bims-prodis Biomed News
on Proteomics in disease
Issue of 2018–12–02
47 papers selected by
Nancy Gough, Bioserendipity
  1. Integrated Eutopic Endometrium and Non-Depleted Serum Quantitative Proteomic Analysis Identifies Candidate Serological Markers of Endometriosis.
  2. Quantitative Urinary Proteome Reveals Potential Biomarkers for Ureteropelvic Junction Obstruction.
  3. Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps.
  4. iTRAQ-based quantitative proteomic analysis reveals potential early diagnostic markers in serum of acute cellular rejection after liver transplantation.
  5. iTRAQ Based Quantitative Proteomics Approach Identifies Novel Diagnostic Biomarkers that were Essential for Glutamine Metabolism and Redox Homeostasis for Gastric Cancer.
  6. Proteomic Analysis and Biochemical Correlates of Mitochondrial Dysfunction following Low-Intensity Primary Blast Exposure.
  7. Hippocampal proteomic alteration in triple transgenic mouse model of Alzheimer's disease and implication of PINK 1 regulation in donepezil treatment.
  8. Proteomics of the acid-soluble fraction of whole and major gland saliva in burning mouth syndrome patients.
  9. TMT-Based Quantitative Proteomic Analysis Reveals Proteomic Changes Involved in Longevity.
  10. Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease.
  11. Circulating proteomic patterns in AF related left atrial remodeling indicate involvement of coagulation and complement cascade.
  12. Altered plasma proteins released from platelets and endothelial cells are associated with human patent ductus arteriosus.
  13. Plasma proteome correlates of lipid and lipoprotein: Biomarkers of metabolic diversity and inflammation in children of rural Nepal.
  14. Data-independent acquisition mass spectrometry to quantify protein levels in FFPE tumor biopsies for molecular diagnostics.
  15. Quantitative Proteomics Evaluation of Human Multipotent Stromal Cell for β Cell Regeneration.
  16. Proteomic approaches for cancer epigenetics research.
  17. Integrated Genomic and Proteomic Analyses Reveal Novel Mechanisms of the Methyltransferase SETD2 in Renal Cell Carcinoma Development.
  18. Proteomics of Bronchoalveolar Lavage Fluid Reveals a Lung Oxidative Stress Response in Murine Herpesvirus-68 Infection.
  19. Comparative exoproteome profiling of an invasive and a commensal Staphylococcus haemolyticus isolate.
  20. Differential analysis of quantitative proteome and acetyl-proteome profiling between premenopausal and postmenopausal ovarian tissues.
  21. Differential protein expression in human knee articular cartilage and medial meniscus using two different proteomic methods: a pilot analysis.
  22. iTRAQ-Based Differential Proteomic Analysis Reveals the Pathways Associated with Tigecycline Resistance in Acinetobacter baumannii.
  23. Visceral white adipose tissue and serum proteomic alternations in metabolically healthy obese patients undergoing bariatric surgery.
  24. Proteomic Profiling of Human Hepatic Stellate Cell Line LX2 Responses to Irradiation and TGF-β1.
  25. Differential expression of proteins in genetically distinct Trypanosoma cruzi samples (TcI and TcII DTUs) isolated from chronic Chagas disease cardiac patients.
  26. Mass Spectrometry: A Platform for Biomarker Discovery and Validation for Alzheimer's and Parkinson's Diseases.
  27. Dynamic phosphoproteomics uncovers signaling pathways modulated by anti-neoplastic sphingolipid analogs.
  28. Immunoproteomics and Surfaceomics of the Adult Tapeworm Hymenolepis diminuta.
  29. Proteomic profiling of LPS-induced macrophage derived exosomes indicates their involvement in acute liver injury.
  30. Urinary Proteomics for the Early Diagnosis of Diabetic Nephropathy in Taiwanese Patients.
  31. Helicobacter pylori Growth Stage Determines the Size, Protein Composition and Preferential Cargo Packaging of Outer Membrane Vesicles.
  32. High-throughput detection of low abundance sialylated glycoproteins in human serum by TiO2 enrichment and targeted LC-MS/MS analysis: application to a prostate cancer sample set.
  33. Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia.
  34. Cholinergic activity regulates the secretome of epicardial adipose tissue: Association with atrial fibrillation.
  35. Establishment of microRNA, transcript and protein regulatory networks in Alport syndrome induced pluripotent stem cells.
  36. Protein variability in cerebrospinal fluid and its possible implications for neurological protein biomarker research.
  37. Clinical potential of mass spectrometry-based proteogenomics.
  38. Current understanding of the potential of proteomics and metabolomics approaches in cancer chemoresistance: A focus on Multiple Myeloma.
  39. Increased expression of L-plastin in nasal polyp of patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease.
  40. Correction to: Quantitative phosphoproteomic analysis reveals reciprocal activation of receptor tyrosine kinases between cancer epithelial cells and stromal fibroblasts.
  41. Antibody responses to Zika virus proteins in pregnant and non-pregnant macaques.
  42. Frontal Cortex Proteome Perturbation after Juvenile Rat Secondhand Smoke Exposure.
  43. Alterations of the gut microbiome and plasma proteome in Chinese patients with adolescent idiopathic scoliosis.
  44. Dissecting the Immune Landscape of Acute Myeloid Leukemia.
  45. Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complex.
  46. Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer's Disease.
  47. Neonatal Neurodegeneration in Alzheimer's Disease Transgenic Mouse Model.
  1. Proteomics Clin Appl. 2018 Nov 28. e1800153
    Integrated Eutopic Endometrium and Non-Depleted Serum Quantitative Proteomic Analysis Identifies Candidate Serological Markers of Endometriosis.
    Antigoni Manousopoulou, Mukhri Hamdan, Miltiadis Fotopoulos, Diana J Garay-Baquero, Jie Teng, Spiros D Garbis, Ying Cheong.
       BACKGROUND: Endometriosis affects about 4% of women in the reproductive age and is associated with subfertility. The aim of the present study is to examine the integrated quantitative proteomic profile of eutopic endometrium and serum from women with endometriosis compared to controls in order to identify candidate disease-specific serological markers.
    METHODS: Eutopic endometrium and serum from patients with endometriosis (n = 8 for tissue and n = 4 for serum) are, respectively, compared to endometrium and serum from females without endometriosis (n = 8 for tissue and n = 4 for serum) using a shotgun quantitative proteomics method. All study participants are at the proliferative phase of their menstrual cycle.
    RESULTS: At the tissue and serum level, 1214 and 404 proteins are differentially expressed (DEPs) in eutopic endometrium and serum, respectively, of women with endometriosis versus controls. Gene ontology analysis shows that terms related to immune response/inflammation, cell adhesion/migration, and blood coagulation are significantly enriched in the DEPs of eutopic endometrium, as well as serum. Twenty-one DEPs have the same trend of differential expression in both matrices and can be further examined as potential disease- and tissue-specific serological markers of endometriosis.
    CONCLUSIONS: The present integrated proteomic profiling of eutopic endometrium and serum from women with endometriosis identify promising serological markers that can be further validated in larger cohorts for the minimally invasive diagnosis of endometriosis.
    Keywords:  endometriosis; isobaric tag for relative and absolute quantitation; liquid chromatography-mass spectrometry; proteomics
    DOI:  https://doi.org/10.1002/prca.201800153
  2. Proteomics Clin Appl. 2018 Nov 24. e1800101
    Quantitative Urinary Proteome Reveals Potential Biomarkers for Ureteropelvic Junction Obstruction.
    Honghao Chen, Houwei Lin, Maosheng Xu, Guofeng Xu, Xiaoliang Fang, Lei He, Zhoutong Chen, Zhixiang Wu, Hongquan Geng.
       PURPOSE: Ureteropelvic junction obstruction (UPJO) is a common obstructive disease. To investigate the usefulness urinary biomarkers in UPJO children, we analyzed the urinary proteome in UPJO infants and compared it with normal controls.
    EXPERIMENTAL DESIGN: We performed a TMT-based quantitative proteomics study to analyze the proteome of bladder urine (BU) and pelvis urine (PU) from unilateral UPJO infants with differential renal function less than 40% and compared them with normal control urine (CON). GO analysis was then utilized to analyze general characterization of the proteins. Proteomic results were verified by western blot of selected differential proteins using an independent validation cohort.
    RESULTS: There were 81 and 186 proteins significantly changed in BU and PU groups, respectively, as compared to the CON group. Fifty proteins overlaps were found between these two sets of statistically significant differential proteins. GO enrichment analysis showed these 50 common differential proteins are involved in multiple biological processes including inflammatory response and phagocytosis and so on. The increased urinary abundance of Fetuin-A, AGP1, AGP2, protein AMBP and PGDS were verified by western blot analysis.
    CONCLUSIONS AND CLINICAL RELEVANCE: This proteomic analysis indicated that urinary Fetuin-A, AGP1, AGP2, protein AMBP and PGDS may serve as noninvasive potential biomarkers and these proteins could help to further yield pathological mechanisms involved in UPJO. This article is protected by copyright. All rights reserved.
    Keywords:  biomarker; proteomics; ureteral obstruction; urine
    DOI:  https://doi.org/10.1002/prca.201800101
  3. Int Forum Allergy Rhinol. 2018 Nov 28.
    Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps.
    Sarina K Mueller, Angela L Nocera, Simon T Dillon, Xuesong Gu, Olaf Wendler, Hasan H Otu, Towia A Libermann, Benjamin S Bleier.
       BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscanTM , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature.
    METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscanTM platform was used to simultaneously quantify 1310 biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses.
    RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%.
    CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative "liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets.
    Keywords:  and platelet glycoprotein VI; biosignature; chronic rhinosinusitis; cystatin-SN; exosome; mucus; nasal polyps; peroxiredoxin-5; proteomics
    DOI:  https://doi.org/10.1002/alr.22226
  4. Transpl Immunol. 2018 Nov 22. pii: S0966-3274(18)30076-5. [Epub ahead of print]
    iTRAQ-based quantitative proteomic analysis reveals potential early diagnostic markers in serum of acute cellular rejection after liver transplantation.
    Qi Jiang, Yawei Ru, Yang Yu, Keqiu Li, Yaqing Jing, Jianhai Wang, Guang Li.
