the "Standard Method Under Dynamic Contact Conditions" on the Gram positive S. aureus, and Gram negative E. coli. As confirmed with desorption and characterization studies, the addition of Cu2+/Zn2+ onto the Mt-CP-SR yielded double adsorbed amounts compared to that of the Mt-CP, which indicated that Cu2+/Zn2+ bound to SR- interacted with the Mt surface. In contrary of Zn2+ caused no considerable change in the antibacterial effect of the host, Cu2+ addition enhanced the antibacterial activity. The produced antibacterial agents have the potential use in dyes, polymer composites, personal care products, and topical medicinal applications.
    Keywords:  Antibacterial activity; Cetylpyridinium chloride; Copper/zinc; Inorgano/organo-montmorillonite; Sodium lauroyl sarcosinate
    DOI:  https://doi.org/10.1016/j.colsurfb.2020.110791
  1433. Food Res Int. 2020 Feb;pii: S0963-9969(19)30664-7. [Epub ahead of print]128 108778
    Non-targeted metabolomics analysis reveals dynamic changes of volatile and non-volatile metabolites during oolong tea manufacture.
    Chen S, Liu H, Zhao X, Li X, Shan W, Wang X, Wang S, Yu W, Yang Z, Yu X.
      Oolong tea is a partially fermented tea with distinct tastes and aromas. However, the dynamic biochemical changes during oolong tea processing are not well understood. In this study, we performed metabolomics-based profiling of non-volatile and volatile constituents of oolong tea during its entire processing procedures by UPLC-QTOF MS and GC-TOF MS. A step-wise change of tea metabolome was observed, where catechins and oxidized products, flavonol glycosides and amino acids were identified as key discriminate metabolites. The ZuoQing process comprising alternating YaoQing and TanQing steps was deemed most critical for key metabolic transformation. Extensive YaoQing facilitated the oxidative polymerizations of catechins into theaflavins and proanthocyanidins, lowering the astringency in raw tea. Two direct terpene precursors farnesyl pyrophosphate and geranyl pyrophosphate accumulated to high levels during ZuoQing, which provided more substrates for the synthesis of downstream volatile terpenes. Moreover, both YaoQing and prolonged TanQing facilitated the formation of terpenes as well as fatty acid and benzenoid-derived volatiles, which contributed to the fruity and floral fragrances in oolong tea. The fixation step not only converted amino acids into aromatic compounds, but also lowered the amounts of flavonol glycosides, potentially improving the flavor quality of the final tea product. This study provides a comprehensive profile of flavor-related metabolic changes during oolong tea processing and will contribute to better quality control and flavor improvement of oolong tea.
    Keywords:  Aromas; GC-TOF MS; Metabolomics; Oolong tea; Tastes; Tea processing; UPLC-QTOF MS
    DOI:  https://doi.org/10.1016/j.foodres.2019.108778
  1434. Curr Opin Biotechnol. 2020 Jan 15. pii: S0958-1669(19)30151-X. [Epub ahead of print]62 220-227
    Phenotypic variation in spatially structured microbial communities: ecological origins and consequences.
    D'Souza GG.
      Microbial cells in nature live within dense multispecies conglomerates, forming a self-organizing ecosystem. In such assemblies, genotypes interact with each other in a myriad of ways, driving community dynamics and functionalities. The role of interactions between genotypes and their consequences for spatial structure and functional outcomes are being increasingly studied to understand the ecology and evolution of microbial communities. An increasing body of work with simple microbial populations has elucidated that phenotypic variation, that is, differences within isogenic cells can have important consequences for population dynamics and evolution. However, the role of individual level behavioral differences for community level dynamics is relatively unknown. I argue that it is necessary to study phenotypic variation and microscale processes in order to understand the emergence and consequences of interactions within microbial communities. I highlight possible explanations that can explain the emergence of variation in multi-genotypic assemblages and propose possible consequences on community dynamics.
    DOI:  https://doi.org/10.1016/j.copbio.2019.12.013
  1435. Nat Neurosci. 2020 Jan 20.
    Cell-type-specific drug-inducible protein synthesis inhibition demonstrates that memory consolidation requires rapid neuronal translation.
    Shrestha P, Ayata P, Herrero-Vidal P, Longo F, Gastone A, LeDoux JE, Heintz N, Klann E.
      New protein synthesis is known to be required for the consolidation of memories, yet existing methods of blocking translation lack spatiotemporal precision and cell-type specificity, preventing investigation of cell-specific contributions of protein synthesis. Here we developed a combined knock-in mouse and chemogenetic approach for cell-type-specific drug-inducible protein synthesis inhibition that enables rapid and reversible phosphorylation of eukaryotic initiation factor 2α, leading to inhibition of general translation by 50% in vivo. We use cell-type-specific drug-inducible protein synthesis inhibition to show that targeted protein synthesis inhibition pan-neuronally and in excitatory neurons in the lateral amygdala (LA) impaired long-term memory. This could be recovered with artificial chemogenetic activation of LA neurons, although at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eukaryotic initiation factor 2α in excitatory neurons in the LA enhanced memory strength but reduced memory fidelity and behavioral flexibility. Our findings provide evidence for a cell-specific translation program during consolidation of threat memories.
    DOI:  https://doi.org/10.1038/s41593-019-0568-z
  1436. Infect Dis Model. 2020 ;5 111-128
    A primer on model selection using the Akaike Information Criterion.
    Portet S.
      A powerful investigative tool in biology is to consider not a single mathematical model but a collection of models designed to explore different working hypotheses and select the best model in that collection. In these lecture notes, the usual workflow of the use of mathematical models to investigate a biological problem is described and the use of a collection of model is motivated. Models depend on parameters that must be estimated using observations; and when a collection of models is considered, the best model has then to be identified based on available observations. Hence, model calibration and selection, which are intrinsically linked, are essential steps of the workflow. Here, some procedures for model calibration and a criterion, the Akaike Information Criterion, of model selection based on experimental data are described. Rough derivation, practical technique of computation and use of this criterion are detailed.
    Keywords:  Akaike information criterion; Collection of models; Model calibration; Model selection
    DOI:  https://doi.org/10.1016/j.idm.2019.12.010
  1437. Beilstein J Org Chem. 2020 ;16 50-59
    Understanding the role of active site residues in CotB2 catalysis using a cluster model.
    Raz K, Driller R, Brück T, Loll B, Major DT.
      Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of a large number of terpenes. CotB2 is a diterpene cyclase from Streptomyces melanosporofaciens, which catalyzes the formation of cycloocta-9-en-7-ol, a precursor to the next-generation anti-inflammatory drug cyclooctatin. In this work, we present evidence for the significant role of the active site's residues in CotB2 on the reaction energetics using quantum mechanical calculations in an active site cluster model. The results revealed the significant effect of the active site residues on the relative electronic energy of the intermediates and transition state structures with respect to gas phase data. A detailed understanding of the role of the enzyme environment on the CotB2 reaction cascade can provide important information towards a biosynthetic strategy for cyclooctatin and the biomanufacturing of related terpene structures.
    Keywords:  CotB2 cyclase; active site; diterpene; mechanism; quantum mechanics
    DOI:  https://doi.org/10.3762/bjoc.16.7
  1438. J Clin Neurosci. 2020 Jan 20. pii: S0967-5868(19)32112-5. [Epub ahead of print]
    Dynamic mapping of the corticospinal tract in open cordotomy and myelomeningocele surgery.
    Tsetsou S, Butler W, Borges L, Eskandar EN, Fehnel KP, See RB, Simon MV.
      OBJECT: Spinal cord surgeries carry a high risk for significant neurological impairments. The initial techniques for spinal cord mapping emerged as an aid to identify the dorsal columns and helped select a safe myelotomy site in intramedullary tumor resection. Advancements in motor mapping of the cord have also been made recently, but exclusively with tumor surgery. We hereby present our experiences with dynamic mapping of the corticospinal tract (CST) in other types of spinal cord procedures that carry an increased risk of postoperative motor deficit, and thus could directly benefit from this technique.CASE REPORTS: Two patients with intractable unilateral lower extremity pain due to metastatic disease of the sacrum and a thoraco-lumbar chordoma, respectively underwent thoracic cordotomy to interrupt the nociceptive pathways. A third patient with progressive leg weakness underwent cord untethering and surgical repair of a large thoracic myelomeningocele. In all three cases, multimodality intraoperative neurophysiologic testing included somatosensory and motor evoked potentials monitoring as well as dynamic mapping of the CST.
    CONCLUSION: CST mapping allowed safe advancement of the cordotomy probe and exploration of the meningocele sac with untethering of the anterior-lateral aspect of the cord respectively, resulting in postoperative preservation or improvement of motor strength from the pre-operative baseline. Stimulus thresholds varied likely with the distance between the stimulating probe and the CST as well as with the baseline motor strength in the mapped myotomes.
    Keywords:  Corticospinal tract; Direct spinal cord stimulation; Spinal cord mapping
    DOI:  https://doi.org/10.1016/j.jocn.2020.01.054
  1439. Clin Psychopharmacol Neurosci. 2020 Feb 29. 18(1): 109-115
    Plasma Apelin, Visfatin and Resistin Levels in Patients with First Episode Psychosis and Chronic Schizophrenia.
    Sahpolat M, Ari M, Kokacya MH.
      Objective: This study aims to investigate the possible relationship between plasma concentrations of apelin, visfatin and resistin levels of first episode psychosis patients and chronic schizophrenia patients.Methods: A total number of 29 untreated patients with first episode psychosis, 30 chronic schizophrenia and 29 randomly selected weight- and body mass index-matched healthy volunteers were included. The Diagnostic and Statistical Manual of Mental Disorders 4th edition, Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Scale were applied to the patient groups. The enzyme-linked immunosorbent assay method was used to measure plasma apelin, visfatin and resistin levels.
    Results: There was no difference in age, marital status, occupation, and BMI between the groups. Plasma apelin levels were significantly higher in first episode psychosis group than chronic schizophrenia and control group. There was no statistically significant difference in plasma visfatin levels between the groups: first episode psychosis group, chronic schizophrenia and control group. Plasma resistin levels were higher in both first episode psychosis group and chronic schizophrenia group than the control group. There was no statistically significant correlation between plasma apelin and resistin levels and total PANSS scores in the group of patients.
    Conclusion: To our knowledge, this study is the first which investigates the plasma apelin, visfatin and resistin levels in patients with first episode psychosis and chronic schizophrenia. Based on the results of this study, apelin and resistin may be related with some central nervous system pathologies, including the severity of a psychiatric disorder.
    Keywords:  Apelin; First episode psychosis; Nicotinamide phosphoribosyltransferase; Resistin.; Schizophrenia
    DOI:  https://doi.org/10.9758/cpn.2020.18.1.109
  1440. J Cell Mol Med. 2020 Jan 19.
    Circular RNA hsa_circRNA_002178 silencing retards breast cancer progression via microRNA-328-3p-mediated inhibition of COL1A1.
    Liu T, Ye P, Ye Y, Lu S, Han B.
      Circular RNAs (circRNAs) are a group of non-coding RNAs implicated in the pathogenesis of cancer progression, which exert their functions via regulation of microRNAs (miRNAs) and genes. The present study uses gain- and loss-of-function approaches to evaluate the functions of hsa_circRNA_002178 in angiogenesis along with energy metabolism and underlying downstream signals. The expression pattern of hsa_circRNA_002178 in clinical breast cancer tissues and its association with prognosis were characterized at first. Next, the energy metabolism and angiogenesis as well as cell viability were evaluated when the expression of hsa_circRNA_002178 in breast cancer cells was knocked down by siRNA. The interaction between hsa_circRNA_002178 and its downstream miR-328-3p was identified, followed by the analysis of their functions in regulation of breast cancer cellular behaviours. The target gene of miR-328-3p was predicted and verified, followed by identifying its role in the breast cancer progression. Higher expression of hsa_circRNA_002178 shared an association with worse prognosis in breast cancer. The inhibition of hsa_circRNA_002178 resulted in reductions in cell viability, energy metabolism and tube formation ability. Hsa_circRNA_002178 could competitively bind to miR-328-3p and down-regulated its expression. Restoration of miR-328-3p eliminated the tumour-promoting effects of hsa_circRNA_002178. COL1A1, as a target of miR-328-3p, could be up-regulated by overexpression of hsa_circRNA_002178. In vivo experiments further confirmed the inhibition of tumour growth and inflammation by silencing hsa_circRNA_002178 or up-regulating miR-328-3p. Taken together, hsa_circRNA_002178 is highlighted as a promising target for breast cancer due to the anti-tumour effects achieved by silencing hsa_circRNA_002178.
    Keywords:  COL1A1; Hsa_circRNA_002178; MicroRNA-328-3p; angiogenesis; breast cancer; circular RNA; energy metabolism
    DOI:  https://doi.org/10.1111/jcmm.14875
  1441. Materials (Basel). 2020 Jan 22. pii: E513. [Epub ahead of print]13(3):
    Dual Imaging Gold Nanoplatforms for Targeted Radiotheranostics.
    Silva F, Paulo A, Pallier A, Même S, Tóth É, Gano L, Marques F, Geraldes CFGC, Castro MMCA, Cardoso AM, Jurado AS, López-Larrubia P, Lacerda S, Campello MPC.
      Gold nanoparticles (AuNPs) are interesting for the design of new cancer theranostic tools, mainly due to their biocompatibility, easy molecular vectorization, and good biological half-life. Herein, we report a gold nanoparticle platform as a bimodal imaging probe, capable of coordinating Gd3+ for Magnetic Resonance Imaging (MRI) and 67Ga3+ for Single Photon Emission Computed Tomography (SPECT) imaging. Our AuNPs carry a bombesin analogue with affinity towards the gastrin releasing peptide receptor (GRPr), overexpressed in a variety of human cancer cells, namely PC3 prostate cancer cells. The potential of these multimodal imaging nanoconstructs was thoroughly investigated by the assessment of their magnetic properties, in vitro cellular uptake, biodistribution, and radiosensitisation assays. The relaxometric properties predict a potential T1- and T2- MRI application. The promising in vitro cellular uptake of 67Ga/Gd-based bombesin containing particles was confirmed through biodistribution studies in tumor bearing mice, indicating their integrity and ability to target the GRPr. Radiosensitization studies revealed the therapeutic potential of the nanoparticles. Moreover, the DOTA chelating unit moiety versatility gives a high theranostic potential through the coordination of other therapeutically interesting radiometals. Altogether, our nanoparticles are interesting nanomaterial for theranostic application and as bimodal T1- and T2- MRI / SPECT imaging probes.
    Keywords:  MRI; PC3 tumor; SPECT; bombesin; gold nanoparticles; multimodality; radiosensitization
    DOI:  https://doi.org/10.3390/ma13030513
  1442. Microb Pathog. 2020 Jan 16. pii: S0882-4010(19)31853-4. [Epub ahead of print] 103983
    Immunogenic cell death: A link between gut microbiota and anticancer effects.
    Chen W, Wang S, Wu Y, Shen X, Guo Z, Li Q, Xing D.
      For years, intratumor injection of bacteria have been purported to be capable of an anticancer effect. However, these bacteria are mostly pathogenic including attenuated and genetically engineered bacteria. The gut microbiota has been discovered to play a key role in immunotherapy. Many remarkable advances have been made in characterizing the immune responses to gut microbiota. Interestingly, accumulating evidence has demonstrated that immunogenic cell death (ICD) plays a key role in the anticancer effect of chemotherapy, radiotherapy, photodynamic therapy and oncolytic virotherapy. Most interestingly, the gut microbiota may impact the ICD process. Given the importance of the gut microbiota in immune responses, cancer progression and the anticancer efficacy of drugs with immune effects. We propose a mechanism in which ICD may be the possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects. However, the study of the relationship between the gut microbiota and ICD is limited, and it is still not clear how gut microbiota affect the ICD pathway. In this review, we discuss the mechanism by which the gut microbiota affects ICD, and suggest that ICD may be a possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects.
    Keywords:  Cancer; Gut microbiota; Immune responses; Immunogenic cell death
    DOI:  https://doi.org/10.1016/j.micpath.2020.103983
  1443. Endocrinology. 2020 Jan 24. pii: bqaa008. [Epub ahead of print]
    C-type natriuretic peptide restores growth impairment under enzyme replacement in mice with mucopolysaccharidosis VII.
    Yamashita T, Fujii T, Yamauchi I, Ueda Y, Hirota K, Kanai Y, Yasoda A, Inagaki N.
      Growth impairment in mucopolysaccharidoses (MPSs) is an unresolved issue as it is resistant to enzyme replacement therapy (ERT) and growth hormone therapy. C-type natriuretic peptide (CNP) is a promising agent that has growth promoting effects. Here, we investigate the effects of CNP on growth impairment of MPSs using Gusbmps-2J mice, a model for MPS type Ⅶ, with combination therapy of CNP and ERT by hydrodynamic gene delivery. Although monotherapies were not sufficient to restore short statures of treated mice, combination therapy resulted in successful restoration. The synergistic effects of CNP and ERT were not only observed in skeletal growth but also in growth plates. ERT reduced cell swelling in the resting zone and increased cell number by accelerating proliferation or inhibiting apoptosis. CNP thickened the proliferative and hypertrophic zones. Regarding changes in the bone, ERT restored bone sclerosis through decreased bone formation and increased bone resorption, and CNP did not adversely affect this process. In addition, improvement of joint deformation by ERT was suggested by analyses of joint spaces and articular cartilage. CNP additively provided restoration of the short stature of MPS Ⅶ mice in combination with ERT which improved abnormalities of growth plates and bone metabolism.
    Keywords:  C-type natriuretic peptide; enzyme replacement therapy; gene delivery; growth impairment; mucopolysaccharidosis VII; short stature
    DOI:  https://doi.org/10.1210/endocr/bqaa008
  1444. Oncotarget. 2019 Jun 18. 10(40): 3996-3997
    Mesothelioma: Hippo pathway as a target, lessons from COMMAND.
    Fennell DA, Baitei EY.
      
    Keywords:  NF2; defactinib; focal adhesion kinase; hippo pathway; mesothelioma
    DOI:  https://doi.org/10.18632/oncotarget.27018
  1445. JACC Cardiovasc Imaging. 2020 Jan 10. pii: S1936-878X(19)30957-X. [Epub ahead of print]
    Routine Use of Cardiovascular Magnetic Resonance in the Work-Up of Patients With Ventricular Arrhythmias?
    Bucciarelli-Ducci C, Berlot B.
      
    Keywords:  additional diagnostic value; arrhythmic substrate; cardiac magnetic resonance; ventricular arrhythmias
    DOI:  https://doi.org/10.1016/j.jcmg.2019.10.006
  1446. Drug Alcohol Depend. 2020 Jan 11. pii: S0376-8716(20)30011-9. [Epub ahead of print]208 107846
    Is time elapsed between cannabis use and sleep start time associated with sleep continuity? An experience sampling method.
    Sznitman SR, Shochat T, Greene T.
      BACKGROUND: A substantial proportion of people using cannabis report using it to improve sleep. Yet, little research exists on the associations between the timing of cannabis use and sleep. This study examines the time elapsed between cannabis use and sleep start time and its association with two of the main indicators of sleep continuity: (1) sleep onset latency (SOL) and (2) number of awakenings (NOA) throughout the night.METHODS: Each morning, for 7 consecutive days, daily cannabis users (n = 54) reported on the timing of previous night's cannabis use and sleep indicators on their smartphones. Mixed effects models examined the relations of within- and between-subjects' time elapsed between previous night cannabis use and sleep start time, with (1) SOL and (2) NOA.
    RESULTS: Within subjects, shorter time elapsed between cannabis use and sleep start time was associated with shorter SOL (β = 0.519, p = 0.010), but not NOA (β = -0.030, p = 0.535). Furthermore, between individuals, the time gap between the previous night cannabis use and sleep start time was not associated with SOL or NOA (p > 0.05).
    CONCLUSIONS: It is possible that cannabis use proximal to bedtime is associated with shorted sleep onset latency but not nighttime awakenings. Cannabis users should be informed about both the potential sleep aid effects of cannabis and its limitations. Pending further evidence of the effects of cannabis on sleep, cannabis users experiencing sleep problems should be provided with evidence-based alternatives to improve sleep, e.g., pharmacological and behavioral treatments.
    Keywords:  Cannabis; Experience sampling method; Insomnia; Nightly awakenings; Sleep; Sleep onset latency
    DOI:  https://doi.org/10.1016/j.drugalcdep.2020.107846
  1447. J Pak Med Assoc. 2020 Jan;70(1): 1-2
    The Journal Impact Factor- Does it reflect the quality of a journal?
    Jawad F.
      
  1448. Mol Microbiol. 2020 Jan 21.
    A link between mitochondrial gene expression and life stage morphologies in Trypanosoma cruzi.
    Ramirez-Barrios R, Susa EK, Smoniewski CM, Faacks SP, Liggett CK, Zimmer SL.
      The protozoan Trypanosoma cruzi has a complicated dual-host life cycle, and starvation can trigger transition from the replicating insect stage to the mammalian-infectious nonreplicating insect stage (epimastigote to trypomastigote differentiation). Abundance of some mature RNAs derived from its mitochondrial genome increase during culture starvation of T. cruzi for unknown reasons. Here we examine T. cruzi mitochondrial gene expression in the mammalian intracellular replicating life stage (amastigote), and uncover implications of starvation-induced changes in gene expression. Mitochondrial RNA levels in general were found to be lowest in actively replicating amastigotes. We discovered that mitochondrial respiration decreases during starvation in insect-stage cells, despite the previously-observed increases in mitochondrial mRNAs encoding electron transport chain components. Surprisingly, T. cruzi epimastigotes in replete medium grow at normal rates when we genetically compromised their ability to perform insertion/deletion editing and thereby generate mature forms of some mitochondrial mRNAs. However, these cells, when starved, were impeded in the epimastigote to trypomastigote transition. Further, they experience a short-flagella phenotype that may also be linked to differentiation. We hypothesize a scenario where levels of mature RNA species or editing in the single T. cruzi mitochondrion are linked to differentiation by a yet-unknown signaling mechanism.
    Keywords:  Gene Expression; Life Cycle Stages; Organelles; RNA editing; Ribonuclease; Trypanosomiasis
    DOI:  https://doi.org/10.1111/mmi.14466
  1449. ESMO Open. 2020 Jan;pii: e000642. [Epub ahead of print]5(1):
    In the literature: December 2019.
    Gambardella V, Insa A, Cejalvo JM, Cervantes A.
      
    DOI:  https://doi.org/10.1136/esmoopen-2019-000642
  1450. Science. 2020 Jan 24. 367(6476): 464-468
    Phase separation provides a mechanism to reduce noise in cells.
    Klosin A, Oltsch F, Harmon T, Honigmann A, Jülicher F, Hyman AA, Zechner C.
      Expression of proteins inside cells is noisy, causing variability in protein concentration among identical cells. A central problem in cellular control is how cells cope with this inherent noise. Compartmentalization of proteins through phase separation has been suggested as a potential mechanism to reduce noise, but systematic studies to support this idea have been missing. In this study, we used a physical model that links noise in protein concentration to theory of phase separation to show that liquid droplets can effectively reduce noise. We provide experimental support for noise reduction by phase separation using engineered proteins that form liquid-like compartments in mammalian cells. Thus, phase separation can play an important role in biological signal processing and control.
    DOI:  https://doi.org/10.1126/science.aav6691
  1451. Front Microbiol. 2019 ;10 2962
    Dual NDP52 Function in Persistent CSFV Infection.
    Fan S, Wu K, Luo C, Li X, Zhao M, Song D, Ma S, Zhu E, Chen Y, Ding H, Yi L, Li J, Zhao M, Chen J.
      Viruses have evolved many mechanisms to escape host antiviral responses. Previously, we found that classical swine fever virus (CSFV) infection induces autophagy using the autophagosome as a self-replication site, thereby evading the host immune response and promoting long-term infection. However, the underlying mechanisms used by CSFV to enter autophagosomes and the mechanism by which autophagy promotes viral replication remain unclear. We found that CSFV infection inhibited autophagy receptor nuclear dot protein 52 kDa (NDP52) expression, ubiquitination, and SUMO2-4 modification. Further analyses revealed that CSFV mediated ubiquitination and SUMOylation of NDP52 via Pten-induced kinase 1 (PINK1)-Parkin. Moreover, NDP52 inhibition also inhibited CSFV replication and the induction of mitophagy marker proteins expression. Inhibition of NDP52 reduced CD63 expression and binding to CSFV E2 protein, which has an essential role in persistent CSFV infection. As NDP52 has a close relationship with the NF-κB innate immunity pathway and plays an important role in the antiviral response, we investigated whether NDP52 inhibited CSFV replication through the release of immune factors and antivirus signals. Our results showed that inhibiting NDP52 boosted interferon and TNF release and promoted NF-κB pathway activation. In summary, we found that NDP52 inhibition not only reduces CSFV binding and entry into autophagic vesicles, but also inhibits CSFV replication by active NF-κB antiviral immune pathways. Our data reveal a novel mechanism by which NDP52, an autophagy receptor, mediates CSFV infection, and provide new avenues for the development of antiviral strategies.
    Keywords:  CD63; NDP52; NF-κB; classical swine fever virus; ubiquitination
    DOI:  https://doi.org/10.3389/fmicb.2019.02962
  1452. Toxicol In Vitro. 2020 Jan 17. pii: S0887-2333(19)30745-3. [Epub ahead of print] 104776
    Development of an in vitro system and model-based translational framework to assess haemolysis risk following intravenous abuse of medications containing polyethylene oxide.
    Persich P, Engels GE, van Oeveren W, Galia E, Benay S, Thun S.
      Multiple cases of potentially life-threatening thrombotic microangiopathy (TMA) have resulted from intravenous abuse of medications containing polyethylene oxide (PEO), most often Opana ER (oxymorphone hydrochloride extended release). No validated models are available to assess the risk of TMA with different formulations and extraction methods following intravenous abuse. We have developed an in vitro system that involves passing pooled blood containing the excipient of interest through a syringe needle and assessing haemolysis via haemoglobin release. Haemolysis is induced by high shear stress caused by the flow of blood containing PEO through a narrow-bore syringe needle, recapitulating the mechanism in small blood vessels. Using the in vitro system, we demonstrate that high-molecular-weight PEO (>1 MDa) induces haemolysis in a concentration-dependent manner under flowing but not static conditions. We use data from the in vitro system and published in vivo data to predict the timecourse of the haemolytic response in vivo via a pharmacometric model. The in vitro system is a novel method for investigating factors influencing PEO-induced haemolysis. In combination with our model-based translational framework, the in vitro system allows straightforward assessment of the haemolytic potential of PEO-containing medications, and may find application in gauging TMA risk following intravenous abuse.
    Keywords:  Haemolysis; Opana ER; Opioid abuse; Polyethylene oxide; Thrombotic microangiopathy; Translational
    DOI:  https://doi.org/10.1016/j.tiv.2020.104776
  1453. Aging (Albany NY). 2020 Jan 24. 12
    Identification of a nomogram based on long non-coding RNA to improve prognosis prediction of esophageal squamous cell carcinoma.
    Li W, Liu J, Zhao H.
      PURPOSE: Esophageal squamous cell carcinoma (ESCC) remains a common aggressive malignancy in the world. Several long non-coding RNAs (lncRNAs) are reported to predict the prognosis of ESCC. Therefore, an in-depth research is urgently needed to further investigate the prognostic value of lncRNAs in ESCC.RESULTS: From the training set, we identified a eight-lncRNA signature (including AP000487, AC011997, LINC01592, LINC01497, LINC01711, FENDRR, AC087045, AC137770) which separated the patients into two groups with significantly different overall survival (hazard ratio, HR = 3.79, 95% confidence interval, 95% CI [2.56-5.62]; P < 0.001). The signature was applied to the validation set (HR = 2.73, 95%CI [1.65-4.53]; P < 0.001) and showed similar prognostic values. Stratified, univariate and multivariate Cox regression analysis indicated that the signature was an independent prognostic factor for patients with ESCC. A nomogram based on the lncRNAs signature, age, grade and stage was developed and showed good accuracy for predicting 1-, 3- and 5-year survival probability of ESCC patients. We found a strong correlation between the gene significance for the survival time and T stage. Eight modules were constructed, among which the key module most closely associated with clinical information was identified.
    CONCLUSIONS: Our eight-lincRNA signature and nomogram could be practical and reliable prognostic tools for esophageal squamous cell carcinoma.
    METHODS: We downloaded the lncRNA expression profiles of ESCC patients from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets and separated to training and validation cohort. The univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to identify a lncRNA-based signature. The predictive value of the signature was assessed using the Kaplan-Meier method, receiver operating characteristic (ROC) curves and area under curve (AUC). Weighted gene co-expression network analysis (WGCNA) was applied to predict the intrinsic relationship between gene expressions. In addition, we further explored the combination of clinical information and module construction.
    Keywords:  esophageal squamous cell carcinoma; long non-coding RNA; nomogram; signature; weighted gene co-expression network analysis
    DOI:  https://doi.org/10.18632/aging.102697
  1454. Eur Rev Med Pharmacol Sci. 2020 Jan;pii: 19945. [Epub ahead of print]24(1): 452-460
    Effect of rosiglitazone on myocardial injury in septic rats through NF-κB pathway.
    Zhang SM, Cai XF, Ma YL, Lu Q.
      INTRODUCTION: To explore the effect of rosiglitazone on myocardial injury in septic rats through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway.MATERIALS AND METHODS: A total of 60 healthy adult female Sprague-Dawley (SD) rats were randomly divided into 4 groups, namely, group A (sepsis model group, n=15), group B (sham operation group, n=15), group C (sepsis model + 3 mg/kg rosiglitazone, n=15), and group D (sham operation group + 3 mg/kg rosiglitazone, n=15), respectively. After the sepsis model was successfully established, the rats were administered with 3 mg/kg rosiglitazone by gavage, with a gavage volume of 1 mL, once a day for a total of 3 days. Blood was taken from the abdominal aorta, while lactate dehydrogenase (LDH) and creatine phosphokinase kits were used to detect the levels of LDH and creatine phosphokinase in serum. Then, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was adopted to identify myocardial tissue apoptosis, hematoxylin and eosin staining (H&E) was applied to detect myocardial tissue morphology, and enzyme-linked immunosorbent assay (ELISA) was utilized to examine the protein expression level of tumor necrosis factor-alpha (TNF-α) in rat serum. Subsequently, the messenger ribonucleic acid (mRNA) level of TNF-α in myocardial tissues was measured via fluorescence quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) method, and the activity of NF-κB was detected by electrophoretic mobility shift assay (EMSA).
    RESULTS: Compared with those in group A, apoptotic cells in group B and group D were notably increased (p<0.05). At 3 days after administration with rosiglitazone (3 mg/kg), apoptotic cells were markedly decreased (p<0.05). H&E staining results manifested that 3 mg/kg rosiglitazone prominently improved myocardial tissue morphology in rats. The protein level of TNF-α in serum, the mRNA expression level of TNF-α in myocardial tissues, and the activity of NF-κB in group C treated with rosiglitazone were lower than those in group A (p<0.05).
    CONCLUSIONS: Rosiglitazone can alleviate myocardial injury in septic rats by suppressing the TNF-α expression and this process is associated with the regulation on the NF-κB signal transduction pathway.
    DOI:  https://doi.org/10.26355/eurrev_202001_19945
  1455. J Pharmacol Toxicol Methods. 2019 Sep - Oct;99:pii: S1056-8719(19)30230-8. [Epub ahead of print]99 106595
    Evaluation of cardiovascular risk related to a monoclonal antibody mediated increase in vascular endothelial growth factor in conscious normal rats.
    Derakhchan K, Reeves R, Keefe D, Parker S, Carey G.
      
    DOI:  https://doi.org/10.1016/j.vascn.2019.05.117
  1456. Clin Obes. 2020 Jan 21. e12356
    Bariatric surgery-induced weight loss in patients with and without type 2 diabetes mellitus.
    Carvalho TA, Ronsoni MF, Hohl A, van de Sande-Lee S.
      Surgical treatment of obesity leads to weight loss and metabolic improvement, but it is unclear if the response differs between patients with and without type 2 diabetes. Retrospective cohort study comparing weight loss and metabolic outcomes between patients with and without type 2 diabetes, matched for body mass index (BMI), gender and age, 12 months after Roux-en-Y gastric bypass. Forty-eight patients with type 2 diabetes (D) and 48 without type 2 diabetes (ND) were evaluated, 87.5% female, mean age 42.2 ± 0.9 years. The mean baseline weight and BMI of the D and ND groups were, respectively, 120.3 ± 21.6 vs 123.7 ± 20.8 kg (P = .45) and 47.2 ± 7.5 vs 47.2 ± 6.9 kg/m2 (P = .70). After 12 months, there was no significant difference in weight (40.4 ± 16.9 vs 44.1 ± 12.2 kg, P = .28) and BMI (15.8 ± 6.5 vs 16.9 ± 4.5 kg/m2 , P = .26) variation between groups. The parameters that presented significant variation were (D vs ND): fasting blood glucose (41.6 ± 43.0 vs 12.7 ± 17.2 mg/dL, P < .01), HbA1c (1.8 ± 1.6 vs 0.6 ± 0.7%; P < .01), triglycerides (91.1 ± 100.4 vs 54.2 ± 43.8 mg/dL; P = .04), low-density lipoprotein (27.2 ± 41.5 vs 37.5 ± 24.2 mg/dL; P < .01) and gamma glutamyl transferase (46.5 ± 55.3 vs 17.7 ± 11.9 UI/L; P = .04). Weight loss 12 months after a gastric bypass was similar in patients with and without type 2 diabetes, the greater metabolic benefits appearing in patients with type 2 diabetes as they had more pronounced changes at baseline.
    Keywords:  bariatric surgery; obesity; type 2 diabetes mellitus; weight loss
    DOI:  https://doi.org/10.1111/cob.12356
  1457. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31719-X. [Epub ahead of print]30(3): 932-946.e7
    Transcriptional Programming of Human Mechanosensory Neuron Subtypes from Pluripotent Stem Cells.
    Nickolls AR, Lee MM, Espinoza DF, Szczot M, Lam RM, Wang Q, Beers J, Zou J, Nguyen MQ, Solinski HJ, AlJanahi AA, Johnson KR, Ward ME, Chesler AT, Bönnemann CG.
      Efficient and homogeneous in vitro generation of peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. We discover that, by overexpressing NGN2 and BRN3A, human pluripotent stem cells can be transcriptionally programmed to differentiate into a surprisingly uniform culture of cold- and mechano-sensing neurons. Although such a neuronal subtype is not found in mice, we identify molecular evidence for its existence in human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produce two additional populations of sensory neurons, including a specialized touch receptor neuron subtype. Finally, we apply this system to model a rare inherited sensory disorder of touch and proprioception caused by inactivating mutations in PIEZO2. Together, these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.
    Keywords:  DRG; PIEZO2; TRPM8; differentiation; human; iPSC; mechanosensation; neural crest; neuron; sensory
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.062
  1458. ACS Appl Mater Interfaces. 2020 Jan 22.
    Quantitative Interpretation of Hydration Dynamics Enabled the Fabrication of Zwitterionic Antifouling Surface.
    Choi W, Jin J, Park S, Kim JY, Lee MJ, Sun H, Kwon JS, Lee H, Choi SH, Hong J.
      In the medical industry, zwitterionic brushes have received significant attention owing to their antifouling effect that arose from their hydration ability. However, sufficient understanding of the hydration dynamics of zwitterionic brushes is required to fabricate the precisely controlled antifouling medical devices. In this paper, we successfully show that hydration, the interaction between water molecules and zwitterionic brushes, and its dynamics can be evaluated logically and quantitatively using 1) water contact angle, 2) molecular dynamic simulation, and 3) RAMAN spectroscopy. Based on the intuitive results on hydration, we precisely optimized the antifouling property of the model medical device, a removable orthodontic retainer, with various grafting efficiencies of 2-methacryloyloxyethyl phosphate choline (MPC). As a result, the model device reduced nonspecific adsorption of proteins and bacteria, indicating an improved antifouling effect, and also inhibited the formation of biofilm. Furthermore, the device showed excellent physical properties desirable for application in the orthodontic field, meaning the balance between the antibacterial property and mechanical strength.
    DOI:  https://doi.org/10.1021/acsami.9b21566
  1459. Nutrients. 2020 Jan 21. pii: E282. [Epub ahead of print]12(2):
    A Special Amino-Acid Formula Tailored to Boosting Cell Respiration Prevents Mitochondrial Dysfunction and Oxidative Stress Caused by Doxorubicin in Mouse Cardiomyocytes.
    Tedesco L, Rossi F, Ragni M, Ruocco C, Brunetti D, Carruba MO, Torrente Y, Valerio A, Nisoli E.
      Anthracycline anticancer drugs, such as doxorubicin (DOX), can induce cardiotoxicity supposed to be related to mitochondrial damage. We have recently demonstrated that a branched-chain amino acid (BCAA)-enriched mixture (BCAAem), supplemented with drinking water to middle-aged mice, was able to promote mitochondrial biogenesis in cardiac and skeletal muscle. To maximally favor and increase oxidative metabolism and mitochondrial function, here we tested a new original formula, composed of essential amino acids, tricarboxylic acid cycle precursors and co-factors (named 5), in HL-1 cardiomyocytes and mice treated with DOX. We measured mitochondrial biogenesis, oxidative stress, and BCAA catabolic pathway. Moreover, the molecular relevance of endothelial nitric oxide synthase (eNOS) and mechanistic/mammalian target of rapamycin complex 1 (mTORC1) was studied in both cardiac tissue and HL-1 cardiomyocytes. Finally, the role of Krüppel-like factor 15 (KLF15), a critical transcriptional regulator of BCAA oxidation and eNOS-mTORC1 signal, was investigated. Our results demonstrate that the 5 mixture prevents the DOX-dependent mitochondrial damage and oxidative stress better than the previous BCAAem, implying a KLF15/eNOS/mTORC1 signaling axis. These results could be relevant for the prevention of cardiotoxicity in the DOX-treated patients.
    Keywords:  Krüppel-like factor 15; branched-chain amino acids; cardiomyocytes; doxorubicin; endothelial nitric oxide synthase; mechanistic/mammalian target of rapamycin; mitochondria; oxidative stress; peroxisome proliferator-activated receptor coactivator 1; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/nu12020282
  1460. Nat Commun. 2020 Jan 23. 11(1): 459
    Wild primates copy higher-ranked individuals in a social transmission experiment.
    Canteloup C, Hoppitt W, van de Waal E.
      Little is known about how multiple social learning strategies interact and how organisms integrate both individual and social information. Here we combine, in a wild primate, an open diffusion experiment with a modeling approach: Network-Based Diffusion Analysis using a dynamic observation network. The vervet monkeys we study were not provided with a trained model; instead they had access to eight foraging boxes that could be opened in either of two ways. We report that individuals socially learn the techniques they observe in others. After having learnt one option, individuals are 31x more likely to subsequently asocially learn the other option than individuals naïve to both options. We discover evidence of a rank transmission bias favoring learning from higher-ranked individuals, with no evidence for age, sex or kin bias. This fine-grained analysis highlights a rank transmission bias in a field experiment mimicking the diffusion of a behavioral innovation.
    DOI:  https://doi.org/10.1038/s41467-019-14209-8
  1461. Insects. 2020 Jan 22. pii: E75. [Epub ahead of print]11(2):
    Inter-Individual Nectar Chemistry Changes of Field Scabious, Knautia arvensis.
    Venjakob C, Leonhardt S, Klein AM.
      Nectar is crucial to maintain plant-pollinator mutualism. Nectar quality (nutritional composition) can vary strongly between individuals of the same plant species. The factors driving such inter-individual variation have however not been investigated closer. We investigated nectar quality of field scabious, Knautia arvensis in different grassland plant communities varying in species composition and richness to assess whether nectar quality can be affected by the surrounding plant community. We analyzed (with high performance liquid chromatography) the content of carbohydrates, overall amino acids, and essential amino acids. Amino acid and carbohydrate concentrations and proportions varied among plant individuals and with the surrounding plant community but were not related to the surrounding plant species richness. Total and individual carbohydrate concentrations were lowest, while proportions of the essential amino acids, valine, isoleucine, leucine (all phagostimulatory), and lysine were highest in plant species communities of the highest diversity. Our results show that K. arvensis nectar chemistry varies with the composition of the surrounding plant community, which may alter the taste and nutritional value and thus affect the plant's visitor spectrum and visitation rate. However, the strong inter-individual variation in nectar quality requires additional studies (e.g., in semi-field studies) to disentangle different biotic and abiotic factors contributing to inter-individual nectar chemistry in a plant-community context.
    Keywords:  Jena Experiment; amino acids; carbohydrates; flower-visiting insects; insect nutrition
    DOI:  https://doi.org/10.3390/insects11020075
  1462. BMJ. 2020 Jan 22. 368 m262
    US cancer centre leaders secretly worked for China, internal report finds.
    Dyer O.
      
    DOI:  https://doi.org/10.1136/bmj.m262
  1463. Nat Rev Gastroenterol Hepatol. 2020 Jan 21.
    Shining a spotlight on somatic mutations in ulcerative colitis.
    Ray K.
      
    DOI:  https://doi.org/10.1038/s41575-020-0268-x
  1464. Sci Rep. 2020 Jan 23. 10(1): 1018
    Consciousness & Brain Functional Complexity in Propofol Anaesthesia.
    Varley TF, Luppi AI, Pappas I, Naci L, Adapa R, Owen AM, Menon DK, Stamatakis EA.
      The brain is possibly the most complex system known to mankind, and its complexity has been called upon to explain the emergence of consciousness. However, complexity has been defined in many ways by multiple different fields: here, we investigate measures of algorithmic and process complexity in both the temporal and topological domains, testing them on functional MRI BOLD signal data obtained from individuals undergoing various levels of sedation with the anaesthetic agent propofol, replicating our results in two separate datasets. We demonstrate that the various measures are differently able to discriminate between levels of sedation, with temporal measures showing higher sensitivity. Further, we show that all measures are strongly related to a single underlying construct explaining most of the variance, as assessed by Principal Component Analysis, which we interpret as a measure of "overall complexity" of our data. This overall complexity was also able to discriminate between levels of sedation and serum concentrations of propofol, supporting the hypothesis that consciousness is related to complexity - independent of how the latter is measured.
    DOI:  https://doi.org/10.1038/s41598-020-57695-3
  1465. ACS Appl Mater Interfaces. 2020 Jan 24.
    Efficient Spin-Orbit Torque Switching with Non-Epitaxial Chalcogenide Heterostructures.
    Chen TY, Peng CW, Tsai TY, Liao WB, Wu CT, Yen HW, Pai CF.
      The spin-orbit torques (SOTs) generated from topological insulators (TIs) have gained increasing attention in recent years. These TIs, which are typically formed by epitaxially grown chalcogenides, possess extremely high SOT efficiencies and have great potential to be employed in the next-generation spintronics devices. However, epitaxy of these chalcogenides is required to ensure the existence of topologically-protected surface state (TSS), which limits the feasibility of using these materials in industry. In this work, we show that non-epitaxial BixTe1-x/ferromagnet heterostructures prepared by conventional magnetron sputtering possess giant SOT efficiencies even without TSS. Through harmonic voltage measurement and hysteresis loop shift measurement, we find that the damping-like SOT efficiencies originated from the bulk spin-orbit interactions of such non-epitaxial heterostructures can reach values greater than 100% at room temperature. We further demonstrate current-induced SOT switching in these BixTe1-x-based heterostructures with thermally stable ferromagnetic layers, which indicates that such non-epitaxial chalcogenide materials can be potential efficient SOT sources in future SOT magnetic memory devices.
    DOI:  https://doi.org/10.1021/acsami.9b20844
  1466. J Dairy Sci. 2020 Jan 15. pii: S0022-0302(20)30041-2. [Epub ahead of print]
    Short communication: Clostridial spore counts in vat milk of Alpine dairies-A status quo report.
    Burtscher J, Hobl L, Kneifel W, Domig KJ.
      One of the most severe quality defects in hard and semi-hard cheese, the late blowing defect, is caused by endospore-forming bacteria of the genus Clostridium. To minimize financial losses and waste of resources due to cheese spoilage, raw milk with elevated clostridial spore counts should not be used for the production of certain cheese types. In this context, threshold values of clostridial spore concentrations that cause quality defects in cheese are still under debate. To improve our understanding about late blowing defects, further information on the correlation between clostridial spore concentrations in milk and cheese quality is indispensable. Thus, the aim of this study was to monitor the microbiological quality of milk used for Alpine cheese production regarding clostridial endospore levels to facilitate the establishment of threshold spore concentrations that guarantee the absence of quality defects in Austrian cheese. For this purpose, we monitored clostridial endospore levels in vat milk of 4 Alpine dairies throughout the summer grazing period in 2018. Surprisingly, we observed almost complete absence of butyric acid-producing clostridia in milk and no blowing defects in cheese. Hence, critical clostridial spore concentrations could not be verified. Moreover, the observed low spore levels reveal that silage feeding and good farming practices effectively minimize clostridial endospore counts in milk and ensure the manufacture of high-quality cheese even if technological possibilities are limited.
    Keywords:  Alpine dairy; Clostridium; cheese; endospore
    DOI:  https://doi.org/10.3168/jds.2019-17559
  1467. Mol Neurobiol. 2020 Jan 24.
    Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model.
    Thapa S, Abdelaziz DH, Abdulrahman BA, Schatzl HM.
      Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrPSc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.
    Keywords:  ER stress; Prion; Prion infection; Protein misfolding; Sephin1; UPR
    DOI:  https://doi.org/10.1007/s12035-020-01880-y
  1468. J Pak Med Assoc. 2020 Jan;70(1): 53-57
    Diagnosis of inherited metabolic disorders by selective metabolite testing: three years' experience at a tertiary care center in Rawalpindi.
    Hafeez A, Ijaz A, Chaudhry N, Ali O, Khadim MT.
      OBJECTIVE: To determine the pattern of various inherited metabolic disorders specifically through plasma amino acid and urine organic acid testing in high-risk paediatric population..METHODS: The cross-sectional retrospective study was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, and comprised data from April 2015 to March 2018 of children referred to the Department of Chemical Pathology and Endocrinology for work-up of suspected inherited metabolic disorders. Complete clinical history, baseline biochemical investigations, plasma amino acid and urine organic acid profiles, where indicated, were collected. Quantitative plasma amino acid and analysis was carried out by Ion Exchange Chromatography on Biochrome 30+ amino acid analyser, and urine organic acid analysis by Gas Chromatography-Mass Spectrometry. Findings were linked to the identified disorders. SPSS 21 was used for data analysis.
    RESULTS: Of the 805 cases reviewed, 49(6%) had an inherited metabolic disorder. Male:Female ratio of the cases was 1.5:1, and the median age was 240 days (interquartile range: 1-15695 days). The most common presenting symptom was seizures 316(39.3%) followed by lethargy 283(35.2%). Of the diagnosed cases, aminoacidopathies were 28(57%) and in them, non-ketotic hyperglycaemia accounted for 7(25%.). There were 12(24.5%) cases of organic acidurias followed by 9(18.4%) that were other than the two diagnoses.
    CONCLUSIONS: The cases of inherited metabolic disorder detected indicated significant prevalence. Non-ketotic hyperglycinemia was the commonest disorder diagnosed.
    Keywords:   Ion Exchange Chromatography, Aminoacidopathies, Inherited Metabolic Disorders, Organic Aciduria.
    DOI:  https://doi.org/10.5455/JPMA.301908
  1469. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30086-6. [Epub ahead of print]49(1): 127-141
    Psychosocial Aspects of Diabetes Technology Use: The Child and Family Perspective.
    Papadakis JL, Anderson LM, Garza K, Feldman MA, Shapiro JB, Evans M, Thompson LG, Weissberg-Benchell J.
      This article offers a systematic review of the literature on psychosocial aspects of technology use in children and adolescents with type 1 diabetes and their families, searching for relevant articles published the past 5 years. Topics included continuous subcutaneous insulin infusion, continuous glucose monitoring, predictive low-glucose suspend, and artificial pancreas systems. The review indicates there are positive and negative psychosocial aspects to diabetes technology use among youth and their families. Although consistent findings were revealed, contradictions exist. Discussed are recommendations for future research and implications for how health care providers can collaborate with families to discuss and manage diabetes technology.
    Keywords:  Pediatric; Psychosocial; Technology; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.004
  1470. Respirology. 2020 Jan 23.
    Silicosis: An ancient disease in need of a dose of modern medicine.
    Hoy R, Chambers DC.
      
    Keywords:  interstitial lung disease; occupational health; silicosis
    DOI:  https://doi.org/10.1111/resp.13766
  1471. Arthroscopy. 2020 Jan 15. pii: S0749-8063(20)30040-2. [Epub ahead of print]
    Patellofemoral contact pressure for medial patellofemoral ligament reconstruction using suture tape varies with the knee flexion angle: A biomechanical evaluation.
    Sakamoto Y, Sasaki S, Kimura Y, Yamamoto Y, Tsuda E, Ishibashi Y.
      PURPOSE: The purpose of this study was to evaluate the effect of the knee flexion angle during graft fixation on patellofemoral (PF) contact pressure in medial patellofemoral ligament (MPFL) reconstruction using polyester suture tape and knotless anchors.METHODS: Nine human knees (mean age: 71.2 ± 14.2 y) were used in this study. Polyester suture tape was fixed at the medial edge of the patella with two 3.5-mm knotless anchors and then to the femur with a 4.75-mm knotless anchor at four different knee flexion angles (0°, 30°, 60°, and 90°). A pressure sensor was used to measure the maximum contact pressure (MCP) of the medial and lateral PF joints in the intact knee and in post-reconstruction knees at each knee flexion angle (0°, 30°, 60°, and 90°). Each MCP was normalized to that of the intact knee. A statistical comparison was made between MCP in the intact and reconstructed knees.
    RESULTS: The normalized MCP of the medial PF joint fixed at either 0° or 30° significantly increased at 60° of knee flexion (p=0.036 and 0.042, respectively) and at 90° of knee flexion (p=0.002 and 0.001, respectively). Conversely, the normalized MCP fixed at 60° and 90° remained at the same level as the intact knees at all angles of knee flexion. The normalized MCP of the lateral PF joint showed no significant difference at any fixation angle compared with intact knees.
    CONCLUSION: To avoid excessive PF joint contact pressure after MPFL reconstruction, it may be best to fix polyester suture tape between 60º to 90º of knee flexion.
    CLINICAL RELEVANCE: Fixation of the polyester suture tape with a knotless anchor for MPFL reconstruction should be at 60º to 90º of knee flexion to most closely restore PF joint contact pressures to that of the intact knee.
    DOI:  https://doi.org/10.1016/j.arthro.2019.12.027
  1472. Nutrients. 2020 Jan 18. pii: E249. [Epub ahead of print]12(1):
    Fermented Morinda citrifolia (Noni) Alleviates DNCB-Induced Atopic Dermatitis in NC/Nga Mice through Modulating Immune Balance and Skin Barrier Function.
    Kim SH, Seong GS, Choung SY.
      Morinda citrifolia, a fruit generally known as "Noni", has been traditionally used in parts of East Asia to relieve inflammatory diseases. Although several studies using noni have been reported, the effect of fermented Morinda citrifolia (F.NONI) on atopic dermatitis (AD) has not been investigated. Thus, we aimed to investigate the improving effect of F.NONI treatment on AD-like skin lesions and elucidate molecular mechanisms. F.NONI was prepared by the fermentation of noni fruit with probiotics and then extracted. F.NONI was orally administrated to NC/Nga mice to evaluate its therapeutic effect on 2,4-dinitrochlorobenzene (DNCB)-induced AD. Oral administration of F.NONI significantly alleviated AD lesions and symptoms such as dermatitis scores, ear thickness, scratching behavior, epidermal thickness, and infiltration of inflammatory cells (e.g., mast cells and eosinophils). In addition, F.NONI treatment reduced the levels of histamine, IgE and IgG1/IgG2a ratio, thymus and activation regulated chemokine (TARC), and thymic stromal lymphopoietin (TSLP) in serum and beneficially modulated the expressions of Th1, Th2, Th17, and Th22-mediated cytokines in lesioned skin and splenocytes. Furthermore, the expressions of the skin barrier-related proteins including filaggrin (FLG), loricrin (LOR), involucrin (IVL), zonula occludens-1 (ZO-1), and occludin (OCC) were restored by F.NONI treatment. Taken together, these results suggest that F.NONI could be a therapeutic agent to attenuate AD-like skin lesions through modulating the immune balance and skin barrier function.
    Keywords:  NC/Nga; Th1; Th2; atopic dermatitis; fermented Morinda citrifolia; immune balance; skin barrier function
    DOI:  https://doi.org/10.3390/nu12010249
  1473. J Cell Biol. 2020 Mar 02. pii: e201908142. [Epub ahead of print]219(3):
    Dynamics of Auxilin 1 and GAK in clathrin-mediated traffic.
    He K, Song E, Upadhyayula S, Dang S, Gaudin R, Skillern W, Bu K, Capraro BR, Rapoport I, Kusters I, Ma M, Kirchhausen T.
      Clathrin-coated vesicles lose their clathrin lattice within seconds of pinching off, through the action of the Hsc70 "uncoating ATPase." The J- and PTEN-like domain-containing proteins, auxilin 1 (Aux1) and auxilin 2 (GAK), recruit Hsc70. The PTEN-like domain has no phosphatase activity, but it can recognize phosphatidylinositol phosphate head groups. Aux1 and GAK appear on coated vesicles in successive transient bursts, immediately after dynamin-mediated membrane scission has released the vesicle from the plasma membrane. These bursts contain a very small number of auxilins, and even four to six molecules are sufficient to mediate uncoating. In contrast, we could not detect auxilins in abortive pits or at any time during coated pit assembly. We previously showed that clathrin-coated vesicles have a dynamic phosphoinositide landscape, and we have proposed that lipid head group recognition might determine the timing of Aux1 and GAK appearance. The differential recruitment of Aux1 and GAK correlates with temporal variations in phosphoinositide composition, consistent with a lipid-switch timing mechanism.
    DOI:  https://doi.org/10.1083/jcb.201908142
  1474. Foods. 2020 Jan 21. pii: E111. [Epub ahead of print]9(2):
    Yogurt as an Alternative Ingredient to Improve the Functional and Nutritional Properties of Gluten-Free Breads.
    Graça C, Raymundo A, Sousa I.
      Absence of gluten in bakery goods is a technological challenge, generating gluten-free breads with low functional and nutritional properties. However, these issues can be minimized using new protein sources, by the addition of nutritional added-value products. Fresh yogurt represents an interesting approach since it is a source of protein, polysaccharides, and minerals, with potential to mimic the gluten network, while improving the nutritional value of gluten-free products. In the present work, different levels of yogurt addition (5% up to 20% weight/weight) were incorporated into gluten-free bread formulations, and the impact on dough rheology properties and bread quality parameters were assessed. Linear correlations (R2 > 0.9041) between steady shear (viscosity) and oscillatory (elastic modulus, at 1 Hz) values of the dough rheology with bread quality parameters (volume and firmness) were obtained. Results confirmed that the yogurt addition led to a significant improvement on bread quality properties, increasing the volume and crumb softness and lowering the staling rate, with a good nutritional contribution in terms of proteins and minerals, to improve the daily diet of celiac people.
    Keywords:  gluten-free bread; rheology; yogurt
    DOI:  https://doi.org/10.3390/foods9020111
  1475. Disabil Rehabil. 2020 Jan 22. 1-9
    Post-traumatic stress disorder in a population of 2008 Wenchuan earthquake survivors with disabilities: the role of environmental barriers.
    Reinhardt JD, Zhang X, Van Dyke C, Ehrmann C, Li L, Zhao Z, Zhou M, Li H.
      Purpose: Earthquake survivors whose physical injuries result in disability may be at increased risk for prolonged and severe post-traumatic stress disorder. We estimated the prevalence of post-traumatic stress disorder, functional limitations, and environmental barriers in 289 survivors with disabilities induced by the 2008 Wenchuan earthquake eight years after the disaster. We also investigated the relationship of post-traumatic stress disorder symptom severity with function, considering a mediating role of environmental barriers.Methods: Post-traumatic stress disorder was measured with post-traumatic stress disorder checklist-civilian version. Physical and mental functioning was assessed with Medical Outcomes Short Form-36 and perceived environmental barriers were evaluated with Nottwil Environmental Factors Inventory-Short Form. Path analysis was employed to examine the relationship of exposures, post-traumatic stress disorder symptom severity, environmental barriers, and physical and mental function.Results: Prevalence of probable post-traumatic stress disorder was 18.68% (95% CI: 14.19-23.18%). Earthquake survivors with lower physical and mental functioning perceived more environmental barriers, and those who perceived more barriers demonstrated more severe post-traumatic stress disorder symptoms, confirming a mediating role of environmental barriers.Conclusions: Long-term community-based health services for earthquake survivors with disabilities should combine both mental and physical rehabilitation and focus on creating disability-inclusive environments.Implications for rehabilitationEarthquake survivors whose physical injuries result in permanent disability may experience two different types of psychological trauma. The first originates from the initial psychological impact of the disaster and their injuries and the second arises from the added difficulty of coping with environmental barriers given the limitations imposed by their impairments.Even years after the disaster, prevalence of post-traumatic stress disorder is likely high in earthquake survivors with acquired musculoskeletal or neurological impairments and needs to be considered in the rehabilitation process.Physical and mental functioning, as well as environmental barriers, are important intervention targets to reduce post-traumatic stress disorder symptoms.Long-term community-based health services for earthquake survivors with disabilities are needed that combine both mental health and physical rehabilitation components with advocating for disability-inclusive environments.
    Keywords:  Post-traumatic stress disorder; disability; earthquake; environmental barriers; functioning
    DOI:  https://doi.org/10.1080/09638288.2020.1714756
  1476. Small. 2020 Jan 23. e1904619
    Photocatalytically Active Graphitic Carbon Nitride as an Effective and Safe 2D Material for In Vitro and In Vivo Photodynamic Therapy.
    Taheri H, Unal MA, Sevim M, Gurcan C, Ekim O, Ceylan A, Syrgiannis Z, Christoforidis KC, Bosi S, Ozgenç O, Gómez MJ, Turktas Erken M, Soydal Ç, Eroğlu Z, Bitirim CV, Cagin U, Arı F, Ozen A, Kuçuk O, Delogu LG, Prato M, Metin Ö, Yilmazer A.
      Thanks to its photocatalytic property, graphitic carbon nitride (g-C3 N4 ) is a promising candidate in various applications including nanomedicine. However, studies focusing on the suitability of g-C3 N4 for cancer therapy are very limited and possible underlying molecular mechanisms are unknown. Here, it is demonstrated that photoexcitation of g-C3 N4 can be used effectively in photodynamic therapy, without using any other carrier or additional photosensitizer. Upon light exposure, g-C3 N4 treatment kills cancer cells, without the need of any other nanosystem or chemotherapeutic drug. The material is efficiently taken up by tumor cells in vitro. The transcriptome and proteome of g-C3 N4 and light treated cells show activation in pathways related to both oxidative stress, cell death, and apoptosis which strongly suggests that only when combined with light exposure, g-C3 N4 is able to kill cancer cells. Systemic administration of the mesoporous form results in elimination from urinary bladder without any systemic toxicity. Administration of the material significantly decreases tumor volume when combined with local light treatment. This study paves the way for the future use of not only g-C3 N4 but also other 2D nanomaterials in cancer therapy.
    Keywords:  2D materials; antitumor activity; graphitic carbon nitride; omic approaches; photodynamic therapy
    DOI:  https://doi.org/10.1002/smll.201904619
  1477. Genetics. 2020 Jan 23. pii: genetics.302860.2019. [Epub ahead of print]
    New Roles for the Heterochronic Transcription Factor LIN-29 in Cuticle Maintenance and Lipid Metabolism at the Larval-to-Adult Transition in Caenorhabditis elegans.
    Abete-Luzi P, Fukushige T, Yun S, Krause MW, Eisenmann DM.
      Temporal regulation of gene expression is a crucial aspect of metazoan development. In the roundworm Caenorhabditis elegans, the heterochronic pathway controls multiple developmental events in a time-specific manner. The most downstream effector of this pathway, the zinc-finger transcription factor LIN-29, acts in the last larval stage (L4) to regulate elements of the larval-to-adult switch. Here, we explore new LIN-29 targets and their implications for this developmental transition. We used RNA-Seq to identify genes differentially expressed between animals misexpressing LIN-29 at an early time point and control animals. Among 230 LIN-29-activated genes, we found that genes encoding cuticle collagens were overrepresented. Interestingly, expression of lin-29 and some of these collagens was increased in adults with cuticle damage, suggesting a previously unknown function for LIN-29 in adult cuticle maintenance. On the other hand, genes involved in fat metabolism were enriched among 350 LIN-29-down-regulated targets. We used mass spectrometry to assay lipid content in animals overexpressing LIN-29 and observed reduced fatty acid levels. Many LIN-29-repressed genes are normally expressed in the intestine, suggesting cell non-autonomous regulation. We identified several LIN-29-up-regulated genes encoding signaling molecules that may act as mediators in the regulation of intestinally-expressed genes encoding fat metabolic enzymes and vitellogenins. Overall, our results support the model of LIN-29 as a major regulator of adult cuticle synthesis and integrity, and as the trigger for metabolic changes that take place at the important transition from rapid growth during larval life to slower growth and offspring production during adulthood.
    Keywords:  C. elegans; collagen; gene expression; heterochronic; metabolism
    DOI:  https://doi.org/10.1534/genetics.119.302860
  1478. Sci Total Environ. 2020 Feb 25. pii: S0048-9697(19)35768-7. [Epub ahead of print]705 135773
    The effects of hydrodynamics on the three-dimensional downstream migratory movement of Atlantic salmon.
    Silva AT, Bærum KM, Hedger RD, Baktoft H, Fjeldstad HP, Gjelland KØ, Økland F, Forseth T.
      Anthropogenic structures in rivers are major threats for fish migration and effective mitigation is imperative given the worldwide expansion of such structures. Fish behaviour is strongly influenced by hydrodynamics, but little is known on the relation between hydraulics and fish fine scale-movement. We combined 3D Computational fluid dynamics modelling (CFD) with 2D and 3D fish positioning to investigate the relation between hydrodynamics and the downstream movement of Atlantic salmon smolts (Salmo salar). We show that fish use fine-scale flow velocity and turbulence as navigation cues of fine-scale movement behaviour. Tri-dimensional swimming speed and swimming direction can be explained by adjustments of fish to flow motion, which are linked to fish swimming mode. Fish diverge from the flow by swimming at speeds within or higher than their prolonged speeds (0.38-0.73 m s-1). Flow direction plays a pivotal role on fish swimming performance, with high upstream and downwards velocities impacting swimming the most. Turbulence is also influential, by benefiting swimming performance at low TKE (< 0.03 m2 s-2) or constraining it at higher levels. We show that fish behaviour is affected by interactions of several hydraulic variables that should be considered jointly.
    Keywords:  2D and 3D-telemetry; Atlantic salmon smolts; Downstream migration; Fish behaviour; Fish migration; Hydraulics
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.135773
  1479. Eur J Pharmacol. 2020 Jan 20. pii: S0014-2999(20)30032-7. [Epub ahead of print]871 172940
    JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages.
    Hashimoto R, Kakigi R, Miyamoto Y, Nakamura K, Itoh S, Daida H, Okada T, Katoh Y.
      In atherosclerosis progression, atherosclerotic plaques develop upon accumulated foam cells derived from macrophages that take up modified low-density lipoprotein (LDL). CD36 and CD204 are the principal scavenger receptors responsible for the uptake of modified LDL. Lipopolysaccharide (LPS) exacerbates atherosclerosis by enhancing the expression of scavenger receptors and thus increasing the uptake of modified LDL into macrophages. However, the signaling pathways that mediate LPS and scavenger receptor expression have not been fully elucidated. We used mouse bone marrow-derived macrophages and investigated the effects of LPS in vitro. LPS enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-1 (STAT-1). Inhibitors of the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) pathway (U0126 and PD0325901) suppressed the uptake of acetylated-LDL (Ac-LDL) and the expression of CD204 but not CD36 in LPS-activated macrophages. Inhibitors of the Janus tyrosine kinase (JAK)-STAT pathway (ruxolitinib and tofacitinib) suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. We next injected LPS into the peritoneal cavity of mice and analyzed the effects of LPS. MEK inhibitor U0126 suppressed the uptake of Ac-LDL and the expression of CD204 but not CD36 in LPS-activated macrophages. JAK inhibitor ruxolitinib suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. These results suggest that scavenger receptors in LPS-activated mouse macrophages are regulated through a JAK-STAT-dependent pathway. Although further evaluation is necessary, JAK-STAT inhibition could be useful in atherosclerosis therapy, at least for atherosclerosis exacerbated by LPS.
    Keywords:  Atherosclerosis; Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway; Lipopolysaccharide (LPS); Macrophages; Scavenger receptors
    DOI:  https://doi.org/10.1016/j.ejphar.2020.172940
  1480. J Nat Prod. 2020 Jan 24.
    Scientific and Regulatory Approach to Botanical Drug Development: A U.S. FDA Perspective.
    Wu C, Lee SL, Taylor C, Li J, Chan YM, Agarwal R, Temple R, Throckmorton D, Tyner K.
      The United States FDA has received over 800 botanical investigational new drug applications (IND) and pre-IND meeting requests (PIND) in the years preceding 2018. The current data show that indications for submitted INDs cover nearly every review division of the FDA. Despite increasing global interest in the investigation of botanical mixtures as drug products, only two botanical new drug applications (NDA) have been approved in the U.S.: Veregen in 2006 and Fulyzaq (also known as Mytesi) in 2012. Given botanicals' chemical and biological complexity, efforts in characterizing their pharmacology, demonstrating therapeutic efficacy, and ensuring quality consistency remain scientific and regulatory challenges. The FDA published a revised Botanical Drug Development Guidance for Industry document in December 2016 to address developmental considerations for late-phase trials and to provide recommendations intended to facilitate botanical drug development. Herein, we present an analysis of botanical INDs showing their variety of botanical raw materials (e.g., coming from different geographic regions, single vs multiple herbs), the varied levels of previous human experience, and therapeutic areas, as well as provide an overview of experience and challenges in reviewing botanical drugs.
    DOI:  https://doi.org/10.1021/acs.jnatprod.9b00949
  1481. Am J Surg. 2020 Jan 10. pii: S0002-9610(20)30010-6. [Epub ahead of print]
    The association of preoperative thyroid-stimulating hormone level and the risk of differentiated thyroid cancer in patients with thyroid nodules: A systematic review and meta-analysis.
    Su A, Zhao W, Wu W, Wei T, Ruan M, Li Z, Zhu J.
      BACKGROUND: This systematic review and meta-analysis was conducted to determine the value of preoperative thyroid-stimulating hormone (TSH) levels in assessing the risk of differentiated thyroid cancer (DTC) in patients with thyroid nodules.METHODS: This meta-analysis included 23,799 subjects (15,406 non-Chinese and 8,393 Chinese) with thyroid nodules. Multivariate and individual adjusted odds ratios (OR) were calculated for a 1 mU/L increase in preoperative TSH levels to determine the risk of malignant DTC.
    RESULTS: The OR for DTC in relation to preoperative TSH levels was significant in Chinese (1.25 [1.11, 1.40], Z = 3.67, p = 0.0002) and non-Chinese subjects (1.12 [1.03, 1.22], Z = 2.72, p = 0.006). The overall random-effects model indicated that there was a significantly increased risk for DTC in patients with thyroid nodules (OR 1.16 [1.06, 1.27], Z = 3.29, p = 0.007).
    CONCLUSIONS: A significant association between higher TSH levels and risk of DTC was observed in both population groups investigated, with higher ORs for Chinese subjects.
    Keywords:  Differentiated thyroid cancer; Preoperative; Thyroid carcinoma; Thyroid nodules; Thyroid-stimulating hormone
    DOI:  https://doi.org/10.1016/j.amjsurg.2020.01.009
  1482. Clin Imaging. 2020 Jan 09. pii: S0899-7071(20)30023-1. [Epub ahead of print]61 27-32
    Technical and nidus-specific factors associated with adequacy of intraprocedural biopsy samples preceding radiofrequency ablation of osteoid osteoma.
    Soliman MM, Aguado A, Sutton C, Hameed M, Hwang S, Healey JH, Maybody M.
      PURPOSE: To examine the diagnostic yield of intraprocedural percutaneous biopsy performed at the time of radiofrequency ablation of suspected Osteoid Osteoma (OO) and identify technical and nidus-specific factors associated with diagnostic adequacy.MATERIALS AND METHODS: Following IRB approval, a total of 42 patients (male: 28, female: 14; mean age: 29 years) who underwent intraprocedural biopsy immediately prior to RFA between June 2010 and June 2017 were retrospectively identified. The nidi were located in various locations. The nidi had a mean size of 6.3 mm (range: 3-11 mm, Standard deviation (SD): 2.26). Core biopsies were performed by one of 15 operators. Biopsies were performed with two needle types ranging from 11-G to 15-G with a mean number of samples of 1.8 (range: 1-5, SD: 1.01). Electronic records and imaging were reviewed for demographics, nidus characteristics, biopsy details and diagnostic yield. Multivariate logistic regression of nidus-specific and biopsy-specific factors was performed.
    RESULTS: A total of 22/42 (52.3%) of the biopsies were adequate for histological diagnosis of OO. For the two experienced operators, the diagnostic yield was 67% (6/9) and 80% (8/10). Biopsy adequacy was significantly correlated with presence of an osteoid matrix (p = 0.03), obtaining >1 core sample (p = 0.03), the needle track passing through the nidus (p = 0.0003) and thinner (2.5 mm) intraprocedural CT slices (p = 0.03). On multivariate analysis, use of thinner intraprocedural CT slices was found to be associated with adequate biopsy (p = 0.02).
    CONCLUSION: Intraprocedural percutaneous biopsy samples of nidi highly-suspected to be OO at the time of RFA were diagnostic in 52% of patients. Multivariate analysis shows thinner intraprocedural CT slices to be a significantly associated with biopsy adequacy.
    Keywords:  Ablation; Diagnostic yield; Image-guided biopsy; Osteoid Osteoma; Percutaneous
    DOI:  https://doi.org/10.1016/j.clinimag.2020.01.010
  1483. Ocul Surf. 2020 Jan 17. pii: S1542-0124(20)30014-8. [Epub ahead of print]
    Endocrine disrupting chemicals associated with dry eye syndrome.
    Pontelli RCN, Rocha BA, Garcia DM, Pereira LA, Souza MCO, Barbosa F, Rocha EM.
      BACKGROUND: Dry eye syndrome (DES) is a multifactorial disease that causes changes in the tear film and occurs more frequently in women. Sex hormones (SHs) influence tear production, and SHs imbalance is associated with DES. Endocrine-disrupting chemicals (EDCs) are compounds that can bind to SHs receptors, changing the SHs action in several organs and tissues.METHODS: The levels of 21 EDCs were measured in the urine of DES patients and healthy controls. All individuals were submitted to eye exams for DES and responded to the questionnaire "Ocular Surface Disease Index (OSDI)". DES was considered present when the OSDI score was > 20 and one of the DES tests surpassed the established thresholds.
    RESULTS: Methyl-protocatechuic acid (OHMeP), had higher urine levels in DES individuals than in control individuals (p = 0.0189). On the other hand, triclocarban (TCC) exhibited lower urine levels in DES individuals than in control individuals (p = 0.0081). Statistically significant positive associations were found between MeP, EtP (ethyl paraben) and OHMeP with fluorescein staining test; between TCC and Tear breakup time test and between OHMeP and OSDI score. Significant negative associations were found between EtP and OHMeP and schirmer test; between OHMeP and Tear breakup time test; between TCC and the OSDI score and fluorescein and lissamine staining test.The quadratic discriminant function classified 94.4% of individuals in their groups based on the urine levels of EDCs.
    CONCLUSION: The following EDCs, MeP, EtP, and OHMeP, were associated with signs and symptoms of DES. TCC had a paradoxical protective effect against DES. These findings suggest that EDCs are associated with DES and the exposure should be included in the investigation of causes and risk factors for DES.
    Keywords:  bisphenol A; dry eye syndrome; endocrine disrupting chemicals; environmental contaminants; ocular surface; parabens; triclocarban
    DOI:  https://doi.org/10.1016/j.jtos.2020.01.001
  1484. Nat Chem Biol. 2020 Feb;16(2): 106
    Lipid hijacking.
    Bucci M.
      
    DOI:  https://doi.org/10.1038/s41589-020-0465-5
  1485. IEEE Trans Med Imaging. 2020 Jan 17.
    Intraoperative Correction of Liver Deformation Using Sparse Surface and Vascular Features via Linearized Iterative Boundary Reconstruction.
    Heiselman JS, Jarnagin WR, Miga MI.
      During image guided liver surgery, soft tissue deformation can cause considerable error when attempting to achieve accurate localization of the surgical anatomy through image-to-physical registration. In this paper, a linearized iterative boundary reconstruction technique is proposed to account for these deformations. The approach leverages a superposed formulation of boundary conditions to rapidly and accurately estimate the deformation applied to a preoperative model of the organ given sparse intraoperative data of surface and subsurface features. With this method, tracked intraoperative ultrasound (iUS) is investigated as a potential data source for augmenting registration accuracy beyond the capacity of conventional organ surface registration. In an expansive simulated dataset, features including vessel contours, vessel centerlines, and the posterior liver surface are extracted from iUS planes. Registration accuracy is compared across increasing data density to establish how iUS can be best employed to improve target registration error (TRE). From a baseline average TRE of 11.4 ± 2.2 mm using sparse surface data only, incorporating additional sparse features from three iUS planes improved average TRE to 6.4 ± 1.0 mm. Furthermore, increasing the sparse coverage to 16 tracked iUS planes improved average TRE to 3.9 ± 0.7 mm, exceeding the accuracy of registration based on complete surface data available with more cumbersome intraoperative CT without contrast. Additionally, the approach was applied to three clinical cases where on average error improved 67% over rigid registration and 56% over deformable surface registration when incorporating additional features from one independent tracked iUS plane.
    DOI:  https://doi.org/10.1109/TMI.2020.2967322
  1486. Phys Rev E. 2019 Dec;100(6-1): 062128
    Optimization induced by stability and the role of limited control near a steady state.
    Gonzalez-Ayala J, Guo J, Medina A, Roco JMM, Calvo Hernández A.
      A relationship between stability and self-optimization is found for weakly dissipative heat devices. The effect of limited control on operation variables around an steady state is such that, after instabilities, the paths toward relaxation are given by trajectories stemming from restitution forces which improve the system thermodynamic performance (power output, efficiency, and entropy generation). Statistics over random trajectories for many cycles shows this behavior as well. Two types of dynamics are analyzed, one where an stability basin appears and another one where the system is globally stable. Under both dynamics there is an induced trend in the control variables space due to stability. In the energetic space this behavior translates into a preference for better thermodynamic states, and thus stability could favor self-optimization under limited control. This is analyzed from the multiobjective optimization perspective. As a result, the statistical behavior of the system is strongly influenced by the Pareto front (the set of points with the best compromise between several objective functions) and the stability basin. Additionally, endoreversible and irreversible behaviors appear as very relevant limits: The first one is an upper bound in energetic performance, connected with the Pareto front, and the second one represents an attractor for the stochastic trajectories.
    DOI:  https://doi.org/10.1103/PhysRevE.100.062128
  1487. Diagn Microbiol Infect Dis. 2019 Dec 17. pii: S0732-8893(19)30980-0. [Epub ahead of print] 114969
    Comparison of Lowenstein-Jensen medium and MGIT culture system for recovery of Mycobacterium tuberculosis from abscess samples.
    Ma Y, Fan J, Li S, Dong L, Li Y, Wang F, Huo F, Pang Y, Qin S.
      PURPOSE: In this study, our aim was to assess Lowenstein-Jensen (L-J) medium and MGIT culture system for recovery of Mycobacterium tuberculosis (MTB) from abscess samples in skeletal tuberculosis (TB) cases.METHODS: Abscess samples were collected from patients suggestive of skeletal TB in Beijing Chest Hospital for laboratory examination, including smear microscopy, L-J culture and MGIT culture.
    RESULTS: Of the 232 abscess samples, 72 (31.0%) were culture-positive for mycobacteria. Of 72 isolates recovered, 94.4% were detected in MGIT 960 and 75.0% on L-J medium. MGIT could recover significantly higher rate of MTB isolates from smear-positive specimens than L-J medium. The mean time to detection of MTB in MGIT 960 was significantly lower than that on L-J medium.
    CONCLUSION: The BACTEC MGIT 960 outperforms the conventional L-J medium in recovering MTB from abscess samples. The combination of MGIT and L-J method also increases the overall recovery rate of MTB in culture.
    Keywords:  Abscess; Culture; Recovery; Skeletal tuberculosis
    DOI:  https://doi.org/10.1016/j.diagmicrobio.2019.114969
  1488. J Endocrinol. 2020 Feb;pii: JOE-19-0502. [Epub ahead of print]244(2): R17-R32
    What can seasonal models teach us about energy balance?
    Diedrich V, Haugg E, Dreier C, Herwig A.
      Torpid states are used by many endotherms to save energy during winter. During torpor, metabolic rate is downregulated to fractions of resting metabolic rate and often associated with a severe drop in body temperature that challenges mammalian physiology. Understanding the mechanisms regulating this extreme depression of metabolism bears enormous potential for biomedical research. Torpor behavior has been extensively studied in the Djungarian hamster, also known as Siberian hamster. It is dependent on many preparatory adaptations of physiological and endocrine systems that are likely to be integrated by the hypothalamus eventually controlling metabolism. Although substantial knowledge exists about prerequisites and characteristics of torpor in this species, the cascade of events and their mechanisms of action are not well understood. This review summarizes the current state of knowledge about mechanisms of metabolic regulation in the Djungarian hamster focusing on the potential roles of thyroid hormone and glucose metabolism.
    Keywords:  Siberian hamster; glucose; tanycytes; thyroid hormones; torpor
    DOI:  https://doi.org/10.1530/JOE-19-0502
  1489. Nat Commun. 2020 Jan 23. 11(1): 433
    Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma.
    Yang Y, Luo M, Zhang K, Zhang J, Gao T, Connell DO, Yao F, Mu C, Cai B, Shang Y, Chen W.
      Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.
    DOI:  https://doi.org/10.1038/s41467-020-14324-x
  1490. Cell Death Dis. 2020 Jan 22. 11(1): 46
    Cross-talk between autophagy and apoptosis regulates testicular injury/recovery induced by cadmium via PI3K with mTOR-independent pathway.
    Wang M, Wang XF, Li YM, Chen N, Fan Y, Huang WK, Hu SF, Rao M, Zhang YZ, Su P.
      Autophagy and apoptosis are two major modes of cell death. A balanced interplay between both is vital for phagocytic clearance of apoptotic testicular cells. Here, generating a SD rats model-treated with cadmium (Cd) to mimic environmental exposure on human, we show that autophagy and apoptosis present synchronous change trends in Cd-induced testicular injury/self-recovery. Further, the cross-talk of autophagy and apoptosis is investigated in four testicular cell lines (GC-1/GC-2/TM3/TM4 cells) respectively. Results reveal that Cd-exposure for five consecutive weeks induces reproductive toxicity in male rats. After one cycle of spermatogenesis within 8 weeks without Cd, toxic effects are ameliorated significantly. In vitro, we find that PI3K inhibitor 3-MA regulates apoptosis by inhibiting autophagy with mTOR-independent pathway in Cd-treated testicular cells. Conclusively, cross-talk between autophagy and apoptosis regulates testicular injury/recovery induced by Cd via PI3K with mTOR-independent pathway.
    DOI:  https://doi.org/10.1038/s41419-020-2246-1
  1491. J Urol. 2020 Jan 22. 101097JU000000000000064401
    Editorial Comment.
    Patel HV, Singer EA.
      
    DOI:  https://doi.org/10.1097/JU.0000000000000644.01
  1492. ACS Omega. 2020 Jan 14. 5(1): 422-429
    Performance of WO3-Incorporated Carbon Electrodes for Ambient Mesoscopic Perovskite Solar Cells.
    Bhandari S, Roy A, Ghosh A, Mallick TK, Sundaram S.
      The stability of perovskite solar cells (PSC) is often compromised by the organic hole transport materials (HTMs). We report here the effect of WO3 as an inorganic HTM for carbon electrodes for improved stability in PSCs, which are made under ambient conditions. Sequential fabrication of the PSC was performed under ambient conditions with mesoporous TiO2/Al2O3/CH3NH3PbI3 layers, and, on the top of these layers, the WO3 nanoparticle-embedded carbon electrode was used. Different concentrations of WO3 nanoparticles as HTM incorporated in carbon counter electrodes were tested, which varied the stability of the cell under ambient conditions. The addition of 7.5% WO3 (by volume) led to a maximum power conversion efficiency of 10.5%, whereas the stability of the cells under ambient condition was ∼350 h, maintaining ∼80% of the initial efficiency under light illumination. At the same time, the higher WO3 concentration exhibited an efficiency of 9.5%, which was stable up to ∼500 h with a loss of only ∼15% of the initial efficiency under normal atmospheric conditions and light illumination. This work demonstrates an effective way to improve the stability of carbon-based perovskite solar cells without affecting the efficiency for future applications.
    DOI:  https://doi.org/10.1021/acsomega.9b02934
  1493. Nutrients. 2020 Jan 21. pii: E280. [Epub ahead of print]12(2):
    The Importance of Fatty Acids as Nutrients during Post-Exercise Recovery.
    Lundsgaard AM, Fritzen AM, Kiens B.
      It is well recognized that whole-body fatty acid (FA) oxidation remains increased for several hours following aerobic endurance exercise, even despite carbohydrate intake. However, the mechanisms involved herein have hitherto not been subject to a thorough evaluation. In immediate and early recovery (0-4 h), plasma FA availability is high, which seems mainly to be a result of hormonal factors and increased adipose tissue blood flow. The increased circulating availability of adipose-derived FA, coupled with FA from lipoprotein lipase (LPL)-derived very-low density lipoprotein (VLDL)-triacylglycerol (TG) hydrolysis in skeletal muscle capillaries and hydrolysis of TG within the muscle together act as substrates for the increased mitochondrial FA oxidation post-exercise. Within the skeletal muscle cells, increased reliance on FA oxidation likely results from enhanced FA uptake into the mitochondria through the carnitine palmitoyltransferase (CPT) 1 reaction, and concomitant AMP-activated protein kinase (AMPK)-mediated pyruvate dehydrogenase (PDH) inhibition of glucose oxidation. Together this allows glucose taken up by the skeletal muscles to be directed towards the resynthesis of glycogen. Besides being oxidized, FAs also seem to be crucial signaling molecules for peroxisome proliferator-activated receptor (PPAR) signaling post-exercise, and thus for induction of the exercise-induced FA oxidative gene adaptation program in skeletal muscle following exercise. Collectively, a high FA turnover in recovery seems essential to regain whole-body substrate homeostasis.
    Keywords:  AMP-activated protein kinase (AMPK); adipose tissue lipolysis; carnitine palmitoyltransferase I (CPT1); fatty acid oxidation; lipid metabolism; lipoprotein lipase (LPL); molecular mechanism; post-exercise recovery; pyruvate dehydrogenase (PDH); skeletal muscle
    DOI:  https://doi.org/10.3390/nu12020280
  1494. J Control Release. 2020 Jan 21. pii: S0168-3659(20)30057-2. [Epub ahead of print]
    pH-sensitive MOF integrated with glucose oxidase for glucose-responsive insulin delivery.
    Zhang C, Hong S, Liu MD, Yu WY, Zhang MK, Zhang L, Zeng X, Zhang XZ.
      Glucose-responsive insulin delivery system mimicking the function of pancreatic β-cells to maintain blood glucose homeostasis would effectively alleviate diabetes. Here, a new glucose-responsive delivery (ZIF@Ins&GOx) for self-regulated insulin release was constructed by encapsulating insulin and glucose oxidase (GOx) into pH-sensitive zeolitic imidazole framework-8 (ZIF-8) nanocrystals. After entering the cavities of ZIF-8, glucose can be oxidized into gluconic acid by GOx, causing a decrease in local pH. Then, ZIF-8 nanocrystals would be degraded under the acidic microenvironment that in turn triggers the release of insulin in a glucose responsive fashion. In vitro studies indicated that the biological activity of insulin could be protected by the rigid structure of ZIF-8 and the release of insulin could be modulated in response to glucose concentrations. In vivo experiments demonstrated that a single subcutaneous injection of the ZIF@Ins&GOx would facilitate the stabilization of blood glucose level of normoglycemic state for up to 72 h in type 1 diabetes (T1D). The multifunctional insulin delivery system shows a new proof-of-concept for T1D treatment by using ZIF-8 nanocrystals loaded with insulin and enzyme.
    Keywords:  Diabetes; Glucose oxidase; Glucose-response; Insulin; Metal-organic framework
    DOI:  https://doi.org/10.1016/j.jconrel.2020.01.038
  1495. BMC Genomics. 2020 Jan 21. 21(1): 67
    CRISPR/Cas9-mediated precise genome modification by a long ssDNA template in zebrafish.
    Bai H, Liu L, An K, Lu X, Harrison M, Zhao Y, Yan R, Lu Z, Li S, Lin S, Liang F, Qin W.
      BACKGROUND: Gene targeting by homology-directed repair (HDR) can precisely edit the genome and is a versatile tool for biomedical research. However, the efficiency of HDR-based modification is still low in many model organisms including zebrafish. Recently, long single-stranded DNA (lssDNA) molecules have been developed as efficient alternative donor templates to mediate HDR for the generation of conditional mouse alleles. Here we report a method, zLOST (zebrafish long single-stranded DNA template), which utilises HDR with a long single-stranded DNA template to produce more efficient and precise mutations in zebrafish.RESULTS: The efficiency of knock-ins was assessed by phenotypic rescue at the tyrosinase (tyr) locus and confirmed by sequencing. zLOST was found to be a successful optimised rescue strategy: using zLOST containing a tyr repair site, we restored pigmentation in at least one melanocyte in close to 98% of albino tyr25del/25del embryos, although more than half of the larvae had only a small number of pigmented cells. Sequence analysis showed that there was precise HDR dependent repair of the tyr locus in these rescued pigmented embryos. Furthermore, quantification of zLOST knock-in efficiency at the rps14, nop56 and th loci by next generation sequencing demonstrated that zLOST showed a clear improvement. We utilised the HDR efficiency of zLOST to precisely model specific human disease mutations in zebrafish with ease. Finally, we determined that this method can achieve a germline transmission rate of up to 31.8%.
    CONCLUSIONS: In summary, these results show that zLOST is a useful method of zebrafish genome editing, particularly for generating desired mutations by targeted DNA knock-in through HDR.
    Keywords:  CRISPR/Cas9; Disease modeling; Genome editing; Homology-directed repair; Long single-stranded DNA; Next-generation sequencing; Zebrafish
    DOI:  https://doi.org/10.1186/s12864-020-6493-4
  1496. Inhal Toxicol. 2020 Jan 23. 1-11
    Time-course transcriptomic alterations reflect the pathophysiology of polyhexamethylene guanidine phosphate-induced lung injury in rats.
    Song MK, Kim DI, Lee K.
      Objective: Humidifier-disinfectant-induced lung injury is a new syndrome associated with a high mortality rate and characterized by severe hypersensitivity pneumonitis, acute interstitial pneumonia, or acute respiratory distress syndrome. Polyhexamethylene guanidine phosphate (PHMG-P), a guanidine-based antimicrobial agent, is a major component associated with severe lung injury. In-depth studies are needed to determine how PHMG-P affects pathogenesis at the molecular level. Therefore, in this study, we analyzed short-term (4 weeks) and long-term (10 weeks) PHMG-P-exposure-specific gene-expression patterns in rats to improve our understanding of time-dependent changes in fibrosis.Materials and methods: Gene-expression profiles were analyzed in rat lung tissues using DNA microarrays and bioinformatics tools.Results: Clustering analysis of gene-expression data showed different gene-alteration patterns in the short- and long-term exposure groups and higher sensitivity to gene-expression changes in the long-term exposure group than in the short-term exposure group. Supervised analysis revealed 34 short-term and 335 long-term exposure-specific genes, and functional analysis revealed that short-term exposure-specific genes were involved in PHMG-P-induced initial inflammatory responses, whereas long-term exposure-specific genes were involved in PHMG-P-related induction of chronic lung fibrosis.Conclusion: The results of transcriptomic analysis were consistent with lung histopathology results. These findings indicated that exposure-time-specific changes in gene expression closely reflected time-dependent pathological changes in PHMG-P-induced lung injury.
    Keywords:  Humidifier disinfectant; lung injury; pathophysiological change; polyhexamethylene guanidine phosphate (PHMG-P); transcriptomic analysis
    DOI:  https://doi.org/10.1080/08958378.2019.1707912
  1497. J Cell Physiol. 2020 Jan 24.
    Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase-independent cell death pathway: Central role of apoptosis-inducing factor.
    Das D, Fayazzadeh E, Li X, Koirala N, Wadera A, Lang M, Zernic M, Panick C, Nesbitt P, McLennan G.
      Hepatocellular carcinoma (HCC) is a major health problem worldwide and in the United States as its incidence has increased substantially within the past two decades. HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A-HSCs) are the key cell types involved in hepatic fibrosis/cirrhosis. A-HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A-HSCs an important therapeutic target in hepatic fibrosis/cirrhosis as well as in HCC. Although many studies have reported the role of A-HSCs in cancer generation and investigated the therapeutic potential of A-HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q-HSCs) in cancer growth or arrest. Here we report that Q-HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q-HSCs (Q-HSCCM) induces cancer cell death through a caspase-independent mechanism that involves an increase in apoptosis-inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q-HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy.
    Keywords:  apoptosis-inducing factor; cell death; doxorubicin; hepatic stellate cell; hepatocellular carcinoma
    DOI:  https://doi.org/10.1002/jcp.29545
  1498. Ann Emerg Med. 2020 Feb;pii: S0196-0644(19)31315-0. [Epub ahead of print]75(2): 307-308
    Closed Loop.
    Schmidt L.
      
    DOI:  https://doi.org/10.1016/j.annemergmed.2019.10.013
  1499. J Exp Bot. 2020 Jan 24. pii: eraa041. [Epub ahead of print]
    Symplasmic Isolation Marks Cell Fate Changes During Somatic Embryogenesis.
    Godel-Jedrychowska K, Kulinska-Lukaszek K, Horstman A, Soriano M, Li M, Malota K, Boutilier K, Kurczynska EU.
      Cell-to-cell signalling is a major mechanism controlling plant morphogenesis. Transport of signalling molecules through plasmodesmata (PD) is one way in which plants promote or restrict intercellular signalling over short distances. PD are membrane lined pores between cells that regulate the intercellular flow of signalling molecules through changes in their size, creating symplasmic fields of connected cells. Here we examined the role of PD and symplasmic communication in the establishment of plant cell totipotency, using somatic embryo induction from Arabidopsis (Arabidopsis thaliana) explants as a model system. Cell-to-cell communication was evaluated using fluorescent tracers, supplemented with histological and ultrastructural analysis, and correlated with expression of a WOX2 embryo reporter. We show that embryogenic cells are isolated symplasmically from non-embryogenic cells regardless of the explant type (immature zygotic embryos or seedlings) and inducer system [2,4-dichlorophenoxyacetic acid (2,4-D) or the BABY BOOM (BBM) transcription factor], but that the symplasmic domains in different explants differ with respect to the maximum size of molecules capable of moving through the PD. Callose deposition in PD preceded WOX2 expression in future sites of somatic embryo development, but later, was greatly reduced in WOX2-expressing domains. Callose deposition was also associated with a decrease DR5 auxin response in embryogenic tissue. Treatment of explants with the callose biosynthesis inhibitor 2-deoxy-D-glucose supressed somatic embryo formation in all three systems studied, and also blocked the observed decrease in DR5 expression. Together this data suggests that callose deposition at PD is required for symplasmic isolation and establishment of cell totipotency in Arabidopsis.
    Keywords:   Arabidopsis thaliana ; BABY BOOM ; WOX2 ; PD SEL; auxin; plasmodesmata; somatic embryogenesis; symplasmic communication; symplasmic domain
    DOI:  https://doi.org/10.1093/jxb/eraa041
  1500. Brain Behav. 2020 Jan 20. e01534
    Differential roles of exogenous protein disulfide isomerase A3 on proliferating cell and neuroblast numbers in the normal and ischemic gerbils.
    Yoo DY, Cho SB, Jung HY, Kim W, Nam SM, Kim JW, Moon SM, Yoon YS, Kim DW, Choi SY, Hwang IK.
      INTRODUCTION: We examined the effects of exogenous protein disulfide isomerase A3 (PDIA3) on hippocampal neurogenesis in gerbils under control and ischemic damage.METHODS: To facilitate the delivery of PDIA3 to the brain, we constructed Tat-PDIA3 protein and administered vehicle (10% glycerol) or Tat-PDIA3 protein once a day for 28 days. On day 24 of vehicle or Tat-PDIA3 treatment, ischemia was transiently induced by occlusion of both common carotid arteries for 5 min.
    RESULTS: Administration of Tat-PDIA3 significantly reduced ischemia-induced spontaneous motor activity, and the number of NeuN-positive nuclei in the Tat-PDIA3-treated ischemic group was significantly increased in the CA1 region compared to that in the vehicle-treated ischemic group. Ki67- and DCX-immunoreactive cells were significantly higher in the Tat-PDIA3-treated group compared to the vehicle-treated control group. In vehicle- and Tat-PDIA3-treated ischemic groups, the number of Ki67- and DCX-immunoreactive cells was significantly higher as compared to those in the vehicle- and Tat-PDIA3-treated control groups, respectively. In the dentate gyrus, the numbers of Ki67-immunoreactive cells were comparable between vehicle- and Tat-PDIA3-treated ischemic groups, while more DCX-immunoreactive cells were observed in the Tat-PDIA3-treated group. Transient forebrain ischemia increased the expression of phosphorylated cAMP-response element-binding protein (pCREB) in the dentate gyrus, but the administration of Tat-PDIA3 robustly increased pCREB-positive nuclei in the normal gerbils, but not in the ischemic gerbils. Brain-derived neurotrophic factor (BDNF) mRNA expression was significantly increased in the Tat-PDIA3-treated group compared to that in the vehicle-treated group. Transient forebrain ischemic increased BDNF mRNA levels in both vehicle- and Tat-PDIA3-treated groups, and there were no significant differences between groups.
    CONCLUSIONS: These results suggest that Tat-PDIA3 enhances cell proliferation and neuroblast numbers in the dentate gyrus in normal, but not in ischemic gerbils, by increasing BDNF mRNA and phosphorylation of pCREB.
    Keywords:  cell proliferation; dentate gyrus; differentiated neuroblasts; protein disulfide isomerase A3; transient forebrain ischemia
    DOI:  https://doi.org/10.1002/brb3.1534
  1501. Beilstein J Nanotechnol. 2020 ;11 51-60
    Recent progress in perovskite solar cells: the perovskite layer.
    Dai X, Xu K, Wei F.
      Perovskite solar cells (PSCs) are set to be game changing components in next-generation photovoltaic technology due to their high efficiency and low cost. In this article, recent progress in the development of perovskite layers, which are the basis of PSCs, is reviewed. Achievements in the fabrication of high-quality perovskite films by various methods and techniques are introduced. The reported works demonstrate that the power conversion efficiency of the perovskite layers depends largely on their morphology and the crystalline quality. Furthermore, recent achievements concerning the scalability of perovskite films are presented. These developments aim at manufacturing large-scale perovskite solar modules at high speed. Moreover, it is shown that the development of low-dimensional perovskites plays an important role in improving the long-term ambient stability of PSCs. Finally, these latest advancements can enhance the competitiveness of PSCs in photovoltaics, paving the way for their commercialization. In the closing section of this review, some future critical challenges are outlined, and the prospect of commercialization of PSCs is presented.
    Keywords:  coating techniques; perovskite layer; perovskite solar cells (PSCs); perovskite structure; photovoltaic technology; scalability
    DOI:  https://doi.org/10.3762/bjnano.11.5
  1502. J Proteomics. 2020 Jan 17. pii: S1874-3919(20)30018-X. [Epub ahead of print] 103650
    Global discovery the PstP interactions using Mtb proteome microarray and revealing novel connections with EthR.
    Li KK, Qu DH, Zhang HN, Chen FY, Xu L, Wang MY, Su HY, Tao SC, Wu FL.
      Mycobacterium tuberculosis (Mtb) serine/threonine protein phosphatase PstP plays an important role in regulating Mtb cell division and growth by reversible phosphorylation signaling. However, the substrates of Mtb with which the PstP interacts, and the underlying molecular mechanisms are still largely unknown. In this study, we performed an Mtb proteome microarray to globally identify the PstP bindings. In this way, we discovered 78 interactors between PstP and Mtb proteins, and found a novel connections with EthR. The interaction between PstP and EthR has been validated by Bio-Layer interferometry and Yeast-two-hybrid. And functional studies showed that PstP significantly enhances the binding between EthR and related DNA domain through its interaction with EthR. Phenotypically, overexpression of PstP promoted the resistance of Mycobacterium smegmatis with the antibiotic of ethionamide. Overall, we hopefully wish that the PstP interactors identified in this study will serve as a useful resource for further systematic studies of the roles that PstP plays in the regulation of Mtb dephosphorylation. SIGNIFICANCE: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which is responsible of ~1.5 million death per year. Understanding the knowledge about the basic biological regulation pathways in Mtb is an effective approach to discover the novel drug targets for cure TB. PstP is a serine/threonine protein phosphatase in Mtb, and plays important roles in regulating Mtb cell division and growth by reversible phosphorylation signaling. In this study, we identified 78 PstP interacting Mtb proteins using Mtb proteome microarray, which could preliminarily explain the roles of PstP played in Mtb. Moreover, functional analysis showed that a novel transcription factor EthR had been found regulated by PstP through binding, which could enhance the resistance to the antibiotic ETH. Overall, this network constructed with PstP-Mtb proteins could serve as a valuable resource for studying Mtb growth.
    Keywords:  EthR; Ethionamide; Mtb; Protein microarray; PstP
    DOI:  https://doi.org/10.1016/j.jprot.2020.103650
  1503. Am J Respir Crit Care Med. 2020 Jan 24.
    Treatment of Acute Exacerbation of IPF - A Call to Arms.
    Kreuter M, Maher TM.
      