      Liver transplantation (LT) is the most effective treatment method for advanced stage liver disease but acute cellular rejection (ACR) seriously affects the prognosis of LT. To discover novel diagnostic biomarkers of ACR after LT, Isobaric Tags for Relative and Absolute Quantitation (iTRAQ)-based mass spectrometry was performed to characterize alterations of serum proteins among patients validated to be pathologically ACR or pathologically no-ACR after LT and healthy controls. As a result, 10 differentially expressed proteins were found out between the ACR group and the No-ACR group; 88 differentially expressed proteins were found out between the ACR group and the Healthy Control group; 39 differentially expressed proteins were found out between No-ACR group and Healthy Control group. After analysis and ELISA validation, the results showed that CFHR1, CFHR5 and CFH could be candidate protein biomarkers for the early diagnosis of ACR after LT.
    Keywords:  ACR; Early Diagnosis; Liver Transplantation; Protein Markers; iTRAQ
    DOI:  https://doi.org/10.1016/j.trim.2018.11.005
  5. Proteomics Clin Appl. 2018 Nov 28. e1800038
    iTRAQ Based Quantitative Proteomics Approach Identifies Novel Diagnostic Biomarkers that were Essential for Glutamine Metabolism and Redox Homeostasis for Gastric Cancer.
    Zhen Jiang, Chenghua Zhang, Li Gan, Yuewang Jia, Yu Xiong, Yujiang Chen, Zhi Wang, Linfeng Wang, Hao Luo, Juexi Li, Rui Zhu, Xingli Ji, Qin Yu, Li Wang.
       PURPOSE: To screen the novel biomarkers for gastric cancer and determine the values of glutaminase 1 (GLS1) and gamma-glutamylcyclotransferase (GGCT) for detecting gastric cancer.
    EXPERIMENTAL DESIGN: A discovery group of four paired gastric cancer tissue samples were labeled with iTRAQ agents and identified with LC-ESI-MS/MS. A validation group of 168 gastric cancer samples and 30 healthy controls were used to validate the expression of GLS1 and GGCT.
    RESULTS: Four hundred and thirty one proteins were found differentially expressed in gastric cancer tissues. Of these proteins, GLS1 and GGCT were found over expressed in gastric cancer patients, with sensitivity of 75.6% (95%CI: 69%-82.2%) and specificity of 81% (95%CI: 75%-87%) for glutaminase 1, and with sensitivity of 63.1% (95%CI: 55.7%-71.5%) and specificity of 60.7% (95%CI: 53.3%-68.2%) for gamma-glutamylcyclotransferase. The co-expression of GLS1 and GGCT in gastric cancer tissues has sensitivity of 78.1% (95%CI: 70.1%-86.1%) and specificity of 86.5% (95%CI: 79.5-93.4%). Moreover, both GLS1 and GGCT presented higher expression of 82.6% (95%CI: 68.5%-99.4%) and 73.9% (95%CI: 54.5%-93.3%) in lymph node metastasis specimen than those in non lymph node metastasis specimen. The areas under ROC curves were up to 0.734 for the co-expression of GLS1 and GGCT in gastric cancer. The co-expression of GLS1 and GGCT was strongly associated with histological grade, lymph node metastasis and TNM stage Ⅲ/Ⅳ.
    CONCLUSIONS AND CLINICAL RELEVANCE: The present study provides the quantitative proteomic analysis of gastric cancer tissues to identify prognostic biomarkers of gastric cancer. The co-expression level of GLS1 and GGCT is of great clinical values to serve as diagnostic and therapeutic biomarkers for early gastric cancer. This article is protected by copyright. All rights reserved.
    Keywords:  GGCT; GLS1; Gastric cancer; Glutaminolysis; Redox; iTRAQ
    DOI:  https://doi.org/10.1002/prca.201800038
  6. J Neurotrauma. 2018 Nov 28.
    Proteomic Analysis and Biochemical Correlates of Mitochondrial Dysfunction following Low-Intensity Primary Blast Exposure.
    Hailong Song, Mei Chen, Chen Chen, Jiankun Cui, Catherine E Johnson, Jianlin Cheng, Xiaowan Wang, Russell Swerdlow, Ralph DePalma, Weiming Xia, Zezong Gu.
      Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures over 100-kPa, while understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with an peak overpressure at 46.6-kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. In this study, we used tandem mass tagged (TMT) quantitative proteomics and bioinformatics analysis to seek insights into the molecular mechanisms underlying ultrastructural pathology. Changes in global- and phospho-proteomes were determined at 3 and 24 hours, 7 and 30 days post injury (DPI), in order to investigate the biochemical and molecular correlates of mitochondrial dysfunction. Results showed striking dynamic changes in a total of 2216 proteins and 459 phosphorylated proteins at vary time points after blast. Disruption of key canonical pathways included evidence of mitochondrial dysfunction, oxidative stress, axonal / cytoskeletal / synaptic dysregulation, and neurodegeneration. Bioinformatic analysis identified blast induced trends in networks related to cellular growth / development / movement / assembly and cell-to-cell signaling interactions. With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration-relevant enzyme activities. Insights on the early pathogenesis of primary LIB-induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers and targets for intervention.
    Keywords:  ANIMAL STUDIES; MILITARY INJURY; MITOCHONDRIA; OXIDATIVE STRESS; PROTEOMICS
    DOI:  https://doi.org/10.1089/neu.2018.6114
  7. J Proteome Res. 2018 Nov 28.
    Hippocampal proteomic alteration in triple transgenic mouse model of Alzheimer's disease and implication of PINK 1 regulation in donepezil treatment.
    Xinhua Zhou, Wei Xiao, Zhiyang Su, Jiehong Cheng, Chengyou Zheng, Zaijun Zhang, Yuqiang Wang, Liang Wang, Benhong Xu, Shupen Li, Xifei Yang, Maggie Pui Man Hoi.
       BACKGROUND: Donepezil is a clinically approved acetylcholinesterase inhibitor (AChEI) for cognitive improvement in Alzheimer's disease (AD). Donepezil has been used as a first-line therapeutics for the symptomatic treatment of AD, but its ability to modify disease pathology and underlying mechanisms are not clear.
    METHODS: We investigated the protective effects and underlying mechanisms of donepezil in AD-related triple transgenic (APPSwe/PSEN1M146V/MAPTP301L) mouse model (3×Tg-AD). Mice (8-month old) were treated with donepezil (1.3 mg/kg) for 4 months and evaluated by behavioral tests for assessment of cognitive functions and the hippocampal tissues were examined by protein analysis and quantitative proteomics.
    RESULTS: Behavioral tests showed that donepezil significantly improved the cognitive capabilities of 3xTg-AD mice. The levels of soluble and insoluble amyloid beta proteins (Aβ1-40 and Aβ1-42) and senile plaques were reduced in the hippocampus. Golgi staining of the nervous tissue showed that donepezil prevented dendritic spine loss in hippocampal neurons of 3xTg-AD mice. Proteomic studies of the hippocampal tissues identified 3131 proteins with altered expression related to AD pathology, of which 262 could be significantly reversed with donepezil treatment. Bioinformatics with functional analysis and protein-protein interaction (PPI) network mapping showed that donepezil significantly elevated the protein levels of PINK 1, NFASC, MYLK2, and NRAS in the hippocampus, and modulated the biological pathways of axon guidance, mitophagy, mTOR and MAPK signaling. The substantial upregulation of PINK 1 with donepezil was further verified by western blotting.
    CONCLUSIONS: Donepezil exhibited neuroprotective effects via multiple mechanisms. In particular, PINK 1 is related to mitophagy and cellular protection from mitochondrial dysfunction, which might play important roles in AD pathogenesis and represent a potential therapeutic target.
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00818
  8. Arch Oral Biol. 2018 Nov 20. pii: S0003-9969(18)30378-9. [Epub ahead of print]98 148-155
    Proteomics of the acid-soluble fraction of whole and major gland saliva in burning mouth syndrome patients.
    Tiziana Cabras, Barbara Manconi, Massimo Castagnola, Maria Teresa Sanna, Morena Arba, Shikha Acharya, Jörgen Ekström, Anette Carlén, Irene Messana.
       OBJECTIVE: In the present study the salivary proteome of burning mouth syndrome patients and healthy subjects was characterized by a top-down proteomic approach and compared to highlight possible qualitative and quantitative differences that may give suggestions about the causes of this pathology which are still unknown.
    MATERIALS AND METHODS: Resting and stimulated whole saliva, stimulated parotid and submandibular/sublingual saliva samples were collected from burning mouth syndrome patients (n = 16) and age- and gender-matched healthy subjects (n = 14). An equal volume of 0.2% trifluoroacetic acid was added to each sample immediately after collection and the supernatants were analysed by liquid chromatography coupled to electrospray-ionisation mass spectrometry. Proteins and peptides were quantified using a label-free approach measuring the extracted ion current peak areas of the main salivary proteins and peptides.
    RESULTS: The quantitation of the main salivary proteins and peptides revealed a higher concentration of cystatin SN in resting saliva of burning mouth syndrome patients with respect to healthy controls and no other conspicuous changes.
    CONCLUSIONS: The reported data showed that the salivary protein profile was not affected, in composition and relative abundance, by the burning mouth syndrome, except for the cystatin SN, a protein up-regulated in several pathological conditions, that might be considered potentially indicative of the disease.
    Keywords:  Burning mouth syndrome; Cystatin SN; Proteomics; Top-down; saliva
    DOI:  https://doi.org/10.1016/j.archoralbio.2018.11.020
  9. Proteomics Clin Appl. 2018 Nov 22. e1800024
    TMT-Based Quantitative Proteomic Analysis Reveals Proteomic Changes Involved in Longevity.
    Zongkui Wang, Rong Zhang, Fengjuan Liu, Peng Jiang, Jun Xu, Haijun Cao, Xi Du, Li Ma, Fangzhao Lin, Lu Cheng, Xuefeng Zhou, Zhihui Shi, Yeheng Liu, Yaojing Huang, Shengliang Ye, Changqing Li.
       PURPOSE: Individual lifespans vary widely, and longevity is the main concern from ancient to modern times. This study is aimed to identify plasma proteins associated with longevity by proteomics technique.