    DOI:  https://doi.org/10.1164/rccm.202001-0057ED
  1504. Plant Mol Biol. 2020 Jan 21.
    Comprehensive transcriptome analysis provides insights into metabolic and gene regulatory networks in trichomes of Nicotiana tabacum.
    Nautiyal AK, Gani U, Sharma P, Kundan M, Fayaz M, Lattoo SK, Misra P.
      KEY MESSAGE: Comprehensive transcriptome analysis suggested that the primary metabolism is modulated to augment the supply of substrates towards secondary metabolism operating in the glandular trichomes of Nicotiana tabacum. The comparative gene expression and co-expression network analysis revealed that certain members of transcription factor genes belonging to the MYB, HD-ZIP, ERF, TCP, SRS, WRKY and DOF families may be involved in the regulation of metabolism and/other aspects in the glandular trichomes of N. tabacum The glandular trichomes of Nicotiana tabacum are highly productive in terms of secondary metabolites and therefore have been projected to be used as a prognostic platform for metabolic engineering of valuable natural products. For obvious reasons, detailed studies pertaining to the metabolic and gene regulatory networks operating in the glandular trichomes of N. tabacum are of pivotal significance to be undertaken. We have carried out next-generation sequencing of glandular trichomes of N. tabcaum and investigated differential gene expression among different tissues, including trichome-free leaves. We identified a total of 37,269 and 37,371 genes, expressing in trichome free leaf and glandular trichomes, respectively, at a cutoff of FPKM ≥ 1. The analysis revealed that different pathways involved with the primary metabolism are modulated in glandular trichomes of N. tabacum, providing a plausible explanation for the enhanced biosynthesis of secondary metabolism in the glandular trichomes. Further, comparative gene expression analysis revealed several genes, which display preferential expression in the glandular trichomes and thereby seem to be potential candidate genes for future studies in connection to the discovery of novel trichome specific promoters. The present study also led to the comprehensive identification of 1750 transcription factor genes expressing at a cutoff of FPKM ≥ 1 in the glandular trichomes of N. tabacum. The clustering and co-expression analysis suggested that transcription factor genes belonging to HD-ZIP, ERF, WRKY, MYB, TCP, SRS and DOF families may be the major players in the regulation of gene expression in the glandular trichomes of N. tabacum. To the best of our knowledge, the present work is the first effort towards detailed identification of genes, especially regulatory genes expressing in the glandular trichomes of N. tabacum. The data resource and the empirical findings from present work in all probability must, therefore, provide a reference and background context for future work aiming at deciphering molecular mechanism of regulation of secondary metabolism and gene expression in the glandular trichomes of N. tabacum.
    Keywords:  Glandular trichomes; Metabolism; Nicotiana tabacum; Transcription factors; Transcriptome sequencing
    DOI:  https://doi.org/10.1007/s11103-020-00968-2
  1505. Sci Total Environ. 2020 Jan 03. pii: S0048-9697(19)36419-8. [Epub ahead of print]713 136423
    Preparation, characterization, and application of magnetic activated carbon for treatment of biologically treated papermaking wastewater.
    Feng Z, Chen H, Li H, Yuan R, Wang F, Chen Z, Zhou B.
      In view of the urgent need for tertiary treatment of papermaking wastewater and the difficulty in separating powdered activated carbon (PAC) from water, the magnetic activated carbon (33%-MPAC, 50%-MPAC and 67%-MPAC) were prepared by chemical coprecipitation method for adsorption of biologically treated papermaking wastewater (BTPW). A series of characterization of MPAC and PAC were carried out and show that the content of iron oxides is negatively related to the proportion of micropores in MPAC. The loaded iron oxides is mainly the mixture of magnetite and maghemite, and the maximum saturation magnetization of MPAC can reach 29.68 emu/g. Batch mode experiments were performed, and found that the adsorption effect of MPAC is slightly worse than that of PAC, the adsorption capacity of COD in MPAC can reach about 65 mg/g, and pH = 2 and 10 °C are more favorable for adsorption. The adsorption isotherms and kinetics were well fitted by the Freundlich model and pseudo-second-order kinetic model, respectively. The selective adsorption was studied by using the excitation emission matrix (EEM) fluorescence spectrum and high-performance size exclusion chromatography (HPSEC). It is concluded that all adsorbents are preferred to adsorb humic acid-like substances (HA). And all adsorbents are preferred to adsorb low apparent molecular weight substances (LAMW, AMW < 1500 Da), with the increase of iron oxides content, the phenomenon of MPAC preferentially adsorbed LAMW became less obvious.
    Keywords:  Biologically treated papermaking wastewater; EEM fluorescence spectrum; High-performance size exclusion chromatography; Magnetic activated carbon; Selective adsorption
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.136423
  1506. Environ Sci Technol. 2020 Jan 22.
    Sulfate Radical Scavenging by Mineral Surfaces in Persulfate-Driven Oxidation Systems: Reaction Rate Constants and Implications.
    Crincoli KR, Green C, Huling SG.
      Activated persulfate (PS) is a common method used to generate sulfate radicals (SO4•-), a powerful oxidant capable of degrading a broad array of environmental contaminants. The reaction of SO4•- with nontarget species (i.e., scavenging) contributes significantly to treatment inefficiency. Radical scavenging in this manner has been quantified for nontarget chemical species in the aqueous phase but has never been quantified for solid phase media. Kinetic analysis and laboratory methods were developed to quantify the SO4•- scavenging rate constant (k≡S) for alumina, a naturally occurring mineral in soil and aquifer materials. SO4•- were generated in UV and thermally activated persulfate (UV-APS, T-APS) batch systems, and the loss of rhodamine B (RhB) served as an indicator of SO4•- activity. k≡S for alumina was 2.42 × 104 and 2.03 × 104 m-2 s-1 for UV-APS and T-APS oxidative treatment systems, respectively. At [alumina] >5 g L-1, the reaction of SO4•- with solid phase media increased over the aqueous phase reactions with RhB and aqueous scavengers. SO4•- scavenging by solid surfaces was orders of magnitude greater than the reaction with the target compound and scavengers in the aqueous phase, underscoring the significant role of solid surfaces in scavenging SO4•-.
    DOI:  https://doi.org/10.1021/acs.est.9b06442
  1507. Cancer Prev Res (Phila). 2020 Jan 22. pii: canprevres.0484.2019. [Epub ahead of print]
    Bridging Behavioral Science with Cancer Prevention and Control: Contributions of an NCI Working Group (2009-2019).
    Klein W, Rothman AJ, Suls J.
      Human behavior plays a central role in cancer morbidity and mortality. Much behavior is, in turn, attributable to several core biological, cognitive, emotional, motivational, and interpersonal processes. Understanding the systematic and interactive impact of these processes can inform efforts to address cancer-relevant outcomes such as tobacco use, reliance on cancer misinformation, engagement in genetic testing, adherence to treatment, and acceptance of palliative care. Here we review efforts of the NCI-supported Cognitive, Affective, and Social Processes in Health Research (CASPHR) working group. Since 2009, this group has endeavored to advance the integration of basic behavioral science with cancer prevention and control by addressing topics such as the degree to which behavioral interventions alter cognitions underlying behavior, how technological innovations might facilitate behavioral measurement and intervention in areas such as smoking cessation, whether decision science principles might be applied to genetic testing decisions, how the cognitive effects of chemotherapy impair self-regulation, and the extent to which emotional factors drive palliative care decisions. The group has initiated numerous activities to build capacity for research in these areas including state-of-the-science meetings, written syntheses, conference symposia, and training workshops. We conclude with reflections about future needs as well as how to sustain such integrative efforts.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-19-0484
  1508. Nat Nanotechnol. 2020 Jan 20.
    Single-molecule resonance Raman effect in a plasmonic nanocavity.
    Jaculbia RB, Imada H, Miwa K, Iwasa T, Takenaka M, Yang B, Kazuma E, Hayazawa N, Taketsugu T, Kim Y.
      Tip-enhanced Raman spectroscopy (TERS) is a versatile tool for chemical analysis at the nanoscale. In earlier TERS experiments, Raman modes with components parallel to the tip were studied based on the strong electric field enhancement along the tip. Perpendicular modes were usually neglected. Here, we investigate an isolated copper naphthalocyanine molecule adsorbed on a triple-layer NaCl on Ag(111) using scanning tunnelling microscope TERS imaging. For flat-lying molecules on NaCl, the Raman images present different patterns depending on the symmetry of the vibrational mode. Our results reveal that components of the electric field perpendicular to the tip should be considered aside from the parallel components. Moreover, under resonance excitation conditions, the perpendicular components can play a substantial role in the enhancement. This single-molecule study in a well-defined environment provides insights into the Raman process at the plasmonic nanocavity, which may be useful in the nanoscale metrology of various molecular systems.
    DOI:  https://doi.org/10.1038/s41565-019-0614-8
  1509. Am J Physiol Renal Physiol. 2020 Jan 21.
    High Protein Diet Accelerates Diabetes and Kidney Disease in the BTBRob/ob Mouse.
    Granqvist AB, Ericsson A, Sanchez J, Tonelius P, William-Olsson L, Dahlqvist U, Andersson AK, Tesan Tomic T, Hudkins KL, Alpers CE, Pellegrini G, Söderberg M.
      There is a need for improved animal models that better translate to human kidney disease to predict outcome of pharmacological effects in the patient. The diabetic BTBRob/ob mouse model mimics key features of early diabetic nephropathy in humans, but with chronic injury limited to glomeruli. To explore if we could induce an accelerated and more advanced disease phenotype that closer translates to human disease, we challenged BTBRob/ob mice with a high protein diet (HPD, 30%) and followed the progression of metabolic and renal changes up to 20 weeks of age. Animals on HPD showed enhanced metabolic derangements, evidenced by further increased levels of glucose, HbA1C, cholesterol and alanine aminotransferase. The urinary albumin creatinine ratio (UACR) was markedly increased with a 53-fold change compared with lean controls, whereas BTBRob/ob on standard diet only presented an 8-fold change. HPD resulted in more advanced mesangial expansion already at 14 weeks of age as compared with BTBRob/ob mice on standard diet, and also aggravated glomerular pathology as well as interstitial fibrosis. Gene expression analysis revealed that HPD triggered expression of markers of fibrosis and inflammation in kidney and increased oxidative stress markers in urine. This study showed that HPD significantly aggravated renal injury in BTBRob/ob by further advancing albuminuria, glomerular and tubulointerstitial pathology by 20 weeks age. This mouse model offers closer translation to humans and enables exploration of new end-points for pharmacological efficacy studies that also holds promise to shorten study length.
    Keywords:  diabetic nephropathy
    DOI:  https://doi.org/10.1152/ajprenal.00484.2019
  1510. Curr Biol. 2020 Jan 10. pii: S0960-9822(19)31680-X. [Epub ahead of print]
    Stabilization of Gaze during Early Xenopus Development by Swimming-Related Utricular Signals.
    Lambert FM, Bacqué-Cazenave J, Le Seach A, Arama J, Courtand G, Tagliabue M, Eskiizmirliler S, Straka H, Beraneck M.
      Locomotor maturation requires concurrent gaze stabilization improvement for maintaining visual acuity [1, 2]. The capacity to stabilize gaze, in particular in small aquatic vertebrates where coordinated locomotor activity appears very early, is determined by assembly and functional maturation of inner ear structures and associated sensory-motor circuitries [3-7]. Whereas utriculo-ocular reflexes become functional immediately after hatching [8, 9], semicircular canal-dependent vestibulo-ocular reflexes (VORs) appear later [10]. Thus, small semicircular canals are unable to detect swimming-related head oscillations, despite the fact that corresponding acceleration components are well-suited to trigger an angular VOR [11]. This leaves the utricle as the sole vestibular origin for swimming-related compensatory eye movements [12, 13]. We report a remarkable ontogenetic plasticity of swimming-related head kinematics and vestibular end organ recruitment in Xenopus tadpoles with beneficial consequences for gaze-stabilization. Swimming of older larvae generates sinusoidal head undulations with small, similar curvature angles on the left and right side that optimally activate horizontal semicircular canals. Young larvae swimming causes left-right head undulations with narrow curvatures and strong, bilaterally dissimilar centripetal acceleration components well suited to activate utricular hair cells and to substitute the absent semicircular canal function at this stage. The capacity of utricular signals to supplant semicircular canal function was confirmed by recordings of eye movements and extraocular motoneurons during off-center rotations in control and semicircular canal-deficient tadpoles. Strong alternating curvature angles and thus linear acceleration profiles during swimming in young larvae therefore represents a technically elegant solution to compensate for the incapacity of small semicircular canals to detect angular acceleration components.
    Keywords:  gaze stabilization; kinematics; locomotion; otolith organ; semicircular canal; swimming; vestibular system; vestibulo-ocular reflex; xenopus
    DOI:  https://doi.org/10.1016/j.cub.2019.12.047
  1511. J Neuroinflammation. 2020 Jan 18. 17(1): 27
    Microglial depletion and repopulation in brain slice culture normalizes sensitized proinflammatory signaling.
    Coleman LG, Zou J, Crews FT.
      BACKGROUND: Microglia are critical mediators of neuroimmune pathology across multiple neurologic disorders. Microglia can be persistently activated or "primed" by Toll-like receptor (TLR) activation, ethanol, stress, and other insults. Thus, strategies to prevent or reverse microglial priming may be beneficial for conditions that involve progressively increasing microglial activation. Microglial depletion with repopulation is emerging as a potential therapy to normalize chronic immune activation. Primary organotypic hippocampal slice culture (OHSC) allows for the study of neuroimmune activation as well as microglial depletion and repopulation without involvement of peripheral immune activation. OHSC undergoes functional maturation and retains cytoarchitecture similar to in vivo.METHODS: OHSC underwent microglial depletion with the CSF1R antagonist PLX3397 with or without repopulation after removal of PLX3397. Immune, trophic, and synaptic gene changes in response to agonists of TLRs 2, 3, 4, 7, and 9 as well as ethanol were assessed in the settings of microglial depletion and repopulation. Gi-DREADD inhibition of microglia was used to confirm select findings seen with depletion. The ability of microglial repopulation to prevent progressive proinflammatory gene induction by chronic ethanol was also investigated.
    RESULTS: Microglia were depleted (> 90%) by PLX3397 in OHSC. Microglial depletion blunted proinflammatory responses to several TLR agonists as well as ethanol, which was mimicked by Gi-DREADD inhibition of OHSC microglia. Removal of PLX3397 was followed by complete repopulation of microglia. OHSCs with repopulated microglia showed increased baseline expression of anti-inflammatory cytokines (e.g., IL-10), microglial inhibitory signals (e.g., CX3CL1), and growth factors (e.g., BDNF). This was associated with blunted induction (~ 50%) of TNFα and IL-1β in response to agonists to TLR4 and TLR7. Further, chronic cycled ethanol from 4 days in vitro (DIV) to 16DIV caused immediate 2-fold inductions of TNFα and IL-1β that grew to ~4-fold of age-matched control slices by 40DIV. This persistent inflammatory gene expression was completely reversed by microglial depletion and repopulation after chronic ethanol.
    CONCLUSIONS: Microglia in OHSCs mediate proinflammatory responses to TLR agonists and ethanol. Microglial repopulation promoted an anti-inflammatory, trophic neuroenvironment and normalized proinflammatory gene expression. This supports the possibility of microglial depletion with repopulation as a strategy to reverse chronic neuroimmune activation.
    Keywords:  CSF1R; Ethanol; Microglia; Microglial depletion; Microglial repopulation; Priming; Toll-like receptors
    DOI:  https://doi.org/10.1186/s12974-019-1678-y
  1512. Phys Rev E. 2019 Dec;100(6-1): 063109
    Upper bound on angular momentum transport in Taylor-Couette flow.
    Ding Z, Marensi E.
      We investigate the upper bound on angular momentum transport in Taylor-Couette flow theoretically and numerically by a one-dimensional background field method. The flow is bounded between a rotating inner cylinder of radius R_{i} and a fixed outer cylinder of radius R_{o}. A variational problem is formulated and solved by a pseudo-time-stepping method up to a Taylor number Ta=10^{9}. The angular momentum transport, characterized by a Nusselt number Nu, is bounded by Nu≤cTa^{1/2}, where the prefactor c depends on the radius ratio η=R_{i}/R_{o}. Three typical radius ratios are investigatedi.e., η=0.5,0.714,and0.909, and the corresponding prefactors c=0.0049,0.0075,and0.0086 are found to improve (lower) the rigorous upper bounds by Doering and Constantin [C. Doering and P. Constantin, Phys. Rev. Lett. 69, 1648 (1992)PRLTAO0031-900710.1103/PhysRevLett.69.1648] and Constantin [P. Constantin, SIAM Rev. 36, 73 (1994)SIREAD0036-144510.1137/1036004] by at least one order of magnitude. Furthermore, we show, via an inductive bifurcation analysis, that considering a three-dimensional background velocity field is unable to lower the bound.
    DOI:  https://doi.org/10.1103/PhysRevE.100.063109
  1513. J Assoc Physicians India. 2020 Jan;68(1): 97
    Correlation of Serum Prolactin Level with Child Pugh Scoring System in Cirrhosis of Liver.
    Karekar S, Krishnan L, Darshan A.
      
  1514. Int J Food Microbiol. 2019 Dec 30. pii: S0168-1605(19)30435-0. [Epub ahead of print]320 108504
    Different carbon sources result in differential activation of sigma B and stress resistance in Listeria monocytogenes.
    Crespo Tapia N, Dorey AL, Gahan CGM, den Besten HMW, O'Byrne CP, Abee T.
      Listeria monocytogenes is an important food-borne pathogen that is ubiquitous in the environment. It is able to utilize a variety of carbon sources, to produce biofilms on food-processing surfaces and to survive food preservation-associated stresses. In this study, we investigated the effect of three common carbon sources, namely glucose, glycerol and lactose, on growth and activation of the general stress response Sigma factor, SigB, and corresponding phenotypes including stress resistance. A fluorescent reporter coupled to the promoter of lmo2230, a highly SigB-dependent gene, was used to determine SigB activation via quantitative fluorescence spectroscopy. This approach, combined with Western blotting and fluorescence microscopy, showed the highest SigB activation in lactose grown cells and lowest in glucose grown cells. In line with this observation, lactose grown cells showed the highest resistance to lethal heat and acid stress, the highest biofilm formation, and had the highest adhesion/invasion capacity in Caco-2-derived C2Bbe1 cell lines. Our data suggest that lactose utilisation triggers a strong SigB dependent stress response and this may have implications for the resistance of L. monocytogenes along the food chain.
    Keywords:  Acid stress; Adhesion assay; Biofilm; C2Bbe1 cell line; Carbon source; Glucose; Glycerol; Heat stress; Invasion assay; Lactose; Listeria monocytogenes; SigB; Sigma B; Stress; Stress response; Virulence
    DOI:  https://doi.org/10.1016/j.ijfoodmicro.2019.108504
  1515. Chem Commun (Camb). 2020 Jan 22.
    Stereoselective synthesis of trifluoromethyl-substituted 2H-furan-amines from enaminones.
    Liang X, Guo P, Yang W, Li M, Jiang C, Sun W, Loh TP, Jiang Y.
      A straightforward strategy for synthesis of highly functionalized trifluoromethyl 2H-furans is described. The copper catalyzed method relies on a cascade cyclic reaction between enaminones and N-tosylhydrazones. This method allows the synthesis of 2-amino-3-trifluoromethyl-substituted 2H-furan derivatives carrying a quaternary stereogenic center as single diastereomers. The proposed reaction mechanism involves an amino-cyclopropane intermediate formed in the cyclopropanation of enaminones. The developed method tolerates a broad spectrum of functionalities, and the obtained 2H-furan derivatives are useful synthetic intermediates for preparing other trifluoromethyl-substituted compounds.
    DOI:  https://doi.org/10.1039/c9cc08582c
  1516. Colloids Surf B Biointerfaces. 2020 Jan 16. pii: S0927-7765(20)30024-2. [Epub ahead of print]188 110794
    Interaction of nitrofurantoin with lipid langmuir monolayers as cellular membrane models distinguished with tensiometry and infrared spectroscopy.
    Machado AC, Caseli L.
      Knowing how a drug interacts with cell membranes is important to understand and predict its effects at the molecular level. Therefore, we aimed to study the interaction of nitrofurantoin (NFT), a compound with potential antibiotic and antitumor properties, with lipidic biological interfaces using Langmuir monolayers. We employed the phospholipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS), which were spread on the surface of water to form Langmuir films, to investigate the membrane-drug interactions. The interaction of the drug with the lipid monolayers was evaluated by using surface pressure-area isotherms, surface pressure-time kinetic curves, Brewster angle microscopy (BAM), and polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). Nitrofurantoin shifted the isotherms to lower DPPC molecular areas, indicating monolayer condensation, and to higher DPPS molecular areas, indicating monolayer expansion. Meanwhile, BAM images showed the appearance of interfacial aggregates for DPPS, but not for DPPC, in the presence of NFT. PM-IRRAS spectra showed that bands related to methylene stretches changed their relative intensities and maximum position related to their asymmetric and symmetric modes for both lipids. This suggested an alteration of the monolayer packing degree and the conformational order of the lipid alkyl chains, which were related to an increase in configurational order for DPPS, but disorder for DPPC. In conclusion, NFT caused distinctive changes in the thermodynamic, morphological, and structural properties of DPPC and DPPS monolayers, which may be associated with its bioactivity in cellular membranes and other lipidic interfaces of pharmaceutical interest.
    Keywords:  Air-Water interface; Bactericide; Langmuir; Monolayers; Nitrofurantoin
    DOI:  https://doi.org/10.1016/j.colsurfb.2020.110794
  1517. Indian J Ophthalmol. 2020 Feb;68(2): 281-284
    Universal health care: Can Indian ophthalmologist community set an example?
    Rao GN.
      
    DOI:  https://doi.org/10.4103/ijo.IJO_83_20
  1518. Contact Dermatitis. 2020 Jan 22.
    Effects of hair dye ingredients on the oxidative stress response: modulation of the mRNA expressions of NRF2, HO-1 and FOS in HaCaT keratinocytes.
    de Ávila RI, Rodrigues TL, Valadares MC.
      
    Keywords:  allergic contact dermatitis; antioxidant response element; hair dyes; skin sensitization
    DOI:  https://doi.org/10.1111/cod.13478
  1519. J Assoc Physicians India. 2020 Jan;68(1): 52
    Study of Right Ventricular Dysfunction in Type 2 Diabetes Mellitus Patients Attending Medicine OPD in Dr. Bram Hospital, Raipur.
    Behra G, Varma S, Khande M.
      
  1520. Eur J Paediatr Neurol. 2020 Jan 10. pii: S1090-3798(20)30009-X. [Epub ahead of print]
    Precision medicine in sodium channelopathies - Moving beyond seizure control towards disease modification.
    Brunklaus A.
      
    Keywords:  Epilepsy; SCN1A; SCN2A; SCN8A; Sodium channel
    DOI:  https://doi.org/10.1016/j.ejpn.2020.01.008
  1521. Sci Rep. 2020 Jan 20. 10(1): 674
    Signalling architectures can prevent cancer evolution.
    Oña L, Lachmann M.
      Cooperation between cells in multicellular organisms is preserved by an active regulation of growth through the control of cell division. Molecular signals used by cells for tissue growth are usually present during developmental stages, angiogenesis, wound healing and other processes. In this context, the use of molecular signals triggering cell division is a puzzle, because any molecule inducing and aiding growth can be exploited by a cancer cell, disrupting cellular cooperation. A significant difference is that normal cells in a multicellular organism have evolved in competition between high-level organisms to be altruistic, being able to send signals even if it is to their detriment. Conversely, cancer cells evolve their abuse over the cancer's lifespan by out-competing their neighbours. A successful mutation leading to cancer must evolve to be adaptive, enabling a cancer cell to send a signal that results in higher chances to be selected. Using a mathematical model of such molecular signalling mechanism, this paper argues that a signal mechanism would be effective against abuse by cancer if it affects the cell that generates the signal as well as neighbouring cells that would receive a benefit without any cost, resulting in a selective disadvantage for a cancer signalling cell. We find that such molecular signalling mechanisms normally operate in cells as exemplified by growth factors. In scenarios of global and local competition between cells, we calculate how this process affects the fixation probability of a mutant cell generating such a signal, and find that this process can play a key role in limiting the emergence of cancer.
    DOI:  https://doi.org/10.1038/s41598-020-57494-w
  1522. J Assoc Physicians India. 2020 Jan;68(1): 87
    Association of serum bicarbonate level in predicting short term mortality in patients presenting with shock.
    Modak R, Srivastava SL, Thakur RK, Anand R.
      
  1523. Nat Rev Clin Oncol. 2020 Jan 21.
    AI outperforms radiologists in mammographic screening.
    Killock D.
      
    DOI:  https://doi.org/10.1038/s41571-020-0329-7
  1524. Nat Chem Biol. 2020 Jan 20.
    Structural equilibrium underlying ligand-dependent activation of β2-adrenoreceptor.
    Imai S, Yokomizo T, Kofuku Y, Shiraishi Y, Ueda T, Shimada I.
      G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins mediating cellular signals in response to extracellular stimuli. Although three-dimensional structures showcase snapshots that can be sampled in the process and nuclear magnetic resonance detects conformational equilibria, the mechanism by which agonist-activated GPCRs interact with various effectors remains elusive. Here, we used paramagnetic nuclear magnetic resonance for leucine amide resonances to visualize the structure of β2-adrenoreceptor in the full agonist-bound state, without thermostabilizing mutations abolishing its activity. The structure exhibited a unique orientation of the intracellular half of the transmembrane helix 6, forming a cluster of G-protein-interacting residues. Furthermore, analyses of efficacy-dependent chemical shifts of the residues near the pivotal PIF microswitch identified an equilibrium among three conformations, including one responsible for the varied signal level in each ligand-bound state. Together, these results provide a structural basis for the dynamic activation of GPCRs and shed light on GPCR-mediated signal transduction.
    DOI:  https://doi.org/10.1038/s41589-019-0457-5
  1525. ACS Appl Mater Interfaces. 2020 Jan 24.
    Manganese-mediated Growth of ZnS Shell on KMnF3:Yb,Er Cores towards Enhanced Up/downconversion Luminescence.
    Ning H, Jing L, Hou Y, Kalytchuk S, Li Y, Huang X, Gao M.
      Epitaxially growing a semiconductor shell on the surface of up-conversion nanocrystals to form core/shell structure is believed to be a promising strategy to improve the luminescent efficiency of lanthanide ions doped in particle cores, and meanwhile enrich the optical properties of the resulting nanocrystals. However, liquid-phase synthesis of such core/shell structured nanocrystals comprised of lanthanide ion-doped core and semiconductor shell remains challenging due to the chemical incompatibilities between lanthanides and most intermediate-gap semiconductors. In this context, the successful growth of ZnS shell on KMnF3 core co-doped with Yb3+/Er3+ ions is reported to enhance the upconversion luminescence of Er3+ ions. The underlying core/shell formation mechanism is elucidated in detail combining hard-soft-acid-base theory with structural analysis of the resulting nanocrystals. Quite unexpectedly, Mn2+ diffusion across the core/shell interface occurs during ZnS shell growth, giving rise to Mn2+ emission from the ZnS shell. Thus, the resulting core/shell particles exhibited unique up/downconversion luminescence from doped lanthanide metal ions and transition metal ions, respectively. By manipulating the ion diffusion and shell growth kinetics, the upconversion and downconversion luminescent performance of KMnF3:Yb,Er@ZnS nanocrystals are further optimized and the related mechanisms are discussed. Further temperature-dependent upconversion and downconversion photoluminescence properties of KMnF3:Yb,Er@ZnS nanocrystals show potential for ratiometric luminescence temperature sensing.
    DOI:  https://doi.org/10.1021/acsami.9b21832
  1526. Phys Ther Sport. 2020 Jan 13. pii: S1466-853X(19)30468-7. [Epub ahead of print]42 107-115
    Effects of a foot strengthening program on foot muscle morphology and running mechanics: A proof-of-concept, single-blind randomized controlled trial.
    Taddei UT, Matias AB, Ribeiro FIA, Bus SA, Sacco ICN.
      OBJECTIVES: To investigate the effects of a foot training program on muscle morphology and strength as well as running biomechanics in healthy recreational runners.DESIGN: Proof-of-concept, single-blind randomized controlled trial.
    SETTINGS: Runners were allocated to a control (CG) or an intervention (IG) group. The intervention focused on strengthening the intrinsic foot muscles and their activation during weight-bearing activities. All participants were assessed at baseline and after 8-weeks.
    PARTICIPANTS: Twenty-eight healthy recreational long-distance runners not habituated to minimalist running shoes or barefoot running.
    MAIN OUTCOMES MEASURES: Outcomes were hallux and toes strength; foot function, cross-sectional area and volume of the abductor hallucis (ABH), abductor digiti minimi (ABV), flexor digitorum brevis (FDB), and flexor hallucis brevis; medial longitudinal arch range of motion and stiffness; vertical and antero-posterior propulsive impulses during running.
    RESULTS: Compared to the CG, an increase was found in the IG for the volume of all muscles investigated and for vertical propulsive impulse during running. Correlations were found between vertical propulsive impulse and volume of ABH(r = 0.40), ABV(r = 0.41), and FDB(r = 0.69).
    CONCLUSION: The foot exercise protocol effectively increased intrinsic foot muscle volume and propulsive forces in recreational runners. This shows that intrinsic muscle strengthening affects running mechanics and suggests that it may improve running performance.
    Keywords:  Exercise therapy; Foot; Running; Sports injuries
    DOI:  https://doi.org/10.1016/j.ptsp.2020.01.007
  1527. Curr Biol. 2019 Dec 31. pii: S0960-9822(19)31525-8. [Epub ahead of print]
    Suppression of Leaf Blade Development by BLADE-ON-PETIOLE Orthologs Is a Common Strategy for Underground Rhizome Growth.
    Toriba T, Tokunaga H, Nagasawa K, Nie F, Yoshida A, Kyozuka J.
      Rhizomes are modified stems that grow horizontally underground in various perennial species, a growth habit that is advantageous for vigorous asexual proliferation. In Oryza longistaminata, a rhizomatous wild relative of cultivated rice (Oryza sativa), leaves in the aerial shoots consist of a distal leaf blade and a proximal leaf sheath [1]. Leaf blade formation is, however, suppressed in rhizome leaves. In O. sativa, BLADE-ON-PETIOLE (BOP) genes are the main regulators of proximal-distal leaf patterning [2]. During the juvenile phase of O. sativa, BOP expression is maintained at high levels by the small regulatory RNA microRNA156 (miR156), leading to formation of leaves consisting predominantly of the sheath. Here, we show that in O. longistaminata, high expression of BOPs caused by miR156 was responsible for suppression of the blade in rhizomes and that bop loss-of-function mutants produced leaves consisting of the leaf blade only. Rhizome growth in soil was also hampered in the mutants due to a severe reduction in rhizome tip stiffness. Leaf blade formation is also suppressed in the stolons of Zoysia matrella, a monocot species, and in the rhizomes of Houttuynia cordata, a dicot species, indicating that leaf blade suppression is widely conserved. We also show that strong expression of BOP homologs in both rhizome and stolon leaves rather than in aerial leaves is another conserved feature. We propose that suppression of the leaf blade by BOP is an evolutionary strategy that has been commonly recruited by both rhizomatous and stoloniferous species to establish their unique growth habit.
    Keywords:  BLADE-ON-PETIOLE; Houttuynia cordata; Oryza longistaminata; Zoysia matrella; leaf blade; leaf sheath; miR156; rhizome; stolon
    DOI:  https://doi.org/10.1016/j.cub.2019.11.055
  1528. Cancer. 2020 Jan 24.
    Anal cancer prevention: Solving the puzzle piece by piece.
    Goldstone SE.
      
    Keywords:  HIV-associated malignancies; anal HSIL; anal cancer; electrocautery ablation of anal HSIL; postablation recurrence
    DOI:  https://doi.org/10.1002/cncr.32726
  1529. Asia Pac J Clin Oncol. 2020 Jan 22.
    The mechanism of propofol in cancer development: An updated review.
    Gao X, Mi Y, Guo N, Luan J, Xu H, Hu Z, Wang N, Zhang D, Gou X, Xu L.
      Cancer is a key cause of death worldwide. Despite the development of radiotherapy, chemotherapy and even immunotherapy, surgery remains the standard treatment for cancer patients. Recently, many studies have shown that propofol, a commonly used anesthetic drug, can affect the prognosis of cancer. In this review, we provide an overview of the molecular mechanisms of propofol in the development of cancer. Propofol not only affects epigenetic pathways, such as those involving miRNA, lncRNA and histone acetylation, but also modulates genetic signaling pathways, including the hypoxia, NF-κB, MAPK, SLUG and Nrf2 pathways. In addition, propofol influences the immune function of patients and impacts the degree of immunosuppression. Furthermore, we briefly summarize the clinical trials on the effect of propofol in cancer development. Ultimately, further studies distinguishing the types of tumors in clinical trials are needed to clarify the correlation between propofol and cancer.
    Keywords:  cancer; epigenetic pathways; immune function; molecular mechanism; propofol
    DOI:  https://doi.org/10.1111/ajco.13301
  1530. J Thorac Cardiovasc Surg. 2019 Dec 14. pii: S0022-5223(19)37092-8. [Epub ahead of print]
    Commentary: Mitochondria to the rescue?
    Pal N, Butterworth J.
      
    DOI:  https://doi.org/10.1016/j.jtcvs.2019.11.109
  1531. Tumori. 2020 Jan 22. 300891619900805
    Duration of one-lung ventilation as a risk factor for postoperative pulmonary complications after McKeown esophagectomy.
    Lai G, Guo N, Jiang Y, Lai J, Li Y, Lai R.
      OBJECTIVE: To assess whether the duration of one-lung ventilation (OLV) affects postoperative pulmonary complications after McKeown esophagectomy for esophageal cancer.METHODS: A retrospective analysis of data stored in a database for esophageal cancer was carried out to identify predictors of postoperative pulmonary complications in patients undergoing McKeown esophagectomy at Sun Yat-sen University Cancer Center between 2010 and 2012.
    RESULTS: Patients in the OLV ⩾150 minutes group had a higher incidence of postoperative pulmonary complications than those in the OLV <150 minutes group (18.0% vs 7.3%, p < 0.001). Among them, the number of patients who developed pneumonia and atelectasis was also significantly higher (9.0% vs 4.1% [p = 0.031] and 8.7% vs 3.7% [p = 0.018] for the OLV ⩾150 minutes group vs OLV <150 minutes group, respectively). OLV ⩾150 minutes was associated with a prolonged hospital stay (24.2 ± 9.7 vs 21.5 ± 9.2 days, p = 0.001). Multivariate analysis revealed that history of diabetes (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.65-7.68; p = 0.001), chronic obstructive pulmonary disease (OR, 10.65; 95% CI, 5.65-20.08; p < 0.001), and OLV ⩾150 minutes (OR, 3.80; 95% CI, 1.97-7.31; p < 0.001) were independent predictors of postoperative pulmonary complications.
    CONCLUSION: Long duration of OLV appears to be an important risk factor for postoperative pulmonary complications after McKeown esophagectomy. OLV <150 minutes appears to be the better approach for thoracic surgery. Lung protective measures should be taken when prolonged OLV is anticipated.
    Keywords:  McKeown esophagectomy; One-lung ventilation; postoperative pulmonary complications
    DOI:  https://doi.org/10.1177/0300891619900805
  1532. Mol Genet Metab. 2020 Jan 16. pii: S1096-7192(19)31291-0. [Epub ahead of print]
    Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.
    Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH.
      Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.
    Keywords:  Branched-chain amino acids; Liver transplantation; Maple syrup urine disease; Natural history
    DOI:  https://doi.org/10.1016/j.ymgme.2020.01.006
  1533. WMJ. 2019 Dec;118(4): 169-176
    Survey of Radon Testing and Mitigation by Wisconsin Residents, Landlords, and School Districts.
    Denu RA, Maloney J, Tomasallo CD, Jacobs NM, Krebsbach JK, Schmaling AL, Perez E, Bersch AJ, LeCaire TJ, Meiman JG, Malecki KM, LoConte NK.
      INTRODUCTION: Radon is the second-leading cause of lung cancer in the United States, the leading cause of lung cancer in nonsmokers, and is estimated to cause 21,000 deaths every year. Radon is especially prevalent in the upper Midwest. This study aimed to assess radon testing and mitigation practices among residential homeowners, landlords, and school districts in Wisconsin.METHODS: Two survey sample datasets were used to assess radon testing and mitigation in residential homes: the Survey of the Health of Wisconsin (SHOW) and Wisconsin Behavioral Risk Factor Surveillance System (BRFSS) survey. Wisconsin landlords and school administrators were surveyed to assess radon testing and mitigation in rental properties and schools, respectively.
    RESULTS: Approximately 30% of Wisconsin homeowners (22.1% from SHOW and 39.9% from BRFSS) have tested their properties for radon. Similarly, 31.0% of Wisconsin landlords (40/129) and 35.1% of Wisconsin school districts (78/222) have tested their schools for radon. Of homeowners with elevated radon, about 60% mitigated. School districts whose radon levels tested high most commonly did not mitigate, with costs and/or lack of funding cited as the most common barrier.
    DISCUSSION/CONCLUSION: Radon testing and mitigation practices are inadequate in Wisconsin, and future work will seek to determine the best methods to increase testing and mitigation and reduce radon-induced lung cancer deaths in Wisconsin.
  1534. Nutrients. 2020 Jan 16. pii: E228. [Epub ahead of print]12(1):
    Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.
    Tardy AL, Pouteau E, Marquez D, Yilmaz C, Scholey A.
      Vitamins and minerals are essential to humans as they play essential roles in a variety of basic metabolic pathways that support fundamental cellular functions. In particular, their involvement in energy-yielding metabolism, DNA synthesis, oxygen transport, and neuronal functions makes them critical for brain and muscular function. These, in turn, translate into effects on cognitive and psychological processes, including mental and physical fatigue. This review is focused on B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12), vitamin C, iron, magnesium and zinc, which have recognized roles in these outcomes. It summarizes the biochemical bases and actions of these micronutrients at both the molecular and cellular levels and connects them with cognitive and psychological symptoms, as well as manifestations of fatigue that may occur when status or supplies of these micronutrients are not adequate.
    Keywords:  B vitamins; anemia; cognition; energy production; iron; magnesium; mental and physical fatigue; mood.; vitamin C; zinc
    DOI:  https://doi.org/10.3390/nu12010228
  1535. Arch Biochem Biophys. 2020 Jan 21. pii: S0003-9861(19)31173-7. [Epub ahead of print] 108234
    Mitochondrial Rieske iron-sulfur protein in pulmonary artery smooth muscle: A key primary signaling molecule in pulmonary hypertension.
    Truong L, Zheng YM, Wang YX.
      Rieske iron-sulfur protein (RISP) is a catalytic subunit of the complex III in the mitochondrial electron transport chain. Studies for years have revealed that RISP is essential for the generation of intracellular reactive oxygen species (ROS) via delicate signaling pathways associated with many important molecules such as protein kinase C-ε, NADPH oxidase, and ryanodine receptors. More significantly, mitochondrial RISP-mediated ROS production has been implicated in the development of hypoxic pulmonary vasoconstriction, leading to pulmonary hypertension, right heart failure, and death. Investigations have also shown the involvement of RISP in ROS-dependent cardiac ischemic/reperfusion injuries. Further research may provide novel and valuable information that can not only enhance our understanding of the functional roles of RISP and the underlying molecular mechanisms in the pulmonary vasculature and other systems, but also elucidate whether RISP targeting can act as preventative and restorative therapies against pulmonary hypertension, cardiac diseases, and other disorders.
    Keywords:  Hypoxia; Mitochondria; Pulmonary hypertension; Reactive oxygen species; Rieske iron-sulfur protein
    DOI:  https://doi.org/10.1016/j.abb.2019.108234
  1536. J Assoc Physicians India. 2020 Jan;68(1): 45
    A Study of Serum Free Testosterone Level in Type 2 Diabetes Mellitus Male Patients at Tertiary Care Hospital: A Case Control Study.
    Kumar M, Nawal C, Chejara RS, Singh R.
      
  1537. J Obes. 2019 ;2019 5903621
    Maximum Phonation Time in People with Obesity Not Submitted or Submitted to Bariatric Surgery.
    Fonseca ALF, Salgado W, Dantas RO.
      Background: Our aim in this investigation was to evaluate maximum phonation time in people with obesity not submitted to surgery and in people with obesity submitted to bariatric surgery and compare it with maximum phonation time of healthy volunteers. The hypothesis was that the reduced maximum phonation time in people with obesity would be corrected after surgery due to weight loss.Method: Maximum phonation time was evaluated in 52 class III patients (Group A), 62 class III patients who were treated by surgery 3 to 115 months before (Group B), 20 controls (Group C), and 15 class III patients whose maximum phonation time was evaluated before and two to six months after surgery (Group D). Maximum phonation time was measured in the sitting position with the vowels /A/, /I/, and /U/.
    Results: Maximal phonation time was shorter in groups A and B compared with that of controls. There was an increase in maximal phonation time after surgery (Group B); however, the difference was not significant when compared with that in group A. In group D, maximal phonation time for /A/ increased after the surgery. In group A, there was a negative correlation between maximal phonation time and weight or body mass index and a positive correlation between maximal phonation time and height. In group B, there was an almost significant positive relation between percentage of weight loss and maximal phonation time for /A/ (p=0.08) and /I/ (p=0.07). Mean values of spirometry testing (FEV1, FVC, and FEV1/FVC) in people with obesity (groups A and B), expressed as percentage of the predicted value, were within the normal range.
    Conclusion: Compared with healthy controls, maximal phonation time is shorter in people with obesity, with a tendency to increase after bariatric surgery, as a possible consequence of weight loss.
    DOI:  https://doi.org/10.1155/2019/5903621
  1538. Virchows Arch. 2020 Jan 24.
    Methodological approach to microscopic colitis diagnosis: reply.
    Gonzalez RS.
      
    DOI:  https://doi.org/10.1007/s00428-020-02758-z
  1539. J Neurol Sci. 2020 Jan 09. pii: S0022-510X(20)30013-7. [Epub ahead of print]410 116677
    Therapeutic effects of forced exercise cycling in individuals with Parkinson's disease.
    Miner DG, Aron A, DiSalvo E.
      Currently there is no cure for the progressive movement disorders associated with Parkinson's Disease (PD). Pharmacological management of movement disorders in PD are associated with significant negative side effects. Exercise improves the efficacy of anti-parkinsonian medication, but does not ameliorate the side effects. Consensus on the optimal mode of exercise training or dosing to improve motor function for individuals with PD is lacking. The new concept of forced exercise is gaining traction in the literature as a mode of exercise which has the potential to improve motor function in individuals with PD. The purpose of this article is to review the effects of forced exercise on specific components of motor function that would help guide clinical decision making and exercise prescription for the PD patient population. Collectively, the evidence provided in this review suggests that forced exercise may be safely added as an ancillary therapy to the medical management of PD.
    Keywords:  Forced exercise; Parkinson's disease; Rehabilitation
    DOI:  https://doi.org/10.1016/j.jns.2020.116677
  1540. Phys Chem Chem Phys. 2020 Jan 22.
    Spin-flip methods in quantum chemistry.
    Casanova D, Krylov AI.
      This Perspective discusses salient features of the spin-flip approach to strong correlation and describes different methods that sprung from this idea. The spin-flip treatment exploits the different physics of low-spin and high-spin states and is based on the observation that correlation is small for same-spin electrons. By using a well-behaved high-spin state as a reference, one can access problematic low-spin states by deploying the same formal tools as in the excited-state treatments (i.e., linear response, propagator, or equation-of-motion theories). The Perspective reviews applications of this strategy within wave function and density functional theory frameworks as well as the extensions for molecular properties and spectroscopy. The utility of spin-flip methods is illustrated by examples. Limitations and proposed future directions are also discussed.
    DOI:  https://doi.org/10.1039/c9cp06507e
  1541. J Chromatogr A. 2020 Jan 10. pii: S0021-9673(20)30039-X. [Epub ahead of print] 460874
    Characterization of E 472 food emulsifiers by high-performance thin-layer chromatography with fluorescence detection and mass spectrometry.
    Oellig C, Link K, Schwack W.
      Esters of fruit acids including acetic acid and mono- and diacylglycerols (MAG and DAG), also known as E 472 emulsifiers, are used in the food industry as food additives to adjust techno-functional properties like viscosity, emulsion stability and foaming stability in various products, mainly dairy products. Based on the respective acids, E 472 emulsifiers are classified in several categories with acetic acid esters (ACETEM, E 472a), lactic acid esters (LACTEM, E 472b), citric acid esters (CITREM, E 472c), and mono- and diacetyl tartaric acid esters (DATEM, E 472e) as the most prominent representatives. Besides fruit acid esters, E 472 emulsifiers mainly comprise MAG, DAG, triacylglycerols, free fatty acids, free fruit acids and free glycerol in different amounts. Here we present an innovative and sensitive method for the characterization of the composition of E 472 emulsifiers by high-performance thin-layer chromatography with fluorescence detection (HPTLC-FLD). For HPTLC-FLD, technical emulsifiers were simply dissolved and analyzed on HPTLC silica gel plates after a two-fold development and derivatization with primuline, enabling the easy characterization and direct visual comparison of the emulsifier pattern (fingerprint) through the fluorescent lipid components under UV 366 nm. Thus, the HPTLC-FLD fingerprint approach represents a simple tool for the comparison of different samples, batches and categories of E 472. Coupling of HPTLC to mass spectrometry moreover enabled the identification of constituents of interest.
    Keywords:  ACETEM; CITREM; DATEM; Food emulsifiers; Fruit acid esters of mono- and diacylglycerols; HPTLC–MS; LACTEM
    DOI:  https://doi.org/10.1016/j.chroma.2020.460874
  1542. Pestic Biochem Physiol. 2020 Feb;pii: S0048-3575(19)30472-9. [Epub ahead of print]163 76-83
    Nematicidal activity of 5-iodoindole against root-knot nematodes.
    Rajasekharan SK, Kim S, Kim JC, Lee J.
      Multi-drug resistance in nematodes is a serious problem as lately several resistant phenotypes have emerged following the intermittent usage of synthetic nematicides. Contemporary research continues to focus on developing and/or repurposing small molecule inhibitors that are eco-friendly. Here, we describe the repurposing of the indole derivative, 5-iodoindole, as a nematicide for the root-knot nematode, Meloidogyne incognita. 5-Iodoindole effectively killed juveniles and freshly hatched juveniles by inducing multiple vacuole formation. Notably, at higher dosage (50 μg/mL), 5-iodoindole induced rapid juvenile death within 6 h. Microscopic analysis confirmed that the rapid death was due to the generation of reactive oxygen species (ROS). Computational docking attributed this ROS production to the antagonistic effect of 5-iodoindole on glutathione S-transferase (GST), which is known to play a critical role in the suppression of ROS in nematode models. Furthermore, 5-iodoindole also effectively reduced the gall formations and eggs masses of M. incognita on Solanum lycopersicum roots in pot experiments, and importantly it did not harm the physiological properties of the plant. Overall, the study provides valuable insights on the use of 5-iodoindole as an alternate measure to control root-knot nematodes. Overall, our findings suggest the efficacy of 5-iodoindole should be studied under field conditions.
    Keywords:  5-Iodoindole; GST; Juveniles; M. incognita; ROS; Root-knot nematode
    DOI:  https://doi.org/10.1016/j.pestbp.2019.10.012
  1543. Hear Res. 2020 Jan 13. pii: S0378-5955(19)30524-6. [Epub ahead of print] 107882
    Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B.
    Lee J, Nist-Lund C, Solanes P, Goldberg H, Wu J, Pan B, Schneider BL, Holt JR.
      Viral delivery of exogenous coding sequences into the inner ear has the potential for therapeutic benefit for patients suffering genetic or acquired hearing loss. To devise improved strategies for viral delivery, we investigated two injection techniques, round window membrane injection or a novel utricle injection method, for their ability to safely and efficiently transduce sensory hair cells and neurons of the mouse inner ear. In addition, we evaluated three synthetic AAV vectors (Anc80L65, AAV9-PHP.B, AAV2.7m8) encoding enhanced green fluorescent protein (eGFP) and three promoters (Cmv, Synapsin, Gfap) for their ability to transduce and drive expression in desired cell types. We found the utricle injection method with AAV9-PHP.B and a Cmv promoter was the most efficient combination for driving robust eGFP expression in both inner and outer hair cells. We found eGFP expression levels rose over 3-5 days post-injection, a viral dose of 1.5 × 109 gc yielded half maximal eGFP expression and that the utricle injection method yielded transduced hair cells even when delivered as late as postnatal day 16. Sensory transduction and auditory thresholds were unaltered in injected mice relative to uninjected wild-type controls. Vestibular end organs were also transduced without affecting balance behavior. The Synapsin promoter and the Gfap promoter drove strong eGFP expression in inner ear neurons and supporting cells, respectively. We conclude the AAV9-PHP.B vector and the utricle injection method are well-suited for delivery of exogenous gene constructs into inner ears of mouse models of auditory and vestibular dysfunction.
    DOI:  https://doi.org/10.1016/j.heares.2020.107882
  1544. Blood. 2020 Jan 21. pii: blood.2019002920. [Epub ahead of print]
    Long-term outcomes of Sleeping Beauty generated CD19specific CAR T-cell therapy for relapsed-refractory B-cell lymphomas.
    Srour S, Singh H, McCarty J, de Groot E, Huls H, Rondon G, Qazilbash MH, Ciurea SO, Bardelli G, Buck J, Alousi A, Nieto Y, Rezvani K, Marin D, Popat U, Hosing C, Shpall EJ, Wierda WG, Kantarjian H, Champlin R, Cooper L, Kebriaei P.
      
    DOI:  https://doi.org/10.1182/blood.2019002920
  1545. Nature. 2020 Jan;577(7791): 453
    An iconic structure in London moonlights as a scientific tool.
      