    EXPERIMENTAL DESIGN: Tandem mass tags (TMT)-based proteomics analysis is performed for the plasma of Bama longevity group and a control group to analyze the differentially expressed proteins (DEPs). A validation set is used to verify the results of TMT-based proteomics.
    RESULTS: Between Bama natives and the control individuals, the authors identify 175 DEPs, which are mainly involved in complement and coagulation cascades, metabolism of glyco and lipid, and regulation of actin cytoskeleton. Consistent with the proteomic analysis, plasma levels of MMP2, CCL5, and PF4 are significantly lower in Bama participants than in controls, whereas IGFBP2 and C9 increase in Bama individuals, in the validation set. By ROC analysis, combinations of these five proteins result in a high AUC value (0.991, 95% CI, 0.929-1.000, p < 0.0001) to distinguish longevous participants from controls.
    CONCLUSIONS AND CLINICAL RELEVANCE: The results highlight the roles of complement and coagulation cascades, metabolism of glyco and lipid, and inflammatory and immune response may play important roles in longevity. And the DEPs may serve as clinically useful biomarkers for healthy aging and predicting longevity.
    Keywords:  TMT; bama longevity hotspot; complement and coagulation cascades; gluconeogenesis/glycolysis; proteomics
    DOI:  https://doi.org/10.1002/prca.201800024
  10. J Nephrol. 2018 Nov 29.
    Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease.
    Tobias Feldreich, Christoph Nowak, Tove Fall, Axel C Carlsson, Juan-Jesus Carrero, Jonas Ripsweden, Abdul Rashid Qureshi, Olof Heimbürger, Peter Barany, Peter Stenvinkel, Nicolas Vuilleumier, Philip A Kalra, Darren Green, Johan Ärnlöv.
       INTRODUCTION: Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years).
    RESULTS: In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26-2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03-2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort.
    CONCLUSIONS: Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.
    Keywords:  CVD; ESRD; Proteomics
    DOI:  https://doi.org/10.1007/s40620-018-0556-5
  11. PLoS One. 2018 ;13(11): e0198461
    Circulating proteomic patterns in AF related left atrial remodeling indicate involvement of coagulation and complement cascade.
    Jelena Kornej, Petra Büttner, Elke Hammer, Beatrice Engelmann, Borislav Dinov, Philipp Sommer, Daniela Husser, Gerhard Hindricks, Uwe Völker, Andreas Bollmann.
       BACKGROUND: Left atrial (LA) electro-anatomical remodeling and diameter increase in atrial fibrillation (AF) indicates disease progression and is associated with poor therapeutic success. Furthermore, AF leads to a hypercoagulable state, which in turn promotes the development of a substrate for AF and disease progression in the experimental setting. The aim of this study was to identify pathways associated with LA remodeling in AF patients using untargeted proteomics approach.
    METHODS: Peripheral blood samples of 48 patients (62±10 years, 63% males, 59% persistent AF) undergoing AF catheter ablation were collected before ablation. 23 patients with left atrial low voltage areas (LVA), defined as <0.5 mV, and 25 patients without LVA were matched for age, gender and CHA2DS2-VASc score. Untargeted proteome analysis was performed using LC-ESI-Tandem mass spectrometry in a label free intensity based workflow. Significantly different abundant proteins were identified and used for pathway analysis and protein-protein interaction analysis.
    RESULTS: Analysis covered 280 non-redundant circulating plasma proteins. The presence of LVA correlated with 30 differentially abundant proteins of coagulation and complement cascade (q<0.05).
    CONCLUSIONS: This pilot proteomic study identified plasma protein candidates associated with electro-anatomical remodeling in AF and pointed towards an imbalance in coagulation and complement pathway, tissue remodeling and inflammation.
    DOI:  https://doi.org/10.1371/journal.pone.0198461
  12. J Cell Physiol. 2018 Nov 27.
    Altered plasma proteins released from platelets and endothelial cells are associated with human patent ductus arteriosus.
    Hai-Tao Hou, Xi-Zhang, Jun Wang, Li-Xin Liu, Jian-Feng Zhang, Qin Yang, Guo-Wei He.
      Patent ductus arteriosus is the third most common congenital heart disease and resulted from the persistence of ductal patency after birth. Ductus arteriosus closure involves functional and structural remodeling, controlled by many factors. The changes in plasma protein levels associated with PDA closure are not known. Here we for the first time demonstrate six key differential plasma proteins in human patent ductus arteriosus patients using proteomic technology and present a model to illustrate the constriction and closure of ductus arteriosus. Differentially expressed proteins were analyzed by using isobaric tags for relative and absolute quantification and validated by enzyme-linked immunosorbent assay in new samples. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD008568. We found 74 upregulated and 98 downregulated proteins in the plasma of patients with PDA. Five decreased proteins (platelet factor 4, fibrinogen, von Willebrand factor, collagen, and mannose binding lectin-associated serine protease-2) and one increased protein (fibronectin) may increase the risk of patent ductus arteriosus. Those proteins are closely related to platelet activation and coagulation cascades, complement mannan-binding-lectin, and other systemic signaling pathways. Our findings for the first time indicate that the differential proteins involved in different pathways may play key roles in the nonclosure of the ductus arteriosus in humans and may be developed as biomarkers for diagnosis. All those findings may be served as the basis of understanding the etiology and pathogenesis of patent ductus arteriosus.
    Keywords:  congenital heart disease; patent ductus arteriosus; proteomics
    DOI:  https://doi.org/10.1002/jcp.27433
  13. J Lipid Res. 2018 Nov 25. pii: jlr.P088542. [Epub ahead of print]
    Plasma proteome correlates of lipid and lipoprotein: Biomarkers of metabolic diversity and inflammation in children of rural Nepal.
    Sun Eun Lee, Kerry Schulze, Christine P Stewart, Robert N Cole, Lee S F Wu, Abdulkerim Eroglu, James D Yager, John Groopman, Parul Christian, Keith P West.
      Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL-cholesterol concentrations were common especially in children with subclinical inflammation. Among 982 proteins analyzed, relative abundance of 11, 12 and 52 plasma proteins were correlated with LDL-cholesterol (r=-0.43~0.70), triglycerides (r=-0.39~0.53) and HDL-cholesterol (r=-0.49~0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4~40% and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis and tissue repair lower by 3~20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease.
    Keywords:  HDL; Inflammation; LDL; Proteomics; Triglycerides
    DOI:  https://doi.org/10.1194/jlr.P088542
  14. J Proteome Res. 2018 Nov 27.
    Data-independent acquisition mass spectrometry to quantify protein levels in FFPE tumor biopsies for molecular diagnostics.
    Yeoun Jin Kim, Steve M Sweet, Jarrett D Egertson, Andrew J Sedgewick, Sunghee Woo, Wei-Li Liao, Gennifer E Merrihew, Brian C Searle, Charlie Vaske, Robert Heaton, Michael J MacCoss, Todd Hembrough.
      Mass spectrometry-based protein quantitation is currently used to measure therapeutically relevant protein biomarkers in CAP/CLIA setting to predict likely responses of known therapies. Selected reaction monitoring (SRM) is the method of choice due to its outstanding analytical performance. However, data-independent acquisition (DIA) is now emerging as a proteome-scale clinical assay. We evaluated the ability of DIA to profile the patient-specific proteomes of sample-limited tumor biopsies and to quantify proteins of interest in a targeted fashion using formalin-fixed, paraffin-embedded (FFPE) tumor biopsies (n=12) selected from our clinical laboratory. DIA analysis on the tumor biopsies provided 3,713 quantifiable proteins including actionable biomarkers currently in clinical use, successfully separated two gastric cancers from colorectal cancer specimen solely based on global proteomic profiles, and identified subtype-specific proteins with prognostic or diagnostic value. We demonstrate the potential use of DIA-based quantitation to inform therapeutic decision-making using TUBB3, for which clinical cut-off expression levels have been established by SRM. Comparative analysis of DIA-based proteomic profiles and mRNA expression levels found positively and negatively correlated protein-gene pairs, a finding consistent with previously reported results from fresh-frozen tumor tissues.
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00699
  15. Cell Rep. 2018 Nov 27. pii: S2211-1247(18)31729-7. [Epub ahead of print]25(9): 2524-2536.e4
    Quantitative Proteomics Evaluation of Human Multipotent Stromal Cell for β Cell Regeneration.
    Miljan Kuljanin, Ruth M Elgamal, Gillian I Bell, Dimetri Xenocostas, Anargyros Xenocostas, David A Hess, Gilles A Lajoie.
      Human multipotent stromal cells (hMSCs) are one of the most versatile cell types used in regenerative medicine due to their ability to respond to injury. In the context of diabetes, it has been previously shown that the regenerative capacity of hMSCs is donor specific after transplantation into streptozotocin (STZ)-treated immunodeficient mice. However, in vivo transplantation models to determine regenerative potency of hMSCs are lengthy, costly, and low throughput. Therefore, a high-throughput quantitative proteomics assay was developed to screen β cell regenerative potency of donor-derived hMSC lines. Using proteomics, we identified 16 proteins within hMSC conditioned media that effectively identify β cell regenerative hMSCs. This protein signature was validated using human islet culture assay, ELISA, and the potency was confirmed by recovery of hyperglycemia in STZ-treated mice. Herein, we demonstrated that quantitative proteomics can determine sample-specific protein signatures that can be used to classify previously uncharacterized hMSC lines for β cell regenerative clinical applications.
    Keywords:  NOD/SCID; diabetes; human multipotent stromal cells; islet regeneration; label free quantitation; mass spectrometry; proteomics; secretome; targeted proteomics; β cell regeneration
    DOI:  https://doi.org/10.1016/j.celrep.2018.10.107
  16. Expert Rev Proteomics. 2018 Nov 27. 1-15
    Proteomic approaches for cancer epigenetics research.
    Dylan M Marchione, Benjamin A Garcia, John Wojcik.
       INTRODUCTION: Epigenetic dysregulation drives or supports numerous human cancers. The chromatin landscape in cancer cells is often marked by abnormal histone post-translational modification (PTM) patterns and by aberrant assembly and recruitment of protein complexes to specific genomic loci. Mass spectrometry-based proteomic analyses can support the discovery and characterization of both phenomena. Areas covered: We broadly divide this literature into two parts: 'modification-centric' analyses that link histone PTMs to cancer biology; and 'complex-centric' analyses that examine protein-protein interactions that occur de novo as a result of oncogenic mutations. We also discuss proteomic studies of oncohistones. We highlight relevant examples, discuss limitations, and speculate about forthcoming innovations regarding each application. Expert commentary: 'Modification-centric' analyses have been used to further understanding of cancer's histone code and to identify associated therapeutic vulnerabilities. 'Complex-centric' analyses have likewise revealed insights into mechanisms of oncogenesis and suggested potential therapeutic targets, particularly in MLL-associated leukemia. Proteomic experiments have also supported some of the pioneering studies of oncohistone-mediated tumorigenesis. Additional applications of proteomics that may benefit cancer epigenetics research include middle-down and top-down histone PTM analysis, chromatin reader profiling, and genomic locus-specific protein identification. In the coming years, proteomic approaches will remain powerful ways to interrogate the biology of cancer.
    Keywords:  Affinity proteomics; cancer; chromatin; epigenetics; histones; middle-down; readers; top-down
    DOI:  https://doi.org/10.1080/14789450.2019.1550363
  17. Mol Cell Proteomics. 2018 Nov 28. pii: mcp.RA118.000957. [Epub ahead of print]
    Integrated Genomic and Proteomic Analyses Reveal Novel Mechanisms of the Methyltransferase SETD2 in Renal Cell Carcinoma Development.
    Lin Li, Weili Miao, Ming Huang, Preston Williams, Yinsheng Wang.
      Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC in humans. SET domain-containing 2 (SETD2), a lysine methyltransferase for histone and other proteins, has been found to be frequently lost in ccRCC. However, the mechanisms through which deficiency in SETD2 contributes to ccRCC development remain largely unknown. Here, we used a human embryonic kidney epithelial cell line with the SETD2 gene knocked out using CRISPR/Cas9 technology. Using ChIP-seq analysis, we showed that SETD2 loss leads to diminished occupancy of histone H3K36me3 and H4K16ac on actively transcribed genes. Transcriptome sequencing of the knockout cells revealed diminished expression of genes involved in metabolic pathways and elevated expression of genes involved in regulation of RNA polymerase II-mediated transcription. Quantitative proteomic analysis of chromatin-associated proteins showed that genetic ablation of SETD2 leads to elevated chromatin occupancy of proteins involved in chromatin remodeling and RNA polymerase II transcription regulation, and diminished chromatin binding of proteins involved in translation elongation and RNA splicing. Interestingly, we found that SETD2 depletion attenuates cell proliferation, and this can be rescued by knockdown of CDK1. Taken together, we illustrate multiple SETD2-regulated cellular pathways that suppress cancer development and uncover mechanisms underlying aberrant cell cycle regulation in SETD2-depleted cells.
    Keywords:  Cancer Biology*; Cell biology*; Oncogenes*; PLK1-CDK1 Pathway; Proteogenomics; RNA SEQ; SETD2
    DOI:  https://doi.org/10.1074/mcp.RA118.000957
  18. Viruses. 2018 Nov 27. pii: E670. [Epub ahead of print]10(12):
    Proteomics of Bronchoalveolar Lavage Fluid Reveals a Lung Oxidative Stress Response in Murine Herpesvirus-68 Infection.
    Eric Bortz, Ting-Ting Wu, Parthive Patel, Julian P Whitelegge, Ren Sun.
      Murine herpesvirus-68 (MHV-68) productively infects mouse lungs, exhibiting a complex pathology characteristic of both acute viral infections and chronic respiratory diseases. We sought to discover proteins differentially expressed in bronchoalveolar lavage (BAL) from mice infected with MHV-68. Mice were infected intranasally with MHV-68. After nine days, as the lytic phase of infection resolved, differential BAL proteins were identified by two-dimensional (2D) electrophoresis and mass spectrometry. Of 23 unique proteins, acute phase proteins, vitamin A transport, and oxidative stress response factors Pdx6 and EC-SOD (Sod3) were enriched. Correspondingly, iNOS2 was induced in lung tissue by seven days post-infection. Oxidative stress was partly a direct result of MHV-68 infection, as reactive oxygen species (ROS) were induced in cultured murine NIH3T3 fibroblasts and human lung A549 cells infected with MHV-68. Finally, mice infected with a recombinant MHV-68 co-expressing inflammatory cytokine murine interleukin 6 (IL6) showed exacerbated oxidative stress and soluble type I collagen characteristic of tissue recovery. Thus, oxidative stress appears to be a salient feature of MHV-68 pathogenesis, in part caused by lytic replication of the virus and IL6. Proteins and small molecules in lung oxidative stress networks therefore may provide new therapeutic targets to ameliorate respiratory virus infections.
    Keywords:  BAL; MHV-68; bronchoalveolar lavage fluid; murine herpesvirus-68; oxidative stress; proteomics
    DOI:  https://doi.org/10.3390/v10120670
  19. J Proteomics. 2018 Nov 22. pii: S1874-3919(18)30403-2. [Epub ahead of print]
    Comparative exoproteome profiling of an invasive and a commensal Staphylococcus haemolyticus isolate.
    Jorunn Pauline Cavanagh, Maria Pain, Fatemeh Askarian, Jack-Ansgar Bruun, Ilona Urbarova, Sun Nyunt Wai, Frank Schmidt, Mona Johannessen.
      Staphylococcus haemolyticus is a skin commensal emerging as an opportunistic pathogen. Nosocomial isolates of S. haemolyticus are the most antibiotic resistant members of the coagulase negative staphylococci (CoNS), but information about other S. haemolyticus virulence factors is scarce. Bacterial membrane vesicles (MVs) are one mediator of virulence by enabling secretion and long distance delivery of bacterial effector molecules while protecting the cargo from proteolytic degradation from the environment. We wanted to determine if the MV protein cargo of S. haemolyticus is strain specific and enriched in certain MV associated proteins compared to the totalsecretome. The present study shows that both clinical and commensal S. haemolyticus isolates produce membrane vesicles. The MV cargo of both strains was enriched in proteins involved in adhesion and acquisition of iron. The MV cargo of the clinical strain was further enriched in antimicrobial resistance proteins. Data are available via ProteomeXchange with identifier PXD010389. BIOLOGICAL SIGNIFICANCE: Staphylococcus haemolyticus is an emerging opportunistic pathogen of which clinical isolates are usually multidrug resistant. The information on factors discriminating clinical and commensal isolates is scarce. The present study shows that both clinical and commensal S. haemolyticus isolates produce membrane vesicles (MV). A proteomic approach was utilized to identify strain specific secreted and membrane vesicle associated proteins. Our findings suggests that the MV cargo is strain specific, and that the MVs secreted by the clinical S.haemolyticus isolate are enriched in virulence and antimicrobial resistance proteins.
    Keywords:  Membrane; Opportunistic pathogen; Staphylococcus haemolyticus; Total secretome; Vesicle cargo; Virulence factors
    DOI:  https://doi.org/10.1016/j.jprot.2018.11.013
  20. Clin Proteomics. 2018 ;15 36
    Differential analysis of quantitative proteome and acetyl-proteome profiling between premenopausal and postmenopausal ovarian tissues.
    Jinling Yi, Huatianshu Hu, Peipei Shi, Song Shi, Junda Zhao, Linna Xu, Weining Yang, Bin Li, Jin Zhu, Shien Zou.
       Background: Natural menopause is always accompanied by specific signs and symptoms, suggesting physiological changes in this peoriod. However, no systematic study has assessed the changes at molecular level in the ovaries during the menopausal transition so far. This study integrated quantitative proteome and acetyl-proteome to comprehensively uncover the changes of ovarian protein and protein-acetylation profiles in this transitional period. The findings would provide novel insights into the biology of menopause and help relieve and treat the associated signs and symptoms, further improving the women's health care.
    Methods: Freshly thawed ovarian tissue samples obtained from premenopausal and postmenopausal women were assessed with Tandem Mass Tags for the quantitative analysis of the global profile and acetyl-proteomes by 2-dimensional separation and LC-MS/MS.
    Results: Comprehensively, 4210 types of protein, with 3551 types quantifiable were detected. 3047 acetylated sites in 1583 types of protein with 2256 quantifiable in 1248 proteins were detected. By comparing the global and acetylated proteome profiles for postmenopausal women and premenopausal women, 151 types of proteins were found upregulated and 65 were downregulated, along with 23 acetylated sites upregulated and 220 sites downregulated. For Immune response, the complement and coagulation cascades plus the citrate cycle and cellular detoxification were found to be significantly enhanced, while the extracellular structure and matrix organization, ECM-receptor interactions plus the infections were markedly suppressed. In addition, the amino acids around the acetylated sites were enriched by motif analysis, which can help us uncover amino acid sequence and search for the specific target in the subsequent study.
    Conclusion: Global and acetylated proteome Profiles in ovary differ between the premenopausal and postmenopausal groups. These proteomic-level changes may offer some potential biological markers to identify the pathological changes in ovary and help relieve and treat the associated signs and symptoms, and ultimately improve women's health care.
    Keywords:  Acetyl-proteome; Human ovarian; Menopause; Proteome
    DOI:  https://doi.org/10.1186/s12014-018-9214-0
  21. BMC Musculoskelet Disord. 2018 Nov 29. 19(1): 416
    Differential protein expression in human knee articular cartilage and medial meniscus using two different proteomic methods: a pilot analysis.
    Elin Folkesson, Aleksandra Turkiewicz, Martin Englund, Patrik Önnerfjord.
       BACKGROUND: Proteomics is an emerging field in the study of joint disease. Our two aims with this pilot analysis were to compare healthy human knee articular cartilage with meniscus, two tissues both known to become affected in the osteoarthritic disease process, and to compare two mass spectrometry (MS)-based methods: data-dependent acquisition (DDA) and data-independent acquisition (DIA).
    METHODS: Healthy knee articular cartilage taken from the medial tibial condyle and medial meniscus samples taken from the body region were obtained from three adult forensic medicine cases. Proteins were extracted from tissue pieces and prepared for MS analysis. Each sample was subjected to liquid chromatography (LC)-MS/MS analysis using an Orbitrap mass spectrometer, and run in both DDA and DIA mode. Linear mixed effects models were used for statistical analysis.