    Keywords:  Physics
    DOI:  https://doi.org/10.1038/d41586-020-00052-1
  1546. Clin Radiol. 2020 Jan 20. pii: S0009-9260(20)30009-X. [Epub ahead of print]
    Marrow outside marrow: imaging of extramedullary haematopoiesis.
    Malla S, Razik A, Das CJ, Naranje P, Kandasamy D, Kumar R.
      Extramedullary haematopoiesis (EMH) refers to the formation of non-neoplastic blood cell lines outside the bone marrow and is a common incidental finding when patients with haematological disorders are imaged. EMH presenting as mass (tumefactive EMH) has long been a radiological conundrum as it resembles neoplasms. Several imaging findings have been described in EMH, and these vary depending on the activity of the underlying haematopoiesis. The older lesions are easier to diagnose as they often demonstrate characteristic findings such as haemosiderin and fat deposition. In comparison, the newer, actively haematopoietic lesions often mimic neoplasms. Molecular imaging, particularly 99mTc labelled sulphur colloid scintigraphy, may be helpful in such cases. Although imaging is extremely useful in detecting and characterising EMH, imaging alone is often non-diagnostic as no single mass shows all the typical findings. Hence, a judgement based on the clinical background, combination of imaging findings, and slow interval growth may be more appropriate and practical in making the correct diagnosis. In every case, an effort has to be made in providing an imaging-based diagnosis as it may prevent a potentially risky biopsy. When confident differentiation is not possible, biopsy has to be resorted to. This article describes the causes, pathophysiology, and theories underlying the genesis of EMH, followed by the general and location-specific imaging findings. The purpose is to provide a thorough understanding of the condition as well as enable the clinical radiologist in making an imaging-based diagnosis whenever possible and identify the situations where biopsy has to be performed.
    DOI:  https://doi.org/10.1016/j.crad.2019.12.016
  1547. Eur J Nucl Med Mol Imaging. 2020 Jan 20.
    Quantifying the effects of absorbed dose from radioembolisation on healthy liver function with [99mTc]TcMebrofenin.
    Willowson KP, Schembri GP, Bernard EJ, Chan DL, Bailey DL.
      PURPOSE: To quantify the effects of absorbed radiation dose on healthy liver parenchyma following radioembolisation (RE) using [99mTc]TcMebrofenin to analyse both global and regional liver function.METHODS: Patients having RE to treat hepatic disease underwent a [99mTc]TcMebrofenin hepatobilliary scintigraphy (HBS) study at both baseline and 8 weeks following treatment. Changes in global liver uptake rate were compared with healthy liver absorbed dose measures derived from the post-treatment 90Y PET/CT, including average dose, minimum dose to 70% of the volume (D70) and volume receiving at least 50 Gy (V50). Changes in functional burden associated with treatment and spared liver volumes in patients receiving lobar RE were also assessed, as were changes experienced by regional volumes corresponding to various dose ranges. Standard liver function pathology tests (LFTs) (bilirubin, albumin, ALP, AST, ALT and GGT) were examined for changes between baseline and post-treatment.
    RESULTS: Thirty-five patients were included in the study, of which, 9 had lobar treatment. A significant linear correlation was found between both baseline global liver uptake rate (negative) and D70 with change in global liver uptake rate. Patients undergoing lobar treatments demonstrated a shift in functional burden, and a significant difference was seen between the mean dose corresponding to liver volumes that increased their functional burden (9 Gy) and those that decreased their functional burden (35 Gy). No baseline LFTs predicted a decrease in global liver function; however, D70 demonstrated a linear correlation with changes in bilirubin and GGT.
    CONCLUSIONS: Given the significant negative relationship between baseline and change in global liver uptake rate, baseline HBS studies should not be used alone to disqualify patients considered for RE. In terms of treatment planning and evaluation, D70 may be the most appropriate metric of dose, with values greater than 15 Gy indicative of a likely drop in global liver function. The evidence of increasing functional burden in spared liver volumes suggests that patients at risk of complications could benefit from a lobar approach to treatment.
    Keywords:  Dose; Hepatobiliary scintigraphy; Liver; Mebrofenin; Radioembolisation
    DOI:  https://doi.org/10.1007/s00259-020-04686-1
  1548. Sci Rep. 2020 Jan 20. 10(1): 694
    TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice.
    Ono Y, Maejima Y, Saito M, Sakamoto K, Horita S, Shimomura K, Inoue S, Kotani J.
      Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin-proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.
    DOI:  https://doi.org/10.1038/s41598-020-57714-3
  1549. J Diabetes Res. 2019 ;2019 4912174
    Impact of Short-Term Continuous and Interval Exercise Training on Endothelial Function and Glucose Metabolism in Prediabetes.
    Malin SK, Gilbertson NM, Eichner NZM, Heiston E, Miller S, Weltman A.
      Introduction: The impact of interval (INT) vs. continuous (CONT) exercise training on endothelial function in relation to glucose metabolism prior to clinically meaningful weight loss is unknown in adults with prediabetes.Methods: Twenty-six subjects with prediabetes (60 ± 1 y; 33 ± 1 kg/m2; 2-hr-PG OGTT: 145 ± 7 mg/dl) were randomized to 60 min of CONT (n = 12; 70% of HRpeak) or work-matched INT exercise training (n = 14; alternating 3 min at 90 and 50% HRpeak) for 2 weeks. Aerobic fitness (VO2peak) and body composition (bioelectrical impedance) were assessed before and after training. Flow-mediated dilation (FMD) was measured during a 2 h 75 g OGTT (0, 60, and 120 min) to assess endothelial function. Postprandial FMD was calculated as incremental area under the curve (iAUC). Glucose tolerance and insulin were also calculated by iAUC. Fasting plasma VCAM, ICAM, and hs-CRP were also assessed as indicators of vascular/systemic inflammation.
    Results: Both interventions increased VO2peak (P = 0.002) but had no effect on body fat (P = 0.20). Although both treatments improved glucose tolerance (P = 0.06) and insulin iAUC (P = 0.02), VCAM increased (P = 0.01). There was no effect of either treatment on ICAM, hs-CRP, or fasting as well as postprandial FMD. However, 57% of people improved fasting and iAUC FMD following CONT compared with only 42% after INT exercise (each: P = 0.04). Elevated VCAM was linked to blunted fasting FMD after training (r = -0.38, P = 0.05). But, there was no correlation between fasting FMD or postprandial FMD with glucose tolerance (r = 0.17, P = 0.39 and r = 0.02, P = 0.90, respectively) or insulin iAUC following training (r = 0.34, P = 0.08 and r = 0.04, P = 0.83, respectively).
    Conclusion: Endothelial function is not improved consistently after short-term training, despite improvements in glucose and insulin responses to the OGTT in obese adults with prediabetes.
    DOI:  https://doi.org/10.1155/2019/4912174
  1550. Nanoscale. 2020 Jan 23.
    RNA-DNA hybrid nanoshapes that self-assemble dependent on ligand binding.
    Chen S, Hermann T.
      Self-assembly of nucleic acid nanostructures is driven by selective association of oligonucleotide modules through base pairing between complementary sequences. Herein, we report the development of RNA-DNA hybrid nanoshapes that conditionally assemble under the control of an adenosine ligand. The design concept for the nanoshapes relies on ligand-dependent stabilization of DNA aptamers that serve as connectors between marginally stable RNA corner modules. Ligand-dependent RNA-DNA nanoshapes self-assemble in an all-or-nothing process by coupling adenosine binding to the formation of circularly closed structures which are stabilized through continuous base stacking in the resulting polygons. By screening combinations of various DNA aptamer constructs with RNA corner modules for the formation of stable complexes, we identified adenosine-dependent nanosquares whose shape was confirmed by atomic force microscopy. As a proof-of-concept for sensor applications, adenosine-responsive FRET-active nanosquares were obtained by dye conjugation of the DNA aptamer components.
    DOI:  https://doi.org/10.1039/c9nr09706f
  1551. BMC Anesthesiol. 2020 Jan 22. 20(1): 20
    Volume of tidal gas movement in the nonventilated lung during one-lung ventilation and its relevant factors.
    Wei J, Gao L, Sun F, Zhang M, Gu W.
      BACKGROUND: The passive ventilation of nonventilated lung results in tidal gas movement (TGM) and thus affects lung collapse. The present study aimed to measure the volume of TGM and to analyse the relevant factors of the TGM index (TGM/body surface area).METHODS: One hundred eight patients scheduled for elective thoracoscopic surgeries were enrolled. Lung isolation was achieved with a double-lumen endobronchial tube (DLT). The paediatric spirometry sensor was connected to the double-lumen connector of the nonventilated lung to measure the volume of TGM during one-lung ventilation (OLV) in the lateral position. The TGM index was calculated. The multiple linear regression was analysed using the TGM index as the dependent variables. Independent variables were also recorded: 1) age, sex, body mass index (BMI); 2) forced vital capacity (FVC), FEV1/FVC, minute ventilation volume (MVV); 3) dynamic lung compliance (Cdyn) and peak inspiratory pressure (PIP) during dual lung ventilation; 4) the side of OLV; and 5) whether lung puncture for localization of the pulmonary nodule was performed on the day of surgery. The oxygen concentration in the nonventilated lung was measured at 5 min after OLV, and its correlation with the TGM index was analysed.
    RESULTS: The volume of TGM in the nonventilated lung during OLV was 78 [37] mL. The TGM index was 45 [20] mL/m2 and was negatively correlated with the oxygen concentration in the nonventilated lung at 5 min after OLV. The multiple linear regression model for the TGM index was deduced as follows: TGM index (mL/m2) = C + 12.770 × a - 3.987 × b-1.237 × c-2.664 × d, where C is a constant 95.621 mL/m2, a is 1 for males and 0 for females, b is 1 for right OLV and 0 for left OLV, c is BMI (kg/m2), and d is PIP (cmH2O).
    CONCLUSIONS: The TGM index is negatively correlated with the oxygen concentration of the nonventilated lung at 5 min after OLV. Sex, side of OLV, BMI and PIP are independently correlated with the TGM index.
    TRIAL REGISTRATION: This study was registered at ChiCTR (www.chictr.org.cn, ChiCTR1900024220) on July 1, 2019.
    Keywords:  Double-lumen endobronchial tube; Dynamic lung compliance; Lung collapse; One-lung ventilation; TGM index; Thoracoscopy; Tidal gas movement
    DOI:  https://doi.org/10.1186/s12871-020-0937-x
  1552. Eur J Med Chem. 2019 Dec 19. pii: S0223-5234(19)31133-X. [Epub ahead of print]189 111981
    Efficient identification of novel anti-glioma lead compounds by machine learning models.
    Neves BJ, Agnes JP, Gomes MDN, Henriques Donza MR, Gonçalves RM, Delgobo M, Ribeiro de Souza Neto L, Senger MR, Silva-Junior FP, Ferreira SB, Zanotto-Filho A, Andrade CH.
      Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumor. Pharmacological treatment of this malignance is limited by the selective permeability of the blood-brain barrier (BBB) and relies on a single drug, temozolomide (TMZ), thus making the discovery of new compounds challenging and urgent. Therefore, aiming to discover new anti-glioma drugs, we developed robust machine learning models for predicting anti-glioma activity and BBB penetration ability of new compounds. Using these models, we prioritized 41 compounds from our in-house library of compounds, for further in vitro testing against three glioma cell lines and astrocytes. Subsequently, the most potent and selective compounds were resynthesized and tested in vivo using an orthotopic glioma model. This approach revealed two lead candidates, 4m and 4n, which efficiently decreased malignant glioma development in mice, probably by inhibiting thioredoxin reductase activity, as shown by our enzymological assays. Moreover, these two compounds did not promote body weight reduction, death of animals, or altered hematological and toxicological markers, making then good candidates for lead optimization as anti-glioma drug candidates.
    Keywords:  Cancer; Glioblastoma; Machine learning; Orthotopic glioma model; Predictive modeling; Thioredoxin reductase
    DOI:  https://doi.org/10.1016/j.ejmech.2019.111981
  1553. Nucleic Acids Res. 2020 Jan 25. pii: gkaa043. [Epub ahead of print]
    Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.
    Maestroni L, Reyes C, Vaurs M, Gachet Y, Tournier S, Géli V, Coulon S.
      Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE. Telomere cluster association to the NE relies on Rap1-Bqt4 interaction, which is impacted by the length of telomeric sequences. In quiescent cells, reducing telomere length or deleting bqt4, both result in an increase in transcription of the telomeric repeat-containing RNA (TERRA). In the absence of Bqt4, telomere shortening leads to deep increase in TERRA level and the concomitant formation of subtelomeric rearrangements (STEEx) that accumulate massively in quiescent cells. Taken together, our data demonstrate that Rap1-Bqt4-dependent telomere association to NE preserves telomere integrity in post-mitotic cells, preventing telomeric transcription and recombination. This defines the nuclear periphery as an area where recombination is restricted, creating a safe zone for telomeres of post-mitotic cells.
    DOI:  https://doi.org/10.1093/nar/gkaa043
  1554. Neurotoxicology. 2020 Jan 18. pii: S0161-813X(20)30001-2. [Epub ahead of print]
    Perfluoroalkyl chemicals in neurological health and disease: Human concerns and animal models.
    Piekarski DJ, Diaz KR, McNerney MW.
      Perfluoroalkyl acids (PFAAs) are man-made organic pollutants that are found ubiquitously in the environment and may impact human health. Here, we review the published literature concerning PFAA impacts on neurobiological, neuroendocrine, and neurobehavioral outcomes. We find that there are many mechanisms through which PFAAs may enter the brain and interact with biochemical endpoints to impact neurological function. These results are supported by epidemiological evidence in humans and experimental evidence in animals that demonstrate numerous and varied PFAA impacts on the nervous system. However, the methods commonly used in animal models of PFAA exposure result in durations of exposure and serum PFAA concentrations in blood that may not appropriately mimic human absorption, distribution, metabolism, and excretion. If animal models lack validity, confidence in mechanistic inferences regarding PFAA exposure and brain function is reduced, limiting these studies' utility. Finally, we end by suggesting some potential impacts of PFAA exposure in human neurological health and disease states whose associations may not readily present themselves in the epidemiological literature.
    Keywords:  PFAA; PFAS; animal models; brain; neuroendocrinology; perfluoroalkyl substances
    DOI:  https://doi.org/10.1016/j.neuro.2020.01.001
  1555. Molecules. 2020 Jan 18. pii: E404. [Epub ahead of print]25(2):
    Synthesis of Novel Structural Hybrids between Aza-Heterocycles and Azelaic Acid Moiety with a Specific Activity on Osteosarcoma Cells.
    Micheletti G, Calonghi N, Farruggia G, Strocchi E, Palmacci V, Telese D, Bordoni S, Frisco G, Boga C.
      Nine compounds bearing pyridinyl (or piperidinyl, benzimidazolyl, benzotriazolyl) groups bound to an azelayl moiety through an amide bond were synthesized. The structural analogy with some histone deacetylase inhibitors inspired their syntheses, seeking new selective histone deacetylase inhibitors (HDACi). The azelayl moiety recalls part of 9-hydroxystearic acid, a cellular lipid showing antiproliferative activity toward cancer cells with HDAC as a molecular target. Azelayl derivatives bound to a benzothiazolyl moiety further proved to be active as HDACi. The novel compounds were tested on a panel of both normal and tumor cell lines. Non-specific induction of cytotoxicity was observed in the normal cell line, while three of them induced a biological effect only on the osteosarcoma (U2OS) cell line. One of them induced a change in nuclear shape and size. Cell-cycle alterations are associated with post-transcriptional modification of both H2/H3 and H4 histones. In line with recent studies, revealing unexpected HDAC7 function in osteoclasts, molecular docking studies on the active molecules predicted their proneness to interact with HDAC7. By reducing side effects associated with the action of the first-generation inhibitors, the herein reported compounds, thus, sound promising as selective HDACi.
    Keywords:  9-hydroxystearic acid; azelaic acid; cancer; molecular docking; osteosarcoma; pyridine; pyrimidine
    DOI:  https://doi.org/10.3390/molecules25020404
  1556. Prostate. 2020 Jan 22.
    Exendin-4 enhances the sensitivity of prostate cancer to enzalutamide by targeting Akt activation.
    Wenjing H, Shao Y, Yu Y, Huang W, Feng G, Li J.
      BACKGROUND: Glucagon-like peptide 1 (GLP-1) and its analogs are first-line choices for the treatment of type 2 diabetes mellitus. Recent studies have shown that they exhibit antitumor properties in some tumors. We previously found that a GLP-1 analog, exendin-4 (Ex-4), inhibited the growth of prostate cancer cells through suppressing the PI3K/Akt/mTOR pathway, which is activated in response to enzalutamide treatment and reported to be closely related to resistance to enzalutamide. So we speculated that exendin-4 may enhance the sensitivity of prostate cancer to enzalutamide through inhibiting Akt activation.METHODS: LNCap and CWR22RV1 cell lines, as well as mice bearing xenografts formed from the two cells, were used.
    RESULTS: Exendin-4 in combination with enzalutamide dramatically suppressed tumor growth of prostate cancer cells compared to enzalutamide alone; exendin-4 is capable of antagonizing enzalutamide-induced invasion and migration of both prostate cancer cells (P < .05). Furthermore, the combination treatment significantly reduced Akt and mTOR levels that were triggered by enzalutamide administration, caused a further decrease in nuclear AR localization compared with the enzalutamide as a monotherapy (P < .5), though exendin-4 treatment alone showed no effect on nuclear AR.
    CONCLUSION: Our study demonstrated that exendin-4 alleviated resistance to enzalutamide, and suggested that exendin-4 combined with enzalutamide may be a more efficacious treatment for patients with advanced prostate cancer.
    Keywords:  enzalutamide; exendin-4; prostate cancer; sensitivity
    DOI:  https://doi.org/10.1002/pros.23951
  1557. J Theor Biol. 2020 Jan 15. pii: S0022-5193(20)30020-5. [Epub ahead of print] 110164
    Cultural specialization and genetic diversity: killer whales and beyond.
    Whitehead H.
      Culturally-transmitted ecological specialization can reduce niche breadths with demographic and ecological consequences. I use agent-based models, grounded in killer whale biology, to investigate the potential consequences of cultural specialization for genetic diversity. In these models, cultural specialization typically reduces the number of mitochondrial haplotypes, mitochondrial haplotype diversity, mitochondrial nucleotide diversity, and heterozygosity at nuclear loci. The causal route of this decline is mostly indirect, being ascribed to a reduction in absolute population size resulting from cultural specialization. However, small group size exacerbates the decline in genetic diversity, presumably because of increased founder effects at the initiation of each cultural ecotype. These results are concordant with measures of low genetic diversity in the killer whale, although culturally-transmitted ecological specialization alone might not be sufficient to fully account for the species' very low mitochondrial diversity. The process may also operate in other species.
    Keywords:  Culture; Evolution; Mitochondrial diversity; Natural selection; Nuclear diversity; Orcinus orca
    DOI:  https://doi.org/10.1016/j.jtbi.2020.110164
  1558. J Cell Physiol. 2020 Jan 20.
    α-Mangostin attenuates stemness and enhances cisplatin-induced cell death in cervical cancer stem-like cells through induction of mitochondrial-mediated apoptosis.
    Chien HJ, Ying TH, Hsieh SC, Lin CL, Yu YL, Kao SH, Hsieh YH.
      Cancer stem cells (CSCs) exhibit specific characteristics including decontrolled self-renewal, tumor-initiating, promoting, and metastatic potential, abnormal stemness signaling, and chemotherapy resistance. Thus, targeting CSC is becoming an emerging cancer treatment. α-Mangostin has been shown to have potent and multiple anticancer activities. Accordingly, we hypothesized that α-mangostin may diminish the stemness and proliferation of CSC-like cervical cancer cells. In our results, comparing to the parent cells, CSC-like SiHa and HeLa cells highly expressed CSC marker Sox2, Oct4, Nanog, CK-17, and CD49f. α-Mangostin significantly reduced the cell viability, sphere-forming ability, and expression of the CSC stemness makers of CSC-like cervical cancer cells. Further investigation showed that α-mangostin induced mitochondrial depolarization and mitochondrial apoptosis signaling, including upregulation of Bax, downregulation of Mcl-1 and Bcl-2, and activation of caspase-9/3. Moreover, α-mangostin synergically enhanced the cytotoxicity of cisplatin on CSC-like SiHa cells by promoting mitochondrial apoptosis and inhibiting the expression of CSC markers. Consistent with in vitro findings, in vivo tumor growth assay revealed that α-mangostin administration significantly inhibited the growth of inoculated CSC-like SiHa cells and synergically enhanced the antitumor effect of cisplatin. Our findings indicate that α-mangostin can reduce the stemness and proliferation of CSC-like SiHa and HeLa cells and promote the cytotoxicity of cisplatin, which may attribute to the mitochondrial apoptosis activation. Thus, it suggests that α-mangostin may have clinical potential to improve chemotherapy for cervical cancer by targeting cervical CSC.
    Keywords:  apoptosis; cervical cancer stem cells; cisplatin; stemness; α-mangostin
    DOI:  https://doi.org/10.1002/jcp.29489
  1559. Neurology. 2020 Jan 21. pii: 10.1212/WNL.0000000000009001. [Epub ahead of print]
    Posterior primary progressive prosopagnosia: Structural and molecular imaging.
    Pascual B, Masdeu JC, Funk Q, Zanotti-Fregonara P, Shyer M, Rockers E, Schulz PE.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000009001
  1560. J Hazard Mater. 2020 Jan 13. pii: S0304-3894(20)30066-2. [Epub ahead of print]388 122080
    Phytohormones-induced senescence efficiently promotes the transport of cadmium from roots into shoots of plants: A novel strategy for strengthening of phytoremediation.
    Zhu H, Chen L, Xing W, Ran S, Wei Z, Amee M, Wassie M, Niu H, Tang D, Sun J, Du D, Yao J, Hou H, Chen K, Sun J.
      Due to the long growth period of plants, phytoremediation is time costly. Improving the accumulation of cadmium (Cd) in shoots of plants will promote the efficiency of phytoremediation. In this study, two senescence-relative phytohormones, abscisic acid (ABA) and salicylic acid (SA), were applied to strengthening phytoremediation of Cd by tall fescue (Festuca arundinacea S.). Under hydroponic culture, phytohormones treatment increased the Cd content of shoots 11.4-fold over the control, reaching 316.3 mg/kg (dry weight). Phytohormones-induced senescence contributes to the transport of heavy metals, and HMA3 was found to play a key role in this process. Additionally, this strategy could strengthen the accumulation of Cu and Zn in tall fescue shoots. Moreover, in soil pot culture, the strategy increased shoot Cd contents 2.56-fold over the control in tall fescue, and 2.55-fold over the control in Indian mustard (Brassica juncea L.), indicating its comprehensive adaptability and potential use in the field. In summary, senescence-induced heavy metal transport is developed as a novel strategy to strengthen phytoremediation. The strategy could be applied at the end of phytoremediation with an additional short duration (7 days) with comprehensive adaptability, and markedly strengthen the phytoremediation in the field.
    Keywords:  Cadmium; Phytohormones; Phytoremediation; Strengthening strategy; Tall fescue
    DOI:  https://doi.org/10.1016/j.jhazmat.2020.122080
  1561. J Cell Mol Med. 2020 Jan 21.
    Dracorhodin perchlorate inhibits osteoclastogenesis through repressing RANKL-stimulated NFATc1 activity.
    Liu Y, Wang Z, Ma C, Wei Z, Chen K, Wang C, Zhou C, Chen L, Zhang Q, Chen Z, He W, Xu J.
      Osteolytic skeletal disorders are caused by an imbalance in the osteoclast and osteoblast function. Suppressing the differentiation and resorptive function of osteoclast is a key strategy for treating osteolytic diseases. Dracorhodin perchlorate (D.P), an active component from dragon blood resin, has been used for facilitating wound healing and anti-cancer treatments. In this study, we determined the effect of D.P on osteoclast differentiation and function. We have found that D.P inhibited RANKL-induced osteoclast formation and resorbed pits of hydroxyapatite-coated plate in a dose-dependent manner. D.P also disrupted the formation of intact actin-rich podosome structures in mature osteoclasts and inhibited osteoclast-specific gene and protein expressions. Further, D.P was able to suppress RANKL-activated JNK, NF-κB and Ca2+ signalling pathways and reduces the expression level of NFATc1 as well as the nucleus translocation of NFATc1. Overall, these results indicated a potential therapeutic effect of D.P on osteoclast-related conditions.
    Keywords:  dracorhodin perchlorate; nuclear factor of activated T cells 1; osteoclast; osteolysis; receptor-activated nuclear factor kappa-B ligand
    DOI:  https://doi.org/10.1111/jcmm.15003
  1562. Virus Res. 2020 Jan 20. pii: S0168-1702(19)30803-2. [Epub ahead of print] 197867
    Structural insights into NS5B protein of novel equine hepaciviruses and pegiviruses complexed with polymerase inhibitors.
    de Albuquerque PPLF, Santos LHS, Antunes D, Caffarena ER, Figueiredo AS.
      Infections produced by hepaciviruses have been associated with liver disease in horses. Currently, at least three viruses belonging to the Flaviviridae family are capable of producing a chronic infection in equines: non-primate hepacivirus (NPHV), Theiler's disease-associated virus (TDAV), and equine pegivirus (EPgV). The RNA-dependent RNA polymerases of viruses (RdRp) (NS5 protein), from the flavivirus family, use de novo RNA synthesis to initiate synthesis. The two antiviral drugs currently used to treat hepatitis C (HCV), sofosbuvir and dasabuvir, act on the viral NS5B polymerase as nucleoside and non-nucleoside inhibitors, respectively. Both drugs have shown significant clinical inhibition of viral response. In this work, we aimed to model the NS5B polymerase of the equine hepacivirus (EHCV) subtypes 1 and 2, TDAV and EPgV, to assess whether current direct-acting antiviral drugs against HCV interact with these proteins. Crystal structures of HCV-NS5B were used as templates for modeling target sequences in both conformations (open and closed). Also, molecular docking of sofosbuvir and dasabuvir were performed to predict their possible binding modes at the modeled NS5B polymerase binding sites. We observed that the NS5B models of the EHCV and EPgV shared well-conserved 3D structures to HCV-NS5B and other RdRps, suggesting functional conservation. Interactions of EHCV subtypes 1, 2 and TDAV polymerases with sofosbuvir showed a similar molecular interaction pattern compared to HCV-NS5B, while interactions with dasabuvir were less conserved. In silico studies of molecular interactions between these modeled structures and sofosbuvir suggest that this compound could be efficient in combating equine pathogens, thus contributing to animal welfare.
    Keywords:  NS5B; comparative modeling; hepacivirus; molecular docking; pegivirus; polymerase inhibitor
    DOI:  https://doi.org/10.1016/j.virusres.2020.197867
  1563. Int J Mol Sci. 2020 Jan 21. pii: E689. [Epub ahead of print]21(3):
    Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma.
    Pires-Afonso Y, Niclou SP, Michelucci A.
      Abstract: Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as 'cold tumours' with very little lymphocyte infiltration, they can contain up to 30-40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients.
    Keywords:  cellular heterogeneity; glioblastoma; immunotherapy; precision medicine; tumour-associated microglia/macrophages
    DOI:  https://doi.org/10.3390/ijms21030689
  1564. Circ Cardiovasc Imaging. 2020 Jan;13(1): e010410
    In This Issue of the Journal.
    Gropler RJ.
      
    DOI:  https://doi.org/10.1161/CIRCIMAGING.119.010410
  1565. Langmuir. 2020 Jan 19.
    Fluorescence Spectroscopy Analysis of the Bacteria-Mineral Interface: Adsorption of lipopolysaccharides to Silica and Alumina.
    Eltaboni FB, Caseley E, Katsikogianni M, Swanson L, Swift T, Romero-Gonzalez ME.
      We present here a quantification of the sorption process and molecular conformation involved in the attachment of bacterial cell wall lipopolysaccharides (LPS), extracted from Escherichia coli, to silica (SiO2) and alumina (Al2O3) particles. We propose that interfacial forces govern the physicochemical interactions of bacterial cell wall with minerals in the natural environment, and the molecular conformation of LPS cell wall components depends on both the local charge at the point of binding and hydrogen bonding potential. This has an effect on bacterial adaptation to the host environment through adhesion, growth, function and ability to form biofilms. Photophysical techniques were used to investigate adsorption of fluorescently-labelled LPS onto mineral surfaces as model systems for bacterial attachment. Adsorption of macromolecules in dilute solutions was studied as a function of pH and ionic strength in the presence of alumina and silica via fluorescence, potentiometric and mass spectrometry techniques. The effect of silica and alumina particles on bacterial growth as a function of pH was also investigated using spectrophotometry. The alumina and silica particles were used to mimic active sites on the surface of clay and soil particles, which serve as point of attachment of bacteria in natural systems. It was found that lipopolysaccharides had a high adsorption affinity for Al2O3 whilst adsorbing weakly to SiO2 surfaces. Strong adsorption was observed at low pH for both minerals and varied with both pH and mineral concentration, likely in part due to conformational rearrangement of the LPS macromolecule. Bacterial growth was also enhanced in the presence of the particles at low pH values. This demonstrates that at molecular level, bacterial cell wall components are able to adapt their conformation, depending on the solution pH, in order to maximize attachment to substrates and guarantee community survival.
    DOI:  https://doi.org/10.1021/acs.langmuir.9b02158
  1566. J Chromatogr A. 2019 Dec 09. pii: S0021-9673(19)31223-3. [Epub ahead of print] 460775
    Chemotyping and identification of protected Dalbergiatimber using gas chromatography quadrupole time of flight mass spectrometry.
    Shang D, Brunswick P, Yan J, Bruno J, Duchesne I, Isabel N, VanAggelen G, Kim M, Evans PD.
      The international trade in illegally logged and environmentally endangered timber has spurred enforcement agencies to seek additional technical procedures for the identification of wood species. All Dalbergia species are listed under the Convention on International Trade in Endangered Species (CITES) which is the reason this genus was chosen for study. Multiple sources of the heartwood from different Dalbergia species were extracted and chromatographic profiles collected by gas chromatography with high resolution quadrupole Time of Flight mass spectrometry (GC/QToF). The collected data was mined to select peaks and mass ions representative of the investigated Dalbergia species, and used to develop a Microsoft Excel® template offering immediate graphical representation of the results. Using wood specimens sourced from different xylaria, this graphical fingerprint proved adept at definitive identification of Dalbergia species. The CITES Appendix I species, D. nigra, was easily distinguished from D. melanoxylon and look-alike species of other genera. Similarly, a number of other Dalbergia species were differentiated using this current approach. Kernel discrimination analysis (KDA) was applied to increase the confidence of the species identification. The mislabeling of specimens appears to be common, and the emerging technique of GC/QToF in combination with other techniques, offers improved confidence in identification. GC/QToF further provides automation, the dimension of chromatography to avoid interferences, and production of reproducible electron impact positive (EI+) spectra. The prospect of building an EI+ spectral database for future wood identification is an important feature considering the limited accessibility of authenticated wood species specimens.
    Keywords:  Chemotyping; Dalbergia; GC/QToF; Identification; Illegal logging; Rosewood
    DOI:  https://doi.org/10.1016/j.chroma.2019.460775
  1567. Nature. 2020 Jan;577(7791): 470-471
    Paris taught me how to do what is necessary to combat climate change.
    Figueres C.
      
    Keywords:  Climate sciences; Policy
    DOI:  https://doi.org/10.1038/d41586-020-00112-6
  1568. Data Brief. 2020 Feb;28 105092
    Data on the recovery of glycinergic neurons after spinal cord injury in lampreys.
    Valle-Maroto SM, Barreiro-Iglesias A, Fernández-López B, Rodicio MC.
      We used immunohistochemical methods to quantify changes in the number of glycine-immunoreactive neurons of the dorsomedial, lateral and cerebrospinal fluid contacting cell populations of the spinal cord of larval sea lampreys after a complete spinal cord injury. The data presented here are quantifications of the number of glycine-immunoreactive neurons located in the rostral and caudal stumps of the spinal cord and the corresponding statistical analyses. These data show that, glycine immunoreactivity is lost in glycinergic neurons immediately after injury and that the number of glycine-immunoreactive neurons is recovered in the following two weeks. These data are useful for researchers investigating determinants that underlie the spontaneous recovery of locomotion following spinal injuries in regenerating animal models, and for analysing the role of glycinergic neurons in spinal cord repair after an injury.
    Keywords:  Central nervous system repair; Glycine; Neuronal regeneration; Neurotransmitter; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.dib.2019.105092
  1569. Nature. 2020 Jan;577(7791): 452
    How hummingbirds garb themselves in rainbow hues.
      
    Keywords:  Evolution
    DOI:  https://doi.org/10.1038/d41586-020-00073-w
  1570. Int J Cancer. 2020 Jan 19.
    FGF13 promotes metastasis of triple-negative breast cancer.
    Johnstone CN, Pattison AD, Harrison PF, Powell DR, Lock P, Ernst M, Anderson RL, Beilharz TH.
      Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes, due to the high propensity to develop distant metastases. Hence, new molecular targets for therapeutic intervention are needed for TNBC. We recently conducted a rigorous phenotypic and genomic characterization of four isogenic populations of MDA-MB-231 human triple-negative breast cancer cells that possess a range of intrinsic spontaneous metastatic capacities in vivo, ranging from non-metastatic (MDA-MB-231_ATCC) to highly metastatic to lung, liver, spleen and spine (MDA-MB-231_HM). Gene expression profiling of primary tumours by RNA-Seq identified the fibroblast growth factor homologous factor, FGF13, as highly upregulated in aggressively metastatic MDA-MB-231_HM tumours. Clinically, higher FGF13 mRNA expression was associated with significantly worse relapse free survival in both luminal A and basal-like human breast cancers but was not associated with other clinical variables and was not upregulated in primary tumours relative to normal mammary gland. Stable FGF13 depletion restricted in vitro colony forming ability in MDA-MB-231_HM TNBC cells but not in oestrogen receptor (ER) positive MCF-7 or MDA-MB-361 cells. However, despite augmenting MDA-MB-231_HM cell migration and invasion in vitro, FGF13 suppression almost completely blocked the spontaneous metastasis of MDA-MB-231_HM orthotopic xenografts to both lung and liver while having negligible impact on primary tumour growth. Together, these data indicate that FGF13 may represent a therapeutic target for blocking metastatic outgrowth of certain TNBCs. Further evaluation of the roles of individual FGF13 protein isoforms in progression of the different subtypes of breast cancer is warranted. This article is protected by copyright. All rights reserved.
    Keywords:  FGF13; metastasis; mouse model; triple-negative breast cancer; xenograft
    DOI:  https://doi.org/10.1002/ijc.32874
  1571. Sensors (Basel). 2020 Jan 22. pii: E605. [Epub ahead of print]20(3):
    A Digital Signal Processor Based Acoustic Sensor for Outdoor Noise Monitoring in Smart Cities.
    López JM, Alonso J, Asensio C, Pavón I, Gascó L, de Arcas G.
      Presently, large cities have significant problems with noise pollution due to human activity. Transportation, economic activities, and leisure activities have an important impact on noise pollution. Acoustic noise monitoring must be done with equipment of high quality. Thus, long-term noise monitoring is a high-cost activity for administrations. For this reason, new alternative technological solutions are being used to reduce the costs of measurement instruments. This article presents a design for a versatile electronic device to measure outdoor noise. This device has been designed according to the technical standards for this type of instrument, which impose strict requirements on both the design and the quality of the device's measurements. This instrument has been designed under the original equipment manufacturer (OEM) concept, so the microphone-electronics set can be used as a sensor that can be connected to any microprocessor-based device, and therefore can be easily attached to a monitoring network. To validate the instrument's design, the device has been tested following the regulations of the calibration laboratories for sound level meters (SLM). These tests allowed us to evaluate the behavior of the electronics and the microphone, obtaining different results for these two elements. The results show that the electronics and algorithms implemented fully fit within the requirements of type 1 noise measurement instruments. However, the use of an electret microphone reduces the technical features of the designed instrument, which can only fully fit the requirements of type 2 noise measurement instruments. This situation shows that the microphone is a key element in this kind of instrument and an important element in the overall price. To test the instrument's quality and show how it can be used for monitoring noise in smart wireless acoustic sensor networks, the designed equipment was connected to a commercial microprocessor board and inserted into the infrastructure of an existing outdoor monitoring network. This allowed us to deploy a low-cost sub-network in the city of Málaga (Spain) to analyze the noise of conflict areas due to high levels of leisure noise. The results obtained with this equipment are also shown. It has been verified that this equipment meets the similar requirements to those obtained for type 2 instruments for measuring outdoor noise. The designed equipment is a two-channel instrument, that simultaneously measures, in real time, 86 sound noise parameters for each channel, such as the equivalent continuous sound level (Leq) (with Z, C, and A frequency weighting), the peak level (with Z, C, and A frequency weighting), the maximum and minimum levels (with Z, C, and A frequency weighting), and the impulse, fast, and slow time weighting; seven percentiles (1%, 5%, 10%, 50%, 90%, 95%, and 99%); as well as continuous equivalent sound pressure levels in the one-third octave and octave frequency bands.
    Keywords:  digital signal processing; multirate filters; outdoors noise; sound level meter
    DOI:  https://doi.org/10.3390/s20030605
  1572. J Neurol Sci. 2020 Jan 13. pii: S0022-510X(20)30017-4. [Epub ahead of print]410 116681
    Complex pathophysiology of non-ketotic hyperglycemic chorea-ballism with atypical findings on brain magnetic resonance imaging.
    Choi HY, Kim YS, Shin HW.
      
    DOI:  https://doi.org/10.1016/j.jns.2020.116681
  1573. Cells. 2020 Jan 16. pii: E222. [Epub ahead of print]9(1):
    Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells.
    Kuznetsov AV, Javadov S, Grimm M, Margreiter R, Ausserlechner MJ, Hagenbuchner J.
      Elucidation of the mitochondrial regulatory mechanisms for the understanding of muscle bioenergetics and the role of mitochondria is a fundamental problem in cellular physiology and pathophysiology. The cytoskeleton (microtubules, intermediate filaments, microfilaments) plays a central role in the maintenance of mitochondrial shape, location, and motility. In addition, numerous interactions between cytoskeletal proteins and mitochondria can actively participate in the regulation of mitochondrial respiration and oxidative phosphorylation. In cardiac and skeletal muscles, mitochondrial positions are tightly fixed, providing their regular arrangement and numerous interactions with other cellular structures such as sarcoplasmic reticulum and cytoskeleton. This can involve association of cytoskeletal proteins with voltage-dependent anion channel (VDAC), thereby, governing the permeability of the outer mitochondrial membrane (OMM) to metabolites, and regulating cell energy metabolism. Cardiomyocytes and myocardial fibers demonstrate regular arrangement of tubulin beta-II isoform entirely co-localized with mitochondria, in contrast to other isoforms of tubulin. This observation suggests the participation of tubulin beta-II in the regulation of OMM permeability through interaction with VDAC. The OMM permeability is also regulated by the specific isoform of cytolinker protein plectin. This review summarizes and discusses previous studies on the role of cytoskeletal proteins in the regulation of energy metabolism and mitochondrial function, adenosine triphosphate (ATP) production, and energy transfer.
    Keywords:  cytoskeletal proteins; energy metabolism; heart; mitochondria; mitochondrial interactions; plectin; signaling; tubulin beta
    DOI:  https://doi.org/10.3390/cells9010222
  1574. World Neurosurg. 2020 Jan 16. pii: S1878-8750(20)30069-3. [Epub ahead of print]
    Perioperative Outcomes of Spinal Cord Stimulator Placement in Patients with Complex Regional Pain Syndrome (CRPS) Compared to Patients Without CRPS.
    Martini ML, Caridi JM, Zeldin L, Neifert SN, Nistal DA, Kim JD, Khelemsky Y, Gal JS.
      
    Keywords:  Complex Regional Pain Syndrome; Intraoperative Outcomes; Numeric Rating Scale; Opioid Use; Perioperative Outcomes; Resource Utilization; Spinal Cord Stimulation
    DOI:  https://doi.org/10.1016/j.wneu.2020.01.061
  1575. Br J Anaesth. 2020 Jan 21. pii: S0007-0912(19)30965-1. [Epub ahead of print]
    Sarah Joyce O'Malley, Irish anaesthetist (1896-1959).
    O'Brien K, O'Brien B.
      
    Keywords:  Association of Anaesthetists of the United Kingdom; Leadership; anaesthesia; history; women in medicine
    DOI:  https://doi.org/10.1016/j.bja.2019.12.007
  1576. Radiat Oncol. 2020 Jan 20. 15(1): 18
    Squamous cell carcinoma (SCC) of the Pyriform sinus with multiple metachronous brain metastases, a case report.
    Cristaudo A, Stefanelli A, Ursino S, Delishaj D, Baldaccini D, Gonnelli A, Paiar F.
      BACKGROUND: Distant Metastases from Head and Neck Squamous cell carcinomas are uncommon (9-11%) and they are usually found in the lung and less frequently in the liver, kidney and adrenals. Central nervous system (CNS) metastases are extremely rare (2-8%), and they are described mainly in patients who already have extracranial metastases. So there's scarcity of data about their optimal management .METHODS AND RESULTS: A patient presented CNS metastases after having been successfully treated with induction chemotherapy and definitive radiotherapy for a pyriform sinus carcinoma. The patient's work up, treatment and outcome are described.
    CONCLUSIONS: CNS metastases from Head and Neck carcinomas are exceptionally rare. Nevertheless, clinicians should be alert of neurological symptoms in these patients, in order to set up a timely assessment and treatment. Secondarily, given the rarity of this condition, additional research on this topic is warranted in order to improve therapeutic strategies and outcomes of such patients.
    Keywords:  Brain; Head and neck carcinoma; Metastases; Radiotherapy
    DOI:  https://doi.org/10.1186/s13014-020-1472-0
  1577. Eur J Oncol Nurs. 2019 Dec 26. pii: S1462-3889(19)30188-7. [Epub ahead of print]44 101720
    Exploring the impact of lymphoedema on individuals and if lymphatic venous anastomosis surgery effects perceptions on quality of life: A qualitative study.
    Thomas M, Coveney E, Pike C, Morgan K, Noble-Jones R.
      PURPOSE: Lymphoedema is a chronic condition, a cancer consequence and causes physical, psychological, and social implications. A new super-micro surgical treatment Lymphatic Venous Anastomosis (LVA) may improve the symptoms of lymphoedema. This study aims to explore the impact of lymphoedema on individuals and if LVA Surgery changes perceptions on quality of life.METHOD: Semi-structured interviews were conducted with sixteen individual's pre-LVA surgery and repeated six months later post-LVA with ten of the participants. Transcripts were analysed using thematic analysis.
    RESULTS: Themes identified pre-LVA included: Impact of Living with Lymphoedema, Being Different, and Future Hopes and Emotions. Participants reported making significant changes to 'normal' life due to living with lymphoedema. Changes included alteration in shopping, cleaning, hobbies, familial roles, employment and sexual intimacy. The wearing of compression garments engendered feelings of being unattractive. Themes found post-LVA were: I am one of the Lucky Ones and Returning to Former Self. Post-LVA, participants described how life had become more normalised with fear and apprehension of developing cellulitis reduced. Positive changes had enabled usual activities of daily living to recommence. Some participants had decreased pain, aching, heaviness, stiffness and were wearing their compression garments less.
    CONCLUSION: The findings suggest that the real impact of living with lymphoedema is much more challenging than previously identified. The findings suggest that LVA can give a future of greater choice for some of its recipients, but further research should explore longer-term benefits. LVA could offer hope to some people with lymphoedema, but a realistic expectation is essential.
    Keywords:  Adjustments; Cancer consequences; Hope; Lymphatic venous anastomosis; Lymphoedema; Quality of life; Survivorship
    DOI:  https://doi.org/10.1016/j.ejon.2019.101720
  1578. Heart Vessels. 2020 Jan 20.
    Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics.
    Ahmed S, Ahmed A, Säleby J, Bouzina H, Lundgren J, Rådegran G.
      Receptor tyrosine kinases (RTKs) are implicated in cardiovascular growth and remodelling. We aimed to identify the plasma levels of RTKs and related proteins and their association with haemodynamic alterations in heart failure (HF) and related pulmonary hypertension (PH) following heart transplantation (HT). Using proximity extension assay, 28 RTKs and related proteins were analysed in plasma from 20 healthy controls and 26 HF patients before and 1-year after HT. In end-stage HF, out of 28 RTKs, plasma vascular endothelial growth factor-D (VEGF-D) and human epidermal growth factor-4 (HER4) were elevated compared to controls (p < 0.001), but decreased (p < 0.0001) and normalised after HT. Following HT, plasma changes (Δ) of VEGF-D correlated with Δmean pulmonary artery pressure (rs = 0.65, p = 0.00049), Δpulmonary artery wedge pressure (rs = 0.72, p < 0.0001), Δpulmonary arterial compliance (PAC) (rs = - 0.52, p = 0.0083) and Δpulmonary vascular resistance (PVR) (rs = 0.58, p = 0.0032). ΔHER4 correlated with Δmean right atrial pressure (rs = 0.51, p = 0.012), ΔNT-proBNP (rs = 0.48, p = 0.016) and Δcardiac index (rs = - 0.56, p = 0.0044). In HF patients following HT, normalisation of VEGF-D reflected reversal of passive pulmonary congestion and restored PAC and PVR; whereas the normalisation of HER4 reflected decreased volume overload and improved cardiac function. The precise function of these proteins, their potential clinical use and pathophysiological relation in HF and related PH remain to be elucidated.
    Keywords:  Haemodynamics; Heart failure; Heart transplantation; Pulmonary hypertension; Receptor protein-tyrosine kinases
    DOI:  https://doi.org/10.1007/s00380-019-01548-1
  1579. Cancers (Basel). 2020 Jan 22. pii: E267. [Epub ahead of print]12(2):
    Trans-Mucosal Efficacy of Non-Thermal Plasma Treatment on Cervical Cancer Tissue and Human Cervix Uteri by a Next Generation Electrosurgical Argon Plasma Device.
    Wenzel T, Carvajal Berrio DA, Reisenauer C, Layland S, Koch A, Wallwiener D, Brucker SY, Schenke-Layland K, Brauchle EM, Weiss M.
      Non-invasive physical plasma (NIPP) generated by non-thermally operated electrosurgical argon plasma sources is a promising treatment for local chronic inflammatory, precancerous and cancerous diseases. NIPP-enabling plasma sources are highly available and medically approved. The purpose of this study is the investigation of the effects of non-thermal NIPP on cancer cell proliferation, viability and apoptosis and the identification of the underlying biochemical and molecular modes of action. For this, cervical cancer (CC) single cells and healthy human cervical tissue were analyzed by cell counting, caspase activity assays, microscopic and flow-cytometric viability measurements and molecular tissue characterization using Raman imaging. NIPP treatment caused an immediate and persisting decrease in CC cell growth and cell viability associated with significant plasma-dependent effects on lipid structures. These effects could also be identified in primary cells from healthy cervical tissue and could be traced into the basal cell layer of superficially NIPP-treated cervical mucosa. This study shows that NIPP treatment with non-thermally operated electrosurgical argon plasma devices is a promising method for the treatment of human mucosa, inducing specific molecular changes in cells.
    Keywords:  Plasma lipid interactions; Raman imaging; Raman microspectroscopy; cervical intraepithelial neoplasia (CIN); non-invasive plasma treatment (NIPP); non-thermal plasma; tissue penetration
    DOI:  https://doi.org/10.3390/cancers12020267
  1580. J Dairy Sci. 2020 Jan 15. pii: S0022-0302(20)30020-5. [Epub ahead of print]
    Effects of jugular infused methionine, lysine, and histidine as a group or leucine and isoleucine as a group on production and metabolism in lactating dairy cows.
    Yoder PS, Huang X, Teixeira IA, Cant JP, Hanigan MD.
      Essential AA (EAA), particularly leucine, isoleucine, methionine, and histidine, possess signaling properties for promoting cellular anabolic metabolism, whereas methionine, lysine, and histidine are considered also to be substrate limiting AA. The objective of this study was to evaluate production responses to supplementation of 2 AA groups in a 2 × 2 factorial design. Eight cows (99 ± 18 days in milk) were assigned to 4 jugular infusion treatments consisting of saline (CON), methionine plus lysine plus histidine (MKH), isoleucine plus leucine (IL), or MKH plus IL, in a replicated 4 × 4 Latin square design. Periods were 18 d in length, comprising 8 d of rest followed by 10 d of jugular infusion. Daily infusion amounts were 21 g of methionine, 38 g of lysine, 20 g of histidine, 50 g of leucine, and 22 g of isoleucine. Cows were ad libitum fed a common diet consisting of 15.2% crude protein and 1.61 Mcal/kg NEL on a dry matter basis that was predicted to meet rumen degradable protein requirements but was 15% deficient in metabolizable protein. Milk and energy-corrected milk yields increased by 2.3 kg/d and 1.9 kg/d, respectively, with infused IL, and no change was observed for MKH. Milk protein concentration increased by 0.13 percentage units for MKH, whereas milk protein yield increased for both MKH and IL by 84 g/d and 64 g/d, respectively. The milk protein yield increase for MKH+IL was 145 g/d versus CON. Gross feed efficiency tended to increase with IL infusion, and N efficiency tended to increase with MKH infusion. Aggregate arterial EAA concentrations less Met, Lys, and His declined by 7.2% in response to MKH infusion. Arterial EAA less Ile and Leu also declined by 6.2% in response to IL infusion. Net total AA (TAA) and EAA uptake by the udder tended to increase in response to MKH infusion, whereas mammary blood flow increased in response to IL infusion, but TAA and EAA net uptakes were unaffected. Apparent udder affinity increased for TAA and EAA less Met, Lys, and His in response to MKH infusion, whereas affinity for EAA less Ile and Leu increased for IL infusion. Venous Met and Leu concentrations increased by 192% and 35% from the MKH and IL infusions, respectively, compared with CON, which indicates that intracellular concentration of these EAA changed substantially. Increases in milk protein yield were observed from 2 groups of amino acids independently and additively, which contradicts the single limiting amino acid theory that a single EAA will limit milk protein yield.
    Keywords:  histidine; isoleucine; leucine; lysine; methionine; milk protein
    DOI:  https://doi.org/10.3168/jds.2019-17082
  1581. Cell Death Dis. 2020 Jan 24. 11(1): 62
    GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress.
    Plana-Bonamaisó A, López-Begines S, Andilla J, Fidalgo MJ, Loza-Alvarez P, Estanyol JM, Villa P, Méndez A.
      Loss-of-function mutations in the retinal degeneration 3 (RD3) gene cause inherited retinopathy with impaired rod and cone function and fast retinal degeneration in patients and in the natural strain of rd3 mice. The underlying physiopathology mechanisms are not well understood. We previously proposed that guanylate cyclase-activating proteins (GCAPs) might be key Ca2+-sensors mediating the physiopathology of this disorder, based on the demonstrated toxicity of GCAP2 when blocked in its Ca2+-free form at photoreceptor inner segments. We here show that the retinal degeneration in rd3 mice is substantially delayed by GCAPs ablation. While the number of retinal photoreceptor cells is halved in 6 weeks in rd3 mice, it takes 8 months to halve in rd3/rd3 GCAPs-/- mice. Although this substantial morphological rescue does not correlate with recovery of visual function due to very diminished guanylate cyclase activity in rd3 mice, it is very informative of the mechanisms underlying photoreceptor cell death. By showing that GCAP2 is mostly in its Ca2+-free-phosphorylated state in rd3 mice, we infer that the [Ca2+]i at rod inner segments is permanently low. GCAPs are therefore retained at the inner segment in their Ca2+-free, guanylate cyclase activator state. We show that in this conformational state GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. ER stress and mitochondrial swelling are early hallmarks of rd3 retinas preceding photoreceptor cell death, that are substantially rescued by GCAPs ablation. By revealing the involvement of GCAPs-induced ER stress in the physiopathology of Leber's congenital amaurosis 12 (LCA12), this work will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision.
    DOI:  https://doi.org/10.1038/s41419-020-2255-0
  1582. Biom J. 2020 Jan 20.
    Smoothed empirical likelihood inference for ROC curve in the presence of missing biomarker values.
    Cheng W, Tang N.
      This paper considers statistical inference for the receiver operating characteristic (ROC) curve in the presence of missing biomarker values by utilizing estimating equations (EEs) together with smoothed empirical likelihood (SEL). Three approaches are developed to estimate ROC curve and construct its SEL-based confidence intervals based on the kernel-assisted EE imputation, multiple imputation, and hybrid imputation combining the inverse probability weighted imputation and multiple imputation. Under some regularity conditions, we show asymptotic properties of the proposed maximum SEL estimators for ROC curve. Simulation studies are conducted to investigate the performance of the proposed SEL approaches. An example is illustrated by the proposed methodologies. Empirical results show that the hybrid imputation method behaves better than the kernel-assisted and multiple imputation methods, and the proposed three SEL methods outperform existing nonparametric method.
    Keywords:  ROC curve; empirical likelihood; estimating equations; imputation; inverse probability weighted; missing at random
    DOI:  https://doi.org/10.1002/bimj.201900121
  1583. Acc Chem Res. 2020 Jan 22.
    Poly(peptide): Synthesis, Structure, and Function of Peptide-Polymer Amphiphiles and Protein-like Polymers.
    Callmann CE, Thompson MP, Gianneschi NC.
      In this Account, we describe the organization of functional peptides as densely arrayed side chains on polymer scaffolds which we introduce as a new class of material called poly(peptide). We describe two general classes of poly(peptide): (1) Peptide-Polymer Amphiphiles (PPAs), which consist of block copolymers with a dense grouping of peptides arrayed as the side chains of the hydrophilic block and connected to a hydrophobic block that drives micelle assembly, and (2) Protein-like Polymers (PLPs), wherein peptide-brush polymers are composed from monomers, each containing a peptide side chain. Peptides organized in this manner imbue polymers or polymeric nanoparticles with a range of functional qualities inherent to their specific sequence. Therefore, polymers or nanoparticles otherwise lacking bioactivity or responsiveness to stimuli, once linked to a peptide of choice, can now bind proteins, enter cells and tissues, have controlled and switchable biodistribution patterns, and be enzyme substrates (e.g., for kinases, phosphatases, proteases). Indeed, where peptide substrates are incorporated, kinetically or thermodynamically driven morphological transitions can be enzymatically induced in the polymeric material. Synergistically, the polymer enforces changes in peptide activity and function by virtue of packing and constraining the peptide. The scaffold can protect peptides from proteolysis, change the pharmacokinetic profile of an intravenously injected peptide, increase the cellular uptake of an otherwise cell impermeable therapeutic peptide, or change peptide substrate activity entirely. Moreover, in addition to the sequence-controlled peptides (generated by solid phase synthesis), the polymer can carry its own sequence-dependent information, especially through living polymerization strategies allowing well-defined blocks and terminal labels (e.g., dyes, contrast agents, charged moieties). Hence, the two elements, peptide and polymer, cooperate to yield materials with unique function and properties quite apart from each alone. Herein, we describe the development of synthetic strategies for accessing these classes of biomolecule polymer conjugates. We discuss the utility of poly(peptide)-based materials in a range of biomedical applications, including imaging of diseased tissues (myocardial infarction and cancer), delivering small molecule drugs to tumors with high specificity, imparting cell permeability to otherwise impermeable peptides, protecting bioactive peptides from proteolysis in harsh conditions (e.g., stomach acid and whole blood), and transporting proteins into traditionally difficult-to-transfect cell types, including stem cells. Poly(peptide) materials offer new properties to both the constituent peptides and to the polymers, which can be tuned by the design of the oligopeptide sequence, degree of polymerization, peptide arrangement on the polymer backbone, and polymer backbone chemistry. These properties establish this approach as valuable for the development of peptides as medicines and materials in a range of settings.
    DOI:  https://doi.org/10.1021/acs.accounts.9b00518
  1584. Drug Metab Pharmacokinet. 2019 Dec 26. pii: S1347-4367(19)30240-X. [Epub ahead of print]
    Cloning and tissue expression of cytochrome P450 2S1, 4V2, 7A1, 7B1, 8B1, 24A1, 26A1, 26C1, 27A1, 39A1, and 51A1 in marmosets.
    Uehara S, Uno Y, Inoue T, Sasaki E, Yamazaki H.
      Common marmoset (Callithrix jacchus) is an attractive animal model primate species for potential use in drug metabolism and pharmacokinetic studies. In this study, marmoset cytochrome P450 (P450) 2S1, 4V2, 7A1, 7B1, 8B1, 24A1, 26A1, 26C1, 27A1, 39A1, and 51A1 cDNAs were isolated from marmoset tissues (brains, lungs, livers, kidneys, and jejunums). Deduced amino acid sequences (89-98% homologous) of the marmoset P450 gene suggested similarity of molecular characteristics of marmoset P450s to human counterparts, compared with those of pig, rabbit, and rodents. Phylogenetic analysis using amino acid sequences indicated 11 marmoset P450 forms clustered with those of human and other primate counterparts, suggesting marmoset P450s have an evolutionary close relationship to human and other primate counterparts. Tissue expression patterns of these P450 mRNAs except for P450 7B1 mRNA were generally similar to those of human P450s in the five tissue types analyzed. These results suggest similarity of molecular characteristics for P450 2S1, 4V2, 7A1, 7B1, 8B1, 24A1, 26A1, 26C1, 27A1, 39A1, and 51A1 between marmosets and humans, in addition to the orthologs of human P450 1, 2, 3, and 4 families previously identified and characterized in marmosets.
    Keywords:  Cytochrome P450; Deduced amino acid sequence; Marmoset; Tissue distribution pattern
    DOI:  https://doi.org/10.1016/j.dmpk.2019.11.008
  1585. J Exp Clin Cancer Res. 2020 Jan 21. 39(1): 19
    Correction to: Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC).
    Lu YF, Yu JR, Yang Z, Zhu GX, Gao P, Wang H, Chen SY, Zhang J, Liu MY, Niu Y, Wei XM, Wang W, Ye FJ, Zhang LX, Zhao Y, Sun GG.
      In the original publication of this manuscript [1], Fig. 6 contains a repeated image in error (the left image of 'Migration' and the left image of 'Invasion').
    DOI:  https://doi.org/10.1186/s13046-020-1525-0
  1586. J Pak Med Assoc. 2020 Jan;70(1): 190-191
    Radiation induced Wallerian degeneration of corticospinal tract in a case of brain tumour.
    Aleem J, Farooq H, Niazi IK.
      
  1587. Int J Food Microbiol. 2020 Jan 13. pii: S0168-1605(20)30017-9. [Epub ahead of print] 108523
    Genome based safety assessment for Bacillus coagulans strain LBSC (DSM 17654) for probiotic application.
    Saroj DB, Gupta AK.
      The present study on Bacillus coagulans strain LBSC (DSM 17654) describes the use of whole genome sequencing, in correlation with the phenotypic properties to assess the safety of the strain. Analysis of the 16S rRNA sequence of the B. coagulans strain LBSC (DSM 17654), showed 100% homology with 99% coverage with B. coagulans strain HM-08. BLAT (BLAST Like Analysis Tool) analysis for whole genome comparison with B. coagulans ATCC 7050, B. coagulans HM-08 and B. coagulans Slac showed 96%, 99% and 99% sequence identity respectively. Whole genome sequencing results demonstrated a single scaffold of 36,35,902 bp and 3331 coding sequences. Gene ontology segregated the proteins as those with molecular function, cellular component and biological process of the predicted genes from assembled genome. Risk associated sequences like antibiotic resistance genes, biogenic amine producing genes, virulence factor genes and other safety related genes were identified with focus on horizontal gene transfer and its non-functionality. The absence of mobile elements in the vicinity of the genes, render it non-transferable and non-toxic phenotypic properties confirm the non-functionality of the genes. Absence of functional genes of concern and confirmation of absence of mobile elements in the vicinity of other non-clinically significant genes indicated no safety concern. The absence of complete and functional prophage sequences which are deleterious for the genome stability and presence of CRISPR system which are advantageous for genome stability by acting as a barrier to entry of foreign DNA elements indicated the stability of the genome. The molecular approach used in this study satisfies the requirements for the safety assessment of the probiotic strain which could indicate it to be potentially safe.
    Keywords:  Antibiotic resistance; Genome sequence; Genome stability; Taxonomy; Virulence factors
    DOI:  https://doi.org/10.1016/j.ijfoodmicro.2020.108523
  1588. ACS Chem Neurosci. 2020 Jan 22.
    Expression of Oatp2 in the Brain and Liver of Alzheimer Disease Mouse Model.
    Wen J, Zhao M, Liu L.
      The purpose of this study was to explore the expression of Oatp2 transporter in the liver and brain of Alzheimer's disease (AD) mice. The results showed that the protein expression of Oatp2 in the brain significantly decreased in Alzheimer disease mice. On the contrary, protein expression of Oatp2 in liver tissue of AD mice was significantly higher compared with that in normal mice. For mRNA expression of Oatp2, the results showed that, compared with normal mice, it was significantly lower in the brain but significantly higher in liver tissue. Based on the current research, we cannot confirm the relationship between Oatp2 expression and Alzheimer disease. However, it may be a very novel and interesting discovery and may become a new target for the pathogenesis, drug development, and treatment of AD.
    Keywords:  Alzheimer’s disease; Oatp2; brain; liver
    DOI:  https://doi.org/10.1021/acschemneuro.9b00636
  1589. Nat Commun. 2020 Jan 20. 11(1): 380
    Emergence of chirality and structural complexity in single crystals at the molecular and morphological levels.
    di Gregorio MC, Shimon LJW, Brumfeld V, Houben L, Lahav M, van der Boom ME.
      Naturally occurring single crystals having a multidomain morphology are a counterintuitive phenonomon: the macroscopic appearance is expected to follow the symmetry of the unit cell. Growing such crystals in the lab is a great challenge, especially from organic molecules. We achieve here uniform metallo-organic crystals that exhibit single crystallinity with apparently distinct domains and chirality. The chirality is present at both the molecular and macroscopic levels, although only achiral elements are used. "Yo-yo"-like structures having opposite helical handedness evolve from initially formed seemingly achiral cylinders. This non-polyhedral morphology coexists with a continuous coordination network forming homochiral channels. This work sheds light on the enigmatic aspects of fascinating crystallization processes occurring in biological mineralization. Our findings open up opportunities to generate new porous and hierarchical chiral materials.
    DOI:  https://doi.org/10.1038/s41467-019-13925-5
  1590. Front Oncol. 2019 ;9 1452
    Association Between the Microsatellite Instability Status and the Efficacy of Postoperative Adjuvant Chemoradiotherapy in Patients With Gastric Cancer.
    Dai D, Zhao X, Li X, Shu Y, Shen B, Chen X, Chen D, Wang D.
      Purpose: The effect of microsatellite instability (MSI) on the response to radiotherapy remains unknown. The aim of this study was to investigate the association between the MSI status and the outcomes of gastric cancer (GC) treated by surgical resection with or without postoperative adjuvant chemoradiotherapy. Methods: The records of patients who underwent surgical resection of stage IB-III GC with or without postoperative adjuvant chemoradiotherapy were retrospectively retrieved from the Affiliated Hospital of Jiangsu University (n = 89), The Cancer Genome Atlas (n = 202), and the Asian Cancer Research Group (n = 138). The primary endpoint was overall survival (OS). Results: The MSI status had no significant influence on OS in all cohorts. Compared with surgery alone, adjuvant chemoradiotherapy improved or tended to improve OS of patients with stage III disease, irrespective of the MSI status, in all cohorts. Among patients with stage Ib/II disease, only those with microsatellite stability (MSS) benefited from chemoradiotherapy in terms of OS, whereas those with MSI showed no improvement in OS. A comparison of gene expression profiles between MSI stage Ib/II GC and MSS stage Ib/II GC revealed that MSI correlated with the overexpression of thymidylate synthetase, a marker of fluoropyrimidine resistance. Furthermore, tumor hypoxia scoring for stage Ib/II lesions showed significantly greater hypoxia in MSI tumors than in MSS tumors. Conclusions: The findings of this study suggest that postoperative adjuvant chemoradiotherapy is effective for stage III GC, regardless of the MSI status. However, MSI may predict a poor response to postoperative adjuvant chemoradiotherapy in patients with stage Ib/II GC.
    Keywords:  adjuvant therapy; chemoradiotherapy; gastric cancer; microsatellite instability; tumor hypoxia
    DOI:  https://doi.org/10.3389/fonc.2019.01452
  1591. Eur J Paediatr Neurol. 2020 Jan 07. pii: S1090-3798(20)30002-7. [Epub ahead of print]
    Use of eye tracking in girls with Rett syndrome.
    Schwartzman JS, Xavier JS, Arvigo MC, Barbosa LK.
      