    RESULTS: A total of 653 proteins were identified in the DDA analysis, of which the majority was present in both tissue types. Only proteins with quantitation information in both tissues (n = 90) were selected for more detailed analysis, of which the majority did not statistically significantly differ in abundance between the two tissue types, in either of the MS analyses. However, 21 proteins were statistically significantly different (p < 0.05) between meniscus and cartilage in the DIA analysis. Out of these, 11 proteins were also significantly different in the DDA analysis. Aggrecan core protein was the most abundant protein in articular cartilage and significantly differed between the two tissues in both methods. The corresponding protein in meniscus was serum albumin. Dermatopontin exhibited the highest meniscus vs articular cartilage ratio among the statistically significant proteins. The DIA method led to narrower confidence intervals for the abundance differences between the two tissue types than DDA.
    CONCLUSIONS: Although articular cartilage and meniscus had similar proteomic composition, we detected several differences by MS. Between the two analyses, DIA yielded more precise estimates and more statistically significant different proteins than DDA, and had no missing values, which makes it preferable for future LC-MS/MS analyses.
    Keywords:  Articular cartilage; Data-dependent acquisition; Data-independent acquisition; Knee; Meniscus; Osteoarthritis; Proteomics
    DOI:  https://doi.org/10.1186/s12891-018-2346-6
  22. Cell Physiol Biochem. 2018 Nov 27. 51(3): 1327-1339
    iTRAQ-Based Differential Proteomic Analysis Reveals the Pathways Associated with Tigecycline Resistance in Acinetobacter baumannii.
    Ni Yang, Yuan Liu, Ping He, Rui Ke, Yujie Zhao, Yanjing Feng, Rong Jing, Shuzhen Ma, Congrui Liu, Yan Geng, Xiaokang Wu, Yang Wei.
       BACKGROUND/AIMS: Acinetobacter baumannii is an aerobic and Gram-negative bacterial pathogen with high morbidity and mortality. It remains a serious public health problem arising from its multidrug-resistant and extensive antibiotic resistance spectrum.
    METHODS: In the present study, iTRAQ coupled with 2D LC-MS/MS was used to evaluate the proteome in standard Acinetobacter baumannii standard strains and tigecycline-resistant strains.
    RESULTS: A total of 3639 proteins were identified and 961 proteins were identified to be differentially expressed in tigecycline-resistant Acinetobacter baumannii strains compared to the standard strains. 506 (52.6%) proteins were up-regulated and 455 (47.4%) proteins were down-regulated. Based on the GO enrichment analysis and KEGG pathway analysis, we concluded that most differentially expressed proteins were associated with stress responses, cellular component organization, proteins synthesis, degradation and function. Moreover, β-lactam resistance, the longevity regulating pathway and other related pathways were also involved in the regulation of tigecycline-resistant Acinetobacter baumannii. The differential expression of key proteins were evaluated by transcript analysis using quantitative RT-PCR.
    CONCLUSION: These results may provide new insights into the mechanisms of drug resistance in Acinetobacter baumannii.
    Keywords:  Acinetobacter baumannii; Drug resistance; Protein degradation; Tigecycline; iTRAQ
    DOI:  https://doi.org/10.1159/000495551
  23. Cytokine. 2018 Nov 21. pii: S1043-4666(18)30428-9. [Epub ahead of print]
    Visceral white adipose tissue and serum proteomic alternations in metabolically healthy obese patients undergoing bariatric surgery.
    Ilias P Doulamis, Panagiotis Konstantopoulos, Aspasia Tzani, Asier Antoranz, Angeliki Minia, Afroditi Daskalopoulou, Anestis Charalampopoulos, Leonidas Alexopoulos, Depsina N Perrea, Evangelos Menenakos.
      Metabolically healthy obesity is characterized as a comorbidity-free obesity status, however the exact pathogenetic mechanisms implicated in its transition to unhealthy obesity have not yet been unveiled. Our aim was to investigate the effect of metabolic health on the proteomic profile both in serum and visceral fat of morbidly obese subjects. 28 patients undergoing bariatric surgery were prospectively enrolled. They were divided into two groups: metabolically healthy (MHO, n = 18) and unhealthy (MUO, n = 10) obese patients. 30 biomarkers were measured in serum and visceral adipose tissue with the use of targeted proteomic analysis (Luminex assays). TNF weak inducer of apoptosis (TWEAK) (p = 0.043), TNF related apoptosis inducing ligand (TRAIL) (p = 0.037), Growth differentiation factor-15 (GDF-15) (p = 0.04), Resistin (RETN) (p = 0.047), Matrix metalloproteinase-9 (MMP-9) (p = 0.011) and C-terminal telopeptide (ICTP) (p = 0.022) were up-regulated in the MUO group in the visceral white adipose tissue. Moreover, C-C motif ligand-3 (CCL-3) (p = 0.056), Interleukin-20 (IL-20) (p = 0.04), Prokineticin-1 (PROK-1) (p = 0.028) and TWEAK (p = 0.016) were found to be suppressed in the serum of MHO group. Significant correlations between serum and adipose tissue levels of certain cytokines were also observed, while 16 biomarkers were associated with BMI. Our results indicate metabolic health substantially attenuates the expression of TWEAK, TRAIL, GDF-15, RETN, MMP-9 and ICTP expression locally, in the visceral white adipose tissue, and the expression of CCL-3, IL-20, PROK-1 and TWEAK in the peripheral blood. Intriguingly, different cytokines -except for TWEAK- are up-regulated in each site, suggesting that obesity is not a homogenous but a multi-dimensional disease.
    Keywords:  Inflammation; Metabolic health; Obesity; Proteomics; TRAIL; TWEAK
    DOI:  https://doi.org/10.1016/j.cyto.2018.11.017
  24. J Proteome Res. 2018 Nov 29.
    Proteomic Profiling of Human Hepatic Stellate Cell Line LX2 Responses to Irradiation and TGF-β1.
    Baoying Yuan, Yuhan Chen, Zhifeng Wu, Li Zhang, Yuan Zhuang, Xiaomei Zhao, Hao Niu, Jason Chia-Hsien Cheng, ZhaoChong Zeng.
      Hepatic stellate cells (HSCs) are the main target of radiation damage and primarily contribute to the development of radiation-induced liver fibrosis. However, the molecular events underlying the radiation-induced activation of HSCs are not fully elucidated. In the present study, human HSC line LX2 was treated with X-ray irradiation and/or TGF-β1 and profibrogenic molecules were evaluated. The iTRAQ LC-MS/MS technology was performed to identify global protein expression profiles in LX2 following exposure to different stimuli. Irradiation or TGF-β1 alone increased expression of α-SMA, collagen 1, CTGF, PAI-1 and fibronectin. Irradiation and TGF-β1 cooperatively induced expression of these profibrotic markers. In total, 102, 137, 155 dysregulated proteins were identified in LX2 cell samples affected by irradiation, TGF-β1 or co-treatment, respectively. Bioinformatic analyses showed that the three differentially expressed protein sets were commonly associated with cell cycle and protein processing in endoplasmic reticulum. The expression of a set of proteins were properly validated: CDC20, PRC1, KIF20A, CCNB1, SHCBP, TACC3 upregulated upon irradiation or irradiation and TGF-β1 co-stimulation, whereas SPARC and THBS1 elevated by TGF-β1 or TGF-β1 plus irradiation treatment. Furthermore, CDC20 inhibition suppresses expression of profibrotic markers in irradiated and TGF-β1-stimulated LX2 cells. Detailed data on potential molecular mechanisms causing the radiation-induced HSC activation presented here would be instrumental in developing radiotherapy strategies that minimize radiation-induced liver fibrosis.
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00814
  25. Parasit Vectors. 2018 Nov 29. 11(1): 611
    Differential expression of proteins in genetically distinct Trypanosoma cruzi samples (TcI and TcII DTUs) isolated from chronic Chagas disease cardiac patients.
    Maykon Tavares de Oliveira, Karina Taciana Santos Silva, Leandro Xavier Neves, Max Jean de Ornelas Toledo, William Castro-Borges, Marta de Lana.
       BACKGROUND: Trypanosoma cruzi, a hemoflagellate protozoan parasite and the etiological agent of Chagas disease (CD), exhibits great genetic and biological diversity. Infected individuals may present clinical manifestations with different levels of severity. Several hypotheses have been proposed to attempt to correlate the diversity of clinical signs and symptoms to the genetic variability of T. cruzi. This work aimed to investigate the differential expression of proteins from two distinct genetic groups of T. cruzi (discrete typing units TcI and TcII), isolated from chronically infected individuals displaying the cardiac form of CD. For this purpose, epimastigote forms of the two isolates were cultured in vitro and the cells recovered for protein extraction. Comparative two-dimensional (2D) gel electrophoreses were performed and differentially expressed spots selected for identification by mass spectrometry, followed by database searching and protein categorization.
    RESULTS: The 2D electrophoretic profiles revealed the complex composition of the T. cruzi extracted proteome. Protein spots were distributed along the entire pH and molecular mass ranges attesting for the integrity of the protein preparations. In total, 46 differentially expressed proteins were identified present in 40 distinct spots found in the comparative gel analyses. Of these, 16 displayed upregulation in the gel from TcI-typed parasites and 24 appeared overexpressed in the gel from TcII-typed parasites. Functional characterization of differentially expressed proteins revealed major alterations associated with stress response, lipid and amino acid metabolism in parasites of the TcII isolate, whilst those proteins upregulated in the TcI sample were primarily linked to central metabolic pathways.
    CONCLUSIONS: The comparative 2D-gel electrophoresis allowed detection of major differences in protein expression between two T. cruzi isolates, belonging to the TcI and TcII genotypes. Our findings suggest that patients displaying the cardiac form of the disease harbor parasites capable of exhibiting distinct proteomic profiles. This should be of relevance to disease prognosis and treatment.
    Keywords:  Chagas disease; DTUs; Differential proteomics; Trypanosoma cruzi
    DOI:  https://doi.org/10.1186/s13071-018-3181-1
  26. J Neurochem. 2018 Nov 26.
    Mass Spectrometry: A Platform for Biomarker Discovery and Validation for Alzheimer's and Parkinson's Diseases.
    Eugene M Cilento, Lorrain Jin, Tessandra Stewart, Min Shi, Lifu Sheng, Jing Zhang.
      Accurate, reliable, and objective biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), and related age-associated neurodegenerative disorders are urgently needed to assist in both diagnosis, particularly at early stages, and monitoring of disease progression. Technological advancements in protein detection platforms over the last few decades have resulted in a plethora of reported molecular biomarker candidates for both AD and PD; however, very few of these candidates are developed beyond the discovery phase of the biomarker discovery pipeline, a reflection of the current bottleneck within the field. In this review, the expanded use of selected reaction monitoring (SRM) targeted mass spectrometry will be discussed in detail as a platform for systematic verification of large panels of protein biomarker candidates prior to costly validation testing. We also advocate for the coupling of discovery-based proteomics with modern targeted-MS based approaches (e.g. SRM) within a single study in future workflows to expedite biomarker development and validation for AD and PD. It is our hope that improving the efficiency within the biomarker development process by use of an SRM pipeline may ultimately hasten the development of biomarkers that both decrease misdiagnosis of AD and PD and ultimately lead to detection at early stages of disease and objective assessment of disease progression. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/jnc.14635
  27. Mol Cell Proteomics. 2018 Nov 27. pii: mcp.RA118.001053. [Epub ahead of print]
    Dynamic phosphoproteomics uncovers signaling pathways modulated by anti-neoplastic sphingolipid analogs.
    Peter Kubiniok, Brendan T Finicle, Fanny Piffaretti, Alison N McCracken, Michael Perryman, Stephen Hanessian, Aimee L Edinger, Pierre Thibault.
      The anti-neoplastic sphingolipid analog SH-BC-893 starves cancer cells to death by down-regulating cell surface nutrient transporters and blocking lysosomal trafficking events. These effects are mediated by the activation of protein phosphatase 2A (PP2A). To identify putative PP2A substrates, we used quantitative phosphoproteomics to profile the temporal changes in protein phosphorylation in FL5.12 cells following incubation with SH-BC-893 or the specific PP2A inhibitor LB-100. These analyses enabled the profiling of more than 15,000 phosphorylation sites, of which 958 sites on 644 proteins were dynamically regulated. We identified 114 putative PP2A substrates including several nutrient transporter proteins, GTPase regulators (e.g. Agap2, Git1), and proteins associated with actin cytoskeletal remodeling (e.g. Vim, Pxn). To identify SH-BC-893-induced cell signaling events that disrupt lysosomal trafficking, we compared phosphorylation profiles in cells treated with SH-BC-893 or C2-ceramide, a non-vacuolating sphingolipid that does not impair lysosomal fusion. These analyses combined with functional assays uncovered the differential regulation of Akt and Gsk3b by SH-BC-893 (vacuolating) and C2-ceramide (non-vacuolating). Dynamic phosphoproteomics of cells treated with compounds affecting PP2A activity thus enabled the correlation of cell signaling with phenotypes to rationalize their mode of action.
    Keywords:  Cancer Biology*; Cell biology*; Phosphoproteome; Phosphorylation; Quantification
    DOI:  https://doi.org/10.1074/mcp.RA118.001053
  28. Front Immunol. 2018 ;9 2487
    Immunoproteomics and Surfaceomics of the Adult Tapeworm Hymenolepis diminuta.
    Daniel Młocicki, Anna Sulima, Justyna Bień, Anu Näreaho, Anna Zawistowska-Deniziak, Katarzyna Basałaj, Rusłan Sałamatin, David Bruce Conn, Kirsi Savijoki.
      In cestodiasis, mechanical and molecular contact between the parasite and the host activates the immune response of the host and may result in inflammatory processes, leading to ulceration and intestinal dysfunctions. The aim of the present study was to identify antigenic proteins of the adult cestode Hymenolepis diminuta by subjecting the total protein extracts from adult tapeworms to 2DE immunoblotting (two-dimensional electrophoresis combined with immunoblotting) using sera collected from experimentally infected rats. A total of 36 protein spots cross-reacting with the rat sera were identified using LC-MS/MS. As a result, 68 proteins, including certain structural muscle proteins (actin, myosin, and paramyosin) and moonlighters (heat shock proteins, kinases, phosphatases, and glycolytic enzymes) were identified; most of these were predicted to possess binding and/or catalytic activity required in various metabolic and cellular processes, and reported here as potential antigens of the adult cestode for the first time. As several of these antigens can also be found at the cell surface, the surface-associated proteins were extracted and subjected to in-solution digestion for LC-MS/MS identification (surfaceomics). As a result, a total of 76 proteins were identified, from which 31 proteins, based on 2DE immunoblotting, were predicted to be immunogenic. These included structural proteins actin, myosin and tubulin as well as certain moonlighting proteins (heat-shock chaperones) while enzymes with diverse catalytic activities were found as the most dominating group of proteins. In conclusion, the present study shed new light into the complexity of the enteric cestodiasis by showing that the H. diminuta somatic proteins exposed to the host possess immunomodulatory functions, and that the immune response of the host could be stimulated by diverse mechanisms, involving also those triggering protein export via yet unknown pathways.
    Keywords:  Hymenolepis diminuta; cestoda; host–parasite interactions; immunoblotting; mass spectrometry; proteomics; surface proteins; tapeworm
    DOI:  https://doi.org/10.3389/fimmu.2018.02487
  29. Proteomics. 2018 Nov 26. e1800274
    Proteomic profiling of LPS-induced macrophage derived exosomes indicates their involvement in acute liver injury.
    Guozhen Wang, Siyi Jin, Xuguang Ling, Yang Li, Ye Hu, Yijie Zhang, Yun Huang, Tingting Chen, Jiayi Lin, Zuowei Ning, Ying Meng, Xu Li.
      Exosomes are typically involved in cellular communication and signaling. Macrophages played key role in lipopolysaccharide (LPS) induced sepsis. However, the molecular comparison of exosomes derived from LPS induced macrophage has not been well analyzed. We validated the macrophage-exosomes and investigated the protein composition of those exosomes by iTRAQ mass spectrometry. 5056 proteins were identified in macrophage-exosomes. 341 increased proteins and 363 reduced proteins were discovered in LPS treated macrophages-exosomes compared with control-exosomes. In addition, gene ontology analysis demonstrated that macrophage-exosomes proteins were mostly linked to cell, organelle, extracellular region and membrane. The bioinformatics analysis also indicated that these proteins were mainly involved in cellular process, single-organism process, metabolic process, and biological regulation. Among these 341 up-regulated proteins, KEGG analysis revealed that 22 proteins were involved in the NOD-like receptor signaling pathway. Finally, hepatocytes could uptake macrophages-exosomes and subsequently NLRP3 inflammasome was activated in vitro and in vivo. These data emphasize the fundamental importance of macrophages-exosomes in sepsis induced liver injury. Therefore, the iTRAQ proteomic strategy brought new insights into macrophages derived exosomes. It may improve our understanding of macrophages-exosomes' functions and their possible use as therapeutic targets for sepsis. This article is protected by copyright. All rights reserved.
    Keywords:  LPS; NOD-like receptor signaling pathway; exosome; macrophage; proteomi
    DOI:  https://doi.org/10.1002/pmic.201800274
  30. J Clin Med. 2018 Nov 26. pii: E483. [Epub ahead of print]7(12):
    Urinary Proteomics for the Early Diagnosis of Diabetic Nephropathy in Taiwanese Patients.
    Wen-Ling Liao, Chiz-Tzung Chang, Ching-Chu Chen, Wen-Jane Lee, Shih-Yi Lin, Hsin-Yi Liao, Chia-Ming Wu, Ya-Wen Chang, Chao-Jung Chen, Fuu-Jen Tsai.
      Diabetic nephropathy (DN) is a major complication in diabetic patients. Microalbuminuria testing is used to identify renal disease; however, its predictive value is questionable. We aimed to identify urinary biomarkers to early diagnosis nephropathy before identifiable alternations in kidney function or urine albumin excretion occurs. Proteomic approaches were used to identify potential urinary biomarkers and enzyme-linked immunosorbent assay was performed to verify the results. The data identified haptoglobin (HPT) and α-1-microglobulin/bikunin precursor (AMBP) as two biomarkers with the highest ability to distinguish between healthy individuals and patients with nephropathy, and between diabetic patients with and without DN. Further, the HPT-to-creatinine ratio (HCR) was evaluated as an independent predictor of early renal functional decline (ERFD) in a cohort with an average follow-up of 4.2 years. The area under the curve (AUC) value for ERFD prediction was significantly improved when the HCR biomarker was included in the model with albumin to creatinine ratio (ACR) and baseline characteristics (AUC values were 0.803 and 0.759 for HCR and ACR, respectively; p value was 0.0423 for difference between models). In conclusion, our results suggest that HCR represents an early indicator of nephropathy, and a marker related to ERFD among diabetic patients in Taiwan.
    Keywords:  early prediction; nephropathy; proteomics
    DOI:  https://doi.org/10.3390/jcm7120483
  31. Proteomics. 2018 Nov 28. e1800209
    Helicobacter pylori Growth Stage Determines the Size, Protein Composition and Preferential Cargo Packaging of Outer Membrane Vesicles.
    Lauren Zavan, Natalie J Bitto, Ella L Johnston, David W Greening, Maria Kaparakis-Liaskos.
      Gram-negative bacteria release outer membrane vesicles (OMVs) as part of their normal growth that contain a range of cargo from their parent bacterium, including DNA, RNA, and proteins. The protein content of OMVs is suggested to be similar in composition to various sub-cellular locations of their parent bacterium. However, very little is known regarding the effect of bacterial growth stage on the size, content and selective packaging of proteins into OMVs. In this study, we examined the global proteome of Helicobacter pylori and their OMVs throughout bacterial growth to determine if bacterial growth stage affected OMV cargo composition. Analysis of OMVs produced by H. pylori revealed that bacterial growth stage affected the size, composition and selection of protein cargo into OMVs. Proteomic analysis identified that the proteome of H. pylori OMVs was vastly different throughout bacterial growth and that OMVs contained a range of proteins compared to their parent bacteria. In addition, bacterial growth stage affected the ability of OMVs to induce the production of IL-8 by human epithelial cells. Therefore, our findings identify that the size, proteome and immunogenicity of OMVs produced during various stages of bacterial growth is not comparable. Collectively, these findings highlight the importance of considering the bacterial growth stage from which OMVs are isolated from, as this will impact their size, protein composition and ultimately their biological functions. This article is protected by copyright. All rights reserved.