    DOI:  https://doi.org/10.1016/j.ejpn.2020.01.001
  1592. Curr Dev Nutr. 2020 Feb;4(2): nzz143
    Urban Egyptian Women Aged 19-30 Years Display Nutrition Transition-Like Dietary Patterns, with High Energy and Sodium Intakes, and Insufficient Iron, Vitamin D, and Folate Intakes.
    Brouzes CMC, Darcel N, Tomé D, Dao MC, Bourdet-Sicard R, Holmes BA, Lluch A.
      Background: Recent changes in Egyptian dietary habits can be attributed to more urban and sedentary lifestyles and to alterations in the dietary and economic context. The mean BMI of Egyptian women is one of the highest worldwide, and 50% have iron deficiency.Objective: The aim was to quantify food and nutrient intakes of urban Egyptian women and conduct a detailed analysis of micronutrients commonly consumed in inadequate amounts, such as iron, vitamin D, and folate.
    Methods: Urban Egyptian women aged 19-30 y (n = 130) were recruited during 2016-2017. Energy needs were estimated using the Henry equation, assuming a low physical activity level (1.4). Dietary intakes and iron bioavailability were estimated from a 4-d food diary. Macronutrient intakes were compared with WHO/FAO population goals and micronutrient intakes with Egyptian recommendations. Iron needs were determined for each subject.
    Results: The mean BMI (kg/m2) was 27.9 ± 4.9. The mean total energy intake (TEI; 2389 ± 715 kcal/d) was significantly higher than needs (2135 ± 237 kcal/d; P = 0.00018). Total fat (33%TEI) and SFA (11%TEI) intakes were slightly higher than population goals (15-30%TEI and <10%TEI, respectively). Diets provided 18 ± 8 g/d of fiber, 98 ± 54 g/d of total sugars, and nearly twice the recommended sodium intake (intake: 2787 ± 1065 mg/d; recommendation: <1500 mg/d). Estimated dietary iron bioavailability was low (9.2% ± 1.6%), and 79% of women consumed less iron than the average requirement (17.5 ± 7 mg/d). Overall, 82% and 80% of women consumed less vitamin D and folate, respectively, than recommended.
    Conclusions: Egyptian women aged 19-30 y have high intakes of energy and sodium, whereas iron, vitamin D, and folate intakes are insufficient, with only low concentrations of bioavailable iron. These results call for further investigation into measures that would improve this population's diet quality.
    Keywords:  Egypt; bioavailability; diet; iron; malnutrition; nutrition; transition; women
    DOI:  https://doi.org/10.1093/cdn/nzz143
  1593. Hawaii J Health Soc Welf. 2020 Jan;79(1): 28-30
    Social Work in Action: How the Hawai'i CARES Program Aims to Strengthen Addiction Treatment Through a Social Work Lens.
    Bersamira C, Robertson T, Sabagala AP.
      
  1594. Foods. 2020 Jan 23. pii: E120. [Epub ahead of print]9(2):
    Identification and Characterization of Non-Saccharomyces Species Isolated from Port Wine Spontaneous Fermentations.
    Mateus D, Sousa S, Coimbra C, S Rogerson F, Simões J.
      In winemaking, non-Saccharomyces yeast species contribute important organoleptic complexity. Current interest focuses on abundant and dominant strains characteristically present in the early phase of spontaneous alcoholic fermentations. Non-Saccharomyces species are particularly relevant in Port wine production such that the fermentation is prematurely stopped, after the metabolism of only one half of the available sugar, through fortification with aguardente. This work aimed to isolate, identify and characterize non-Saccharomyces species present in spontaneously fermenting Port. To accomplish these goals, yeasts were isolated from a selection of frozen must samples (2012-2016 harvests), using a pre-screening process choosing only the best candidates based on the organoleptic quality of the corresponding fortified wine. From five hundred non-Saccharomyces isolates, twelve species were identified. The three most abundant species, Hanseniaspora uvarum, Lachancea thermotolerans, and Metschnikowia pulcherrima, representing 89% of the isolates, exhibited particularly high diversity with high growth performance variability when exposed to typical stress conditions associated with common enological parameters. Less abundant species included Issatchenkia orientalis, Torulaspora delbrueckii, Hanseniaspora vineae, Hanseniaspora osmophila, Candida zemplinina, Rhodotorula mucilaginosa, Hanseniaspora guilliermondii, Issatchenkia occidentalis, and Zygosaccharomyces bisporus. This is the first study providing insights into the identification and characterization of non-Saccharomyces species responsible for spontaneous Port wine production.
    Keywords:  Port wine; native yeasts; non-Saccharomyces; strain characterization; wine yeasts
    DOI:  https://doi.org/10.3390/foods9020120
  1595. J Chem Theory Comput. 2020 Jan 21.
    Interpolation and extrapolation of global potential energy surfaces for polyatomic systems by Gaussian processes with composite kernels.
    Dai J, Krems RV.
      Gaussian process regression has recently emerged as a powerful, system-agnostic tool for building global potential energy surfaces (PES) of polyatomic molecules. While the accuracy of GP models of PES increases with the number of potential energy points, so does the numerical difficulty of training and evaluating GP models. Here, we demonstrate an approach to improve the accuracy of global PES without increasing the number of energy points. We show that GP models of PES trained by a small number of energy points can be significantly improved by iteratively increasing the complexity of GP kernels. The composite kernels thus obtained maximize the accuracy of GP models for a given distribution of potential energy points. The accuracy can then be further improved by varying the training point distributions. We also show that GP models with composite kernels can be used for physical extrapolation of PES. We illustrate the approach by constructing the six-dimensional PES for H$_3$O$^+$. For the interpolation problem, we show that this algorithm produces a global six-dimensional PES in the energy range between zero and $21,000$ cm$^{-1}$ with the root mean square error $65.8$ cm$^{-1}$ using only 500 randomly selected {\it ab initio} points as input. To illustrate extrapolation, we produce the PES at high energies using the energy points at low energies. We show that one can obtain an accurate global fit of the PES extending to $21,000$ cm$^{-1}$ based on 1500 potential energy points at energies below $10,000$ cm$^{-1}$.
    DOI:  https://doi.org/10.1021/acs.jctc.9b00700
  1596. Neurobiol Learn Mem. 2020 Jan 18. pii: S1074-7427(20)30012-5. [Epub ahead of print] 107168
    Rolipram treatment during consolidation ameliorates long-term object location memory in aged male mice.
    Wimmer ME, Blackwell J, Abel T.
      Normal aging is accompanied by cognitive and memory impairments that negatively impact quality of life for the growing elderly population. Hippocampal function is most vulnerable to the deleterious effects of aging, and deficits in hippocampus-dependent memories are common amongst aged individuals. Moreover, signaling networks such as the cAMP/PKA/CREB pathway, which are critical for memory consolidation, are dampened in healthy aged subjects. Phosphodiesterase (PDE) enzymes that break down cAMP are also affected by aging, and increased break down of cAMP by PDEs may contribute to reduced activity of the cAMP/PKA/CREB signaling network in the brain of aged individuals. Here, we report that the PDE4 inhibitor rolipram administered during consolidation of hippocampus-dependent object location memory improves aged-related spatial memory deficits in aged mice.
    Keywords:  CREB; PDE4; aging; cAMP; hippocampus; spatial memory
    DOI:  https://doi.org/10.1016/j.nlm.2020.107168
  1597. J Hepatol. 2020 Feb;pii: S0168-8278(19)30648-8. [Epub ahead of print]72(2): 320-341
    Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma.
    Sangro B, Chan SL, Meyer T, Reig M, El-Khoueiry A, Galle PR.
      Immune checkpoint inhibitors (ICIs) have reshaped cancer therapy. ICIs enhance T cell activation through various mechanisms and may help reverse the exhausted phenotype of tumour-infiltrating lymphocytes. However, disrupting the key role that checkpoint molecules play in immune homeostasis may result in autoimmune complications. A broad range of immune-related adverse events (irAEs) involve almost every organ but mostly affect the skin, digestive system, lung, endocrine glands, nervous system, kidney, blood cells, and musculoskeletal system. They are usually manageable but can be life-threatening. The incidence of irAEs is not very different in patients with hepatocellular carcinoma (HCC) compared to other tumour types, although there is a trend towards a higher incidence of hepatic irAEs. HCC usually develops on a background of cirrhosis with associated systemic manifestations. Extrahepatic organ dysfunction in cirrhosis may cause signs and symptoms that overlap with irAEs or increase their severity. Available guidelines for the management of irAEs have not specifically considered the assessment of toxicities in the context of patients with liver cancer and cirrhosis. This review addresses the toxicity profile of ICIs in patients with HCC, focusing on the challenges that the underlying liver disease poses to their diagnosis and management. Challenges include late recognition, inadequate work-up and delayed treatment, overdiagnosis and inappropriate interruption of ICIs, complications caused by immunosuppressive therapy, and increased cost. A specific algorithm for the management of hepatic irAEs is provided.
    Keywords:  Durvalumab; Hepatotoxicity; Immunotherapy; Ipilimumab; Nivolumab; Pembrolizumab; Tremelimumab
    DOI:  https://doi.org/10.1016/j.jhep.2019.10.021
  1598. J Cell Physiol. 2020 Jan 22.
    IFN-γ/mTORC1 decreased Rab11 in Schwann cells of diabetic peripheral neuropathy, inhibiting cell proliferation via GLUT1 downregulation.
    Du W, Zhao S, Gao F, Wei M, An J, Jia K, Li F, Zhu L, Hao J.
      Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Rab11 is conserved gene-regulating vesicle traffic and reported to be involved in the pathogenesis of diabetes mellitus by affecting insulin sensitivity. We aimed to investigate the role of Rab11 in the pathogenesis of DPN. In this study, Rab11 expression decreased in the sciatic nerves of diabetic mice with impaired conduction function versus those of normal mice. In vitro experiment revealed interferon-γ (IFN-γ), not high glucose and interleukin 1β was the main factor to lead to Rab11 downregulation in RSC96 cells. Again, both Rab11 knockdown and IFN-γ treatment caused cell viability inhibition and the decrease in BrdU-positive cells. In contrast, overexpression of Rab11 reversed IFN-γ-reduced cell proliferation. Furthermore, mTORC1 not mTORC2 was proven to be suppressed by IFN-γ treatment in RSC96 cells, indicated in decreased phospho-p70S6K. Inhibition of the mTORC1 pathway resulted in Rab11 expression downregulation in RSC96 cells. Activation of the mTORC1 pathway effectively prevented IFN-γ-reduced Rab11 expression in RSC96 cells. Also, glucose transporter 1 (GLUT1) was found to be downregulated in RSC96 cells with Rab11 silence and overexpression of GLUT1 reversed Rab11 blocking-caused proliferation inhibition. Taken together, our findings suggest that IFN-γ decreases Rab11 expression via the inhibition of the mTORC1 signaling pathway, causing reduced cell proliferation in Schwann cells of DPN by GLUT1 downregulation.
    Keywords:  IFN-γ; Rab11; diabetic peripheral neuropathy; mTORC1; proliferation
    DOI:  https://doi.org/10.1002/jcp.29510
  1599. Eur J Med Chem. 2020 Jan 09. pii: S0223-5234(20)30008-8. [Epub ahead of print]189 112041
    Dual-functional conjugates improving cancer immunochemotherapy by inhibiting tubulin polymerization and indoleamine-2,3-dioxygenase.
    Hua S, Chen F, Wang X, Gou S.
      A series of novel conjugates comprising tublin and IDO inhibitors were designed, synthesized and evaluated for their antiproliferative activity. Among them, HI5, composed of combretastatin A-4 (CA-4) and (D)-1-methyltryptophan (D-MT) by a linker, exhibited the most potent antitumor activity, in particular with higher IC50 value (0.07 μM) than CA-4 (0.21 μM) against HeLa cancer cell line. Mechanism studies indicated that HI5 can inhibit tubulin polymerization and cell migration, cause G2/M phase arrest, concurrent induce apoptosis via the mitochondrial dependent apoptosis pathway and cause reactive oxidative stress generation in HeLa cells. Furthermore, HI5 can inhibit IDO expression and decrease kynurenine production, leading to stimulating T cells activation and proliferation to enhance antitumor immunity in vitro. Interestingly, HI5 can effectively limit the tumor growth in the HeLa xenograft mice models without causing significant loss of body weight. Consequently, such a conjugation can be a potent and safe immunochemotherapeutic method for improving cancer therapy.
    Keywords:  Anticancer; Combretastatin-A4; Immunochemotherapy; Immunomodulator; Indoleamine-2,3-dioxygenase
    DOI:  https://doi.org/10.1016/j.ejmech.2020.112041
  1600. J Adv Res. 2020 Mar;22 105-118
    Thermotolerance and plasticity of camel somatic cells exposed to acute and chronic heat stress.
    Saadeldin IM, Swelum AA, Elsafadi M, Mahmood A, Osama A, Shikshaky H, Alfayez M, Alowaimer AN, Magdeldin S.
      The Arabian camel is the largest known mammal that can survive in severe hot climatic conditions. We provide the molecular explanation for the thermotolerance of camel granulosa somatic cells after exposure to 45 °C for 2 (acute heat shock) or 20 h (chronic heat shock). The common features of the cellular responses to acute heat stress were the increase of heat shock proteins and DNA repair enzymes expression. Actin polymerization and Rho signaling were critically activated as a cellular defense against heat shock. Cells exposed to chronic heat shock showed altered cell architecture with a decrease in total detected proteins, metabolic enzymes, and cytoskeletal protein expression. Treatment with transforming growth factor beta (TGFβ) pathway inhibitor SB-431542 suppressed the morphological alterations of cells exposed to chronic heat shock. Moreover, during the recovery stage at 38 °C for 24 h, proteomic changes were partially restored with an exponential increase in HSP70 expression, and the cells restored their normal cellular morphology on the 9th day of recovery. Full proteomics data are available via ProteomeXchange with identifier PXD012159. The strategies of cellular defense and tolerance to both thermal conditions reflect the flexible adaptability of camel somatic cells to conserve life under extremely hot conditions.
    Keywords:  Actin; Anastasis; CB, Cytochalasin B; Camel; GSH, reduced glutathione; HSPs; HSPs, heat shock proteins; IDA, information dependent acquisition; MDA, malondialdehyde; Proteomics; RI, ROCK-inhibitor; ROCK; ROCKs, Rho-associated protein kinases; TGFβ; TGFβ, transforming growth factor beta; TIC, total ion chromatography; Y-27632, ROCK-inhibitor Y-27632
    DOI:  https://doi.org/10.1016/j.jare.2019.11.009
  1601. J Pak Med Assoc. 2020 Feb;70(Suppl 1)(2): S49-S52
    Early tranexamic acid in traumatic brain injury: Evidence for an effective therapy.
    Bukhari NS, Jooma R.
      The guidelines for management of traumatic brain injury (TBI) are based largely on measures to maintain an optimum internal milieu for prevention of secondary brain injury and enhancing recovery. One of the most common reasons for worsening outcomes following TBI is expanding intracranial haematoma which is compounded by the fibrinolytic physiology that follows TBI. Tranexamic acid (TXA) has a time tested role in preventing poor outcomes linked to excessive haemorrhage in trauma patients. Historically, patients with isolated head trauma were excluded from TXA use due to a theoretical increased risk of thrombosis. Recent evidence that redefines the beneficial role of early TXA administration in preventing mortality amongst patients with TBI is now at hand and offers a real prospect of a pharmacological intervention that would be adopted as a recommendation based on Class l evidence.
    Keywords:  Tranexamic Acid, Brain Injuries, Traumatic, Randomized Controlled Trial.
  1602. Gigascience. 2020 Jan 01. pii: giz137. [Epub ahead of print]9(1):
    Compartment and hub definitions tune metabolic networks for metabolomic interpretations.
    Waller TC, Berg JA, Lex A, Chapman BE, Rutter J.
      BACKGROUND: Metabolic networks represent all chemical reactions that occur between molecular metabolites in an organism's cells. They offer biological context in which to integrate, analyze, and interpret omic measurements, but their large scale and extensive connectivity present unique challenges. While it is practical to simplify these networks by placing constraints on compartments and hubs, it is unclear how these simplifications alter the structure of metabolic networks and the interpretation of metabolomic experiments.RESULTS: We curated and adapted the latest systemic model of human metabolism and developed customizable tools to define metabolic networks with and without compartmentalization in subcellular organelles and with or without inclusion of prolific metabolite hubs. Compartmentalization made networks larger, less dense, and more modular, whereas hubs made networks larger, more dense, and less modular. When present, these hubs also dominated shortest paths in the network, yet their exclusion exposed the subtler prominence of other metabolites that are typically more relevant to metabolomic experiments. We applied the non-compartmental network without metabolite hubs in a retrospective, exploratory analysis of metabolomic measurements from 5 studies on human tissues. Network clusters identified individual reactions that might experience differential regulation between experimental conditions, several of which were not apparent in the original publications.
    CONCLUSIONS: Exclusion of specific metabolite hubs exposes modularity in both compartmental and non-compartmental metabolic networks, improving detection of relevant clusters in omic measurements. Better computational detection of metabolic network clusters in large data sets has potential to identify differential regulation of individual genes, transcripts, and proteins.
    Keywords:  metabolism; metabolite; metabolomic; network
    DOI:  https://doi.org/10.1093/gigascience/giz137
  1603. Endocrinol Metab Clin North Am. 2020 Mar;pii: S0889-8529(19)30094-5. [Epub ahead of print]49(1): 157-166
    Automated Insulin Delivery in Children with Type 1 Diabetes.
    Cengiz E.
      The advent of insulin pump therapy marked an important milestone in diabetes treatment in the past few decades and has become the tipping point for the development of automated insulin delivery systems (AID). Standalone insulin pump systems have evolved over the course of years and have been replaced by modern high-technology insulin pumps with continuous glucose monitor interface allowing real-time insulin dose adjustment to optimize treatment. This review summarizes evidence from AID studies conducted in children with type 1 diabetes and discusses the outlook for future generation AID systems from a pediatric treatment perspective.
    Keywords:  Children; Diabetes; Insulin; Insulin pump
    DOI:  https://doi.org/10.1016/j.ecl.2019.10.012
  1604. Molecules. 2020 Jan 21. pii: E441. [Epub ahead of print]25(3):
    Treatment of Human Lens Epithelium with High Levels of Nanoceria Leads to Reactive Oxygen Species Mediated Apoptosis.
    Hanafy BI, Cave GWV, Barnett Y, Pierscionek B.
      Nanoceria (cerium oxide nanoparticles) have been shown to protect human lens epithelial cells (HLECs) from oxidative stress when used at low concentrations. However, there is a lack of understanding about the mechanism of the cytotoxic and genotoxic effects of nanoceria when used at higher concentrations. Here, we investigated the impact of 24-hour exposure to nanoceria in HLECs. Nanoceria's effects on basal reactive oxygen species (ROS), mitochondrial morphology, membrane potential, ATP, genotoxicity, caspase activation and apoptotic hallmarks were investigated. Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) studies on isolated mitochondria revealed significant uptake and localization of nanoceria in the mitochondria. At high nanoceria concentrations (400 µg mL-1), intracellular levels of ROS were increased and the HLECs exhibited classical hallmarks of apoptosis. These findings concur with the cells maintaining normal ATP levels necessary to execute the apoptotic process. These results highlight the need for nanoceria dose-effect studies on a range of cells and tissues to identify therapeutic concentrations in vitro or in vivo.
    Keywords:  apoptosis; cerium oxide; genotoxicity; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules25030441
  1605. Acc Chem Res. 2020 Jan 24.
    Ensembles of Metastable States Govern Heterogeneous Catalysis on Dynamic Interfaces.
    Zhang Z, Zandkarimi B, Alexandrova AN.
      Heterogeneous catalysis is at the heart of the chemical industry. Being able to tune and design efficient catalysts for processes of interest is of the utmost importance, and for this, a molecular-level understanding of heterogeneous catalysts is the first step and indeed a prime focus of modern catalysis research. For a long time, the single most thermodynamically stable structure of the catalytic interface attained under the reaction conditions had been envisioned as the reactive phase. However, some catalytic interfaces continue to undergo structural dynamics in the steady state, triggered by high temperatures and pressures and binding and changing reagents. Among particularly dynamic interfaces are such widely used catalysts as crystalline and amorphous surfaced supporting (sub)nanometallic clusters. Recently, it became clear that this dynamic fluxionality causes the supported clusters to populate many distinct structural and stoichiometric states under catalytic conditions. Hence, the catalytic interface should be viewed as an evolving statistical ensemble of many structures (rather than one structure). Every member in the ensemble contributes to the properties of the catalyst differently, in proportion to its probability of being populated. This new notion flips the established paradigm and calls for a new theory, new modeling approaches, operando measurements, and updated design strategies. The statistical ensemble nature of surface-supported subnanocluster catalysts can be exemplified by oxide-supported and adsorbate-covered Pt, Pd, Cu, and CuPd clusters, which are catalytic toward oxidative and nonoxidative dehydrogenation. They have access to a variety of 3D and quasi-2D shapes. The compositions of their thermal ensembles are dependent on the cluster size, leading to size-specific catalytic activities and the famous "every atom counts" phenomenon. The support and adsorbates affect catalyst structures, and the state of the reacting species causes the ensemble to change in every reaction intermediate. The most stable member of the ensemble dominates the thermodynamic properties of the corresponding intermediate, whereas the kinetics can be determined by more active but less populated metastable catalyst states, and that suggests that many earlier studies might have overlooked the actual active sites. Both effects depend on the relative time scales of catalyst restructuring and reaction dynamics. The catalyst may routinely operate off-equilibrium. Ensemble phenomena lead to surprising exceptions from established rules of catalysis, such as scaling relations and Arrhenius behavior. Catalyst deactivation is also an ensemble property, and its extent of mitigation can be predicted through the new paradigm. These findings were enabled by advances in theory, such as global optimization and subsequent utilization of multiple local minima and pathways sampling as well as operando catalyst characterization. The fact that the per-site and per-species resolution is needed for the description and prediction of catalyst properties gives theory the central role in catalysis research, as most experiments provide ensemble-average information and cannot detect the crucial minority species that may be responsible for the catalytic activity.
    DOI:  https://doi.org/10.1021/acs.accounts.9b00531
  1606. Br Dent J. 2020 Jan;228(2): 67
    Unique conference to focus on FtP.
      
    DOI:  https://doi.org/10.1038/s41415-020-1224-4
  1607. Heart. 2020 Jan 23. pii: heartjnl-2019-316033. [Epub ahead of print]
    Artificial intelligence and the cardiologist: what you need to know for 2020.
    de Marvao A, Dawes TJ, Howard JP, O'Regan DP.
      
    DOI:  https://doi.org/10.1136/heartjnl-2019-316033
  1608. Comb Chem High Throughput Screen. 2020 Jan 24.
    Three differentially expressed miRNAs as potential biomarkers for lung adenocarcinoma prognosis.
    Wang W, Liu B, Duan X, Feng X, Wang T, Wang P, Ding M, Zhang Q, Feng F, Wu Y, Yao W, Wang Q, Yang Y.
      OBJECTIVE: The aim of this study is to screen MicroRNA (miRNA) related to the prognosis of lung adenocarcinoma (LUAD) and to explore the possible molecular mechanism.METHODS: A total of 535 LUAD data were downloaded from The Cancer Genome Atlas (TCGA) database. The miRNAs for LUAD prognosis were screened by Cox risk proportional regression model and Last Absolute Shrinkage and Selection Operator (LASSO) regression model. The performance of the model was verified by time-dependent Receiver Operating Characteristic (ROC) curve. The possible biological process of miRNAs' target genes was analyzed by Gene Ontology (GO), Kyoto gene and genome encyclopedia (KEGG).
    RESULTS: 127 differentially expressed miRNAs were screened with 111 up-regulated and 16 down-regulated miRNAs. Three key miRNAs, hsa-miR-1293, hsa-miR-490 and hsa-miR-5571, were screened from survival analysis, which are significantly enriched in systemic lupus erythematosus pathways.
    CONCLUSION: Hsa-miR-1293, hsa-miR-490 and hsa-miR-5571 can be used as novel biomarkers for the prediction of prognosis of LUAD.
    Keywords:  Biomarkers; Lung adenocarcinoma; Prognosis; Screening; TCGA; miRNAs
    DOI:  https://doi.org/10.2174/1386207323666200124123103
  1609. Eur J Oncol Nurs. 2019 Dec 20. pii: S1462-3889(19)30182-6. [Epub ahead of print]44 101714
    Development and implementation strategies of a nurse-led symptom self-management program in outpatient cancer centres: The Symptom Navi© Programme.
    Bana M, Ribi K, Kropf-Staub S, Näf E, Schramm MS, Zürcher-Florin S, Peters S, Eicher M.
      PURPOSE: The Symptom Navi© Programme (SN©P) is a structured nurse-led intervention supporting symptom self-management in cancer patients. We describe the development and evaluation of the intervention, implementation strategy, and the evaluation of nurse training for the Symptom Navi© Pilot Study.METHODS: The intervention was developed using multiple methods (e.g. literature synthesis, focus groups) to produce SN©P information leaflets (SN©Flyers in French and German) and standardised training for nurses to deliver semi-structured consultations. We evaluated the SN©P using online surveys, focus groups, interviews, and the Item-Content Validity Index (I-CVI). Nurse training was evaluated in relation to content, acceptability, and confidence in implementing the SN©P. We examined the association between scored on the Work-related Sense of Coherence (Work-SoC) scale and nurses' confidence in implementing the SN©P. Thematic analysis was used to analyse qualitative data. Quantitative data was descriptively analysed and the Kendall Tau test was employed for correlations.
    RESULTS: Patients and health care professionals confirmed that SN©Flyers and semi-structured consultations facilitated symptom self-management. Nurses considered training content/format acceptable and appropriate and felt confident in implementing the SN©P. Overall Work-SoC scores were correlated with nurses' confidence in implementing the SN©P (rπ = .47, p = .04).
    CONCLUSIONS: Health care professionals and cancer patients perceived the SN©P as a useful support. Successful implementation of the SN©P depends on centre-specific factors including time, resources and workflow.
    CLINICAL TRIAL REGISTRY: NCT03649984 and SNCTP000002381.
    Keywords:  Behaviour change; Complex intervention; Implementation research; Neoplasm; Self-management; Symptom management
    DOI:  https://doi.org/10.1016/j.ejon.2019.101714
  1610. Molecules. 2020 Jan 22. pii: E475. [Epub ahead of print]25(3):
    OcUGT1-Catalyzing Glycodiversification of Steroids through Glucosylation and Transglucosylation Actions.
    Xu YL, Kong JQ.
      Steroidal glycosides are important sources of innovative drugs. The increased diversification of steroidal glycosides will expand the probability of discovering active molecules. It is an efficient approach to diversify steroidal glycosides by using steroidal glycosyltransferases. OcUGT1, a uridine diphosphate-d-glucose (UDP-Glc)-dependent glycosyltransferase from Ornithogalum caudatum, is a multifunctional enzyme, and its glycodiversification potential towards steroids has never been fully explored. Herein, the glycodiversification capability of OcUGT1 towards 25 steroids through glucosylation and transglucosylation reactions were explored. Firstly, each of 25 compounds was glucosylated with UDP-Glc. Under the action of OcUGT1, five steroids (testosterone, deoxycorticosterone, hydrocortisone, estradiol, and 4-androstenediol) were glucosylated to form corresponding mono-glucosides and biosides. Next, OcUGT1-mediated transglucosylation activity of these compounds with another sugar donor ortho-nitrophenyl-β-d-glucopyranoside (oNPGlc) was investigated. Results revealed that the same five steroids could be glucosylated to generate mono-glucosides and biosides by OcUGT1 through transglucosylation reactions. These data indicated that OcUGT1-assisted glycodiversification of steroids could be achieved through glucosylation and transglucosylation reactions. These results provide a way to diversify steroidal glycosides, which lays the foundation for the increase of the probability of obtaining active lead compounds.
    Keywords:  glucosylation; glycodiversification; glycosyltransferase; steroidal glycosides; transglucosylation
    DOI:  https://doi.org/10.3390/molecules25030475
  1611. Transl Res. 2019 Dec 27. pii: S1931-5244(19)30257-9. [Epub ahead of print]
    Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array.
    Raglan O, Assi N, Nautiyal J, Lu H, Gabra H, Gunter MJ, Kyrgiou M.
      Obesity and hyperinsulinemia are known risk factors for endometrial cancer, yet the biological pathways underlying this relationship are incompletely understood. This study investigated protein expression in endometrial cancer and benign tissue and its correlation with obesity and insulin resistance. One hundred and seven women undergoing hysterectomy for endometrial cancer or benign conditions provided a fasting blood sample and endometrial tissue. We performed proteomic expression according to body mass index, insulin resistance, and serum marker levels. We used linear regression and independent t test for statistical analysis. Proteomic data from 560 endometrial cancer cases from The Cancer Genome Atlas (TCGA) databank were used to assess reproducibility of results. One hundred and twenty seven proteins were significantly differentially expressed between 66 cancer and 26 benign patients. Protein expression involved in cell cycle progression, impacting cytoskeletal dynamics (PAK1) and cell survival (Rab 25), were most significantly altered. Obese women with cancer had increased PRAS40_pT246; a downstream marker of increased PI3K-AKT signaling. Obese women without cancer had increased mitogenic and antiapoptotic signaling by way of upregulation of Mcl-1, DUSP4, and Insulin Receptor-b. This exploratory study identified a number of candidate proteins specific to endometrioid endometrial cancer and benign endometrial tissues. Obesity and insulin resistance in women with benign endometrium leads to specific upregulation of proteins involved in insulin and driver oncogenic signaling pathways such as the PI3K-AKT-mTOR and growth factor signaling pathways which are mitogenic and also disruptive to metabolism.
    DOI:  https://doi.org/10.1016/j.trsl.2019.12.003
  1612. Elife. 2020 Jan 21. pii: e48092. [Epub ahead of print]9
    T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumor immunity.
    Canel M, Taggart D, Sims AH, Lonergan DW, Waizenegger IC, Serrels A.
      Focal Adhesion Kinase (FAK) inhibitors are currently undergoing clinical testing in combination with anti-PD-1 immune checkpoint inhibitors. However, which patients are most likely to benefit from FAK inhibitors, and what the optimal FAK/immunotherapy combinations are, is currently unknown. We identify that cancer cell expression of the T-cell co-stimulatory ligand CD80 sensitizes murine tumors to a FAK inhibitor and show that CD80 is expressed by human cancer cells originating from both solid epithelial cancers and some hematological malignancies in which FAK inhibitors have not been tested clinically. In the absence of CD80, we identify that targeting alternative T-cell co-stimulatory receptors, in particular OX-40 and 4-1BB in combination with FAK, can drive enhanced anti-tumor immunity and even complete regression of murine tumors. Our findings provide rationale supporting the clinical development of FAK inhibitors in combination with patient selection based on cancer cell CD80 expression, and alternatively with therapies targeting T-cell co-stimulatory pathways.
    Keywords:  FAK; T-cell costimulation; cancer; cancer biology; immunotherapy; mouse
    DOI:  https://doi.org/10.7554/eLife.48092
  1613. Elife. 2020 Jan 20. pii: e47293. [Epub ahead of print]9
    tec-1 kinase negatively regulates regenerative neurogenesis in planarians.
    Karge A, Bonar NA, Wood S, Petersen CP.
      Negative regulators of adult neurogenesis are of particular interest as targets to enhance neuronal repair, but few have yet been identified. Planarians can regenerate their entire CNS using pluripotent adult stem cells, and this process is robustly regulated to ensure that new neurons are produced in proper abundance. Using a high-throughput pipeline to quantify brain chemosensory neurons, we identify the conserved tyrosine kinase tec-1 as a negative regulator of planarian neuronal regeneration. tec-1RNAi increased the abundance of several CNS and PNS neuron subtypes regenerated or maintained through homeostasis, without affecting body patterning or non-neural cells. Experiments using TUNEL, BrdU, progenitor labeling, and stem cell elimination during regeneration indicate tec-1 limits the survival of newly differentiated neurons. In vertebrates, the Tec kinase family has been studied extensively for roles in immune function, and our results identify a novel role for tec-1 as negative regulator of planarian adult neurogenesis.
    Keywords:  S. mediterranea; cell death; developmental biology; neurogenesis; protein kinase; regeneration; signaling
    DOI:  https://doi.org/10.7554/eLife.47293
  1614. Oncol Lett. 2020 Feb;19(2): 1584-1592
    High mobility group AT-hook 2 and c-MYC as potential prognostic factors in pancreatic ductal adenocarcinoma.
    Li K, Yang J, Chen J, Shi Y, Zhang Z, Chen W.
      The present study investigated if c-MYC and high mobility group AT-hook 2 (HMGA2) expression was associated with prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). A total of 102 patients undergoing surgery for PDAC were retrospectively reviewed. Immunohistochemistry was used to detect c-MYC and HMGA2 protein expression in PDAC and peritumoral tissue samples. Expression of c-MYC and HMGA2 was associated with clinicopathological characteristics and prognoses of patients with PDAC using multivariate analysis. HMGA2 and c-MYC protein expression was significantly higher in PDAC tissues compared with peritumoral tissue (P<0.001). HMGA2 and c-MYC expression was also significantly higher in patients with PDAC who had lymph node metastasis, invasion of regional tissues and tumor node metastasis (TNM) stage III or IV disease compared with those who had no lymph node metastasis, no invasion of regional tissues and TNM stage I or II disease (P<0.001). Multivariate logistic regression analysis was used to identify TNM stage (P=0.007) and invasion (P=0.003) as significant independent predictors of c-MYC expression (model AUC=0.8201), and lymph node metastasis (P=0.002) and invasion (P=0.003) as significant independent predictors of HMGA2 expression (model AUC=0.7638). Cox multivariate analysis showed that expression of c-MYC (P=0.019) and HMGA2 (P<0.001), TNM stage (P=0.014) and lymph node metastasis (P=0.032) were associated with reduced overall survival time. HMGA2 and c-MYC may be important biological markers and potential therapeutic targets involved in the tumorigenesis, metastasis, invasion and prognosis of PDAC.
    Keywords:  c-MYC; high mobility group AT-hook 2; immunohistochemistry; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3892/ol.2019.11205
  1615. Cell Stress Chaperones. 2020 Jan 22.
    Astaxanthin supplementation impacts the cellular HSP expression profile during passive heating.
    Fleischmann C, Bar-Ilan N, Horowitz M, Bruchim Y, Deuster P, Heled Y.
      Astaxanthin is a powerful carotenoid antioxidant prevalent in marine organisms and approved as a food supplement. Recent studies have demonstrated Astaxanthin's beneficial attributes in various health states. Following initial reports of potential heat protective properties in Astaxanthin supplemented rats, we present here results of a novel study examining the effect of Astaxanthin supplementation on the heat shock response in rats in relation to core temperature (Tc) and the ensuing physiological strain. Two hours of heat stress at 41 °C during which rats developed their thermoregulatory hyperthermic plateau resulted in progressive increases in HSP72 and HSP27 in the Astaxanthin (Oleoresin)-treated group but not in the control (Olive oil) group. Enhanced elevation in HSPs suggests that Astaxanthin supplementation may augment the cellular stress protective response to heat stress.
    Keywords:  Astaxanthin; Environmental physiology; Heat stress; Nutritional pre-treatment
    DOI:  https://doi.org/10.1007/s12192-019-01061-4
  1616. Spine Deform. 2018 Jul;6(4): 366-372
    Proposal of a New Treatment-Oriented Classification System for Spinal Deformity in Ankylosing Spondylitis.
    Wang Y, Zheng GQ, Zhang YG, Song K, Song DY, Zhang XS, Wang Z, Lu N, Mao KY.
      OBJECTIVE: To describe and apply an optimal classification system for the management of ankylosing spondylitis (AS) that may be appropriate to make a preoperative surgical plan.BACKGROUND: The treatment choices of ankylosing spondylitis kyphosis remain controversial. The lack of a widely accepted classification system contributes to the variation in surgical decision making.
    METHODS: The classification is mainly based on radiographic findings. The sagittal deformity of spine in ankylosing spondylitis is classified according to three criteria: the location of the apex, the lumbar modifier (A, lumbar lordosis <0°, and B, lumbar kyphosis >0°) and the thoracic/thoracolumbar kyphosis severity modifier (- or +).
    RESULTS: The ankylosing spondylitis kyphosis can be divided into 4 types according to the location of the apex: Type I (lumbar), Type II (thoracolumbar), Type III (thoracic), Type IV (cervical or cervicothoracic junction). Either Type II or Type III is further divided into four subtypes based on the lumbar modifier and the thoracic/thoracolumbar kyphosis severity modifier: Type IIA-, Type IIA+, Type IIB-, Type IIB+, Type IIIA-, Type IIIA+, Type IIIB-, and Type IIIB+. Surgical decision making for AS kyphosis can be made according to the new classification.
    CONCLUSION: This new classification system can be used effectively to classify AS kyphosis, which can be used to guide surgical decision making, including determining the site and the levels of osteotomies. Further research may be needed to validate the classification.
    Keywords:  Ankylosing spondylitis; Classification; Kyphosis; Spinal deformity
    DOI:  https://doi.org/10.1016/j.jspd.2017.06.001
  1617. Am J Physiol Regul Integr Comp Physiol. 2020 Jan 22.
    Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat.
    Clayson MS, Devereaux ME, Pamenter ME.
      Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic CO2 that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0-10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain due to modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg⋅kg-1) or a long-lived isoform of substance P (DiMe-C7; 40-400 mg⋅kg-1). We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2-10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signalling network architecture required for a "normal" HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.
    Keywords:  body temperature; hypercapnic metabolic response
    DOI:  https://doi.org/10.1152/ajpregu.00251.2019
  1618. J Laryngol Otol. 2020 Jan 22. 1-3
    Epistaxis and atorvastatin: is there an association and are clinicians aware? A retrospective audit of 100 patients.
    Heward E, Lau AS.
      OBJECTIVE: Epistaxis is a common ENT presentation. The British National Formulary lists epistaxis as a common side effect of atorvastatin. This study aimed to better understand the relationship between epistaxis and atorvastatin use, and determine whether ENT doctors are aware of its side effect profile.METHODS: A retrospective analysis over 10 months identified 100 individuals who presented to hospital with epistaxis. A questionnaire of 24 ENT registrars was undertaken.
    RESULTS: Of the 100 patients admitted with epistaxis, 27 were receiving atorvastatin and 21 simvastatin. None of the 24 ENT registrars were aware that epistaxis was a listed common side effect of atorvastatin.
    CONCLUSION: There was no apparent difference in the proportion of patients admitted with epistaxis taking atorvastatin versus simvastatin. Epistaxis is an unknown side effect of atorvastatin; doctors have an obligation to be aware of the pharmaceutical literature and to consider alternatives, particularly in re-admissions cases.
    Keywords:  Atorvastatin; Epistaxis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nasopharyngitis
    DOI:  https://doi.org/10.1017/S0022215120000122
  1619. J Ayub Med Coll Abbottabad. 2019 Oct-Dec;31(Suppl 1)(4):31(Suppl 1)(4): S656-S659
    Median Nerve Injury In Children Aged 2-11 Years Presenting With Closed Supracondylar Fracture Of Humerus.
    Khan AZ, Zardad S, Adeel M, Iqbal J.
      Background: The supra-condylar humeral fractures are commonest fractures at the elbow in children and represent a third of all limb fractures in children under the age of 7 years. These fractures are associated with neurological deficit and any of the three long nerves of upper arm can be involved in these fractures. This study was conducted to determine the frequency of median nerve injury in children aged 2-11 years presenting with closed supracondylar fracture of humerus.Methods: This descriptive cross-sectional study was conducted at the department of orthopaedics and trauma, Ayub Teaching Hospital Abbottabad from July 2016 to June 2018. One hundred and seventy-one patients with supracondylar fracture of humerus were enrolled. They were treated as per department protocols and the outcome in terms of neurological damage was noted for each study participant.
    Results: The frequency of neurological damage was 21.05% with median nerve affected most commonly (13.45%). A statistically strong association was found between damage to median nerve and type of fracture, arm involvement and sex of patients (p<0.05) while no statistically significant association with age was obtained.
    Conclusion: Neurological damage is a common complication of supracondylar humeral fractures with median nerve being the most commonly affected nerve in these fractures.
    Keywords:   Median Nerve; Supracondylar Fracture; Humerus; Open Reduction; Motor Deficit
  1620. Mol Microbiol. 2020 Jan 24.
    Leishmania Dual Specificity Tyrosine Regulated Kinase 1 (DYRK1) is required for sustaining Leishmania stationary phase phenotype.
    Rocha VPC, Dacher M, Young SA, Kolokousi F, Efstathiou A, Späth GF, Pereira Soares MB, Smirlis D.
      Although the multiplicative and growth-arrested states play key roles in Leishmania development, the regulators of these transitions are largely unknown. In an attempt to gain a better understanding of these processes, we characterised one member of a family of protein kinases with dual specificity, LinDYRK1, which acts as a stasis regulator in other organisms. LinDYRK1 over-expressing parasites displayed a decrease in proliferation and in cell cycle re-entry of arrested cells. Parasites lacking LinDYRK1 displayed distinct fitness phenotypes in logarithmic and stationary growth phases. In logarithmic growth-phase, LinDYRK1-/- parasites proliferated better than control lines, supporting a role of this kinase in stasis, while in stationary growth-phase, LinDYRK1-/- parasites had important defects as they rounded up, accumulated vacuoles and lipid bodies and displayed subtle but consistent differences in lipid composition. Moreover, they expressed less metacyclic-enriched transcripts, displayed increased sensitivity to complement lysis and a significant reduction in survival within peritoneal macrophages. The distinct LinDYRK1-/- growth phase phenotypes were mirrored by the distinct LinDYRK1 localisations in logarithmic (mainly in flagellar pocket area and endosomes) and late stationary phase (mitochondrion). Overall, this work provides first evidence for the role of a DYRK family member in sustaining promastigote stationary phase phenotype and infectivity.
    Keywords:   Leishmania ; DYRK1; growth; kinase; stationary
    DOI:  https://doi.org/10.1111/mmi.14464
  1621. Chin J Nat Med. 2020 Jan;pii: S1875-5364(20)30005-4. [Epub ahead of print]18(1): 57-69
    The crucial role of metabolic regulation in differential hepatotoxicity induced by furanoids in Dioscorea bulbifera.
    Wu ZT, Li ZQ, Shi W, Wang LL, Jiang Y, Li P, Li HJ.
      Diterpenoid lactones (DLs), a group of furan-containing compounds found in Dioscorea bulbifera L. (DB), have been reported to be associated with hepatotoxicity. Different hepatotoxicities of these DLs have been observed in vitro, but reasonable explanations for the differential hepatotoxicity have not been provided. Herein, the present study aimed to confirm the potential factors that contribute to varied hepatotoxicity of four representative DLs (diosbulbins A, B, C, F). In vitro toxic effects were evaluated in various cell models and the interactions between DLs and CYP3A4 at the atomic level were simulated by molecular docking. Results showed that DLs exhibited varied cytotoxicities, and that CYP3A4 played a modulatory role in this process. Moreover, structural variation may cause different affinities between DLs and CYP3A4, which was positively correlated with the observation of cytotoxicity. In addition, analysis of the glutathione (GSH) conjugates indicated that reactive intermediates were formed by metabolic oxidation that occurred on the furan moiety of DLs, whereas, GSH consumption analysis reflected the consistency between the reactive metabolites and the hepatotoxicity. Collectively, our findings illustrated that the metabolic regulation played a crucial role in generating the varied hepatotoxicity of DLs.
    Keywords:  Dioscorea bulbifera; Diterpenoid lactones; Furan moiety; Hepatotoxicity; Metabolic regulation
    DOI:  https://doi.org/10.1016/S1875-5364(20)30005-4
  1622. Eur Urol. 2020 Jan 21. pii: S0302-2838(19)30903-0. [Epub ahead of print]
    Corrigendum re "Periurethral Injection of Autologous Adipose-Derived Stem Cells with Controlled-Release Nerve Growth Factor for the Treatment of Stress Urinary Incontinence in a Rat Model" [Eur Urol 2011;59:155-63].
    Zhao W, Zhang C, Jin C, Zhang Z, Kong D, Xu W, Xiu Y.
      
    DOI:  https://doi.org/10.1016/j.eururo.2019.12.001
  1623. J Cell Biol. 2020 Feb 03. pii: e202001060. [Epub ahead of print]219(2):
    Susana Godinho: Placing cell biology at the center of cancer research.
    O'Donnell MA.
      Godinho investigates the role centrosomes play in cancer cell biology.
    DOI:  https://doi.org/10.1083/jcb.202001060
  1624. Drug Metab Dispos. 2020 Jan 24. pii: dmd.119.090068. [Epub ahead of print]
    Differential role of LXRα and LXRβ in the regulation of UDP-glucuronosyltransferase 1A1 in humanized UGT1 mice.
    Hansmann E, Mennillo E, Yoda E, Verreault M, Barbier O, Chen SJ, Tukey RH.
      Liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate the metabolism of cholesterol and bile acids and are activated by oxysterols. Humanized UGT1 (hUGT1) mice express the 9-human UGT1A genes associated with the UGT1 locus in a Ugt1-null background. The expression of UGT1A1 is developmentally delayed in liver and intestines resulting in the accumulation of serum bilirubin during the neonatal period. Induction of UGT1A1 in newborn hUGT1 mice leads to rapid reduction in total serum bilirubin (TSB) levels, a phenotype measurement that allows for an accurate prediction on UGT1A1 expression. When neonatal hUGT1 mice were treated by oral gavage with the LXR agonist T0901317, TSB levels were dramatically reduced. To determine the LXR contribution to induction of UGT1A1 and the lowering of TSB levels, experiments were conducted in neonatal hUGT1/Lxrα-/-, hUGT1/Lxrβ-/- and hUGT1/Lxrαβ-/- mice treated with T0901317. Induction of liver UGT1A1 was highly dependent upon LXRα, with the induction pattern paralleling induction of LXRα specific Stearoyl-CoA desaturase 1 (SCD1). However, the actions of T0901317 were also shown to display a lack of specificity for LXR, with induction of liver UGT1A1 in hUGT1/Lxrαβ-/- mice, a result associated with activation of both PXR and CAR. An alternative LXR agonist, GW3965, was highly selective towards LXRα, showing no impact on lowering TSB values or inducing UGT1A1 in UGT1/Lxrα-/- mice. An LXR specific enhancer site on the UGT1A1 gene was identified, along with convincing evidence that LXRα is crucial in maintaining constitutive expression of UGT1A1 in adult hUGT1 mice SIGNIFICANCE STATEMENT: Implementing a reverse genetics approach, it has been established that activation of LXRα, and not LXRβ, is responsible for induction of liver UGT1A1 and metabolism of serum bilirubin in neonatal hUGT1 mice. While induction of the human UGT1A1 gene is initiated at a newly characterized LXR enhancer site, allelic deletion of the Lxrα gene drastically reduces constitutive expression of liver UGT1A1 in adult hUGT1 mice. Combined, these findings indicate that LXRα is critical for the developmental expression of UGT1A1.
    Keywords:  animal models; constitutive androstane receptor/CAR; glucuronidation/UDP-glucuronyltransferases/UGT; heme/heme metabolism; liver/hepatic; nuclear receptors; pregnane X receptor/PXR/SXR
    DOI:  https://doi.org/10.1124/dmd.119.090068
  1625. J Assoc Physicians India. 2020 Jan;68(1): 51
    Eff ectiveness of Teneligliptin as an Add-on in T2DM Patients not Controlled on Metformin and Glimepiride.
    Kashiv P, Kumar J.
      
  1626. AACE Clin Case Rep. 2019 Jul-Aug;5(4):5(4): e247-e249
    AN INCIDENTAL COLLISION TUMOR OF THE SELLA TURCICA.
    Levitus CF, Charitou MM.
      Objective: To present a case describing an incidentally discovered pituitary mass that was found to be a collision tumor containing 2 distinct histologic cell types: (1) a growth hormone (GH)-secreting pituitary adenoma, and (2) a gangliocytoma.Methods: Sellar gangliocytomas are very rare benign neuroblastic tumors that originate from the posterior pituitary. The majority are associated with pituitary adenomas. The co-existence of these 2 morphologically distinct tumors is known as a collision tumor, a rare disease entity of which the pathogenesis is not well understood. We present a case of a woman with an incidentally discovered pituitary mass that was found to be a collision tumor.
    Results: A 44-year-old woman presented with an incidentally discovered pituitary mass and was found to have elevated insulin-like growth factor 1 (IGF-1) levels. The patient underwent endoscopic transsphenoidal excision of the pituitary mass. Histopathology of the tumor revealed a mixed pituitary adenoma that stained for GH and prolactin, and a gangliocytoma. Postoperatively, the patient developed temporary central adrenal insufficiency and permanent diabetes insipidus. Postoperative lab studies revealed a normal IGF-1 level, and a magnetic resonance imaging scan showed no residual or recurrent tumor.
    Conclusion: While sellar gangliocytoma is a rare lesion, when it is present, a co-existing pituitary adenoma should also be suspected. Further investigation should be done to determine the pathophysiology of these collision tumors, which could be beneficial in guiding diagnosis and treatment.
    DOI:  https://doi.org/10.4158/ACCR-2019-0013
  1627. Braz J Otorhinolaryngol. 2020 Jan 11. pii: S1808-8694(20)30005-7. [Epub ahead of print]
    Does the video head impulse test replace caloric testing?
    Venosa AR, Ganança MM, Mezzalira R, Bittar RSM, Ganança FF.
      
    DOI:  https://doi.org/10.1016/j.bjorl.2020.01.001
  1628. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31672-9. [Epub ahead of print]30(3): 620-629.e6
    The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans.
    Moreno-Velásquez SD, Tint SH, Del Olmo Toledo V, Torsin S, De S, Pérez JC.
      Integrating nutrient sensing with the synthesis of complex molecules is a central feature of metabolism. Yet the regulatory mechanisms underlying such integration are often unknown. Here, we establish that the transcription regulators Rtg1/3 are key determinants of sphingolipid homeostasis in the human fungal pathogen Candida albicans. Quantitative analysis of the C. albicans lipidome reveals Rtg1/3-dependent alterations in all complex sphingolipids and their precursors, ceramides. Mutations in the regulators render the fungus susceptible to myriocin, a sphingolipid synthesis inhibitor. Rtg1/3 exert control on the expression of several enzymes involved in the synthesis of sphingolipids' building blocks, and the regulators are activated upon engulfment of C. albicans cells by human neutrophils. We demonstrate that Rtg1p and Rtg3p are regulated at two levels, one in response to sphingolipids and the other by the nutrient sensor TOR. Our findings, therefore, indicate that the Rtg1/3 system integrates nutrient sensing into the synthesis of complex lipids.
    Keywords:  Candida albicans; Rtg1; Rtg3; TOR; sphingolipids; yeast
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.022
  1629. Nat Chem Biol. 2020 Feb;16(2): 106
    Noise reduction.
    Miura G.
      
    DOI:  https://doi.org/10.1038/s41589-020-0464-6
  1630. J Affect Disord. 2019 Nov 30. pii: S0165-0327(19)31749-5. [Epub ahead of print]263 396-404
    Indirect effect of parental depression on school victimization through adolescent depression.
    Chen JK, Wu C, Chang CW, Wei HS.
      BACKGROUND: While a link between parental depression and adolescent school victimization is frequently hypothesized, studies on this association have shown mixed results. In addition, adolescent depression has been considered a potential psychosocial mechanism underlying the link between parental depression and adolescent school victimization. However, studies to support this proposition are lacking. This paper examines the direct effect of parental depression on adolescent victimization by peers and teachers in school as well as indirect effect through adolescent depression in an Asian context (Taiwan) and further examines differences in the interrelationships of parental depression, adolescent depression, and school victimization by peers and teachers across gender and school age groups.METHODS: Data were obtained from a random sample of 2,419 students (grades 7-12) and their parents in one of the largest metropolitan areas in Taiwan.
    RESULTS: Parental depression did not have a significant direct association with either type of school victimization. However, parental depression showed a significant indirect association with both types of school victimization through adolescent depression. These findings applied to both males and females and both junior and senior high school students.
    LIMITATION: The study utilized cross-sectional data, and the findings cannot be used to build causal relationships.
    CONCLUSION: Our findings provide empirical support that parental depression has indirect associations with school victimization by peers and teachers through adolescent depression. The results support the importance of including family-based approaches for depression targeting parents and adolescents in future victim intervention/prevention school programs.
    Keywords:  Bullying; Depression; School violence; Victimization
    DOI:  https://doi.org/10.1016/j.jad.2019.11.126
  1631. Int J Mol Sci. 2020 Jan 16. pii: E578. [Epub ahead of print]21(2):
    Pexophagy: A Model for Selective Autophagy.
    Germain K, Kim PK.
      The removal of damaged or superfluous organelles from the cytosol by selective autophagy is required to maintain organelle function, quality control and overall cellular homeostasis. Precisely how substrate selectivity is achieved, and how individual substrates are degraded during selective autophagy in response to both extracellular and intracellular cues is not well understood. The aim of this review is to highlight pexophagy, the autophagic degradation of peroxisomes, as a model for selective autophagy. Peroxisomes are dynamic organelles whose abundance is rapidly modulated in response to metabolic demands. Peroxisomes are routinely turned over by pexophagy for organelle quality control yet can also be degraded by pexophagy in response to external stimuli such as amino acid starvation or hypoxia. This review discusses the molecular machinery and regulatory mechanisms governing substrate selectivity during both quality-control pexophagy and pexophagy in response to external stimuli, in yeast and mammalian systems. We draw lessons from pexophagy to infer how the cell may coordinate the degradation of individual substrates by selective autophagy across different cellular cues.
    Keywords:  metabolism; organelle quality control; peroxisomes; selective autophagy
    DOI:  https://doi.org/10.3390/ijms21020578
  1632. Eur J Pharmacol. 2020 Jan 17. pii: S0014-2999(20)30030-3. [Epub ahead of print] 172938
    α-Lipoic acid prevents the ionizing radiation-induced epithelial-mesenchymal transition and enhances the radiosensitivity in breast cancer cells.
    Tripathy J, Chowdhury AR, Prusty M, Muduli K, Priyadarshini N, Reddy KS, Banerjee B, Elangovan S.
      Radiotherapy is routinely used in the treatment of breast cancer. However, its efficiency is often limited by the development of radioresistance and metastasis. The cancer cells surviving irradiation show epithelial-mesenchymal transition (EMT) along with increased migration, invasion and metastasis. In this study, we have evaluated the role of α-lipoic acid in preventing the radiation-induced EMT and in sensitizing the breast cancer cells to radiation. The breast cancer cell lines, MCF-7 and MDA-MB-231 were pretreated with lipoic acid, irradiated and the changes associated with cell growth, clonogenicity, migration, matrix metalloproteinases (MMPs), EMT and TGFβ signaling were measured. Our data showed that lipoic acid pretreatment sensitized the breast cancer cells to the ionizing radiation and inhibited the radiation-induced migration and the release of MMP2 and MMP9. Lipoic acid also prevented the TGFβ1 release and inhibited the radiation-induced EMT in breast cancer cells. The inhibition of TGFβ signaling by lipoic acid is associated with the inhibition of radiation-induced activation and translocation of NF-κB. These results suggest that α-lipoic acid inhibits the radiation-induced TGFβ signaling and nuclear translocation of NF-κB, thereby inhibiting the radiation-induced EMT and sensitizing the breast cancer cells to ionizing radiation.
    Keywords:  Breast cancer; Epithelial-mesenchymal transition; Ionizing radiation; Lipoic acid; Matrix metalloproteinase; TGFβ
    DOI:  https://doi.org/10.1016/j.ejphar.2020.172938
  1633. Eur J Nutr. 2020 Jan 21.
    Theobromine alleviates diet-induced obesity in mice via phosphodiesterase-4 inhibition.
    Jang MH, Mukherjee S, Choi MJ, Kang NH, Pham HG, Yun JW.
      PURPOSE: Modern science has given much attention to the treatment of obesity by activating brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Recent studies have identified theobromine, a derivative of cocoa, as a potent natural component actively browning white fat cells. Here, we aimed to deduce the anti-obesity effect of theobromine involving phosphodiesterase (PDE) dependent-regulatory pathway in obese animal models.METHODS: For examining activity of theobromine, C57BL/6 mice were fed with high fat diet and treated with theobromine to determine the expression levels of protein markers by immunoblot analysis and gene targets by quantitative real-time PCR. Other methods used include histopathological studies, immunofluorescence and molecular docking approaches.
    RESULTS: Theobromine alleviated diet-induced obesity in mice by browning of iWAT and activating BAT. Further, theobromine actively interacted with PDE4D and inhibited its activity in adipose tissues and cells potentiating energy expenditure. Moreover, the regulatory action of theobromine via inhibition of PDE4D was mediated by β3-AR signaling pathway.
    CONCLUSION: Altogether, the current results signifies critical role of theobromine in reducing obesity by regulation of lipid metabolism through inhibition of PDE4, indicating its potential as a major therapeutic medicinal compound.
    Keywords:  Adipose tissue; Anti-obesity; Fat browning; Phosphodiesterase; Theobromine
    DOI:  https://doi.org/10.1007/s00394-020-02184-6
  1634. Data Brief. 2020 Feb;28 104968
    Joint measurements of NDVI and crop production data-set related to combination of management zones delineation and nitrogen fertilisation levels.
    Cordero E, Longchamps L, Khosla R, Sacco D.
      This research compared four nitrogen (N) management strategies (uniform N rate: UR, variable N rate based on crop proximal sensing: VR-PS, variable N rate based on management zones: VR-MZ and variable N rate based on integrating crop sensing and MZ: VR-PSMZ), evaluating their effect on maize grain yield, partial factor productivity (PFPN), and net return above N fertiliser cost (RANC). The study provided a practical tool for choosing the fertilisation strategy that best performs in each agro-environment. These datasets are a supplementary material to the research paper by [3]. Data were collected over seven site-years experiments conducted in North-Eastern Colorado (USA). In dataset 1, for each site-year, data includes geo-referred points where grain yield and Normalised Difference Vegetation Index (NDVI) were measured, each one associated with its respective N rate, management zone (MZ), PFPN, RANC, and N management strategy. In order to group the observations reflecting homogeneous crop vigour, NDVI values were clustered within NDVI classes. In dataset 2, the main soil properties measured in several geo-referred points in each location are provided.
    Keywords:  Data integration; Management-zones; Variable N rate
    DOI:  https://doi.org/10.1016/j.dib.2019.104968
  1635. Sci Rep. 2020 Jan 23. 10(1): 1027
    Teratological cases of the antennae in the family Aradidae (Hemiptera: Heteroptera).
    Taszakowski A, Kaszyca-Taszakowska N.
      Teratological cases of the antennae in the family Aradidae (Hemiptera: Heteroptera) are widely described for the first time. Four hundred seventy-six specimens of flat bugs were studied, and antennal malformations were found in 14 of them (2.94%) (belonging to eight species and three subfamilies: Aradinae, Aneurinae and Mezirinae). All of the teratologies were observed using optical microscopy; moreover, in order to determine any compensatory regeneration, selected cases were also studied using a scanning electron microscope. In almost all of the specimens, the successful regeneration of the sensory organs to various degrees was observed. Additional results were the discovery of a previously unrecognized type of sensillum in flat bugs - a campaniform sensillum as well as significant differences in the distribution of the sensilla depending on the systematic affiliation.
    DOI:  https://doi.org/10.1038/s41598-020-57891-1
  1636. Biotechnol Bioeng. 2020 Jan 25.
    Construction of yeast producing patchoulol by global metabolic engineering strategy.
    Mitsui R, Nishikawa R, Yamada R, Matsumoto T, Ogino H.
      Patchoulol is a sesquiterpene alcohol found in the leaves of the patchouli plant that can be extracted by steam distillation. Notably, patchoulol is an essential natural product frequently used in the chemical industry. However, patchouli produces an insignificant amount of patchoulol, not to mention steam distillation requires a lot of energy and time. Recombinant microorganisms that can be cultured in mild conditions and can produce patchoulol from renewable biomass resources may be a promising alternative. We previously developed the global metabolic engineering strategy (GMES), which produces a comprehensive metabolic modification in yeast, using the cocktail δ-integration method. In this study, we aimed to produce patchoulol by modifying engineered yeast. The expression of nine genes involved in patchoulol synthesis was modulated using the GMES. Regarding patchoulol production, the resultant strain, YPH499/PAT167/MVA442, showed a concentration of 42.1 mg/L, a production rate of 8.42 mg/L/d, and a yield of 2.05 mg/g-glucose, respectably. These concentration values, production rate, and yield obtained through batch-fermentation in this study were high level when compared to previously reported recombinant microorganism studies. The GMES could be used as a potential strategy for producing secondary metabolites from plants in recombinant Saccharomyces cerevisiae. This article is protected by copyright. All rights reserved.
    Keywords:   Saccharomyces cerevisiae ; Global metabolic engineering; Mevalonate pathway; Patchoulol
    DOI:  https://doi.org/10.1002/bit.27284
  1637. JAMA Netw Open. 2020 Jan 03. 3(1): e1919681
    Associations of Prenatal and Childhood Antibiotic Exposure With Obesity at Age 4 Years.
    Leong KSW, McLay J, Derraik JGB, Gibb S, Shackleton N, Taylor RW, Glover M, Audas R, Taylor B, Milne BJ, Cutfield WS.
      Importance: Although antibiotics are associated with obesity in animal models, the evidence in humans is conflicting.Objective: To assess whether antibiotic exposure during pregnancy and/or early childhood is associated with the development of childhood obesity, focusing particularly on siblings and twins.
    Design, Setting, and Participants: This cross-sectional national study included 284 211 participants (132 852 mothers and 151 359 children) in New Zealand. Data analyses were performed for 150 699 children for whom data were available, 30 696 siblings, and 4188 twins using covariate-adjusted analyses, and for 6249 siblings and 522 twins with discordant outcomes using fixed-effects analyses. Data analysis was performed November 2017 to March 2019.
    Exposure: Exposure to antibiotics during pregnancy and/or early childhood.
    Main Outcomes and Measures: The main outcome is odds of obesity at age 4 years. Anthropometric data from children born between July 2008 and June 2011 were obtained from the B4 School Check, a national health screening program that records the height and weight of 4-year-old children in New Zealand. These data were linked to antibiotics (pharmaceutical records) dispensed to women before conception and during all 3 trimesters of pregnancy and to their children from birth until age 2 years.
    Results: The overall study population consisted of 132 852 mothers and 151 359 children (77 610 [51.3%] boys) who were aged 4 to 5 years when their anthropometrical measurements were assessed. Antibiotic exposure was common, with at least 1 course dispensed to 35.7% of mothers during pregnancy and 82.3% of children during the first 2 years of life. Results from covariate-adjusted analyses showed that both prenatal and early childhood exposures to antibiotics were independently associated with obesity at age 4 years, in a dose-dependent manner. Every additional course of antibiotics dispensed to the mothers yielded an adjusted odds ratio (aOR) of obesity in their children (siblings) of 1.02 (95% CI, 0.99-1.06), which was similar to the odds across pregnancy for the whole population (aOR, 1.06; 95% CI, 1.04-1.07). For the child's exposure, the aOR for the association between antibiotic exposure and obesity was 1.04 (95% CI, 1.03-1.05) among siblings and 1.05 (95% CI, 1.02-1.09) among twins. However, fixed-effects analyses of siblings and twins showed no associations between antibiotic exposure and obesity, with aORs of 0.95 (95% CI, 0.90-1.00) for maternal exposure, 1.02 (95% CI, 0.99-1.04) for child's exposure, and 0.91 (95% CI, 0.81-1.02) for twins' exposure.
    Conclusions and Relevance: Although covariate-adjusted analyses demonstrated an association between antibiotic exposure and odds of obesity, further analyses of siblings and twins with discordant outcomes showed no associations. Thus, these discordant results likely reflect unmeasured confounding factors.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2019.19681
  1638. Hum Gene Ther. 2020 Jan;31(1-2): 12-13
    Gene Therapy Untangles the Problem of Chronic Traumatic Encephalopathy.
    Flotte TR.
      
    DOI:  https://doi.org/10.1089/hum.2019.29104.trf
  1639. Curr Med Imaging Rev. 2019 ;15(2): 122-131
    Attributes, Performance, and Gaps in Current & Emerging Breast Cancer Screening Technologies.
    Ismail HM, Pretty CG, Signal MK, Haggers M, Chase JG.
      BACKGROUND: Early detection of breast cancer, combined with effective treatment, can reduce mortality. Millions of women are diagnosed with breast cancer and many die every year globally. Numerous early detection screening tests have been employed. A wide range of current breast cancer screening methods are reviewed based on a series of searchers focused on clinical testing and performance.DISCUSSION: The key factors evaluated centre around the trade-offs between accuracy (sensitivity and specificity), operator dependence of results, invasiveness, comfort, time required, and cost. All of these factors affect the quality of the screen, access/eligibility, and/or compliance to screening programs by eligible women. This survey article provides an overview of the working principles, benefits, limitations, performance, and cost of current breast cancer detection techniques. It is based on an extensive literature review focusing on published works reporting the main performance, cost, and comfort/compliance metrics considered.
    CONCLUSION: Due to limitations and drawbacks of existing breast cancer screening methods there is a need for better screening methods. Emerging, non-invasive methods offer promise to mitigate the issues particularly around comfort/pain and radiation dose, which would improve compliance and enable all ages to be screened regularly. However, these methods must still undergo significant validation testing to prove they can provide realistic screening alternatives to the current accepted standards.
    Keywords:  Mammography; elastography; magnetic resonance imaging; microwave imaging; thermography; ultrasound
    DOI:  https://doi.org/10.2174/1573405613666170825115032
  1640. Oncol Lett. 2020 Feb;19(2): 1187-1194
    Effects of propofol and sevoflurane on blood glucose, hemodynamics, and inflammatory factors of patients with type 2 diabetes mellitus and gastric cancer.
    Liu J, Yang L.
      Effects of propofol and sevoflurane on blood glucose, hemodynamics, and inflammatory factors of patients with type 2 diabetes mellitus (T2DM) and gastric cancer (GC) were investigated. One hundred and ten patients with T2DM and GC, treated in The First Affiliated Hospital of Baotou Medical College (Baotou, China) from January 2017 to December 2018, were selected. Sixty patients anesthetized by propofol were included in the propofol group, whereas 50 patients anesthetized by sevoflurane were included in the sevoflurane group. The level of blood glucose, hemodynamic indicators, and inflammatory factors of the patients in the two groups were compared at T0 (before anesthesia), T1 (2 min after intubation), T2 (5 min after pneumoperitoneum), and T3 (60 min after surgery). Mini-Mental State Examination (MMSE) cognitive function scores were compared at T0 (before anesthesia), T4 (6 h after surgery), and T5 (72 h after surgery) between the two groups. The anesthetic effect and the incidence of adverse reactions were also compared between the two groups. The heart rate (HR), oxygen saturation (SpO2) and average artery pressure decreased slightly and then increased after the surgery was started; whereas, the levels of the serum inflammatory factors first increased and then decreased, to return to their initial levels. MMSE scores of the patients in two groups at T4 were significantly lower than those at T0 (P<0.05), and the MMSE score at T4 was significantly higher in the propofol group than that in the sevoflurane group (P<0.05). The time of spontaneous breathing, verbal response, eye opening, and extubation in the propofol group was significantly shorter than that in the sevoflurane group (P<0.05). The incidence of adverse reactions in the propofol group was lower than that in the sevoflurane group. The effect of propofol is less than that of sevoflurane, thus propofol is more suitable for the anesthesia of patients with T2DM and GC.
    Keywords:  anesthesia; patients with type 2 diabetes mellitus and gastric cancer; propofol; sevoflurane
    DOI:  https://doi.org/10.3892/ol.2019.11201
  1641. Behav Anal Pract. 2019 Dec;12(4): 805-809
    Cultural Humility in the Practice of Applied Behavior Analysis.
    Wright PI.
      Applied behavior analysis (ABA) has the intent to improve the human condition in a broad range of categories of practice and for diverse groups of individuals across cultures. The data on the diversity of the professionals practicing in the field of ABA are sparse. Access to ABA intervention is inequitable, and cultural differences are not adequately addressed in many current established behavioral interventions. Cultural humility is a framework used by other professional disciplines to address both institutional and individual behavior that contributes to the power imbalance, the marginalization of communities, and disparities in health access and outcomes. This article discusses the adoption of culturally humble practices, specifically through the use of self-reflection, by the field of ABA to address disparities and improve outcomes. A specific framework from the field of social work is shared, and an adaptation to the behavior-analytic practice of self-management is provided.
    Keywords:  Applied behavior analysis; Cultural humility; Disability; Self-reflection; Social service
    DOI:  https://doi.org/10.1007/s40617-019-00343-8
  1642. Phys Rev Lett. 2020 Jan 10. 124(1): 017202
    Topological Magnetic Phase in the Candidate Weyl Semimetal CeAlGe.
    Puphal P, Pomjakushin V, Kanazawa N, Ukleev V, Gawryluk DJ, Ma J, Naamneh M, Plumb NC, Keller L, Cubitt R, Pomjakushina E, White JS.
      We report the discovery of topological magnetism in the candidate magnetic Weyl semimetal CeAlGe. Using neutron scattering we find this system to host several incommensurate, square-coordinated multi-k[over →] magnetic phases below T_{N}. The topological properties of a phase stable at intermediate magnetic fields parallel to the c axis are suggested by observation of a topological Hall effect. Our findings highlight CeAlGe as an exceptional system for exploiting the interplay between the nontrivial topologies of the magnetization in real space and Weyl nodes in momentum space.
    DOI:  https://doi.org/10.1103/PhysRevLett.124.017202
  1643. Rev Med Suisse. 2020 Jan 22. 16(678): 117-122
    [2019 scientific breakthroughs in ambulatory general internal medicine].
    Gouveia A, Wenger-Bonny C, Psychia E, Selby K, Ka Sing Ho L, Kokkinakis I, Chenal R, Pasche O, Favrat B, Bodenmann P.
      In healthy adults, vitamin D does not prevent falls or hip fractures. The diabetogenic effect of topical steroids is significant and dose dependent. Pulmonary embolism can be surely ruled out by the YEARS algorithm adapted to pregnancy. Patients with osteoarthritis treated with tramadol have a higher risk of death when compared to those treated with non-steroidal anti-inflammatory drugs. Inappropriate prescribing in elderly patients can be reduced by an educational intervention deployed in pharmacies. Medical scribes are effective in improving visit quality and job satisfaction of family physicians. Impedance studies lead to new diagnostic approaches in chronic fatigue. In healthy individuals, isolated check-up interventions do not have an impact on morbidity and mortality.
  1644. Am J Ophthalmol. 2019 Oct;pii: S0002-9394(19)30304-6. [Epub ahead of print]206 215-216
    A New Paradigm in the Treatment of Advanced Periocular Basal Cell Carcinoma?
    Unsworth SP, Heisel CJ, Kahana A.
      
    DOI:  https://doi.org/10.1016/j.ajo.2019.06.027
  1645. Mol Plant. 2020 Jan 21. pii: S1674-2052(20)30007-1. [Epub ahead of print]
    Cuscuta, the Merchant of Proteins.
    Patelini A, Helariutta Y.
      
    DOI:  https://doi.org/10.1016/j.molp.2020.01.007
  1646. Nat Immunol. 2020 Feb;21(2): 103
    Nociceptors in antimicrobial defense.
    Visan I.
      
    DOI:  https://doi.org/10.1038/s41590-019-0586-8
  1647. Phys Rev Lett. 2020 Jan 10. 124(1): 015501
    Rigidity-Controlled Crossover: From Spinodal to Critical Failure.
    Borja da Rocha H, Truskinovsky L.
      Failure in disordered solids is accompanied by intermittent fluctuations extending over a broad range of scales. The implied scaling has been previously associated with either spinodal or critical points. We use an analytically transparent mean-field model to show that both analogies are relevant near the brittle-to-ductile transition. Our study indicates that in addition to the strength of quenched disorder, an appropriately chosen global measure of rigidity (connectivity) can be also used to tune the system to criticality. By interpreting rigidity as a timelike variable we reveal an intriguing parallel between earthquake-type critical failure and Burgers turbulence.
    DOI:  https://doi.org/10.1103/PhysRevLett.124.015501
  1648. JAMA. 2020 01 21. 323(3): 217-218
    Hydroxyethyl Starch for Fluid Replacement Therapy in High-Risk Surgical Patients: Context and Caution.
    Zampieri FG, Cavalcanti AB.
      
    DOI:  https://doi.org/10.1001/jama.2019.20141
  1649. Cell Stem Cell. 2020 Jan 07. pii: S1934-5909(19)30525-9. [Epub ahead of print]
    Self-Organizing 3D Human Trunk Neuromuscular Organoids.
    Faustino Martins JM, Fischer C, Urzi A, Vidal R, Kunz S, Ruffault PL, Kabuss L, Hube I, Gazzerro E, Birchmeier C, Spuler S, Sauer S, Gouti M.
      Neuromuscular networks assemble during early human embryonic development and are essential for the control of body movement. Previous neuromuscular junction modeling efforts using human pluripotent stem cells (hPSCs) generated either spinal cord neurons or skeletal muscles in monolayer culture. Here, we use hPSC-derived axial stem cells, the building blocks of the posterior body, to simultaneously generate spinal cord neurons and skeletal muscle cells that self-organize to generate human neuromuscular organoids (NMOs) that can be maintained in 3D for several months. Single-cell RNA-sequencing of individual organoids revealed reproducibility across experiments and enabled the tracking of the neural and mesodermal differentiation trajectories as organoids developed and matured. NMOs contain functional neuromuscular junctions supported by terminal Schwann cells. They contract and develop central pattern generator-like neuronal circuits. Finally, we successfully use NMOs to recapitulate key aspects of myasthenia gravis pathology, thus highlighting the significant potential of NMOs for modeling neuromuscular diseases in the future.
    Keywords:  NMOs; NMPs; central pattern generators; myasthenia gravis; neuromesodermal progenitors; neuromuscular diseases; neuromuscular junction; neuromuscular organoids; skeletal muscles; spinal cord
    DOI:  https://doi.org/10.1016/j.stem.2019.12.007
  1650. Sci Rep. 2020 Jan 21. 10(1): 845
    Lethal methemoglobinemia in the invasive brown treesnake after acetaminophen ingestion.
    Mathies T, Mauldin RE.
      The invasive brown treesnake (Boiga irregularis) has extirpated much of Guam's native birdlife and poses significant threats to other parts of the western Pacific. Acetaminophen (APAP) is a proven lethal oral toxicant in reptiles but the physiological mechanism is unknown. The effects of a lethal APAP oral dose on methemoglobin (MetHb, non-oxygen carrying form) levels and other blood parameters were examined in brown treesnakes. Co-oximetry was used to measure MetHb (%) and other hemoglobin species. Assessment of red blood cell integrity, white blood cell differential counts, and plasma biochemical analyses were conducted to evaluate tissue damage, stress, and liver function. Changes in oxygen carrying capacity were noted in APAP-treated snakes indicated by a 50-60% increase in methemoglobin levels and a 40% decrease in oxyhemoglobin (oxygen-carrying form) levels compared to controls. APAP-treated snakes had decreased lymphocyte and increased monocyte counts while also having increased levels of blood analytes associate with impaired liver function and muscle damage. The proximate cause of death in APAP-treated snakes was likely acute methemoglobinemia and respiratory failure due to severe hypoxia with no observed signs of distress or pain. An orally-ingested lethal dose of APAP appears to be a humane method for lethal control of this species.
    DOI:  https://doi.org/10.1038/s41598-019-56216-1
  1651. Methods Mol Biol. 2020 ;2122 141-150
    Cell Type-Specific Transcriptomics in the Plant Embryo Using an Adapted INTACT Protocol.
    Palovaara J, Weijers D.
      Cells differentiate from undifferentiated precursors in order to establish the tissues of vascular plants. The different cell types and stem cells are first specified in the early embryo. How cell type specification is instructed by transcriptional control on a genome-wide level is poorly understood. A major hurdle has been the technical challenge associated with obtaining cellular transcriptomes in this inaccessible tissue. Recently, we adapted a two-component genetic labeling system called INTACT to isolate nuclei and generate a microarray-based expression atlas of the cell types in the early Arabidopsis thaliana embryo. Here we present a step-by-step description of the adapted INTACT protocol, as well as the approach to generate transcriptomic profiles. This protocol has been adapted to account for using seeds with embryos of various developmental stages as a starting material, and the relatively few cell type-specific nuclei that can be isolated from embryos.
    Keywords:  Cell type-specific; Embryo; Isolation; Nucleus; Transcriptome
    DOI:  https://doi.org/10.1007/978-1-0716-0342-0_11
  1652. Trends Biotechnol. 2020 Jan 15. pii: S0167-7799(19)30309-9. [Epub ahead of print]
    The Pathway Less Traveled: Engineering Biosynthesis of Nonstandard Functional Groups.
    Sulzbach M, Kunjapur AM.
      The field of metabolic engineering has achieved biochemical routes for conversion of renewable inputs to structurally diverse chemicals, but these products contain a limited number of chemical functional groups. In this review, we provide an overview of the progression of uncommon or 'nonstandard' functional groups from the elucidation of their biosynthetic machinery to the pathway optimization framework of metabolic engineering. We highlight exemplary efforts from primarily the last 5 years for biosynthesis of aldehyde, ester, terminal alkyne, terminal alkene, fluoro, epoxide, nitro, nitroso, nitrile, and hydrazine functional groups. These representative nonstandard functional groups vary in development stage and showcase the pipeline of chemical diversity that could soon appear within customized, biologically produced molecules.
    Keywords:  biosynthesis; chemical biology; metabolic engineering; natural products; nonstandard functional groups
    DOI:  https://doi.org/10.1016/j.tibtech.2019.12.014
  1653. Anal Chem. 2020 Jan 24.
    MXene Titanium Carbide-based Biosensor: Strong Dependence of Exfoliation Method on Performance.
    Chia HL, Mayorga-Martinez CC, Antonatos N, Sofer Z, Gonzalez-Julian JJ, Webster RD, Pumera M.
      Transition metal carbides, known as MXenes, are generated via the selective etching of "A" layers from their layered, ternary parent compounds, MAX phases, where M corresponds to early d-transition metal, A being a main group sp-element from either Group 13 or 14 and carbon or nitrogen being denoted by X. MXenes are being recognized as a new and uprising class of 2D materials with extraordinary physical and electrochemical properties. The huge specific surface area and outstanding electrical conductivity of MXenes, make them ideal candidates for sensing and energy applications. Herein, we demonstrated the successful incorporation of pristine MXene, Ti3C2 produced via HF etching and subsequent delamination with TBAOH, as a transducer platform toward the development of a second generation electrochemical glucose biosensor. Chronoamperometric studies demonstrate that the proposed biosensing system exhibits high selectivity and excellent electrocatalytic activity toward the detection of glucose, spanning over wide linear ranges of 50-27 750 μM and possess a low limit of detection of 23.0 μM. The findings reported in this study conceptually proves the probable applications of pristine MXenes toward the field of biosensors and pave ways for the future developments of highly selective and sensitive electrochemical biosensors for biomedical and food sampling applications.
    DOI:  https://doi.org/10.1021/acs.analchem.9b03634
  1654. J Mol Endocrinol. 2020 Jan 01. pii: JME-19-0050.R3. [Epub ahead of print]
    Soluble (pro)renin receptor increased by hypoxia maintains oxidative metabolism in trophoblasts.
    Suda C, Yatabe J, Yatabe M, Yarita M, Ichihara A.
      Elevated soluble (pro)renin receptor [s(P)RR] concentration in maternal blood is associated with gestational hypertension and preeclampsia. Placenta has abundant expression of (P)RR, and the binding of (P)RR with pyruvate dehydrogenase E1 beta subunit (PDHB) is reported to maintain oxidative metabolism. Thus, we hypothesized that placental hypoxia may increase (P)RR, and the increased (P)RR may preserve PDHB expression. Expression and functional analyses were performed using human placental trophoblast cells, mainly JAR cells. (P)RR co-immunoprecipitated and showed co-immunofluorescence with PDHB mainly in the mitochondria. Hypoxia treatment significantly increased intracellular s(P)RR protein expression, but secreted s(P)RR in the culture medium was decreased by hypoxia. Hypoxia treatment did not alter PDHB expression or activity in the basal condition, but when (P)RR was knocked down by siRNA, PDHB protein and activity were reduced by hypoxia. Acetyl-CoA, the product of PDH activity, was significantly reduced by hypoxia treatment with (P)RR siRNA. S(P)RR is generated from full-length PRR when cleaved by specific proteases. Protease inhibitor experiments suggested furin and site 1 protease as the enzymes generating s(P)RR inJAR cells, and only when treated by site 1 protease inhibitor, PF429242, PDHB protein showed a significant trend to decrease with hypoxia. In JAR cells, hypoxia increased intracellular s(P)RR, and (P)RR preserved the expression and function of PDHB during hypoxia. (P)RR may help maintain oxidative metabolism and efficient energy production during placental ischemia in hypertensive disorders of pregnancy.
    DOI:  https://doi.org/10.1530/JME-19-0050
  1655. Genes (Basel). 2020 Jan 16. pii: E100. [Epub ahead of print]11(1):
    Mitochondrial DNA Haplotypes Influence Energy Metabolism across Chicken Transmitochondrial Cybrids.
    Kong M, Xiang H, Wang J, Liu J, Zhang X, Zhao X.
      The association between mitochondrial DNA haplotype and productive performances has been widely reported in chicken breeds. However, there has not been physiological evidence of this seen previously. In this study, chicken transmitochondrial cells were generated using the nucleus of the DF-1 cell line and mitochondria of primary cell lines derived from two native chicken breeds, Tibetan chicken and Shouguang chicken. Generally, Tibetan chicken primary cells showed a stronger metabolic capacity than Shouguang chicken primary cells. However, the Tibetan chicken cybrids had a dramatic drop in relative mtDNA copies and oxygen consumption. Higher rates of oxygen consumption (OCR) and expression levels of mitochondrial biogenesis and fusion genes were observed in Shouguang chicken cybrids, potentially reflecting that the mitochondrial DNA haplotype of Shouguang chicken had better coordination with the DF-1 nucleus than others. Meanwhile, mitonuclear incompatibility occurred in Tibetan chicken cybrids. The results demonstrate functional differences among mitochondrial DNA haplotypes and may shed light on the interaction between the mitochondria and nucleus in Gallus gallus domesticus.
    Keywords:  chicken breed; cybrids; energy metabolism; mitochondrial DNA haplotype
    DOI:  https://doi.org/10.3390/genes11010100
  1656. Curr Opin Urol. 2020 Jan 16.
    Role of primary retroperitoneal lymph node dissection in stage I and low-volume metastatic germ cell tumors.
    Heidenreich A, Paffenholz P, Nestler T, Pfister D, Daneshmand S.
      PURPOSE OF REVIEW: Early-stage testicular cancers are highly curable. Following orchidectomy, management options for stage I disease include active surveillance, nerve-sparing retroperitoneal lymph node dissection (nsRPLND) and primary chemotherapy as recommended by the current guidelines. Primary RPLND has for decades played an integral part of treatment in patients with early-stage testicular germ cell tumors (TGCT), particularly in nonseminomatous germ cell tumors (NSGCT) with focus on reducing the long-term morbidity. We review the role of RPLND in stage I NSCGT as well as stage II A/B NSGCT and as seminoma.RECENT FINDINGS: Radiation therapy and systemic chemotherapy are established treatments for seminoma; however, long-term data has demonstrated the association of such therapies with late toxicity including secondary malignancies, hearing loss, cardiovascular disease as well as metabolic syndromes. Given the well established role of RPLND in NSGCTs, clinicians have developed an interest in utilization of surgery for low-volume retroperitoneal metastatic disease. Two prospective clinical trials (SEMS and PRIMETEST) are underway to determine the role of RPLND alone in low volume metastatic seminoma.
    SUMMARY: RPLND is a highly effective treatment for early-stage germ cell tumors but represents overtreatment in low-volume stage I disease where active surveillance is recommended. RPLND has shown a promising role in low-volume stage II seminomas. Two phase II clinical trials are underway to further determine the curative potential of this approach.
    DOI:  https://doi.org/10.1097/MOU.0000000000000736
  1657. Clin J Pain. 2020 Jan 20.
    The Relationship between Clinical and Quantitative Measures of Pain Sensitization in Knee Osteoarthritis.
    Moore R, Clifford AM, Moloney N, Doody C, Smart KM, O'Leary H.
      OBJECTIVES: Pain sensitization in knee osteoarthritis is associated with greater symptom severity and poorer clinical outcomes. Measures which identify pain sensitization and are accessible to use in clinical practice have been suggested to enable more targeted treatments. This merits further investigation. This study examines the relationship between Quantitative Sensory Testing (QST) and clinical measures of pain sensitization in people with knee osteoarthritis.METHODS: A secondary analysis of data from 134 participants with knee osteoarthritis was performed. Clinical measures included: manual tender point count (MTPC), the Central Sensitization Inventory (CSI) to capture centrally mediated co-morbidities, number of painful sites on a body chart, and neuropathic pain-like symptoms assessed using the modified PainDetect Questionnaire (mPD-Q). Relationships between clinical measures and QST measures of pressure pain thresholds (PPTs), temporal summation (TS) and conditioned pain modulation (CPM) were investigated using correlation and multivariable regression analyses.
    RESULTS: Fair to moderate correlations, ranging from -0.331 to -0.577 (P<0.05), were identified between MTPC, the CSI, number of painful sites, and PPTs. Fair correlations, ranging from 0.28 to 0.30 (P<0.01), were identified between MTPC, the CSI, number of painful sites, and CPM. Correlations between the clinical and self-reported measures and TS were weak and inconsistent (0.09 to 0.25.). In adjusted regression models, MTPC was the only clinical measure consistently associated with QST and accounted for 11-12% of variance in PPTs.
    DISCUSSION: MTPC demonstrated the strongest associations with QST measures and may be the most promising proxy measure to detect pain sensitization clinically.
    DOI:  https://doi.org/10.1097/AJP.0000000000000798
  1658. Br Dent J. 2020 Jan;228(2): 59
    Recruitment and retention.
    Hussain I, Thomson A, Norfolk T.
      
    DOI:  https://doi.org/10.1038/s41415-020-1204-8
  1659. Synapse. 2020 Jan 23. e22149
    Differential calcium channel-mediated dopaminergic modulation in the subthalamonigral synapse.
    Robles-Gómez AA, Vega AV, Floran B, Barral J.
      Dopamine (DA) modulates basal ganglia (BG) activity for initiation and execution of goal-directed movements and habits. While most studies are aimed to striatal function, the cellular and molecular mechanisms underlying dopaminergic regulation in other nuclei of the BG are not well understood. Therefore, we set to analyze the dopaminergic modulation occurring in subthalamo-nigral synapse, in both pars compacta (SNc) and pars reticulata (SNr) neurons, because these synapses are important for the integration of information previously processed in striatum and globus pallidus. In this study, electrophysiological and pharmacological evidence of dopaminergic modulation on glutamate release through calcium channels is presented. By using paired pulse ratio (PPR) measurements and selective blockers of these ionic channels, together with agonists and antagonists of dopamine D2 -like receptors. We found that blockade of the CaV 3 family occludes the presynaptic inhibition produced by the activation of dopamine receptors pharmacologically profiled as D3 -type in the STh-SNc synapses. On the other hand, the blockade of CaV 2 channels, but not CaV 3, occlude with the effect of the D3 agonist, PD 128907, in the STh-SNr synapse. The functional role of this differential distribution of calcium channels that modulate the release of glutamate in the SN implies a fine adjustment of firing for both classes of neurons. Dopaminergic neurons of the SNc establish a DA tone within the SN based on the excitatory/inhibitory inputs; such tone may contribute to processing information from subthalamic nucleus and could also be involved in pathological DA depletion that drives hyperexcitation of SNr neurons.
    Keywords:  CaV3 and CaV2 calcium channels; D3 receptors; Presynaptic modulation; substantia nigra; subthalamo-nigral pathway
    DOI:  https://doi.org/10.1002/syn.22149
  1660. Curr Biol. 2020 Jan 20. pii: S0960-9822(19)31575-1. [Epub ahead of print]30(2): R57-R62
    Crassulacean acid metabolism.
    Gilman IS, Edwards EJ.
      Gilman and Edwards introduce crassulacean acid metabolism and highlight how recent advances in molecular biology are deepening our knowledge of CAM evolution.
    DOI:  https://doi.org/10.1016/j.cub.2019.11.073
  1661. Circ Cardiovasc Interv. 2020 Feb;13(2): e008760
    Competency-Based Assessment of Interventional Cardiology Fellows' Abilities in Intracoronary Physiology and Imaging.
    Flattery E, Rahim HM, Petrossian G, Shlofmitz E, Gkargkoulas F, Matsumura M, Kirtane AJ, Parikh SA, Parikh MA, Moses JW, Karmpaliotis D, Ben-Yehuda O, Leon MB, Jeremias A, Shlofmitz RA, Stone GW, Maehara A, Mahmud E, Mintz GS, Ali ZA.
      
    Keywords:  cardiology; coronary angiography; percutaneous coronary intervention; stents; tomography
    DOI:  https://doi.org/10.1161/CIRCINTERVENTIONS.119.008760
  1662. Pest Manag Sci. 2020 Jan 24.
    NPC1b as a novel target in controlling the cotton bollworm, Helicoverpa armigera.
    Zheng JC, Yue XR, Kuang WQ, Li SL, Tang R, Zhang ZF, Kurban A, Rehman SU, Zhao C, Liu TX, Jing X.
      BACKGROUND: Insects cannot synthesize sterols and must acquire them from food. The mechanisms underlying how insects uptake dietary sterols are largely unknown except that NPC1b, an integral membrane protein, has been shown to be responsible for dietary cholesterol uptake in Drosophila melanogaster. However, whether NPC1b orthologues in other insect species, particularly the economically important pests, function similarly remains to be determined.RESULTS: In this study, we characterized the function of NPC1b in Helicoverpa armigera, a global pest that causes severe yield losses to many important crops. Limiting dietary cholesterol uptake to insects significantly inhibited food ingestion and weight gain. Compared to the wild-type H. armigera, the CRISPR/Cas9-edited NPC1b mutant larvae were incapable of getting adequate cholesterol and died in their early life stage. Gene expression profile and in-situ hybridization analyses indicated that NPC1b was mainly expressed in the midgut where dietary cholesterol was absorbed. Expression of NPC1b was also correlated with the feeding life stages and was especially upregulated during early larval instars. Protein-ligand docking and sequence similarity analyses further demonstrated that NPC1b proteins of lepidopteran insects shared a relatively conserved cholesterol binding region, NPC1b_NTD, which, however, was highly divergent from bees-derived sequences.
    CONCLUSION: NPC1b was crucial for dietary cholesterol uptake and growth of H. armigera, and therefore could serve as an insecticide target for the development of a novel pest-management approach to control this economically significant insect pest with little off-target effect on bees and sterol-autotrophic animals. This article is protected by copyright. All rights reserved.
    Keywords:  CRISPR/Cas9; Helicoverpa armigera; NPC1b; cholesterol absorption
    DOI:  https://doi.org/10.1002/ps.5761
  1663. ACS Appl Mater Interfaces. 2020 Jan 24.
    p-p Heterojunction Sensors of p-Cu3Mo2O9 Micro/Nanorods Vertically Grown on p-CuO Layers for Room Temperature Ultrasensitive and Fast-Recoverable Detection of NO2.
    Adamu BI, Falak A, Tian Y, Tan X, Meng X, Chen P, Wang H, Chu W.
      High sensitivity, low limit of detection (LOD), and short response and recovery times at room temperature (RT) are critical for gas sensors. For NO2, different binary metal oxides-based sensors were developed to achieve superior performance at elevated temperatures instead of RT. Herein, we report on CuO@CuO and Cu3Mo2O9@CuO sensors with CuO and Cu3Mo2O9 micro/nanorods vertically aligned on the CuO layers which were directly fabricated using a facile, low-cost and catalyst-free chemical vapor deposition (CVD) technique. Their sensing performance tests revealed that the Cu3Mo2O9@CuO p-p heterojunction sensors exhibited a high response of 160% to 5 ppm NO2, an excellent sensitivity of 50% ppm-1, low LOD of 2.30 ppb, a short response time of 49 s, and rapid recovery of 241 s at RT, far better than those for CuO@CuO sensors. The superior performance of Cu3Mo2O9@CuO sensors could be attributed to the Schottky heterojunction formed between p-Cu3Mo2O9 micro/nanorods and p-CuO films, the catalytic effect and anisotropic nature of Cu3Mo2O9 micro/nanorods. This study not only provides a simple, low-cost and batchable fabrication method of homo/hetero-junction sensors with micro/nanorods vertically aligned on films but opens an avenue for sensor design by tuning the Schottky barrier height to enhance RT performance.
    DOI:  https://doi.org/10.1021/acsami.9b19971
  1664. Ecotoxicol Environ Saf. 2020 Jan 17. pii: S0147-6513(20)30010-5. [Epub ahead of print]191 110171
    Uptake of atenolol, carbamazepine and triclosan by crops irrigated with reclaimed water in a Mediterranean scenario.
    Beltrán EM, Pablos MV, Fernández Torija C, Porcel MÁ, González-Doncel M.
      Water scarcity is a natural condition in the Mediterranean rim countries. In this region, reuse of reclaimed water (RW) from wastewater treatment plants (WWTPs) is becoming a potential source for highly water-demanding activities such as agriculture. However, the removal capacity of contaminants in regular WWTPs has been found to be limited. Considering a Mediterranean scenario, this research investigated the plant uptake and translocation of three representative pharmaceuticals and personal care products (PPCPs) typically present in RW samples from a WWTP located in an urban area in Spain, and assessed the potential risk to humans from plant consumption. The RW samples were collected and analyzed for three representative PPCPs (atenolol -ATN-, carbamazepine -CBZ- and triclosan -TCS-). The target contaminants were also spiked at two levels in the RW samples to consider two worst-case scenarios. Three plant models (lettuce, maize and radish) were grown outdoors and irrigated with four treatments: tap water; RW samples, and the two spiked RW samples. Generally speaking, results revealed an efficient root uptake for the three PPCPs regardless of plant species and fortification level, and suggested an interaction effect of treatment and plant organ. Different bioaccumulation and translocation potentials of the three PPCPs were seen into the aerial organs of the plants. Overall, these observations support the idea that factors including the physico-chemical properties of the PPCPs and physiological plant variables, could be responsible for the differential accumulation and translocation potentials observed. These variables could be critical for crops irrigated with RW in regions with extended dry seasons, high solar incidence and low annual rainfall such as those in the Mediterranean rim where plants are subjected to high transpiration rates. However, the results obtained from this experimental approach suggested a negligible risk to humans from consumption of edible plants irrigated with RW samples with presence of PPCPs, despite the fact that the three representative PPCPs under study accumulated efficiently in the plants.
    Keywords:  Emerging contaminants; Human exposure risk; Irrigation; Soil accumulation; Uptake
    DOI:  https://doi.org/10.1016/j.ecoenv.2020.110171
  1665. Lancet Psychiatry. 2020 Jan 15. pii: S2215-0366(19)30515-2. [Epub ahead of print]
    Addressing mental health in Aboriginal young people in Australia.
    Wright M, Crisp N, Newnham E, Flavell H, Lin A.
      
    DOI:  https://doi.org/10.1016/S2215-0366(19)30515-2
  1666. Pflugers Arch. 2020 Jan 21.
    Chemerin-9-induced contraction was enhanced through the upregulation of smooth muscle chemokine-like receptor 1 in isolated pulmonary artery of pulmonary arterial hypertensive rats.
    Omori A, Goshima M, Kakuda C, Kodama T, Otani K, Okada M, Yamawaki H.
      Chemerin is an adipocytokine having cardiovascular effects. Chemokine-like receptor 1 (CMKLR1) and chemokine (CC motif) receptor-like 2 (CCRL2) are chemerin receptors. Chemerin-9, an active fragment, causes contraction via smooth muscle CMKLR1 in isolated blood vessels. Pulmonary arterial hypertension (PAH) is a fatal disease resulting ultimately in right heart failure. To test the hypothesis that chemerin affects pulmonary artery (PA) resistance, we examined the effects of chemerin-9 on contractility of isolated PA from PAH rats. Wistar rats were injected with monocrotaline (MCT) for 2 weeks to make PAH rats (MCT rats). Control (Cont) rats received a saline injection. Chemerin-9-induced contraction of isolated intrapulmonary artery (IPA) from left lung was isometrically measured. Protein expression of CMKLR1 and CCRL2 in isolated left lung was determined by Western blotting. Localization of CMKLR1 in IPA of left lung was examined immunohistochemically. Chemerin-9-induced contraction was significantly enhanced in IPA from MCT compared with Cont rats. Protein expression of CMKLR1 was significantly elevated in isolated left lung from MCT compared with Cont rats, while protein expression of CCRL2, a decoy receptor, was significantly decreased. CMKLR1 was localized mainly in endothelium of IPA in Cont rats. The CMKLR1 expression was significantly decreased in endothelium of IPA in MCT rats, while it was significantly elevated in smooth muscle. The present study for the first time demonstrated that the enhanced chemerin-9-induced contraction of isolated IPA from MCT rats was at least partly caused by the increase of CMKLR1 in smooth muscle.
    Keywords:  Adipocytokine; Pulmonary arterial hypertension; Receptor; Smooth muscle; Vascular contractility
    DOI:  https://doi.org/10.1007/s00424-019-02345-5
  1667. Int J Hyg Environ Health. 2019 Dec 18. pii: S1438-4639(19)30708-4. [Epub ahead of print]224 113434
    Disparities in exposure to surrounding greenness related to proportion of the population that were immigrants to the United States.
    Fong KC, Mehta NK, Bell ML.
      The proportion of the United States (US) population who are immigrants (i.e., foreign-born) has been rising. Compared to the US-born, immigrants have different health risks, and prior studies could not fully explain these differences by diet and socioeconomic status. Surrounding greenness, an environmental exposure linked to better health, potentially contributes to differences in health risks between immigrants and the US-born. Using satellite imagery, we assessed exposure to surrounding greenness, as estimated by the normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI), in US Census tracts in 2000 and 2010. We then investigated the association between the percentage of the population that were immigrants and greenness using spatial error regression. Adjusted for median household income, urbanicity, educational attainment, unemployment, elderly and youth population proportion, and ecozone, Census tracts with ~10% higher overall immigrant percentage points were, on average, ~0.06 NDVI/EVI interquartile range lower, indicating lower greenness. The pattern of negative associations was most consistent when the immigrant country of origin was in Latin America. Conversely, when the immigrant country of origin was in Europe, we found mostly positive associations. Our findings suggest an environmental exposure disparity by immigrant status, motivating future work on environmental contributions to health disparities between immigrants and the US-born.
    Keywords:  Environmental disparity; Green space; Immigrant health; Normalized difference vegetation index; Spatial regression; Surrounding greenness
    DOI:  https://doi.org/10.1016/j.ijheh.2019.113434
  1668. ACS Appl Mater Interfaces. 2020 Jan 22.
    Effect of Trapped Solvent on the Interphase between PS-b-PMMA Thin Film and P(S-r-MMA) Brush Layer.
    Sparnacci K, Chiarcos R, Gianotti V, Laus M, Giammaria TJ, Perego M, Munao G, Milano G, De Nicola A, Haese M, Kreuzer LP, Widmann T, Muller-Buschbaum P.
      The orientation of block copolymer (BCP) features in thin films can be obtained by spin-coating a BCP solution on a substrate surface functionalized by a polymer brush layer of the appropriate random copolymer (RCP). Although this approach is well-established, little work reporting the amount and the distribution of residual solvent in the polymer film after the spin-coating process is available. Moreover, no information can be found on the effect of trapped solvent on the interface between the BCP film and the RCP brush. In this work, systems consisting of poly(styrene)-b-poly(methyl methacrylate) thin films deposited on poly(styrene-r-methyl methacrylate) brush layers are investigated by combining neutron reflectivity (NR) experiments with simulation techniques. An increase in the amount of trapped solvent is observed by NR as the BCP film thickness increases accompanied by a significant decrease of the interpenetration length between BCP and RCP, thus suggesting that the interpenetration between grafted chains and block copolymer chains is hampered by the solvent. Hybrid Particle-Field Molecular Dynamics simulations of the analyzed system confirm the experimental observations and demonstrate a clear correlation between the interpenetration length and the amount of trapped solvent.
    DOI:  https://doi.org/10.1021/acsami.9b20801
  1669. J Ethnopharmacol. 2020 Jan 21. pii: S0378-8741(19)33232-5. [Epub ahead of print] 112579
    Phenols fragment of Veronica ciliata Fisch. Ameliorate free radical-induced nonalcoholic fatty liver disease by mediating PI3K/Akt signaling pathway.
    Sun Y, Wang L, Lu Q, He L, Hua W, Zhang S, Wang T, Gu W, Li T, Tang L.
      ETHNOPHARMACOLOGICAL RELEVANCE: Veronica ciliata Fisch. is used in numerous of Tibetan medicine prescriptions because of its hepatoprotective effect.AIMS OF THIS STUDY: Here, we aimed to investigate the hepatoprotective effect and mechanism of phenolic fraction (PF) of V. ciliata Fisch. on liver injury induced by free radical.
    MATERIALS AND METHODS: BRL 3A cells were pre-treated with PF and luteolin (Lut) following tert-butyl hydroperoxide (t-BHP) treatment. The cell viability, lactate dehydrogenase (LDH) levels, reactive oxygen species (ROS) generation, apoptosis, cell cycle and autophagy were analyzed. Apoptotic, inflammatory, and autophagy,- related proteins were analyzed using Western blotting. The combination of molecular docking and drug affinity targeting experiments (DARTS) were first utilized to analysis the target protein of Lut.
    RESULTS: PF effectively suppressed t-BHP-induced apoptosis caused by mitochondrial dysfunction, which were associated with inhibiting ROS generation. Further investigation indicated that PF significantly suppressed apoptosis, inflammation, and autophagy by regulating the expression of related proteins. The results of molecular docking and drug affinity targeting experiments (DARTS) revealed that PI3K was the target protein of PF and Lut. Further studies have shown that PF relieved liver injury induced by t-BHP via suppressing phosphorylated expression of PI3K.
    CONCLUSION: Our results indicate that PF effectively protect against hepatotoxicity induced by t-BHP through inhibiting the abnormal activation of PI3K-Akt signaling pathway and highlight the health benefits of PF regarding oxidative stress, proving it to be an important source of bioactive compounds associated with Nonalcoholic fatty liver disease (NAFLD).
    Keywords:  NAFLD; PI3K; Phenolic fraction; Reactive oxygen species; Veronica ciliata Fisch.
    DOI:  https://doi.org/10.1016/j.jep.2020.112579
  1670. J Exp Bot. 2020 Jan 23. pii: eraa035. [Epub ahead of print]
    Leaf hydraulic conductance is linked to leaf symmetry in bifacial, amphistomatic leaves of Sunflower.
    Richardson F, Jordan GJ, Brodribb TJ.
      The hydraulic implications of stomatal positioning across leaf surfaces and the impact on internal water flow through amphistomatic leaves are not currently well understood. Amphistomaty potentially provides hydraulic efficiencies if the majority of hydraulic resistance in the leaf exists outside the xylem in the mesophyll. Such a scenario would mean that the same xylem network could equally supply a hypostomatic or amphistomatic leaf. Here we examine leaves of Helianthus annuus to determine whether amphistomaty in this species is associated with higher hydraulic efficiency compared with hypostomatic leaves. We identified asymmetry in the positioning of minor veins which were significantly closer to the abaxial than the adaxial leaf surface combined with lower Kleaf when transpiration was driven through the adaxial rather than abaxial surface. We also identified a degree of coordination in stomatal behaviour driven by leaf hydraulics, where the hydraulic conditions experienced by an individual leaf surface affected the stomatal behaviour on the opposite surface. We found no advantage to amphistomaty based on efficiencies in construction costs of the venous system, represented by vein density:stomatal density, only limited hydraulic independence between leaf surfaces. These results suggest that amphistomaty does not substantially increase whole-leaf hydraulic efficiency.
    Keywords:  Amphistomaty; hydraulic conductance; kleaf; leaf water potential; mesophyll; stomata; stomatal ratio; vein density
    DOI:  https://doi.org/10.1093/jxb/eraa035
  1671. J Clin Endocrinol Metab. 2020 Jan 23. pii: dgaa025. [Epub ahead of print]
    AMH as a predictor of the final menstrual period.
    Steiner AZ.
      