    Keywords:  Helicobacter pylori; IL-8; growth stage; outer membrane vesicles; proteomics; size
    DOI:  https://doi.org/10.1002/pmic.201800209
  32. Anal Bioanal Chem. 2018 Nov 28.
    High-throughput detection of low abundance sialylated glycoproteins in human serum by TiO2 enrichment and targeted LC-MS/MS analysis: application to a prostate cancer sample set.
    Caterina Gabriele, Francesco Cantiello, Annalisa Nicastri, Fabio Crocerossa, Giorgio Ivan Russo, Antonio Cicione, Mihai D Vartolomei, Matteo Ferro, Giuseppe Morgia, Giuseppe Lucarelli, Giovanni Cuda, Rocco Damiano, Marco Gaspari.
      Glycopeptide enrichment can be a strategy to allow the detection of peptides belonging to low abundance proteins in complex matrixes such as blood serum or plasma. Though several glycopeptide enrichment protocols have shown excellent sensitivities in this respect, few reports have demonstrated the applicability of these methods to relatively large sample cohorts. In this work, a fast protocol based on TiO2 enrichment and highly sensitive mass spectrometric analysis by Selected Reaction Monitoring (SRM) has been applied to a cohort of serum samples from prostate cancer and benign prostatic hyperplasia patients in order to detect low abundance proteins in a single LC-MS/MS analysis in nanoscale format, without immunodepletion or peptide fractionation. A peptide library of over 700 formerly N-glycosylated peptides was created by data dependent analysis. Then, 16 medium to low abundance proteins were selected for detection by single injection LC-MS/MS based on selected-reaction monitoring. Results demonstrated the consistent detection of the low-level proteins under investigation. Following label-free quantification, four proteins (Adipocyte plasma membrane-associated protein, Periostin, Cathepsin D and Lysosome-associated membrane glycoprotein 2) were found significantly increased in prostate cancer sera compared to the control group. Graphical abstract ᅟ.
    Keywords:  APMAP; CTSD; LAMP2; POSTN; Prostate cancer; Serum proteomics
    DOI:  https://doi.org/10.1007/s00216-018-1497-5
  33. Semin Perinatol. 2018 Nov;pii: S0146-0005(18)30082-X. [Epub ahead of print]42(7): 425-431
    Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia.
    Charitharth Vivek Lal, Vineet Bhandari, Namasivayam Ambalavanan.
      Bronchopulmonary Dysplasia (BPD) is a disorder with a multifactorial etiology and highly variable clinical phenotype. Several traditional biomarkers have been identified, but due to the complex disease phenotype, these biomarkers have low predictive accuracy for BPD. In recent years, newer technologies have facilitated the in-depth and unbiased analysis of 'big data' in delineating the diagnosis, pathogenesis, and mechanisms of diseases. Novel systems-biology based 'omic' approaches, including but not limited to genomics, microbiomics, proteomics, and metabolomics may help define the multiple cellular and humoral interactions that regulate normal as well as abnormal lung development and response to injury that are the hallmarks of BPD.
    Keywords:  BPD; Genetics; Metabolome; Microbiome; Proteome; Systems biology
    DOI:  https://doi.org/10.1053/j.semperi.2018.09.004
  34. J Cell Physiol. 2018 Nov 27.
    Cholinergic activity regulates the secretome of epicardial adipose tissue: Association with atrial fibrillation.
    Marinela Couselo-Seijas, Jose N López-Canoa, Rosa M Agra-Bermejo, Esther Díaz-Rodriguez, Angel L Fernandez, Jose M Martinez-Cereijo, Dario Durán-Muñoz, Susana B Bravo, Alba Velo, Laila González-Melchor, Xesus A Fernández-López, Jose L Martínez-Sande, Javier García-Seara, Jose R González-Juanatey, Moises Rodriguez-Mañero, Sonia Eiras.
      Botulinum toxin injection on epicardial fat, which inhibits acetylcholine (ACh) release, reduced the presence of atrial fibrillation (AF) in patients after heart surgery. Thus, we wanted to study the profile of the released proteins of epicardial adipose tissue (EAT) under cholinergic activity (ACh treatment) and their value as AF predictors. Biopsies, explants, or primary cultures were obtained from the EAT of 85 patients that underwent open heart surgery. The quantification of muscarinic receptors (mAChR) by real-time polymerase chain reaction or western blot showed their expression in EAT. Moreover, mAChR Type 3 was upregulated after adipogenesis induction (p < 0.05). Cholinergic fibers in EAT were detected by vesicular ACh transporter levels and/or acetylcholinesterase activity. ACh treatment modified the released proteins by EAT, which were identified by nano-high-performance liquid chromatography and TripleTOF analysis. These differentially released proteins were involved in cell structure, inflammation, or detoxification. After testing the plasma levels of alpha-defensin 3 (inflammation-involved protein) of patients who underwent open heart surgery ( n = 24), we observed differential levels between the patients who developed or did not develop postsurgery AF (1.58 ± 1.61 ng/ml vs. 6.2 ± 5.6 ng/ml; p < 0.005). The cholinergic activity on EAT might suggest a new mechanism for studying the interplay among EAT, autonomic nervous system dysfunction, and AF.
    Keywords:  atrial fibrillation (AF); cholinergic activity; epicardial fat cells
    DOI:  https://doi.org/10.1002/jcp.27723
  35. Mol Med Rep. 2018 Nov 20.
    Establishment of microRNA, transcript and protein regulatory networks in Alport syndrome induced pluripotent stem cells.
    Wenbiao Chen, Donge Tang, Yong Dai, Hongyan Diao.
      Alport syndrome (AS) is an inherited progressive disease caused by mutations in genes encoding for the α3, α4 and α5 chains, which are an essential component of type IV collagen and are required for formation of the glomerular basement membrane. However, the underlying etiology of AS remains largely unknown, and the aim of the present study was to examine the genetic mechanisms in AS. Induced pluripotent stem cells (iPSCs) were generated from renal tubular cells. The Illumina HiSeq™ 2000 system and iTRAQ‑coupled 2D liquid chromatography‑tandem mass spectrometry were used to generate the sequences of microRNAs (miRNAs), transcripts and proteins from AS‑iPSCs. Integration of miRNA, transcript and protein expression data was used to construct regulatory networks and identify specific miRNA targets amongst the transcripts and proteins. Relative quantitative proteomics using iTRAQ technology revealed 383 differentially abundant proteins, and high‑throughput sequencing identified 155 differentially expressed miRNAs and 1,168 differentially expressed transcripts. Potential miRNA targets were predicted using miRanda, TargetScan and Pictar. All target proteins and transcripts were subjected to network analysis with miRNAs. Gene ontology analysis of the miRNAs and their targets revealed functional information on the iPSCs, including biological process and cell signaling. Kyoto Encyclopedia of Genes and Genomes pathways analysis revealed that the transcripts and proteins were primarily enriched in metabolic and cell adhesion molecule pathways. In addition, the network maps identified hsa‑miRNA (miR)‑4775 as a prominent miRNA that was associated with a number of targets. Similarly, the prominent ELV‑like protein 1‑A and epidermal growth factor receptor (EGFR)‑associated transcripts were identified. Reverse transcription‑quantitative polymerase chain reaction analysis was used to confirm the upregulation of hsa‑miR‑4775 and EGFR. The integrated approach used in the present study provided a comprehensive molecular characterization of AS. The results may also further understanding of the genetic pathogenesis of AS and facilitate the identification of candidate biomarkers for AS.
    DOI:  https://doi.org/10.3892/mmr.2018.9672
  36. PLoS One. 2018 ;13(11): e0206478
    Protein variability in cerebrospinal fluid and its possible implications for neurological protein biomarker research.
    Lukas M Schilde, Steffen Kösters, Simone Steinbach, Karin Schork, Martin Eisenacher, Sara Galozzi, Michael Turewicz, Katalin Barkovits, Brit Mollenhauer, Katrin Marcus, Caroline May.
      Cerebrospinal fluid is investigated in biomarker studies for various neurological disorders of the central nervous system due to its proximity to the brain. Currently, only a limited number of biomarkers have been validated in independent studies. The high variability in the protein composition and protein abundance of cerebrospinal fluid between as well as within individuals might be an important reason for this phenomenon. To evaluate this possibility, we investigated the inter- and intraindividual variability in the cerebrospinal fluid proteome globally, with a specific focus on disease biomarkers described in the literature. Cerebrospinal fluid from a longitudinal study group including 12 healthy control subjects was analyzed by label-free quantification (LFQ) via LC-MS/MS. Data were quantified via MaxQuant. Then, the intra- and interindividual variability and the reference change value were calculated for every protein. We identified and quantified 791 proteins, and 216 of these proteins were abundant in all samples and were selected for further analysis. For these proteins, we found an interindividual coefficient of variation of up to 101.5% and an intraindividual coefficient of variation of up to 29.3%. Remarkably, these values were comparably high for both proteins that were published as disease biomarkers and other proteins. Our results support the hypothesis that natural variability greatly impacts cerebrospinal fluid protein biomarkers because high variability can lead to unreliable results. Thus, we suggest controlling the variability of each protein to distinguish between good and bad biomarker candidates, e.g., by utilizing reference change values to improve the process of evaluating potential biomarkers in future studies.
    DOI:  https://doi.org/10.1371/journal.pone.0206478
  37. Nat Rev Clin Oncol. 2018 Nov 28.
    Clinical potential of mass spectrometry-based proteogenomics.
    Bing Zhang, Jeffrey R Whiteaker, Andrew N Hoofnagle, Geoffrey S Baird, Karin D Rodland, Amanda G Paulovich.