    DOI:  https://doi.org/10.1210/clinem/dgaa025
  1672. Cytokine Growth Factor Rev. 2020 Jan 18. pii: S1359-6101(19)30154-6. [Epub ahead of print]
    Human Papillomavirus and carcinogenesis: Novel mechanisms of cell communication involving extracellular vesicles.
    Chiantore MV, Mangino G, Iuliano M, Capriotti L, Di Bonito P, Fiorucci G, Romeo G.
      A small group of mucosal Human Papillomaviruses are the causative agents of cervical cancer and are also associated with other types of cancers. Certain cutaneous Human Papillomaviruses seem to have a role as co-factors in the UV-induced carcinogenesis of the skin. The main mechanism of the tumorigenesis induced by Human Papillomaviruses is linked to the transforming activity of the viral E6 and E7 oncoproteins. However, other mechanisms, such as the gene expression control by specific microRNAs expression and deregulation of immune inflammatory mediators, may be important in the process of transformation. In this context, the release of Extracellular Vesicles with a specific cargo (microRNAs involved in tumorigenesis, mRNAs of viral oncoproteins, cytokines, chemokines) appears to play a key role.
    Keywords:  Extracellular vesicles; Inflammatory cytokines and chemokines; MicroRNAs; Mucosal and cutaneous HPVs; α-and β-HPVs
    DOI:  https://doi.org/10.1016/j.cytogfr.2019.12.009
  1673. Clin Transl Radiat Oncol. 2020 Mar;21 32-35
    Treatment of oligometastatic lung cancer with brain metastases using stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT).
    Nikitas J, Roach M, Robinson C, Bradley J, Huang J, Perkins S, Tsien C, Abraham C.
      Background: There is increasing interest in treating oligometastatic non-small cell lung cancer (NSCLC) patients with stereotactic radiation. We aimed to address whether patients definitively treated with synchronous thoracic stereotactic body radiation therapy (SBRT) and brain stereotactic radiosurgery (SRS) had favorable outcomes with local therapy.Materials and methods: We reviewed a database of patients receiving lung SBRT as well as a database for brain metastasis patients treated with SRS between June 2004 and January 2016. We selected for cT1-2aN0M1 NSCLC patients with brain metastases and calculated their overall survival (OS), freedom from progression (FFP), and local control (LC) rates.
    Results: Six patients had oligometastatic NSCLC with 1-3 synchronous brain metastases treated with lung SBRT and brain SRS. No patients received immunotherapy and two-thirds did not receive systemic therapy. Median follow-up was 9 months for the entire cohort (range, 2-95 months) and 95 months for the surviving patient. Median OS was 12.4 months (95% confidence interval [CI], 7-18 months). At 1 year, patients had 67% OS (95% CI, 29-100%), 17% FFP (95% CI, 0-46%), and 100% LC. Their brain disease had 80% 1-year LC (95% CI, 45-100%) and 53% 1-year FFP (95% CI, 5-100%). Two patients had no distant progression, two had brain progression, one had adrenal gland progression, and one had bone and liver progression.
    Conclusion: In patients presenting with oligometastatic lung cancer limited to the brain, treatment with both lung SBRT and brain SRS achieves good LC of all sites with encouraging OS.
    Keywords:  Brain metastases; Lung cancer; Oligometastatic; Stereotactic body radiation therapy; Stereotactic radiosurgery
    DOI:  https://doi.org/10.1016/j.ctro.2019.12.001
  1674. Mol Cell Neurosci. 2020 Jan 20. pii: S1044-7431(19)30309-4. [Epub ahead of print]103 103464
    Smart motors and cargo steering drive kinesin-mediated selective transport.
    Nabb AT, Frank M, Bentley M.
      Neurons are polarized cells, with dendrites and axons that require different complements of membrane proteins to fulfill their specialized functions. Membrane proteins are synthesized in the somatodendritic domain and delivered to their target membranes via long-range vesicle transport. Most anterograde vesicle transport is mediated by kinesin motors, but it is unclear how kinesins are targeted to axons or dendrites. Two main models have been proposed to explain kinesin selectivity. In the smart motor model, kinesin selectivity is conferred by a preference of the kinesin motor domain for specific subsets of microtubules. In the cargo steering model, kinesin selectivity is modulated by the vesicular cargo to which the motor is bound. We evaluate the evidence for both models and conclude that while the smart motor model may explain axonal selectivity, cargo steering is required for dendritic selectivity. Future work will determine the relative contributions of these models to polarized transport in living neurons.
    DOI:  https://doi.org/10.1016/j.mcn.2019.103464
  1675. Trends Pharmacol Sci. 2020 Jan 21. pii: S0165-6147(19)30291-3. [Epub ahead of print]
    Identifying Missing Biosynthesis Enzymes of Plant Natural Products.
    Dugé de Bernonville T, Papon N, Clastre M, O'Connor SE, Courdavault V.
      Elucidating plant-specialized biosynthetic pathways has always constituted a laborious task, notably for natural products with high pharmaceutical values. Here, we discuss emerging omics-based strategies that facilitate the identification of genes from these complex metabolic pathways, paving the way to engineered supplies of these compounds through synthetic biology approaches.
    Keywords:  RNA-seq; coexpression network; gene identification; specialized metabolites; whole genome sequencing
    DOI:  https://doi.org/10.1016/j.tips.2019.12.006
  1676. PLoS One. 2020 ;15(1): e0227751
    The importance of transporters and cell polarization for the evaluation of human stem cell-derived hepatic cells.
    Török G, Erdei Z, Lilienberg J, Apáti Á, Homolya L.
      One of the most promising applications of human pluripotent stem cells is their utilization for human-based pharmacological models. Despite the fact that membrane transporters expressed in the liver play pivotal role in various hepatic functions, thus far only little attention was devoted to the membrane transporter composition of the stem cell-derived liver models. In the present work, we have differentiated HUES9, a human embryonic stem cell line, toward the hepatic lineage, and monitored the expression levels of numerous differentiation marker and liver transporter genes with special focus on ABC transporters. In addition, the effect of bile acid treatment and polarizing culturing conditions on hepatic maturation has been assessed. We found that most transporter genes crucial for hepatic functions are markedly induced during hepatic differentiation; however, as regards the transporter composition the end-stage cells still exhibited dual, hepatocyte and cholangiocyte character. Although the bile acid treatment and sandwich culturing only slightly influenced the gene expressions, the stimulated cell polarization resulted in formation of bile canaliculi and proper localization of transporters. Our results point to the importance of membrane transporters in human stem cell-derived hepatic models and demonstrate the relevance of cell polarization in generation of applicable cellular models with correctly localized transporters. On the basis of our observations we suggest that conventional criteria for the evaluation of the quality of stem cell-derived hepatocyte-like cells ought to be augmented with additional elements, such as polarized and functional expression of hepatic transporters.
    DOI:  https://doi.org/10.1371/journal.pone.0227751
  1677. Int J Environ Res Public Health. 2020 Jan 18. pii: E618. [Epub ahead of print]17(2):
    Risk Factors Associated with Outcomes of Recombinant Tissue Plasminogen Activator Therapy in Patients with Acute Ischemic Stroke.
    Tseng YJ, Hu RF, Lee ST, Lin YL, Hsu CL, Lin SW, Liou CW, Lee JD, Peng TI, Lee TH.
      Ischemic stroke is the most common type of stroke, and early interventional treatment is associated with favorable outcomes. In the guidelines, thrombolytic therapy using recombinant tissue-type plasminogen activator (rt-PA) is recommended for eligible patients with acute ischemic stroke. However, the risk of hemorrhagic complications limits the use of rt-PA, and the risk factors for poor treatment outcomes need to be identified. To identify the risk factors associated with in-hospital poor outcomes in patients treated with rt-PA, we analyzed the electronic medical records of patients who were diagnosed with acute ischemic stroke and treated for rt-PA at Chang Gung Memorial Hospitals from 2006 to 2016. In-hospital death, intensive care unit (ICU) stay, or prolonged hospitalization were defined as unfavorable treatment outcomes. Medical history variables and laboratory test results were considered variables of interest to determine risk factors. Among 643 eligible patients, 537 (83.5%) and 106 (16.5%) patients had favorable and poor outcomes, respectively. In the multivariable analysis, risk factors associated with poor outcomes were female gender, higher stroke severity index (SSI), higher serum glucose levels, lower mean corpuscular hemoglobin concentration (MCHC), lower platelet counts, and anemia. The risk factors found in this research could help us study the treatment strategy for ischemic stroke.
    Keywords:  ischemic stroke; outcome analysis; risk factor; rt-PA; thrombolytic therapy
    DOI:  https://doi.org/10.3390/ijerph17020618
  1678. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31741-3. [Epub ahead of print]30(3): 611-619.e4
    Follicular Regulatory T Cells Can Access the Germinal Center Independently of CXCR5.
    Vanderleyden I, Fra-Bido SC, Innocentin S, Stebegg M, Okkenhaug H, Evans-Bailey N, Pierson W, Denton AE, Linterman MA.
      The germinal center (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunization. Control of the GC response is thought to require follicular regulatory T (Tfr) cells, a subset of suppressive Foxp3+ regulatory T cells located within GCs. Relatively little is known about the exact role of Tfr cells within the GC and how they exert their suppressive function. A unique feature of Tfr cells is their reported CXCR5-dependent localization to the GC. Here, we show that the lack of CXCR5 on Foxp3+ regulatory T cells results in a reduced frequency, but not an absence, of GC-localized Tfr cells. This reduction in Tfr cells is not sufficient to alter the magnitude or output of the GC response. This demonstrates that additional, CXCR5-independent mechanisms facilitate Treg cell homing to the GC.
    Keywords:  CXCR5; follicular regulatory T cells; germinal center response
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.076
  1679. Nephrol Dial Transplant. 2020 Jan 25. pii: gfz278. [Epub ahead of print]
    Propensity score matched mortality comparisons of peritoneal and in-centre haemodialysis: systematic review and meta-analysis.
    Elsayed ME, Morris AD, Li X, Browne LD, Stack AG.
      BACKGROUND: Accurate comparisons of haemodialysis (HD) and peritoneal dialysis (PD) survival based on observational studies are difficult due to substantial residual confounding that arises from imbalances between treatments. Propensity score matching (PSM) comparisons confer additional advantages over conventional methods of adjustment by further reducing selection bias between treatments. We conducted a systematic review of studies that compared mortality between in-centre HD with PD using a PSM-based approach.METHODS: A sensitive search strategy identified all citations in the PubMed, Cochrane and EMBASE databases from inception through November 2018. Pooled PD versus HD mortality hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated through random-effects meta-analysis. A subsequent meta-regression explored factors to account for between-study variation.
    RESULTS: The systematic review yielded 214 citations with 17 cohort studies and 113 578 PSM incident dialysis patients. Cohort periods spanned the period 1993-2014. The pooled HR for PD versus HD was 1.06 (95% CI 0.99-1.14). There was considerable variation by country, however, mortality risks for PD versus HD remained virtually unchanged when stratified by geographical region with HRs of 1.04 (95% CI 0.94-1.15), 1.14 (95% CI 0.99-1.32) and 0.98 (0.87-1.10) for European, Asian and American cohorts, respectively. Subgroup meta-analyses revealed similar risks for patients with diabetes [HR 1.09 (95% CI 0.98-1.21)] and without diabetes [HR 0.99 (95% CI 0.90-1.09)]. Heterogeneity was substantial (I2 = 87%) and was largely accounted for by differences in cohort period, study type and country of origin. Together these factors explained a substantial degree of between-studies variance (R2 = 90.6%).
    CONCLUSIONS: This meta-analysis suggests that PD and in-centre HD carry equivalent survival benefits. Reported differences in survival between treatments largely reflect a combination of factors that are unrelated to clinical efficacy.
    Keywords:  haemodialysis; mortality; peritoneal dialysis
    DOI:  https://doi.org/10.1093/ndt/gfz278
  1680. Am J Forensic Med Pathol. 2020 Jan 22.
    Gross and Histopathological Findings in the First Reported Vaping-Induced Lung Injury Death in the United States.
    Youmans AJ, Harwood J.
      The popularity of e-cigarettes (vaping) has been on the rise in recent years, but the adverse effects of vaping have been greatly unknown. In 2019, the use of vaping products has been linked to an outbreak of severe lung disease, some cases of which have progressed to death. One death attributed to vaping is presented with emphasis on the gross and histopathological findings from the autopsy. These findings were correlated with the patient's clinical course and medicolegal investigation to determine the cause of death. To our knowledge, this is the first confirmed death in the United States that was directly attributed to the use of vaping.
    DOI:  https://doi.org/10.1097/PAF.0000000000000533
  1681. Focus (Am Psychiatr Publ). 2019 Apr;17(2): 141-142
    Management of Adolescent Substance Use Disorders, With an Emphasis on Cannabis Use Disorders.
    Wilkins JN.
      
    Keywords:  adolescence; adolescent; alcohol; cannabis; inhalants; parents; substance use; substance use disorders; tobacco; treatment
    DOI:  https://doi.org/10.1176/appi.focus.20190006
  1682. Eur J Surg Oncol. 2020 Jan 15. pii: S0748-7983(20)30023-8. [Epub ahead of print]
    shRNA-mediated inhibition of PhosphoGlycerate Kinase 1 (PGK1) enhances cytotoxicity of intraperitoneal chemotherapy in peritoneal metastasis of gastric origin.
    Archid R, Zieker D, Weinreich FJ, Hönes F, Königsrainer A, Quintanilla-Martínez L, Reymond MA, Solass W.
      BACKGROUND: Phosphoglycerate kinase 1 (PGK1) plays metabolic, kinase and translational roles in Peritoneal metastasis (PM) of gastric origin and is associated with chemoresistance. Silencing PGK1 might potentiate the effect of chemotherapy.METHODS: In an orthoptic xenograft nude mice model, human gastric cancer cells (MKN45) were grown in 22 donor animals. Solid tumors were then grafted into the gastric subserosa of 102 recipient animals and allowed to grow for 10 days. Animals were randomized into 7 groups: Five test groups: 1) Mitomycin C (MMC), 2) MMC and small hairpin RNA silencing of PGK1 with an adenoviral vector (Adv-shPGK1), 3) 5-fluorouracil (5-FU), 4) 5-FU and Adv-shPGK1, 5) Adv-shPGK1 alone; two control groups: 1) Sham (NaCl 0.9%), 2) empty viral vector. Intraperitoneal therapy was administered on postoperative day (POD) 11 and 18. Animals were sacrificed at POD 21, analysis was blinded to therapy.
    RESULTS: Adding Adv-shPGK1 to 5-FU reduced the number (0.23 ± 0.43 vs. 1.36 ± 1.00, p = 0.005) and weight (0,005 ± 0.012 mg vs. 0.05 ± 0.08 mg, p = 0.002) of PM as compared to 5-FU alone. The effect of adding Adv-shPGK1 to MMC did not reach statistical significance. Mortality was not increased by adding Adv-shPGK1 to chemotherapy but was increased by Adv-shPGK1 alone as compared to sham.
    CONCLUSION: In this experimental model, combined therapy with chemotherapy and Adv-shPGK1 improves control of PM of gastric origin as compared to chemotherapy alone and might counteract chemoresistance of PM. A systemic toxicity of Adv-shPGK1 cannot be excluded.
    Keywords:  Adenoviral vector; Gastric cancer; Intraperitoneal chemotherapy; Peritoneal metastasis; Phosphoglycerate-kinase 1 (PGK1); shRNA
    DOI:  https://doi.org/10.1016/j.ejso.2020.01.018
  1683. J Med Imaging (Bellingham). 2020 Jan;7(1): 010102
    2019 List of Reviewers.
      List of reviewers who served JMI in 2019.
    DOI:  https://doi.org/10.1117/1.JMI.7.1.010102
  1684. Cancer Genet. 2020 Jan 02. pii: S2210-7762(19)30157-7. [Epub ahead of print]
    BRCA1-BRCA2 mutation analysis results in 910 individuals: Mutation distribution and 8 novel mutations.
    Solmaz AE, Onay H, Yeniay L, Gökmen E, Özdemir N, Alanyalı S, Oktay A, Özsaran Z, Kapkaç M, Özkınay F.
      
    DOI:  https://doi.org/10.1016/j.cancergen.2019.12.008
  1685. J Surg Case Rep. 2020 Jan;2020(1): rjz386
    Maxillary mesenchymal chondrosarcoma leading to a diagnosis of Li-Fraumeni syndrome.
    Ventura E, Dionísio S, Ferreira Â, Saleiro R, Marques H, Magalhães M, Monteiro C.
      Mesenchymal chondrosarcoma (MCS) is a rare histological variant of chondrosarcoma, with aggressive behaviour. Due to the unique nature of this disease, management strategies are not well established. Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome with a wide tumour spectrum, associated with TP53 germline mutations. We report a case of MCS of the maxilla, treated with surgical excision and adjuvant chemotherapy, in a patient with a past medical history of choroid plexus papilloma and a family history of early age first-degree cervical uterine cancer, that led to the clinical suspicion of a cancer predisposition syndrome and the subsequent diagnosis of LFS. This is the first MCS described in a LFS case. It demonstrates that adjuvant chemotherapy should be considered, in conjunction with surgical excision, in MCS and that cancer predisposition syndromes should be suspected in patients with multiple neoplasms and a strong family history of cancer.
    Keywords:  Li-Fraumeni syndrome; cancer predisposition; maxilla; mesenchymal chondrosarcoma
    DOI:  https://doi.org/10.1093/jscr/rjz386
  1686. CNS Neurol Disord Drug Targets. 2020 Jan 16.
    Stingless bee honey reduces anxiety and improves memory of the metabolic disease-induced rats.
    Arshad N', Lin TS, Yahaya MF.
      BACKGROUND: Evidence suggested the involvement of metabolic syndrome (MetS) in the progression of neurodegenerative diseases through oxidative stress. Consumption of antioxidant compounds was found to be beneficial on brain-health by reducing brain oxidative stress level and improve cognitive performance in animal. Stingless bee honey or locally known as Kelulut honey (KH) exert high phenolic content and widely used as food supplement.OBJECTIVES: In this study, we aim investigate the effects of KH on the brain of MetS-induced rats.
    METHOD: Forty male Wistar rats were divided into 5 groups; 8 weeks (C8) and 16 weeks control groups (C16), groups that received high carbohydrate high fructose (HCHF) diet for 8 weeks (MS8) and 16 weeks (MS16), and a group that received HCHF for 16 weeks with KH supplemented for the last 35 days (KH).
    RESULTS: Serum fasting blood glucose decreased in the KH group compared to MS16 group. HDL levels were significantly decreased in MetS groups compared to control groups. Open field experiments showed KH group exhibits less anxious behavior compared to the MetS group. Probe trial of Morris water maze demonstrated significant memory retention of KH group compared to MS16 group. Nissl staining showed significant decrease in pyramidal hippocampal cell in the MS16 compared to KH group.
    CONCLUSION: KH has the ability to normalise blood glucose and reduce serum triglyceride and LDL levels in MetS rats, while behavior studies complement its effect on anxiety and memory. This shows a promising role of KH in attenuating neurodegenerative diseases through the antioxidant activity of its polyphenolic content.
    Keywords:  Behavior; Brain; Kelulut honey; Metabolic syndrome
    DOI:  https://doi.org/10.2174/1871527319666200117105133
  1687. Eur J Obstet Gynecol Reprod Biol. 2019 Nov 22. pii: S0301-2115(19)30542-1. [Epub ahead of print]
    The diagnostic use of magnetic resonance imaging for acute abdominal and pelvic pain in pregnancy.
    Tarannum A, Sheikh H, Appiah-Sakyi K, Lindow SW.
      OBJECTIVES: Acute abdomino-pelvic pain in pregnancy represents a diagnostic challenge. In many cases, radiological and laparoscopic diagnostic modalities are hazardous or contraindicated. Magnetic Resonance Imaging (MRI) is not commonly used for this indication and the results are not widely published.DESIGN AND SETTING: A single-center retrospective observational study.
    POPULATION: 34 cases of pregnant women with abdomino-pelvic pain who underwent MRI as an additional modality when clinical, laboratory and ultrasound (USS) findings were indeterminate.
    METHODS: Case notes were reviewed where pregnant women underwent a MRI investigation for abdominal-pelvic pain. Primary Obstetric indications for an MRI eg placenta accreta were excluded.
    MAIN OUTCOME MEASURES: The differential diagnosis after; 1) history and physical examination and 2) with the addition of USS and 3) with the further addition of an MRI were all individually compared to the eventual diagnosis.
    RESULTS: The diagnoses reached by MRI corresponded with the final diagnosis in 22 out of 23 cases. In the remaining 11 cases MRI accurately ruled out presence of pathology. MRI was inaccurate in 1 case.
    CONCLUSION: The additional use of MRI was more accurate than clinical assessment and USS combined. The accurate exclusion of pathology in 11 cases is particularly significant. MRI should be considered in cases of abdomino-pelvic pain in pregnant women.
    Keywords:  Abdominal pain; MRI; Magnetic resonance imaging; Pelvic pain; Pregnancy
    DOI:  https://doi.org/10.1016/j.ejogrb.2019.11.027
  1688. Trends Biotechnol. 2020 Jan 17. pii: S0167-7799(19)30314-2. [Epub ahead of print]
    Synthetic Rewiring of Plant CO2 Sequestration Galvanizes Plant Biomass Production.
    Naseem M, Osmanoglu Ö, Dandekar T.
      Synthetically designed alternative photorespiratory pathways in tobacco and rice plants have paved the way to enhanced plant biomass production. Likewise, some in vitro- and in vivo-tested carbon-concentrating cycles hold promise to increase plant biomass. We hypothesize a further increase in plant productivity if photorespiratory bypasses are integrated with carbon-concentrating cycles in plants.
    Keywords:  Calvin cycle; bypass; carbon sequestration; photorespiration; synthetic biology; synthetic pathways
    DOI:  https://doi.org/10.1016/j.tibtech.2019.12.019
  1689. Sci Rep. 2020 Jan 22. 10(1): 966
    Mechanical forces induce an asthma gene signature in healthy airway epithelial cells.
    Kılıç A, Ameli A, Park JA, Kho AT, Tantisira K, Santolini M, Cheng F, Mitchel JA, McGill M, O'Sullivan MJ, De Marzio M, Sharma A, Randell SH, Drazen JM, Fredberg JJ, Weiss ST.
      Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature.
    DOI:  https://doi.org/10.1038/s41598-020-57755-8
  1690. Eur Respir J. 2020 Jan;pii: 1902327. [Epub ahead of print]55(1):
    Single cell analysis of human lung development: knowing what mesenchymal cells are and what they may be.
    Sucre JMS, Hagood J.
      
    DOI:  https://doi.org/10.1183/13993003.02327-2019
  1691. AACE Clin Case Rep. 2019 Mar-Apr;5(2):5(2): e91-e94
    LIMITATIONS OF BASAL CORTISOL IN THE DIAGNOSIS OF CUSHING SYNDROME.
    Barros APT, Lamback EB, Coelho MCA, Neto LV.
      Objective: Cushing syndrome (CS) is one of the most challenging diseases to diagnose due to the difficulties that may arise during laboratory test interpretations. A random serum cortisol level is often obtained by a general practitioner as a first step in the work-up of suspected CS patients. In this respect, it is rarely useful and has limitations.Methods: We report an extremely unusual case of a female patient who presented with adrenocorticotropic hormone-independent CS and corticosteroid-binding globulin (CBG) deficiency.
    Results: The patient was initially misdiagnosed with and treated for adrenal insufficiency because of persistently low basal cortisol levels, in detriment of her exacerbated Cushing features and symptoms.
    Conclusion: We describe the limitations of using basal cortisol in the diagnosis of CS and review the differential diagnosis of patients with CS who have low basal cortisol. CBG variants may explain the findings of high urinary and salivary cortisol, in the absence of increased serum cortisol.
    DOI:  https://doi.org/10.4158/ACCR-2018-0336
  1692. Sci Rep. 2020 Jan 21. 10(1): 1186
    Author Correction: The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation.
    Fais RS, Rodrigues FL, Pereira CA, Mendes AC, Mestriner F, Tostes RC, Carneiro FS.
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    DOI:  https://doi.org/10.1038/s41598-020-58146-9
  1693. Curr Drug Discov Technol. 2020 Jan 22.
    In silico-based approach to investigate the ability of PEGylated rapamycin to inhibit Galectin-3.
    Abdelkarim Maki MA, Kumar PV, Elumalai M, Bayazeid O.
      Galectin-3 (Gal-3) is a binding protein known to play a role in cancer and fibrosis, also implicated in various diseases of lung, liver, kidney, and heart. In this study, we have investigated the ability of modified rapamycin (RP) to bind to the carbohydrate recognition domain of Gal-3. Briefly, various molecular weights of methoxy polyethylene glycols (MPEG) were conjugated with RP to obtain RP-MPEG compounds with molecular weights of 1002.29, 1090.40, 1178.51, 1266.6 and 1354.72 g/mol. Furthermore, the molecules were docked with Gal-3 using MOE.2014 software. According to the results obtained from the molecular modeling algorithm based on shape complementarity principles, RP-MPEG with the molecular weight of 1178.51 g/mol and a logP value of 3.79 has the best affinity for a non-carbohydrate-based Gal-3 inhibitor. Moreover, in vitro hemagglutination assay results revealed that RP analog, everolimus, has possessed potent agglutination inhibition with a minimum inhibitory concentration of 160.77 ± 2.52 μg/mL, which suggested that RP derivatives are potential Gal-3 inhibitors.
    Keywords:  Cancer; Everolimus; Galectin-3; Molecular modeling; PEGylation; Rapamycin
    DOI:  https://doi.org/10.2174/1570163817666200122162042
  1694. Clin Transl Oncol. 2020 Jan 22.
    Regorafenib and ginsenoside combination therapy: inhibition of HepG2 cell growth through modulating survivin and caspase-3 gene expression.
    Wang B, Wang F, Ding A, Zhao H, Bu X.
      BACKGROUND: This work aimed to investigate the inhibitory effect of regorafenib in combination with ginsenoside on the growth of HepG2 liver cancer cells.METHODS: HepG2 liver cancer cells were divided into blank control group, regorafenib single-drug group, ginsenoside single-drug group, and regorafenib/ginsenoside combination group. Cells in the regorafenib single-drug group were treated with regorafenib at 0.25 mg/L, 0.5 mg/L, and 1 mg/L, respectively, while cells in the ginsenoside single-drug group were treated with ginsenoside at 5.0 mg/L, 10.0 mg/L, and 20.0 mg/L, respectively. HepG2 cell proliferation, expression of survivin mRNA, and the apoptotic effector caspase-3 in HepG2 liver cancer cells were assessed.
    RESULTS: An inhibitory effect on the growth of HepG2 liver cancer cells was observed for both the single-drug therapies and the combination therapy. The synergistic inhibitory effect presented by the combination therapy was dependent on the gradient concentration and treatment time. RT-qPCR results showed that both regorafenib and ginsenoside significantly reduced the expression of survivin mRNA in HepG2 liver cancer cells and the expression level of survivin mRNA in the regorafenib/ginsenoside combination group was much lower than those in the regorafenib single-drug group and ginsenoside single-drug group. The two drugs demonstrated synergistic inhibitory effect when used in combination.
    CONCLUSIONS: The findings in this study offered a theoretical insight into clinical use of regorafenib and ginsenoside for treatment of liver cancer.
    Keywords:  Apoptosis; Ginsenoside; HepG2 cells; Liver cancer cells; Regorafenib
    DOI:  https://doi.org/10.1007/s12094-019-02283-9
  1695. Br J Nutr. 2020 Jan 22. 1-29
    THE UTILITY OF ANTHOPOMETRIC INDICATORS TO IDENTIFY CARDIOVASCULAR RISK FACTORS IN VIETNAMESE CHILDREN.
    Mai TMT, Gallegos D, Jones L, Tran QC, Tran TMH, van der Pols JC.
      Body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) can be used for discriminating children and adolescents at risk of cardiovascular diseases. However, consensus on how to use these anthropometric indicators is lacking for children and adolescents in Asia. Discrete criteria are promoted internationally, but continuous variables could be used. Data from a survey of 10,949 Vietnamese school-aged children (6-18 year) was used to evaluate the performance of anthropometric indicators to identify elevated blood pressure (BP), dyslipidaemia, or at least three cardiovascular risk factors (CVRF). Weight, height, waist circumference, and BP were measured using standardised protocols; 1,009 participants had blood lipids were analysed. Area-under-the-curve (AUC) was used to assess the performance, and the Youden Index to identify optimal cut-offs. Prevalence of elevated BP, dyslipidaemia, and CVRF was 26∙5%, 49∙3%, and 12∙2%, respectively. BMI, WC and WHtR, had low capacity to identify elevated BP and dyslipidaemia (AUCs range 0∙61-0∙66), but moderate capacity to identify CVRF (0∙72-0∙74). Optimal BMIZ cut-offs to identify elevated BP, dyslipidaemia, and CVRF were 0∙40 SD, 1∙01 SD, and 1∙1 SD; for waist-circumference-z-score, they were 0∙06 SD, 0∙49 SD, and 0∙62 SD; for waist-to-height-ratio, optimal cut-offs were close to 0∙5. Use of anthropometric indicators as continuous variables did not appear to provide advantages. BMIZ cut-off of 1∙0 SD and waist-to-height-ratio cut-off of 0∙5 would, therefore, be useful criteria to identify Vietnamese children who are likely to have CVRF. However, further validation of these criteria in other studies of Asian children and adolescents is needed.
    Keywords:  Vietnam; Z-score; anthropometric indicators; body mass index; cardiovascular risk factors; children and adolescents; dyslipidaemia; elevated blood pressure; optimal cut-offs; waist circumference; waist-to-height-ratio; weight status
    DOI:  https://doi.org/10.1017/S0007114520000203
  1696. Oxid Med Cell Longev. 2019 ;2019 4310319
    Psoralea corylifolia L. Seed Extract Attenuates Methylglyoxal-Induced Insulin Resistance by Inhibition of Advanced Glycation End Product Formation.
    Truong CS, Seo E, Jun HS.
      Accumulation of advanced glycation end products (AGEs) in the body has been implicated in the pathogenesis of metabolic conditions, such as diabetes mellitus. Methylglyoxal (MGO), a major precursor of AGEs, has been reported to induce insulin resistance in both in vitro and in vivo studies. Psoralea corylifolia seeds (PCS) have been used as a traditional medicine for several diseases, but their potential application in treating insulin resistance has not yet been evaluated. This study is aimed at investigating whether PCS extract could attenuate insulin resistance induced by MGO. Male C57BL/6N mice (6 weeks old) were administered 1% MGO in their drinking water for 18 weeks, and the PCS extract (200 or 500 mg/kg) was orally administered daily from the first day of the MGO administration. We observed that both 200 and 500 mg/kg PCS extract treatment significantly improved glucose tolerance and insulin sensitivity and markedly restored p-Akt and p-IRS1/2 expression in the livers of the MGO-administered mice. Additionally, the PCS extract significantly increased the phosphorylation of Akt and IRS-1/2 and glucose uptake in MGO-treated HepG2 cells. Further studies showed that the PCS extract inhibited MGO-induced AGE formation in the HepG2 cells and in the sera of MGO-administered mice. PCS extract also increased the expression of glyoxalase 1 (GLO1) in the liver tissue of MGO-administered mice. The PCS extract significantly decreased the phosphorylation of ERK, p38, and NF-κB and suppressed the mRNA expression of proinflammatory molecules including TNF-α and IL-1β and iNOS in MGO-administered mice. Additionally, we demonstrated that the PCS extract attenuated oxidative stress, as evidenced by the reduced ROS production in the MGO-treated cells and the enhanced expression of antioxidant enzymes in the liver of MGO-administered mice. Thus, PCS extract ameliorated the MGO-induced insulin resistance in HepG2 cells and in mice by reducing oxidative stress via the inhibition of AGE formation. These findings suggest the potential of PCS extract as a candidate for the prevention and treatment of insulin resistance.
    DOI:  https://doi.org/10.1155/2019/4310319
  1697. J Geriatr Oncol. 2020 Jan 20. pii: S1879-4068(19)30245-0. [Epub ahead of print]
    Tailored communication for older patients with cancer: Using cluster analysis to identify patient profiles based on information needs.
    Bol N, Linn AJ, Smets EMA, Verdam MGE, van Weert JCM.
      INTRODUCTION: Understanding how information needs of older patients with cancer vary is essential for patient-centered communication. Little research has considered the potential complex patterns in information needs among older patients with cancer. This study aims to identify profiles of older patients with cancer based on differences in their information needs.MATERIALS AND METHODS: Two-hundred and twenty-three patients with cancer and survivors aged 70 years or older completed an online survey. Based on an extensive scoping review, we included measures on information needs (i.e., monitoring coping style and type of information needs as measured with QUOTE) and related factors (i.e., psychological distress, ability, motivation, participation in decision making, and demographics). Profiles were identified using k-means cluster analysis.
    RESULTS: Analysis revealed three profiles of older patients with cancer exhibiting differences in monitoring coping style and type of information needs: the so-called "information seeker" (38.8%), the "listener" (47.2%), and the "information avoider" (14.0%). Besides differences in information needs, the profiles differed on psychological distress (i.e., intrusive thinking, cancer worry, and intolerance of uncertainty), ability (i.e., self-efficacy in interaction with physician), and motivation (i.e., information goals and future time perspective).
    DISCUSSION: Our findings revealed a nuanced perspective to information needs of older patients with cancer by combining two measurements of information needs with factors contributing to these needs. Clinicians could use these results to increase their awareness of the complexity and heterogeneity of information needs in older patients with cancer and to tailor their information to the needs of older patients.
    Keywords:  Aging; Cancer; Cluster analysis; Information needs; Older patients; Oncology
    DOI:  https://doi.org/10.1016/j.jgo.2020.01.004
  1698. J Clin Endocrinol Metab. 2020 Jan 22. pii: dgaa029. [Epub ahead of print]
    Implications of the Hemoglobin Glycation Index on the Diagnosis of Prediabetes and Diabetes.
    Hsia DS, Rasouli N, Pittas AG, Lary CW, Peters A, Lewis MR, Kashyap SR, Johnson KC, LeBlanc ES, Phillips LS, Hempe JM, Desouza CV, .
      OBJECTIVE: Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the inter-individual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis.MEASUREMENTS: A linear regression equation [HbA1c (%) = 0.0164 x FPG (mg/dL) + 4.2] was derived using the screening cohort (n=6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n=3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups.
    RESULTS: Proportion of women and Blacks/African Americans increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with HGI's calculation; while mean 2hPG was not significantly different among HGI subgroups.
    CONCLUSIONS: High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Blacks and women as having prediabetes compared to using FPG or 2hPG.
    Keywords:  Diagnosis; Hemoglobin Glycation; Observational study; Oral Glucose Tolerance Test; Pre-Diabetes; Type 2
    DOI:  https://doi.org/10.1210/clinem/dgaa029
  1699. Br J Nutr. 2020 Jan 23. 1
    Dietary addition of zinc-methionine influenced eggshell quality by affecting calcium deposition in eggshell formation of laying hens - CORRIGENDUM.
    Li L, Miao L, Zhu M, Wang L, Zou X.
      
    DOI:  https://doi.org/10.1017/S0007114519003209
  1700. Int J Immunogenet. 2020 Jan 24.
    Polymorphisms in IL-1A are associated with endometrial cancer susceptibility among Chinese Han population: A case-control study.
    Liu Y, Sun Y, Wu J, Xiong Z, Du S, Niu F, Jin T, Guo L.
      Endometrial cancer (EC) is one of the most common malignant tumours of the female genital tract, and it has become a serious malignant disease of the female genital tract in China. Existing researches have revealed the association between polymorphisms of IL-1A and several gynaecological diseases. In this research, we analysed the association between IL-1A gene polymorphisms and endometrial cancer susceptibility in Chinese female population. A total of 81 patients and 198 healthy people were selected. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression. Genetic models and analyses showed that IL-1A rs3783550 TT and rs3783546 CC increased the risk of endometrial cancer under the recessive model, respectively (rs3783550: OR = 2.80, 95%CI: 1.32-5.92, p = .008; rs3783546: OR = 2.79, 95%CI: 1.32-5.89, p = .008). In the recessive model, we also found that both IL-1A rs1609682 and IL-1A rs3783521 increased the risk of endometrial cancer, respectively (rs1609682: OR = 2.79, 95%CI: 1.32-5.89, p = .0081; rs3783521: OR = 2.80, 95%CI: 1.32-5.92, p = .008). Haplotype analysis was performed that did not reveal any significant results. In summary, IL-1A rs3783550, rs3783546, rs1609682 and rs3783521 polymorphisms may be associated with an increased risk of endometrial cancer in Chinese female populations.
    Keywords:  IL-1A gene; case-control study; endometrial cancer; gene polymorphism
    DOI:  https://doi.org/10.1111/iji.12463
  1701. Int J Drug Policy. 2020 Jan 16. pii: S0955-3959(20)30008-6. [Epub ahead of print] 102667
    Between gang talk and prohibition: The transfer of blame for County Lines.
    Spicer J.
      BACKGROUND: The drug supply model termed 'County Lines' has generated extensive attention over recent years in the UK. Associated street violence, the involvement of young people and exploitation have been the source of intense concern. However, little discussion has sought to situate this drug market 'phenomenon' in relation to recent austerity policies and intensifying social exclusion. Drawing on Douglas' (1995) conceptualisation of scapegoating as a process of blame transfer, this paper provides a critical analysis of the ways that attention has been diverted from the social conditions that are arguably fundamental to driving involvement in this supply model and its associated harms.METHODS: A critical discourse analysis was undertaken on publicly available content on the subject of County Lines. Sources included newspaper articles, other media outputs, official publications and parliamentary debates. These were analysed to identify scapegoating discourses. Once established, these were theoretically developed by drawing on a range of extant perspectives.
    RESULTS: Three forms of scapegoating related to County Lines were identified. A familiar process was found in the form of 'gang talk', with County Lines reduced as a product of these 'evil' groups. A notably less familiar outlet of blame was identified in the form of middle class cocaine users, with a range of powerful actors attempting to denounce this 'imagined' population as fuelling the market. A final form was identified in relation to drug legalisation campaigns, with an unwavering focus on prohibition also arguably serving to obfuscate underlying structural drivers.
    DISCUSSION: Scapegoating for the issue of County Lines has taken multiple forms. The role of these discourses in diverting attention away from the social conditions that drive these market harms should be recognised and challenged. In their place, political economy and addressing social exclusion should be at the fore of policy discussions.
    Keywords:  Discourse analysis; Drug markets; Political economy; Scapegoating
    DOI:  https://doi.org/10.1016/j.drugpo.2020.102667
  1702. J Assoc Physicians India. 2020 Jan;68(1): 84
    Insulin resistance in transfusion dependent adult beta thalassemia major subjects with metabolic syndrome.
    Pasricha N, Aggarwal R, Jain SK, Prakash A, Jain A.
      
  1703. Cancer Sci. 2020 Jan 24.
    Tumor-infiltrating M2 macrophage in pretreatment biopsy sample predicts response to chemotherapy and survival in esophageal cancer.
    Yamamoto K, Makino T, Sato E, Noma T, Urakawa S, Takeoka T, Yamashita K, Saito T, Tanaka K, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Mori M, Doki Y, Wada H.
      The association between tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of this study was to evaluate the relationship between TME assessed in pre-therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4+ lymphocytes (with/without Foxp3 expression), CD8+ lymphocytes (with/without PD-1 expression), monocytes (CD14+ ), and macrophages (CD86+ , CD163+ , and CD206+ ) by multiplex immunohistochemistry (IHC). The number of tumor-infiltrating CD206+ macrophages significantly correlated with cT, cM, cStage, and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD-1) was not associated with clinico-pathological features. The high infiltration of CD163+ or CD206+ macrophages significantly associated to poor pathological response to NAC (P=0.0057 and 0.0196, respectively). Expression of arginase-1 in CD163+ macrophages tended to be higher in non-responders (29.4% vs. 18.2%, P=0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without (5-year overall survival 57.2% vs. 71.0%, P=0.0498). Thus, the comprehensive analysis of TME by multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long-term survival in EC patients.
    Keywords:  M2 macrophage; biopsy; esophageal cancer; multiplex immunohistochemistry; neoadjuvant chemotherapy
    DOI:  https://doi.org/10.1111/cas.14328
  1704. Electrophoresis. 2020 Jan 23.
    Capillary electrophoresis-based immuno- and aptamer assays: A review.
    Nevídalová H, Michalcová L, Glatz Z.
      Over the last two decades, the group of techniques called affinity probe capillary electrophoresis has been widely used for the detection and the determination of several types of biomolecules with high sensitivity. These techniques combine the low sample consumption and high separation power of capillary electrophoresis with the selectivity of the probe to the target molecule. The assays can be defined according to the type of probe used: capillary electrophoresis immunoassays - with an antibody as the probe, or aptamer-based capillary electrophoresis - with an aptamer as the probe. Immunoassays are generally divided into homogeneous and heterogeneous groups, and homogeneous can be further performed in competitive or non-competitive formats. Interacting partners are free in solution at homogeneous assay, as opposed to heterogeneous analyses, where one of them is immobilized onto a solid support. Highly sensitive fluorescence, chemiluminescence or electrochemical detections were typically used in this type of study. The use of the aptamers as probes has several advantages over antibodies such as shorter generation time, higher thermal stability, lower price and lower variability. The aptamer-based capillary electrophoresis technique was in practice utilised for the determination of proteins in biological fluids and environmentally or clinically important small molecules. Both techniques were also transferred to microchip. This review is focused on theoretical principles of these techniques and a summary of their applications in research. This article is protected by copyright. All rights reserved.
    Keywords:  Application; aptamer; capillary electrophoresis; immunoassay; microchip
    DOI:  https://doi.org/10.1002/elps.201900426
  1705. Molecules. 2020 Jan 21. pii: E446. [Epub ahead of print]25(3):
    Haemostatic Nanoparticles-Derived Bioactivity of from Selaginella tamariscina Carbonisata.
    Zhao Y, Zhang Y, Kong H, Zhang M, Cheng J, Luo J, Zhao Y, Qu H.
      High-temperature carbonisation is used to prepare many traditional Chinese medicine charcoal drugs, but the bioactive haemostatic substances of these medicines and their mechanisms are still unknown. This study developed and evaluated nanoparticles (NPs) derived from Selaginella pulvinate Carbonisata (STC) for the first time. The haemostatic effect of STC-NPs prepared at 300, 350, and 400 °C were investigated in mouse tail amputation and liver scratch experiments. STC-NPs obtained at 400 °C had the strongest haemostatic effect, and were accordingly characterised by ultraviolet-visible spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, high resolution transmission electron microscopy, X-ray diffractometry, and X-ray photoelectron spectroscopy. STC-NPs averaged 1.4-2.8 nm and exhibited a quantum yield of 6.06% at a maximum excitation wavelength of 332 nm and emission at 432 nm. STC-NPs displayed low toxicity against mouse monocyte macrophage RAW 264.7 cells by CCK-8 assay, and STC-NP treatment significantly shortened bleeding time in rat and mouse models. Coagulation assays showed that the haemostatic effects of STC-NPs were related to improving the fibrinogen and platelet contents, as well as decreasing the prothrombin time that resulted from stimulating extrinsic blood coagulation and activating the fibrinogen system. The STC-NPs had remarkable haemostatic effects in the tail amputation and liver scratch models; these effects may be associated with the exogenous coagulation pathway and activation of the brinogen system, according to the evaluation of the mouse coagulation parameters. This novel evaluation supports the material basis of STC use in traditional Chinese medicine, and this article is worthy of study by authors of clinical pharmacy.
    Keywords:  Selaginella pulvinate Carbonisata; haemostasis; nanoparticles
    DOI:  https://doi.org/10.3390/molecules25030446
  1706. Curr Oncol Rep. 2020 Jan 24. 22(1): 6
    Advances in Therapy for Relapsed or Refractory Hodgkin Lymphoma.
    Choi Y, Diefenbach CS.
      PURPOSE OF REVIEW: The landscape of relapsed or refractory (R/R) Hodgkin lymphoma (HL) treatment has changed significantly since the FDA approval of brentuximab vedotin in 2011. In this review, we summarize the recent advances in the therapy for R/R classical Hodgkin lymphoma (cHL).RECENT FINDINGS: Immunotherapies with pembrolizumab, nivolumab, and ipilimumab, and chimeric antigen receptor (CAR) T cell therapies have shown promising results in early phase trials. Other novel agents under investigation include targeted therapies with histone deacetylase inhibitors, Janus kinase 2 inhibitors, and immunomodulators. While further studies with larger populations and longer follow-up times are needed to determine the safe and effective combinations, these novel approaches represent a growing list of treatment options that are on the horizon to improve the cure rate and increase duration of remission for R/R HL patients.
    Keywords:  Brentuximab vedotin; Hodgkin lymphoma; Nivolumab; Pembrolizumab; Relapsed/refractory
    DOI:  https://doi.org/10.1007/s11912-020-0866-3
  1707. Hormones (Athens). 2020 Jan 20.
    Bicentennial of the discovery of selenium commemorated at the Museum of Natural History in Athens.
    Duntas LH, Dumont J.
      
    Keywords:  Bicentennial; Discovery of selenium; Museum of Natural History in Athens; SELENOP; Selenium
    DOI:  https://doi.org/10.1007/s42000-020-00172-3
  1708. Fungal Genet Biol. 2020 Jan 17. pii: S1087-1845(19)30222-1. [Epub ahead of print] 103334
    Increased activity of the sterol branch of the mevalonate pathway elevates glycosylation of secretory proteins and improves antifungal properties of Trichoderma atroviride.
    Graczyk S, Perlińska-Lenart U, Górka-Nieć W, Lichota R, Piłsyk S, Zembek P, Lenart J, Bernat P, Gryz E, Augustyniak J, Palamarczyk G, Kruszewska JS.
      Some Trichoderma spp. have an ability to inhibit proliferation of fungal plant pathogens in the soil. Numerous compounds with a proven antifungal activity are synthesized via the terpene pathway. Here, we stimulated the activity of the mevalonate pathway in T. atroviride P1 by expressing the Saccharomyces cerevisiae ERG20 gene coding for farnesyl pyrophosphate (FPP) synthase, a key enzyme of this pathway. ERG20-expressing Trichoderma strains showed higher activities of FPP synthase and squalene synthase, the principal recipient of FPP in the mevalonate pathway. We also observed activation of dolichyl phosphate mannose (DPM) synthase, an enzyme in protein glycosylation, and significantly increased O- and N-glycosylation of secreted proteins. The hyper-glycosylation of secretory hydrolases could explain their increased activity observed in the ERG20 transformants. Analysis of the antifungal properties of the new strains revealed that the hydrolases secreted by the transformants inhibited growth of a plant pathogen, Pythium ultimum more efficiently compared to the control strain. Consequently, the biocontrol activity of the transgenic strains, determined as their ability to protect bean seeds and seedlings against harmful action of P. ultimum, was also improved substantially.
    Keywords:  FPP synthase; Trichoderma; antifungal activity; squalene synthase; yeast ERG20 gene
    DOI:  https://doi.org/10.1016/j.fgb.2020.103334
  1709. Ultrasonics. 2020 Jan 10. pii: S0041-624X(20)30004-4. [Epub ahead of print] 106065
    A numerical modeling strategy for passive electro-acoustic transducers.
    Henke C.
      In this paper an alternative numerical/analytical method for determining the directivity-dependent receiving sensitivity of general electro-acoustic transducer is presented. Unfortunately, the computational effort of calculating the directivity-dependent receiving sensitivity is more expensive by orders of magnitude than determining the transmitting sensitivity. Using the underlying integral representation of the problem and the existence of resolvent kernels, a postprocessing approach is derived which enables simulations of the receiving sensitivity with the effort of calculating the transmitting sensitivities.
    Keywords:  Electro-acoustic transducer; Finite element postprocessing; Receiving sensitivity
    DOI:  https://doi.org/10.1016/j.ultras.2020.106065
  1710. Eur J Med Chem. 2019 Dec 30. pii: S0223-5234(19)31170-5. [Epub ahead of print]189 112013
    Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors.
    Xu XT, Deng XY, Chen J, Liang QM, Zhang K, Li DL, Wu PP, Zheng X, Zhou RP, Jiang ZY, Ma AJ, Chen WH, Wang SH.
      In this study, two series of coumarin derivatives 5a∼i and 6a∼i were synthesized, and their inhibitory activity against α-glucosidase was determined. The results indicated that most of the synthesized derivatives exhibited prominent inhibitory activities against α-glucosidase. Among them, compounds 5a and 5b showed the strongest inhibition with the IC50 values of 19.64 μM and 12.98 μM, respectively. Enzyme kinetic studies of compounds 5a and 5b proved that their inhibition was reversible and a mixed type. The KI and KIS values of compound 5a were calculated to be 27.39 μM and 13.02 μM, respectively, and the corresponding values for compound 5b being 27.02 μM and 13.65 μM, respectively. The docking studies showed that compound 5b could be inserted into the active pocket of α-glucosidase and form hydrogen bonds with LYS293 to enhance the binding affinity.
    Keywords:  Cinnamic acid; Coumarin; Enzyme inhibition; Molecular docking; Synthesis; α-Glucosidase
    DOI:  https://doi.org/10.1016/j.ejmech.2019.112013
  1711. JACC Cardiovasc Interv. 2020 Jan 09. pii: S1936-8798(19)32390-8. [Epub ahead of print]
    Transcatheter Aortic Valve Replacement for Failed Surgical Aortic Bioprosthetic Valves: Is the Panacea Approaching?
    Stortecky S, Malebranche D.
      
    Keywords:  SAVR; SVD; TAVR; valve in valve
    DOI:  https://doi.org/10.1016/j.jcin.2019.11.015
  1712. Pancreatology. 2019 Dec 19. pii: S1424-3903(19)30812-9. [Epub ahead of print]
    Somatostatin analogues and the risk of post-operative pancreatic fistulas after pancreatic resection - A systematic review & meta-analysis.
    Li T, D'Cruz RT, Lim SY, Shelat VG.
      BACKGROUND: Post-operative pancreatic fistula (POPF) is a common complication of pancreatic resection. Somatostatin analogues (SA) have been used as prophylaxis to reduce its incidence. The aim of this study is to appraise the current literature on the effects of SA prophylaxis on the prevention of POPF following pancreatic resection.METHODS: The review of the literature was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data from studies that reported the effects of SA prophylaxis on POPF following pancreatic resection were extracted, to determine the effect of SA on POPF morbidity and mortality.
    RESULTS: A total of 15 studies, involving 2221 patients, were included. Meta-analysis revealed significant reductions in overall POPF (Odds ratio: 0.65 (95% CI 0.53-0.81, p < 0.01)), clinically significant POPF (Odds ratio: 0.53 (95% CI 0.34-0.83, p < 0.01)) and overall morbidity (OR: 0.69 (95% CI: 0.50-0.95, p = 0.02)) following SA prophylaxis. There is no evidence that SA prophylaxis reduces mortality (OR: 1.10 (95%CI: 0.68-1.79, p = 0.68)).
    CONCLUSION: SA prophylaxis following pancreatic resection reduces the incidence of POPF. However, mortality is unaffected.
    Keywords:  Distal pancreatectomy; Octreotide; Pancreatic fistula; Pancreatic resection; Pancreaticoduodenectomy; Pasireotide; Post-operative; Somatostatin analogues; Whipple’s procedure
    DOI:  https://doi.org/10.1016/j.pan.2019.12.015
  1713. Am J Pathol. 2020 Jan 20. pii: S0002-9440(20)30013-4. [Epub ahead of print]
    This Month in AJP.
      The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
    DOI:  https://doi.org/10.1016/j.ajpath.2020.01.002
  1714. ISA Trans. 2020 Jan 13. pii: S0019-0578(20)30013-6. [Epub ahead of print]
    Interconnection and damping assignment control based on modified actor-critic algorithm with wavelet function approximation.
    Gheibi A, Ghiasi AR, Ghaemi S, Badamchizadeh MA.
      Passivity-based control (PBC) is model-based, and as a result, it is affected by uncertainties. Besides, for some PBC designs, partial differential equations (PDEs) should be solved in order to obtain the parameters of the controller. Actor-critic (AC) algorithm has been used to regulate PBC parameters instantaneously and solve PDEs online. Despite the benefits of this algorithm, it cannot handle disturbance. The main purpose of this paper is to modify the AC algorithm with an online wavelet function approximation to improve its performance. The proposed method uses PBC and the modified AC algorithm to attenuate the effects of uncertainties. Moreover, the stability analysis is investigated for a nonlinear system. The results show that the new method can handle disturbance and uncertainties more proper than other methods.
    Keywords:  Actor–critic; Boost converter; Observer; Passivity-based control (PBC); Wavelet approximator
    DOI:  https://doi.org/10.1016/j.isatra.2020.01.013
  1715. Biomed Pharmacother. 2020 Jan 17. pii: S0753-3322(20)30023-8. [Epub ahead of print]124 109833
    GC-MS based metabolomic profiling of lung tissue couple with network pharmacology revealed the possible protection mechanism of Pudilan Xiaoyan Oral Liquid in LPS-induced lung injury of mice.
    Tian G, Li C, Zhai Y, Xu J, Feng L, Yao W, Bao B, Zhang L, Ding A.
      Pudilan Xiaoyan Oral Liquid (PDL) originated from "Pudilan" Classic Recipe of traditional Chinese medicine is one kind of anti-inflammatory Chinese patent medicine recorded in Chinese Pharmacopeia. PDL has been used clinically for treating inflammatory diseases of the respiratory tract. However, due to the complex composition of PDL, its potential anti-inflammation and the mechanism remain unknown. To identify the mechanism of the PDL in the treatment of lipopolysaccharide (LPS)-induced lung injury of mice. The mice models of lung injury were established and the changes of biochemical indices in serum and histopathology were detected to explore the effects of PDL. The approach of GC-MS metabolomics was used to find more significant metabolites, and the metabolic pathways were enriched through MetaboAnalyst. Then network analysis was applied to visualize the protein related to the important metabolites, merging into a protein-metabolite network via Cytoscape. The treatment of PDL could attenuate LPS-induced histopathological damage of lung tissues, followed by reducing pro-inflammation mediators including IL-10, TNF-a and NF-ĸB in serum. 11 potential metabolites were identified in lung tissue through metabolomics, which were significantly regulated to recover by PDL treatment. The correlated network was constructed by integrating potential metabolites and pathways. Aspartate and l-cysteine were selected as key metabolites and correlated proteins such as IL4I1 and ASPA were speculated as the potential target to treat LPS-induced lung injury using PDL. These results demonstrated that PDL might prevent the pathological process of lung injury through regulating the disturbed protein-metabolite network.
    Keywords:  LPS-induced lung injury; Metabolomics; Network pharmacology; Protective mechanism; Pudilan Xiaoyan Oral Liquid
    DOI:  https://doi.org/10.1016/j.biopha.2020.109833
  1716. Behav Anal Pract. 2019 Dec;12(4): 899-901
    Letter to the Editor: One Perspective on Diversity in ABA.
    Beene N.
      Our profession of applied behavior analysis is lacking in the area of diversity. We cannot overestimate the importance of perspective when dealing with the issue of diversity. What tools does one use to evaluate another person after meeting the person for the first time? How much of what you "know" about a person is based on the labels you have assigned to him or her? Can your response to meeting someone for the first time be better conceptualized as rule-governed behavior (in other words, verbal generalizations, as opposed to tacts based on previous experience with that person individually)? If your answers to these questions involve behavior that is both contingency shaped and rule governed, then as behavior analysts, we would seem to have an opportunity to affect this behavior in a positive way. If our applied science is to be useful and truly comprehensive, this must be equally true of our behavior surrounding diversity. This letter to the editor includes personal experiences and practical actions we can take to move the needle on diversity (in our field) in the right direction. There is much work to be done, but I am convinced that the science of behavior analysis can provide us with the knowledge and determination to do it.
    Keywords:  ABA; Applied science; Contingency shaped behavior; Diversity; Generalization; Rule-governed behavior; Tacts; Useful and comprehensive science
    DOI:  https://doi.org/10.1007/s40617-019-00378-x
  1717. J Neuroinflammation. 2020 Jan 21. 17(1): 29
    White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer's disease rat model.
    Ivanova N, Liu Q, Agca C, Agca Y, Noble EG, Whitehead SN, Cechetto DF.
      BACKGROUND: Metabolic syndrome, the development of which is associated with high-caloric Western diet (HCD) intake, represent a risk factor for mild cognitive impairment (MCI) and dementia including Alzheimer's disease (AD) later in life. This study aimed to investigate the effect of diet-induced metabolic disturbances on white matter neuroinflammation and cognitive function in a transgenic (TG) Fischer 344 rat carrying a human β-amyloid precursor protein (APP) gene with Swedish and Indiana mutations (APP21 TG), a model of pre-AD and MCI.METHODS: TG and wildtype (WT) rats received either a HCD with 40% kJ from fat supplemented with 20% corn syrup drink or a standard diet for 12 weeks. Body weight, caloric intake, and blood pressure were measured repeatedly. End-point changes in glucose and lipid metabolism were also assessed. Open field task was used for assessment of activity; Morris water maze was used to assess spatial learning and memory. Cerebral white matter microglia and astrocytes, hippocampal neurons, and neuronal synapses were examined using immunohistochemistry.
    RESULTS: Rats maintained on the HCD developed significant obesity, visceral adiposity, dyslipidemia, and hyperinsulinemia, but did not become hypertensive. Impaired glucose tolerance was observed only in WT rats on the HCD. Total microglia number, activated OX-6+ microglia, as well as GFAP+ astrocytes located predominantly in the white matter were greater in the APP21 TG rat model in comparison to WT rats. HCD-driven metabolic perturbations further exacerbated white matter microgliosis and microglia cell activation in the APP21 TG rats and led to detectable changes in spatial reference memory in the comorbid prodromal AD and metabolic syndrome group compared to WT control rats. Neuronal density in the CA1 subregion of the hippocampus was not different between the experimental groups. Synaptic density in the CA1 and CA3 hippocampal subregions was lower in the TG rats compared to WT rats; however, there was no additional effect of the co-morbidity on this measure.
    CONCLUSIONS: These results suggest that white matter neuroinflammation might be one of the possible processes of early interaction of metabolic syndrome with MCI and pre-AD and could be one of the early brain pathologies contributing to cognitive deficits observed in mild cognitive impairment and dementia, including AD cases.
    Keywords:  APP21 Transgenic rat; Hypercaloric diet; Metabolic syndrome; Microglia; Prodromal Alzheimer’s disease; White matter inflammation
    DOI:  https://doi.org/10.1186/s12974-020-1698-7
  1718. Front Neurosci. 2019 ;13 1348
    A Comparison of Functional Networks Derived From Representational Similarity, Functional Connectivity, and Univariate Analyses.
    Pillet I, Op de Beeck H, Lee Masson H.
      The invention of representational similarity analysis [RSA, following multi-voxel pattern analysis (MVPA)] has allowed cognitive neuroscientists to identify the representational structure of multiple brain regions, moving beyond functional localization. By comparing these structures, cognitive neuroscientists can characterize how brain areas form functional networks. Univariate analysis (UNIVAR) and functional connectivity analysis (FCA) are two other popular methods to identify functional networks. Despite their popularity, few studies have examined the relationship between networks from RSA with those from UNIVAR and FCA. Thus, the aim of the current study is to examine the similarities between neural networks derived from RSA with those from UNIVAR and FCA to explore how these methods relate to each other. We analyzed the data of a previously published study with the three methods and compared the results by performing (partial) correlation and multiple regression analysis. Our findings reveal that neural networks resulting from RSA, UNIVAR, and FCA methods are highly similar to each other even after ruling out the effect of anatomical proximity between the network nodes. Nevertheless, the neural network from each method shows unique organization that cannot be explained by any of the other methods. Thus, we conclude that the RSA, UNIVAR and FCA methods provide similar but not identical information on how brain regions are organized in functional networks.
    Keywords:  fMRI; functional connectivity (FC); multi-voxel pattern analysis (MVPA); representational similarity analysis (RSA); univariate analysis
    DOI:  https://doi.org/10.3389/fnins.2019.01348
  1719. Curr Opin Struct Biol. 2020 Jan 19. pii: S0959-440X(19)30146-0. [Epub ahead of print]60 110-116
    The application of helix fusion methods in structural biology.
    Kwon NY, Kim Y, Lee JO.
      Methods generating fusion proteins with rigid and predictable structures have been developed in recent years. Among them, helix fusion methods that link two proteins by connecting their terminal alpha helices into a single and extended alpha helix can be particularly useful because designing fusion helices is conceptually and technically simple. These methods have been shown crucial in obtaining crystals that diffract x-rays to high resolution or attaching large and symmetrical backbone proteins to small target proteins for cryo-EM analysis. The structural rigidity of the fusion helix is crucial for these applications, and the reduction of structural ambiguity and flexibility at the fusion sites will further enhance the usefulness of this method.
    DOI:  https://doi.org/10.1016/j.sbi.2019.12.007
  1720. J Appl Toxicol. 2020 Jan 20.
    Biomarkers of exposure, effect, and susceptibility in occupational exposure to traffic-related air pollution: A review.
    Brucker N, do Nascimento SN, Bernardini L, Charão MF, Garcia SC.
      There is a well-recognized association between environmental air pollution exposure and several human diseases. However, the relationship between diseases related to occupational air pollution exposure on roads and high levels of traffic-related air pollutants (TRAPs) is less substantiated. Biomarkers are essential tools in environmental and occupational toxicology, and studies on new biomarkers are increasingly relevant due to the need to determine early biomarkers to be assessed in exposure conditions. This review aimed to investigate the main advances in the biomonitoring of subjects occupationally exposed to air pollution, as well as to summarize the biomarkers of exposure, effect, and susceptibility. Furthermore, we discuss how biomarkers could be used to complement the current application of methods used to assess occupational exposures to xenobiotics present in air pollution. The databases used in the preparation of this review were PubMed, Scopus, and Science Direct. Considering the significant deleterious effects on health associated with chronic occupational exposure to xenobiotics, this topic deserves attention. As it is difficult to avoid occupational exposure to TRAPs, biomonitoring should be applied as a strategy to reduce the toxic effects of workplace exposure.
    Keywords:  biomonitoring; occupational toxicology; toxicity; workers; xenobiotics
    DOI:  https://doi.org/10.1002/jat.3940
  1721. J Digit Imaging. 2020 Jan 23.
    Real-time Malaria Parasite Screening in Thick Blood Smears for Low-Resource Setting.
    Chibuta S, Acar AC.
      Malaria is a serious public health problem in many parts of the world. Early diagnosis and prompt effective treatment are required to avoid anemia, organ failure, and malaria-associated deaths. Microscopic analysis of blood samples is the preferred method for diagnosis. However, manual microscopic examination is very laborious and requires skilled health personnel of which there is a critical shortage in the developing world such as in sub-Saharan Africa. Critical shortages of trained health personnel and the inability to cope with the workload to examine malaria slides are among the main limitations of malaria microscopy especially in low-resource and high disease burden areas. We present a low-cost alternative and complementary solution for rapid malaria screening for low resource settings to potentially reduce the dependence on manual microscopic examination. We develop an image processing pipeline using a modified YOLOv3 detection algorithm to run in real time on low-cost devices. We test the performance of our solution on two datasets. In the dataset collected using a microscope camera, our model achieved 99.07% accuracy and 97.46% accuracy on the dataset collected using a mobile phone camera. While the mean average precision of our model is on par with human experts at an object level, we are several orders of magnitude faster than human experts as we can detect parasites in images as well as videos in real time.
    Keywords:  Deep learning; Low-cost; Malaria parasites; Microscopy; Object detection
    DOI:  https://doi.org/10.1007/s10278-019-00284-2
  1722. Clin Imaging. 2020 Jan 08. pii: S0899-7071(20)30018-8. [Epub ahead of print]61 20-26
    Optimizing b-values for accurate depiction of pancreatic cancer with tumor-associated pancreatitis on computed diffusion-weighted imaging.
    Tokunaga K, Arizono S, Shimizu H, Fujimoto K, Kurata M, Minamiguchi S, Isoda H, Togashi K.
      PURPOSE: To determine the optimal b-value for accurate depiction of pancreatic cancer (PC) in patients with active tumor-associated pancreatitis (TAP), using computed diffusion-weighted imaging (cDWI) with a range of b-values up to 3000 s/mm2.METHODS: The study protocol was approved by the institutional review board. We retrospectively analyzed 34 consecutive PC cases with active TAP who underwent pancreatectomy without preoperative therapy. Four cDWI datasets with b-values of 1500-3000 s/mm2 (cDWI1500-cDWI3000) were generated from the original DWI datasets with b-values of 0 and 1000 s/mm2 obtained using a 3-T scanner. Two board-certified radiologists evaluated images qualitatively (tumor conspicuity and total image quality), and another two board-certified radiologists placed regions of interest for quantitative evaluations (apparent diffusion coefficient [ADC] values of both lesions, contrast ratio [CR] of PC to active TAP, and volume ratio [VR] of PC to surgical specimen).
    RESULTS: As the b-value increased, tumor conspicuity improved significantly in cDWI2000 and cDWI2500 (P = 0.0121 and 0.0015, respectively), although total image quality decreased in all cDWIs compared with DWI1000 (P < 0.0001). Significantly lower ADC values were seen in PC (P < 0.0001). All cDWI groups showed positive correlation between the tumor conspicuity and ADC difference between PC and TAP. CR increased with the b-value, while VR decreased. Significant equivalence of VR to the surgical specimen was seen on cDWI2000 (P = 0.0031).
    CONCLUSION: Accurate depiction of PC was optimal with cDWI2000 in the presence of active TAP.
    Keywords:  Computed diffusion-weighted imaging; Diffusion-weighted imaging; Magnetic resonance imaging; Pancreatic cancer; Tumor-associated pancreatitis
    DOI:  https://doi.org/10.1016/j.clinimag.2020.01.007
  1723. J Adv Res. 2020 Mar;22 77-84
    CuBr2/EDTA-mediated ATRP for ultrasensitive fluorescence detection of lung cancer DNA.
    Zhang J, Ba Y, Liu Q, Zhao L, Wang D, Yang H, Kong J.
      In this paper, we reported a system for the ultrasensitive fluorescence detection of cytokeratin fragment antigen 21-1 DNA (CYFRA21-1 DNA) for the early diagnosis of lung cancer. The approach used electron transfer atom transfer radical polymerization (ARGET-ATRP) with ethylenediaminetetraacetic acid (EDTA) as the metal ligand. Firstly, thiolated peptide nucleic acid (PNA) was linked to aminated magnetic beads solutions (MBs) by a cross-linking agent and then hybridized with CYFRA21-1 DNA (tDNA). Subsequently, Zr4+ was introduced into the MBs by conjugating with the phosphate group of tDNA, and the initiator of ARGET-ATRP was introduced into via phosphate-Zr4+-carboxylate chemistry. Next, Cu(II)Br/EDTA was reduced to Cu(I)/EDTA by ascorbic acid (AA) to trigger ARGET-ATRP and then a large amount of fluorescein-o-acrylate (FA) molecules were grafted from the surface of the MBs, which amplified significantly the fluorescent signal. Under optimal conditions, a strong linear relationship of tDNA over the range from 0.1 fM to 1 nM (R2 = 0.9988). The limit of detection was as low as 23.8 aM (~143 molecules). The fluorescence detection based on the ARGET-ATRP strategy yielded excellent sensitivity, selectivity, outstanding anti-interference properties, and cost-effectiveness. These results indicated that this strategy has considerable potential for biological detection and early clinical diagnosis.
    Keywords:  ARGET-ATRP; CYFRA21-1; EDTA; Fluorescence detection; Lung cancer
    DOI:  https://doi.org/10.1016/j.jare.2019.11.006
  1724. Kidney Int. 2020 Feb;pii: S0085-2538(19)31143-3. [Epub ahead of print]97(2): 421
    Patient-centered outreach treatment toward micro-elimination of hepatitis C virus infection in hemodialysis patients.
    Huang CF, Chiu YW, Yu ML.
      
    DOI:  https://doi.org/10.1016/j.kint.2019.10.030
  1725. High Blood Press Cardiovasc Prev. 2020 Jan 23.
    Hypertensive Mediated Organ Damage and Hypertension Management. How to Assess Beneficial Effects of Antihypertensive Treatments?
    Piskorz D.
      The presence of hypertensive mediated organ damage is related to increased vascular risk and mortality and its prevention should be a therapeutic target and a surrogate marker of in/adequate blood pressure control. In old adult hypertensive patients the therapeutic target should be to prevent major cardiovascular events, but in young hypertensive subjects the focus should be pointed on preventing the development of hypertensive mediated organ damage, since most of the hard events are preceded by functional and structural tissues injury. Hypertension Guidelines of the European Society of Cardiology and European Society of Hypertension recognizes that some variables like electrocardiographic or echocardiographic left ventricle hypertrophy, chronic kidney disease or advance retinopathy, all considered as hypertensive mediated organ damage, may be modifiers of cardiovascular risk estimated by the SCORE system, and for that reason they should be screened in hypertensive patients. It is well known the problem of limited health systems financial resources in many low and even median income countries which precludes the possibilities of generalizing the search for hypertension mediated organ damage in all hypertensive patients. In these scenario the recommendation to perform a detailed screening should be critically evaluated. Some questions remained unanswered: the screening generalization of hypertensive mediated organ damage should modify the cardiovascular risk score of the patients, if its presence could modify the therapeutic approach, and as a consequence, if the treatment adjustment should prolong life expectancy and ameliorate the quality of life.
    Keywords:  Cardiovascular risk; Hypertension management; Hypertensive mediated organ damage
    DOI:  https://doi.org/10.1007/s40292-020-00361-6
  1726. JACC Cardiovasc Interv. 2020 Jan 27. pii: S1936-8798(19)32048-5. [Epub ahead of print]13(2): 180-183
    Transcatheter Aortic Valve Replacement Like a PRO: Years in the Making.
    Jilaihawi H.
      
    Keywords:  paravalvular leak; self-expanding; transcatheter aortic valve replacement
    DOI:  https://doi.org/10.1016/j.jcin.2019.09.037
  1727. J Spec Pediatr Nurs. 2020 Jan 23. e12287
    A concept analysis of psychological distress in parents related to diabetes management in children and adolescents.
    Arabiat D, Al Jabery M, Whitehead L.
      PURPOSE: To report a concept analysis of parents' psychological distress in the context of diabetes management among children and adolescents. A clear understanding of the possible impact of diabetes management on parents will help to inform how nurses can work with parents to support glycaemic control in children and adolescents.DESIGN AND METHOD: Concept analysis using Walker and Avant's eight-stage approach was used as a guiding framework. PubMed, OVID (CINAHL, Medline, PsychInfo), the Cochrane library and the Joanna Briggs library were searched for the past 50 years.
    RESULTS: Thirty-three studies provided data for the concept analysis. Attributes included difficulty coping, changes in emotional status and manifestations of mental health problems.
    PRACTICE IMPLICATION: Based on the literature synthesis, we suggest all facets of distress related to diabetes can in principle be inferred through the proposed relationship between distress and other interactions of individual coping, caring burden and family relational functioning. The proposed conceptual model linking antecedents' factors and individual characteristics of parents to the concepts of psychological distress may assist researchers to design interventions for supporting diabetes management in children and adolescents.
    Keywords:  adolescents; children; concept analysis; diabetes; parents; psychological distress
    DOI:  https://doi.org/10.1111/jspn.12287
  1728. Database (Oxford). 2020 Jan 01. pii: baz139. [Epub ahead of print]2020
    Human Breathomics Database.
    Kuo TC, Tan CE, Wang SY, Lin OA, Su BH, Hsu MT, Lin J, Cheng YY, Chen CS, Yang YC, Chen KH, Lin SW, Ho CC, Kuo CH, Tseng YJ.
      Breathomics is a special branch of metabolomics that quantifies volatile organic compounds (VOCs) from collected exhaled breath samples. Understanding how breath molecules are related to diseases, mechanisms and pathways identified from experimental analytical measurements is challenging due to the lack of an organized resource describing breath molecules, related references and biomedical information embedded in the literature. To provide breath VOCs, related references and biomedical information, we aim to organize a database composed of manually curated information and automatically extracted biomedical information. First, VOCs-related disease information was manually organized from 207 literature linked to 99 VOCs and known Medical Subject Headings (MeSH) terms. Then an automated text mining algorithm was used to extract biomedical information from this literature. In the end, the manually curated information and auto-extracted biomedical information was combined to form a breath molecule database-the Human Breathomics Database (HBDB). We first manually curated and organized disease information including MeSH term from 207 literatures associated with 99 VOCs. Then, an automatic pipeline of text mining approach was used to collect 2766 literatures and extract biomedical information from breath researches. We combined curated information with automatically extracted biomedical information to assemble a breath molecule database, the HBDB. The HBDB is a database that includes references, VOCs and diseases associated with human breathomics. Most of these VOCs were detected in human breath samples or exhaled breath condensate samples. So far, the database contains a total of 913 VOCs in relation to human exhaled breath researches reported in 2766 publications. The HBDB is the most comprehensive HBDB of VOCs in human exhaled breath to date. It is a useful and organized resource for researchers and clinicians to identify and further investigate potential biomarkers from the breath of patients. Database URL: https://hbdb.cmdm.tw.
    DOI:  https://doi.org/10.1093/database/baz139
  1729. Energy Environ Sci. 2020 Jan 01. 13(1): 96-101
    Accelerated charge transfer in water-layered peptide assemblies.
    Tao K, Donnell JO, Yuan H, Haq EU, Guerin S, Shimon LJW, Xue B, Silien C, Cao Y, Thompson D, Yang R, Tofail SAM, Gazit E.
      Bioinspired assemblies bear massive potential for energy generation and storage. Yet, biological molecules have severe limitations for charge transfer. Here, we report l-tryptophan-d-tryptophan assembling architectures comprising alternating water and peptide layers. The extensive connection of water molecules results in significant dipole-dipole interactions and piezoelectric response that can be further engineered by doping via iodine adsorption or isotope replacement with no change in the chemical composition. This simple system and the new doping strategies supply alternative solutions for enhancing charge transfer in bioinspired supramolecular architectures.
    DOI:  https://doi.org/10.1039/c9ee02875g
  1730. J Surg Oncol. 2020 Jan 22.
    Brazilian consensus on the diagnosis and treatment of extremities soft tissue sarcomas.
    Spencer RMSSB, de Camargo VP, Silva MLG, Pinto FFE, Costa FD, Cequeira WS, Munhoz RR, Mello CA, Schmerling RA, Filho WJD, Coelho TM, Ambrosio AVA, Leite ETT, Hanna SA, Nakagawa SA, Baptista AM, Pinheiro RN, de Oliveira JL, de Araújo MS, de Araujo RLC, Laporte GA, de Almeida Quadros C, de Oliveira AF, Lopes A.
      INTRODUCTION: Soft tissue sarcomas (STSs) are rare tumors and constitute only 1% of all tumors in adults. Indeed, due to their rarity, most cases in Brazil are not treated according to primary international guidelines.METHODS: This consensus addresses the treatment of STSs in the extremities. It was made by workgroups from Brazilian Societies of Surgical Oncology, Orthopaedics, Clinical Oncology, Pathology, Radiology and Diagnostic Imaging, and Radiation Oncology. The workgroups based their arguments on the best level of evidence in the literature and recommendations were made according to diagnosis, staging, and treatment of STSs. A meeting was held with all the invited experts and the topics were presented individually with the definition of the degree of recommendation, based on the levels of evidence in the literature.
    RESULTS: Risk factors and epidemiology were described as well as the pathological aspects and imaging. All recommendations are described with the degree of recommendation and levels of evidence.
    CONCLUSION: Recommendations based on the best literature regional aspects were made to guide professionals who treat STS. Separate consensus on specific treatments for retroperitoneal, visceral, trunk, head and neck sarcomas, and gastrointestinal stromal tumor, are not contemplated into this consensus.
    Keywords:  multidisciplinary sarcoma; sarcoma consensus; sarcoma reference cancer centers; soft tissue sarcomas
    DOI:  https://doi.org/10.1002/jso.25847
  1731. Acta Odontol Scand. 2020 Jan 24. 1-5
    Salivary human beta-defensins and cathelicidin levels in relation to periodontitis and type 2 diabetes mellitus.
    Yilmaz D, Topcu AO, Akcay EU, Altındis M, Gursoy UK.
      Objective: Type 2 diabetes mellitus (T2DM) is a well-defined risk factor of periodontitis and it can affect expression of human beta-defensins (hBDs) and cathelicidin (LL-37) as well. The aim of the present study was to evaluate the impact of periodontitis and T2DM on salivary concentrations of these antimicrobial peptides.Material and methods: Unstimulated saliva samples, together with full-mouth periodontal recordings were collected from 92 individuals with periodontitis (63 with T2DM and 21 smokers) and 86 periodontally healthy controls (58 with T2DM and 21 smokers). Salivary hBD-1, -2, -3, LL-37, and advanced glycalization end products (AGE) concentrations were measured by enzyme-linked immunosorbent assay.Results: Among the periodontitis patients, T2DM group demonstrated lower levels of hBD-1 (p = .006), hBD-2 (p < .001) and hBD-3 (p < .001), and higher levels of LL-37 (p < .001) compared to systemically healthy controls. When only periodontally healthy controls were included into the analysis, higher hBD-1 (p = .002) and LL-37 (p < .001) levels were found in T2DM patients in comparison to systemically healthy controls. Salivary LL-37 levels were associated with HbA1c and periodontitis, while hBD-2, hBD-3 and levels associated only with HbA1c.Conclusion: In the limits of this study, hyperglycaemia can be proposed as a regulator of salivary hBD and cathelicidin levels. Periodontitis, on the other hand, affects only salivary LL-37 levels.
    Keywords:  Antimicrobial peptides; diabetes mellitus; periodontitis; saliva
    DOI:  https://doi.org/10.1080/00016357.2020.1715471
  1732. Med Educ. 2020 Jan 18.
    Exploring transformative learning when developing medical students' non-technical skills.
    Kerins J, Smith SE, Phillips EC, Clarke B, Hamilton AL, Tallentire VR.
      INTRODUCTION: Non-technical skills (NTS) training should be incorporated into medical students' education and simulation-based approaches are often utilised to facilitate this. Such experiences have the potential to foster transformative learning with a reassessment of one's prior assumptions and a significant shift in one's outlook; referred to as the process of perspective transformation. The aim of this research was to explore how NTS training might facilitate transformative learning in final year medical students.METHODS: Following ethical approval, medical student volunteers from four medical schools (Aberdeen, Dundee, Edinburgh and Glasgow) participated in simulation sessions, were debriefed with an emphasis on NTS using a behavioural marker system and then took part in focus groups. Focus groups were semi-structured with questions based on the phases of perspective transformation identified by Mezirow. They were audio recorded, transcribed verbatim, anonymised and analysed using template analysis.
    RESULTS: Thirty-three medical students took part in five focus groups. There was evidence of the following stages of perspective transformation: phase 2 (self-examination with emotional disturbance, including fear, anxiety, guilt, shame and frustration), phase 3 (a critical assessment of assumptions, including undervaluing NTS, recognising that technical skills alone are insufficient, and recognising that it is possible to improve your NTS), phase 5 (exploring options for new roles, relationships and actions) and phase 6 (planning a course of action - for future simulations, as a medical student, and as a doctor).
    CONCLUSION: This study deepens our understanding of how exposure to NTS training in simulation-based education influences the learning of medical students and has shown that it can result in the cognitive phases of transformative learning. It has provided us with valuable insights into medical students' perspectives on their learning of NTS at a pivotal stage in training and is an interesting way of assessing the educational impact of such sessions.
    DOI:  https://doi.org/10.1111/medu.14062
  1733. Expert Opin Pharmacother. 2020 Jan 19. 1-10
    Selinexor for the treatment of multiple myeloma.
    Podar K, Shah J, Chari A, Richardson PG, Jagannath S.
      Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.
    Keywords:  Multiple myeloma; exportin-1; penta-refractoriness; selective inhibitor of nuclear export (sine) compounds
    DOI:  https://doi.org/10.1080/14656566.2019.1707184
  1734. Gene. 2020 Jan 20. pii: S0378-1119(20)30052-4. [Epub ahead of print] 144383
    MicroRNA-574-5p in gastric cancer cells promotes angiogenesis by targeting protein tyrosine phosphatase non-receptor type 3 (PTPN3).
    Zhang S, Zhang R, Xu R, Shang J, He H, Yang Q.
      We elucidate in this study that up-regulation of miR-574-5p in gastric cancer cells under hypoxic conditions contributed to angiogenesis. We found that miR-574-5p and HIF-1α were up-regulated in gastric cancer cells cultured under 2% O2 or in medium containing CoCl2, and in muscle tissues of mice injected with NaNO2, indicating up-regulation of miR-574-5p in vitro or in vivo in response to hypoxic conditions. We hypothesized that up-regulation of miR-574-5p could promote angiogenesis. Transfection of gastric cancer cells with miR-574-5p mimics or inhibitor resulted in increase or decrease in the expression of VEGFA. Viability, migration, invasion and tube formation of HUVECs cultured with conditioned medium from SGC/574 cells transfected with miR-574-5p inhibitor were reduced. Tube formation of HUVECs cultured with conditioned medium from SGC-7901 cells transfected with miR-574-5p mimics was increased. An in vivo study demonstrated that inhibition of miR-574-5p in the tumor xenografts of mice reduced the expression of CD31 one of the endothelial cell markers. We identified PTPN3 a tyrosine phosphatase as a target of miR-574-5p that bound to the 3'UTR of PTPN3 mRNA to inhibit the expression of PTPN3. Furthermore, the data in this study demonstrated that inhibition of PTPN3 in gastric cancer cells enhanced phosphorylation of p44/42 MAPKs and promoted angiogenesis. We conclude that miR-574-5p in gastric cancer cells promoted angiogenesis via enhancing phosphorylation of p44/42 MAPKs by miR-574-5p inhibition of PTPN3 expression.
    Keywords:  MAPK; PTPN3; VEGF; angiogenesis; gastric cancer; miR-574-5p
    DOI:  https://doi.org/10.1016/j.gene.2020.144383
  1735. Pestic Biochem Physiol. 2020 Feb;pii: S0048-3575(19)30454-7. [Epub ahead of print]163 31-38
    Amidase, a novel detoxifying enzyme, is involved in cyflumetofen resistance in Tetranychus cinnabarinus (Boisduval).
    Liu J, Zhang Y, Feng K, Liu X, Li J, Li C, Zhang P, Yu Q, Liu J, Shen G, He L.
      Amidase is an important hydrolytic enzyme in detoxification metabolism. Amidase hydrolyzes a wide variety of nonpeptide carbon‑nitrogen bonds by attacking a cyano group or carbonyl carbon. However, little is known about the relationship between amidase and insecticides. In this study, the amidase activity was significantly higher in cyflumetofen-resistant strain (CyR) than in the susceptible strain (SS) of Tetranychus cinnabarinus, and diethyl-phosphoramidate (an amidase inhibitor) significantly decreased cyflumetofen resistance in T. cinnabarinus. More importantly, an amidase gene, TcAmidase01, was identified in T. cinnabarinus, and the TcAmidase01 overexpression was detected in both two cyflumetofen-resistant strains (CyR and YN-CyR), indicating that it is involved in cyflumetofen resistance in mites. A phylogenetic analysis showed that TcAmidase01 was clustered with deaminated glutathione amidases, which possess hydrolytic activity. The recombinant TcAmidase01 protein showed amidase activity toward succinamate, and the activity could be inhibited by cyflumetofen. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis provided evidence that recombinant TcAmidase01 could decompose cyflumetofen by hydrolysis, and the potential metabolites (2-(4-(tert-butyl) phenyl)-2-cyanoacetate and 2-(trifluoromethyl) benzoic acid) were identified. These results show that TcAmidase01 contribute to cyflumetofen-resistance in T. cinnabarinus by hydrolyzing cyflumetofen, and this is the first study to suggest that amidase has a role in insecticides resistance in arthropods.
    Keywords:  Amidase; Cyflumetofen resistance; Degradation; Tetranychus cinnabarinus
    DOI:  https://doi.org/10.1016/j.pestbp.2019.10.001
  1736. J Assoc Physicians India. 2020 Jan;68(1): 44
    The Prevalence of Vitamin B12 Defi ciency in Patients with Hypothyroidism.
    R P.
      
  1737. Biochem Pharmacol. 2020 Jan 20. pii: S0006-2952(20)30031-9. [Epub ahead of print] 113821
    Protein homodimer sequestration with small molecules: focus on PD-L1.
    Bailly C, Vergoten G.
      Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities and to reduce treatment costs. Thus far, all PD-L1 small molecule inhibitors identified present the unique property to induce and to stabilize the formation of PD-L1 protein homodimers. PD-L1 itself can form heterodimers with B7-1 (CD80) but it is essentially monomeric in solution, although the homolog viral protein vOX2 is known to dimerize. Drug-induced sequestration of PD-L1 homodimers prevents binding of PD-L1 to PD-1, thus blocking the downstream signaling. We have analyzed this phenomenon of drug-induced protein dimerization to show that PD-L1 is not an isolated case. Several examples of drug-mediated protein homodimer stabilization are presented here. In particular, a similar phenomenon has been observed with small molecules, such as NSC13728 and KI-MS2-008, which stabilize Max-Max protein homodimers, to block the formation of Myc-Max heterodimers and the ensuing signalization. PD-L1, Max and ten other examples of drug-stabilized protein homodimers point to a general mechanism of protein regulation by small molecules. Nevertheless, the extent and functions of drug-induced PD-L1 homodimers await validation in vivo.
    Keywords:  Cancer; Immunotherapy; Max; PD-L1; Protein dimer
    DOI:  https://doi.org/10.1016/j.bcp.2020.113821
  1738. Asian J Psychiatr. 2019 Dec 26. pii: S1876-2018(19)31397-8. [Epub ahead of print]48 101914
    An atypical case of early-onset trichotillomania - Management implications.
    Mamidipalli SS, Singh S, Singh LK.
      
    DOI:  https://doi.org/10.1016/j.ajp.2019.101914
  1739. Vaccine. 2020 Jan 17. pii: S0264-410X(20)30012-8. [Epub ahead of print]
    Activity of human serum antibodies in an influenza virus hemagglutinin stalk-based ADCC reporter assay correlates with activity in a CD107a degranulation assay.
    Chromikova V, Tan J, Aslam S, Rajabhathor A, Bermudez-Gonzalez M, Ayllon J, Simon V, García-Sastre A, Salaun B, Nachbagauer R, Krammer F.
      The stalk of the influenza virus hemagglutinin (HA) is an attractive target for antibody-based universal influenza virus vaccine development. While antibodies that target this part of the virus can be neutralizing, it has been shown in recent years that Fc receptor-mediated effector functions are of significant importance for the protective effect of anti-stalk antibodies. Several assays to measure Fc-Fc receptor interaction-based effector functions like antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis exist, but they suffer from limitations such as low throughput and high run-to-run variability. Reporter assays for antibody-dependent cellular cytotoxicity based on reporter cells that express luciferase upon engagement of human FcγRIIIa with the Fc of antigen-bound antibodies have been developed as well. These reporter assays can be used in a higher throughput setting with limited run-to-run assay variability but since they express only one Fc receptor, their biological relevance is unclear. Here we optimized an antibody-dependent cellular cytotoxicity reporter assay to measure the activity of antibodies to the conserved stalk domain of H1 hemagglutinin. The assay was then correlated to a CD107a-based degranulation assay, and a strong and significant correlation could be observed. This data suggests that the FcγRIIIa-based reporter assay is a good substitute for functional assays, especially in settings where larger sample numbers need to be analyzed.
    Keywords:  ADCC; ADCP; Effector functions; Influenza hemagglutinin; Stalk antibodies
    DOI:  https://doi.org/10.1016/j.vaccine.2020.01.008
  1740. Drug Metab Pharmacokinet. 2019 Sep 27. pii: S1347-4367(19)30105-3. [Epub ahead of print]
    Developmental changes in transporter and receptor protein expression levels at the rat blood-brain barrier based on quantitative targeted absolute proteomics.
    Omori K, Tachikawa M, Hirose S, Taii A, Akanuma SI, Hosoya KI, Terasaki T.
      The blood-brain barrier (BBB) transport systems regulate the supply of nutrients, amino acids, vitamins, and hormones to the developing brain, as well as blocking the entry of xenobiotics and drugs. The purpose of this study was to clarify the developmental changes in the absolute protein expression levels of BBB transport-related proteins in developing rat brain capillaries, using quantitative targeted absolute proteomics (QTAP). The changing patterns of ATP-binding cassette (ABC) and solute carrier (SLC) transporters, receptors, and tight junction/adherence junction-related proteins were classified into 4 types: uphill (continuously increasing expression from postnatal day (P) 1 to P56), bell-shape/inverted bell-shape (increased/decreased expression from P1 to P14 followed by decreased/increased expression from P21 to P56), downhill (continuously decreasing expression from P1 to P56), and constant (no significant difference from P1 to P56). Proteins showing uphill-type expression included P-glycoprotein/Mdr1a/Abcb1, Mrp4/Abcc4, Bcrp/Abcg2, Glut1/Slc2a1, Oatp1c1/Slco1c1, FcRn, 4F2hc/Slc3a2, claudin-5, caveolin-1, Cd29/integrin β1. Those showing bell-shape/inverted bell-shape expression included Mct1/Slc16a1, Oat3/Slc22a8, Tfr1, Lrp1, and CD147. On the other hand, Cat1/Slc7a1 and Cd54/Icam-1 showed downhill expression, and Insr showed constant expression. These results suggest that the protein expression levels of transporters and receptors at the BBB change in various ways to meet the changing requirements of the developing brain.
    Keywords:  Blood-brain barrier; Developing brain; Quantitative targeted absolute proteomics; Tight junction; Transport
    DOI:  https://doi.org/10.1016/j.dmpk.2019.09.003
  1741. Semin Reprod Med. 2019 Jul;37(4): 166-173
    Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions.
    Naulé L, Kaiser UB.
      Puberty is a critical period of development regulated by genetic, nutritional, and environmental factors. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP). To date, MKRN3 mutations are the most common known genetic cause of CPP. MKRN3 is a member of the makorin family of ubiquitin ligases, together with MKRN1 and MKRN2. The Mkrn genes have been identified in both vertebrates and invertebrates and show high evolutionary conservation of their gene and protein structures. While the existence of Mkrn orthologues in a wide spectrum of species suggests a vital cellular role of the makorins, their role in puberty initiation and endocrine functions is just beginning to be investigated. In this review, we discuss recent studies that have shown the involvement of Mkrn3 and other makorins in the regulation of pubertal development and other endocrine functions, including metabolism and fertility, as well as their underlying mechanisms of action.
    DOI:  https://doi.org/10.1055/s-0039-3400965
  1742. Int J Genomics. 2020 ;2020 5925126
    Metabonomic-Transcriptome Integration Analysis on Osteoarthritis and Rheumatoid Arthritis.
    Gao N, Ding L, Pang J, Zheng Y, Cao Y, Zhan H, Shi Y.
      Purpose: This study is aimed at exploring the potential metabolite/gene biomarkers, as well as the differences between the molecular mechanisms, of osteoarthritis (OA) and rheumatoid arthritis (RA).Methods: Transcriptome dataset GSE100786 was downloaded to explore the differentially expressed genes (DEGs) between OA samples and RA samples. Meanwhile, metabolomic dataset MTBLS564 was downloaded and preprocessed to obtain metabolites. Then, the principal component analysis (PCA) and linear models were used to reveal DEG-metabolite relations. Finally, metabolic pathway enrichment analysis was performed to investigate the differences between the molecular mechanisms of OA and RA.
    Results: A total of 976 DEGs and 171 metabolites were explored between OA samples and RA samples. The PCA and linear module analysis investigated 186 DEG-metabolite interactions including Glycogenin 1- (GYG1-) asparagine_54, hedgehog acyltransferase- (HHAT-) glucose_70, and TNF receptor-associated factor 3- (TRAF3-) acetoacetate_35. Finally, the KEGG pathway analysis showed that these metabolites were mainly enriched in pathways like gap junction, phagosome, NF-kappa B, and IL-17 pathway.
    Conclusions: Genes such as HHAT, GYG1, and TRAF3, as well as metabolites including glucose, asparagine, and acetoacetate, might be implicated in the pathogenesis of OA and RA. Metabolites like ethanol and tyrosine might participate differentially in OA and RA progression via the gap junction pathway and phagosome pathway, respectively. TRAF3-acetoacetate interaction may be involved in regulating inflammation in OA and RA by the NF-kappa B and IL-17 pathway.
    DOI:  https://doi.org/10.1155/2020/5925126
  1743. J Clin Endocrinol Metab. 2020 Jan 14. pii: dgaa021. [Epub ahead of print]
    Psychological and behavioral determinants of weight loss: A need for research to determine causation.
    Martin CK, Ravussin E.
      
    DOI:  https://doi.org/10.1210/clinem/dgaa021
  1744. Clin Ther. 2020 Jan 17. pii: S0149-2918(19)30599-5. [Epub ahead of print]
    Does Ranolazine Reduce Pain Perception With Cerebral Effect?
    Tolunay H.
      
    DOI:  https://doi.org/10.1016/j.clinthera.2019.12.015
  1745. Anal Verbal Behav. 2019 Dec;35(2): 258-269
    Teaching Children With Autism Spectrum Disorder to Report Past Behavior With the Use of a Speech-Generating Device.
    Shillingsburg A, Marya V, Bartlett B, Thompson T, Walters D.
      
    DOI:  https://doi.org/10.1007/s40616-019-00112-2
  1746. J Food Sci. 2020 Jan 22.
    Intensification of polyphenols extraction from orange peels using infrared as a novel and energy saving pretreatment.
    El Kantar S, Rajha HN, Maroun RG, Louka N.
      This study aims to evaluate the impact of a nonconventional pretreatment technique "infrareds free solvent" on the intensification of polyphenols extraction from orange peels. Orange peels were pretreated with infrared heating using a ceramic infrared transmitter from 5 to 25 min at 50 °C. After the addition of the solvent on the pretreated peels, ultrasound treatment was applied on the mixture using an ultrasound generator connected to a titanium ultrasound probe, from 5 to 30 min, at 50 °C. Results showed that the application of ultrasounds on untreated peels enhanced the extraction of polyphenols by 62.5% compared to the conventional solid-liquid extraction. Twenty minutes of infrared pretreatment improved the extraction of polyphenols by 47% with solid-liquid extraction, and 112% with ultrasounds after 30 min compared to solid-liquid extraction from untreated peels. Different combinations of infrared pretreatment and ultrasound assisted extraction were then applied on orange peels. The most advantageous combination in terms of energy consumption and polyphenols extraction has been found for a 20 min infrared pretreatment time and 5 min ultrasound assisted extraction of polyphenols. PRACTICAL APPLICATION: Orange peels are valuable sources of natural antioxidants such as polyphenols. Ultrasound-assisted extraction can improve the extraction of polyphenols compared to conventional solid-liquid extraction. To intensify the extraction process, infrared heating can be used as a simple, low cost, and energy saving method. The combined effect of "infrareds free solvent" and ultrasounds allowed the extraction of the highest yields of polyphenols with a high antiradical capacity and a low energy consumption in comparison to conventional extraction.
    Keywords:  infrareds; orange peels; polyphenols; pretreatment; ultrasounds
    DOI:  https://doi.org/10.1111/1750-3841.15016
  1747. Spine Deform. 2019 Nov;7(6): 1020-1021
    Are Serum Ion Levels Elevated in Pediatric Patients with Growing Spine Implants vs. Controls?
    Mathew S, Larson AN, Zhang B, Xie Y, Abdel M, van Wijnen AJ, Milbrandt T, Haft G.
      
    DOI:  https://doi.org/10.1016/j.jspd.2019.09.030
  1748. Infect Immun. 2020 Jan 21. pii: IAI.00955-19. [Epub ahead of print]
    Neisseria meningitidis induces pathology-associated cellular and molecular changes in trigeminal Schwann cells.
    Delbaz A, Chen M, Jen FE, Schulz BL, Gorse AD, Jennings MP, St John JA, Ekberg JAK.
      Neisseria meningitidis, a common cause of sepsis and bacterial meningitis, infects the meninges and central nervous system (CNS) primarily via paracellular traversal across the blood-brain or blood-cerebrospinal fluid barrier. N. meningitidis is often present asymptomatically in the nasopharynx, and the nerves extending between the nasal cavity and the brain constitute an alternative route by which the meningococci may reach the CNS. To date, the cellular mechanisms involved in nerve infection are not fully understood. Peripheral nerve glial cells are phagocytic and capable of eliminating microorganisms, but some pathogens may be able to overcome this protection mechanism and instead infect the glia, causing cell death or pathology. Here, we show that N. meningitidis readily infects trigeminal Schwann cells (the glial cells of the trigeminal nerve) in vitro in both two-dimensional and three-dimensional cell cultures. Infection of trigeminal Schwann cells may be one mechanism by which N. meningitidis is able to invade the CNS. Infection of the cells led to multinucleation and the appearance of atypical nuclei, with the presence of horseshoe nuclei and budding of nuclei increasing over time. Using SWATH-MS proteomics followed by bioinformatics pathway analysis, we showed that N. meningitidis induced protein alterations in the glia associated with altered intercellular signalling, cell-cell interactions and cellular movement. The analysis also suggested that the alterations in protein levels were consistent with changes occurring in cancer. Thus, infection of the trigeminal nerve by N. meningitidis may have ongoing adverse effects on the biology of Schwann cells, which may lead to pathology.
    DOI:  https://doi.org/10.1128/IAI.00955-19
  1749. Sci Rep. 2020 Jan 20. 10(1): 666
    Binding of myeloperoxidase to the extracellular matrix of smooth muscle cells and subsequent matrix modification.
    Cai H, Chuang CY, Hawkins CL, Davies MJ.
      The extracellular matrix (ECM) of tissues is susceptible to modification by inflammation-associated oxidants. Considerable data support a role for hypochlorous acid (HOCl), generated by the leukocyte-derived heme-protein myeloperoxidase (MPO) in these changes. HOCl can modify isolated ECM proteins and cell-derived matrix, with this resulting in decreased cell adhesion, modulated proliferation and gene expression, and phenotypic changes. Whether this arises from free HOCl, or via site-specific reactions is unresolved. Here we examine the mechanisms of MPO-mediated changes to human coronary smooth muscle cell ECM. MPO is shown to co-localize with matrix fibronectin as detected by confocal microscopy, and bound active MPO can initiate ECM modification, as detected by decreased antibody recognition of fibronectin, versican and type IV collagen, and formation of protein carbonyls and HOCl-mediated damage. These changes are recapitulated by a glucose/glucose oxidase/MPO system where low continuous fluxes of H2O2 are generated. HOCl-induced modifications enhance MPO binding to ECM proteins as detected by ELISA and MPO activity measurements. These data demonstrate that MPO-generated HOCl induces ECM modification by interacting with ECM proteins in a site-specific manner, and generates alterations that increase MPO adhesion. This is proposed to give rise to an increasing cycle of alterations that contribute to tissue damage.
    DOI:  https://doi.org/10.1038/s41598-019-57299-6
  1750. Food Res Int. 2020 Feb;pii: S0963-9969(19)30700-8. [Epub ahead of print]128 108814
    Metabolomics analysis of Camellia sinensis with respect to harvesting time.
    Zeng C, Lin H, Liu Z, Liu Z.
      The metabolites of green tea influence its quality and physiological characteristics. Therefore, to further increase the utilization of green tea leaves, it is imperative to understand the distribution and variation of their secondary metabolites with respect to different harvesting times. This study compared the metabolomes of young leaves of 'Anji Baicha' between early spring tea and late spring tea in positive and negative ESI modes using UPLC-ESI-Q-TOF/MS. Potential biomarkers were selected by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) of chemometrics methods. Results showed that the metabolic profiles of young leaves in early and late spring tea were significantly different. The metabolite-related pathways associated with these differences included those involved in biosynthesis of flavonoids, phenylpropanoids, flavone and flavonol, phenylalanine, tyrosine, and tryptophan. In early spring tea leaves, concentrations of amino acids (l-glutamine and l-tryptophan), (S)-(-)-limonene, most of the catechins, and flavonol/flavone glycosides were found to be significantly increased, while proanthocyanidins (proanthocyanidin A1, prodelphinidin A1, and prodelphinidin A2 3'-gallate) concentrations were significantly decreased. As a result of the metabolomics analysis of young leaves of green tea plants with respect to different harvesting time, information regarding physiological characteristics and optimal harvesting time was obtained.
    Keywords:  Chemical components; Harvesting time; LC-MS; Metabolic pathways; ‘Anji Baicha’
    DOI:  https://doi.org/10.1016/j.foodres.2019.108814
  1751. Cancers (Basel). 2020 Jan 18. pii: E241. [Epub ahead of print]12(1):
    1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages.
    Casadei-Gardini A, Del Coco L, Marisi G, Conti F, Rovesti G, Ulivi P, Canale M, Frassineti GL, Foschi FG, Longo S, Fanizzi FP, Giudetti AM.
      The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that 1H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan-Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology.
    Keywords:  NMR; OPLS-DA; hepatocellular carcinoma; metabolomics; radiofrequency; sorafenib
    DOI:  https://doi.org/10.3390/cancers12010241
  1752. J Reprod Dev. 2020 Jan 19.
    Involvement of GPR4 in increased growth hormone and prolactin expressions by extracellular acidification in MtT/S cells.
    Musha S, Yoshida S, Murakami S, Kojima R, Deai M, Saso N, Mogi C, Sato K, Okajima F, Tomura H.
      Hormone-secreting pituitary adenomas show unregulated hormonal hypersecretion and cause hyperpituitarism. However, the mechanism of the unregulated hormone production and secretion has not yet been fully elucidated. Solid tumors show reduced extracellular pH, partly due to lactate secretion from anaerobic glycolysis. It is known that extracellular acidification affects hormone secretion. However, whether and how the extracellular acidification influences the unregulated hormone production and secretion remain unknown. In the present study, we found that GPR4, a proton-sensing G protein-coupled receptor, was highly expressed in MtT/S cells, a growth hormone-producing and prolactin-producing pituitary tumor cell line. When we reduced the extracellular pH, growth hormone and prolactin mRNA expressions increased in the cells. Both increased expressions were partially suppressed by a GPR4 antagonist. We also found that extracellular acidification enhanced growth hormone-releasing factor-induced growth hormone secretion from MtT/S cells. These results suggest that GPR4 may play a role in hypersecretion of the hormone from hormone-producing pituitary tumors. A GPR4 antagonist will be a useful tool for preventing the hypersecretion.
    Keywords:  Extracellular acidification; GPR4; Growth hormone; MtT/S; Prolactin
    DOI:  https://doi.org/10.1262/jrd.2019-159
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