      Cancer genomics research aims to advance personalized oncology by finding and targeting specific genetic alterations associated with cancers. In genome-driven oncology, treatments are selected for individual patients on the basis of the findings of tumour genome sequencing. This personalized approach has prolonged the survival of subsets of patients with cancer. However, many patients do not respond to the predicted therapies based on the genomic profiles of their tumours. Furthermore, studies pairing genomic and proteomic analyses of samples from the same tumours have shown that the proteome contains novel information that cannot be discerned through genomic analysis alone. This observation has led to the concept of proteogenomics, in which both types of data are leveraged for a more complete view of tumour biology that might enable patients to be more successfully matched to effective treatments than they would using genomics alone. In this Perspective, we discuss the added value of proteogenomics over the current genome-driven approach to the clinical characterization of cancers and summarize current efforts to incorporate targeted proteomic measurements based on selected/multiple reaction monitoring (SRM/MRM) mass spectrometry into the clinical laboratory to facilitate clinical proteogenomics.
    DOI:  https://doi.org/10.1038/s41571-018-0135-7
  38. Curr Top Med Chem. 2018 Nov 29.
    Current understanding of the potential of proteomics and metabolomics approaches in cancer chemoresistance: A focus on Multiple Myeloma.
    Venkatesh Chanukuppa, Ravindra Taware, Tathagat Chatterjee, Sanjeevan Sharma, Tushar H More, Khushman Taunk, Saravanan Kumar, Manas K Santra, Srikanth Rapole.
      Chemoresistance is one of the major hurdles in cancer treatment leading to recurrence of cancer and affects overall survival of patients. Cancer chemoresistance can be associated with various phenomena including modulation of vital cellular pathways. Unrevealing these alterations could provide better understanding of chemoresistance and assist in identification of new targets to overcome it. Recent advances in the field of proteomics and metabolomics have substantially helped in identification of potential targets for chemoresistance in various cancers. This review highlights the potential of proteomics and metabolomics research to explore the putative targets associated with cancer chemoresistance with a special focus on Multiple Myeloma (MM). MM is a type of hematological malignancy which constitutes about 13% of all blood cell cancers. The therapeutic advancements for MM have increased the median overall survival rate to over 3-fold in the last one and half decade. Although, in recent times significant improvements in the overall survival rate of MM is achieved, MM remains an incurable disease with unpredictable refractory mechanisms. In spite of therapeutic advances, chemoresistance thrives to be a major hurdle in the treatment of multiple myeloma which demands better understanding of chemoresitance. In this review, we have attempted to highlight the potential applications of proteomics and metabolomics research in understanding of chemoresistance in MM.
    Keywords:  Cancer chemoresistance; bortezomib.; metabolomics; multiple myeloma; proteomics
    DOI:  https://doi.org/10.2174/1568026619666181130111202
  39. Allergy. 2018 Nov 26.
    Increased expression of L-plastin in nasal polyp of patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease.
    Tetsuji Takabayashi, Yukie Tanaka, Dai Susuki, Kanako Yoshida, Kaori Tomita, Masafumi Sakashita, Yoshimasa Imoto, Yukinori Kato, Norihiko Narita, Tsugihisa Nakayama, Shinichi Haruna, Robert P Schleimer, Shigeharu Fujieda.
       BACKGROUND: Most patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD) suffer from recurrence of nasal polyps. However, little is known about the specific cellular and molecular mechanisms contributing to the pathogenesis of nasal polyp development in patients with NERD in particular, especially at baseline when cyclooxygenase 1 inhibitors are not present. The objectives of this study were to identify proteins involved in the pathogenesis of nasal polyps in patients with NERD.
    METHODS: We collected nasal polyp tissue from patients with NERD and from patients with aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). Protein profiles were analyzed by 2-dimensional electrophoresis and identified several proteins, including L-plastin, as highly expressed. We examined L-plastin and tissue factor (TF) expression by immunohistochemical and immunofluorescence analyses. To examine the role of L-plastin in eosinophils, we knocked down L-plastin expression in Eol-1 cells by using siRNA transfection.
    RESULTS: L-plastin protein levels in nasal polyp tissue were increased in patients with NERD relative to those in patients with aspirin tolerant CRSwNP. Immunofluorescence analysis revealed that L-plastin was dominantly expressed in eosinophils and L-plastin and TF were co-expressed in eosinophils in NERD nasal polyp tissue. Knockdown of L-plastin in Eol-1 cells disrupted the cell surface distribution of TF by stimulation with granulocyte macrophage colony-stimulating factor.
    CONCLUSIONS: Increased expression of L-plastin by eosinophils may contribute to abnormal fibrin deposition through TF translocation to the eosinophil cell surface in NERD nasal polyp tissue, which in turn may contribute to the pathogenesis of NERD. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/all.13677
  40. Clin Proteomics. 2018 ;15 37
    Correction to: Quantitative phosphoproteomic analysis reveals reciprocal activation of receptor tyrosine kinases between cancer epithelial cells and stromal fibroblasts.
    Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Nandini A Sahasrabuddhe, Raghothama Chaerkady, Mi-Sik Kim, Mary Jo Fackler, Martha Stampfer, Edward Gabrielson, Saraswati Sukumar, Akhilesh Pandey.
      [This corrects the article DOI: 10.1186/s12014-018-9197-x.].
    DOI:  https://doi.org/10.1186/s12014-018-9210-4
  41. PLoS Negl Trop Dis. 2018 Nov 27. 12(11): e0006903
    Antibody responses to Zika virus proteins in pregnant and non-pregnant macaques.
    Anna S Heffron, Emma L Mohr, David Baker, Amelia K Haj, Connor R Buechler, Adam Bailey, Dawn M Dudley, Christina M Newman, Mariel S Mohns, Michelle Koenig, Meghan E Breitbach, Mustafa Rasheed, Laurel M Stewart, Jens Eickhoff, Richard S Pinapati, Erica Beckman, Hanying Li, Jigar Patel, John C Tan, David H O'Connor.
      The specificity of the antibody response against Zika virus (ZIKV) is not well-characterized. This is due, in part, to the antigenic similarity between ZIKV and closely related dengue virus (DENV) serotypes. Since these and other similar viruses co-circulate, are spread by the same mosquito species, and can cause similar acute clinical syndromes, it is difficult to disentangle ZIKV-specific antibody responses from responses to closely-related arboviruses in humans. Here we use high-density peptide microarrays to profile anti-ZIKV antibody reactivity in pregnant and non-pregnant macaque monkeys with known exposure histories and compare these results to reactivity following DENV infection. We also compare cross-reactive binding of ZIKV-immune sera to the full proteomes of 28 arboviruses. We independently confirm a purported ZIKV-specific IgG antibody response targeting ZIKV nonstructural protein 2B (NS2B) that was recently reported in ZIKV-infected people and we show that antibody reactivity in pregnant animals can be detected as late as 127 days post-infection (dpi). However, we also show that these responses wane over time, sometimes rapidly, and in one case the response was elicited following DENV infection in a previously ZIKV-exposed animal. These results suggest epidemiologic studies assessing seroprevalence of ZIKV immunity using linear epitope-based strategies will remain challenging to interpret due to susceptibility to false positive results. However, the method used here demonstrates the potential for rapid profiling of proteome-wide antibody responses to a myriad of neglected diseases simultaneously and may be especially useful for distinguishing antibody reactivity among closely related pathogens.
    DOI:  https://doi.org/10.1371/journal.pntd.0006903
  42. Proteomics. 2018 Nov 26. e1800268
    Frontal Cortex Proteome Perturbation after Juvenile Rat Secondhand Smoke Exposure.
    Liam S C Lewis, Pretal P Muldoon, Pallavi P Pilaka, Andrew K Ottens.
      Secondhand smoke remains a global concern for children's health. Epidemiological studies implicate exposure to secondhand smoke as a major risk factor for behavioral disorders, yet biological causation remains unclear. Model studies have mainly focused on secondhand smoke impacts to prenatal neurodevelopment, yet juvenile exposure represent a separate risk. Using ion mobility-enhanced data-independent mass spectrometry we characterized the effect of juvenile secondhand smoke exposure on the prefrontal cortex, a principal part of the brain involved in behavioral control. The produced dataset includes 800 significantly responsive proteins at a FDR 5% within the juvenile orbital frontal cortex, with 716 showing an increase in abundance. The neuroproteomic response reflects a prominent perturbation within the glutamatergic synaptic system, suggesting aberrant, disorganized excitation as observed underlying psychiatric disorders. The neuroproteomic response also discloses impacts to GABAergic and dopaminergic systems. Overall, the dataset provides a wealth of detail, facilitating further targeted research into the causal mechanisms underlying behavioral disorders associated with juvenile exposure to secondhand smoke and other environmental pollutants. All MS data have been deposited to the ProteomeXchange consortium with identifier PXD007690. This article is protected by copyright. All rights reserved.
    Keywords:  ETS; SHS; behavioral disorders; brain; environmental exposure; environmental tobacco smoke; neurodevelopment; neurotransmission; secondhand smoke
    DOI:  https://doi.org/10.1002/pmic.201800268
  43. Bone. 2018 Nov 24. pii: S8756-3282(18)30440-X. [Epub ahead of print]
    Alterations of the gut microbiome and plasma proteome in Chinese patients with adolescent idiopathic scoliosis.
    Nan Shen, Nan Chen, Xuan Zhou, Bing Zhao, Renxiu Huang, Juping Liang, Xiaoyan Yang, Meijia Chen, Yuanyuan Song, Qing Du.
      The etiology of adolescent idiopathic scoliosis (AIS), the most common rotational deformity of the spine, is still unclear. Emerging evidence suggests that gut microbiota dysbiosis influences musculoskeletal diseases such as arthritis and osteoporosis. However, the alterations of the fecal microbiome in AIS remain unknown. Thus, the current study was conducted to explore the gut microbiota compositions of Chinese AIS patients. Microbiota communities in the feces of 51 AIS patients and 34 age- and sex-matched healthy individuals were investigated using 16S rRNA sequencing. Meanwhile, the changes in the plasma proteome were detected using tandem mass tag (TMT) labeling coupled with liquid chromatography-mass spectrometry (LC-MS). The relationship between gut microbiota and AIS clinical characteristics as well as the correlation between gut microbiota and the changes in plasma proteins were analyzed. The structure of the gut microbiota differed between the AIS and healthy groups, however, the richness was similar. The genera Prevotella, Gelria, and Desulfovibrio were enriched in the feces of AIS patients. In contrast, the abundance of Parasutterella, Tyzzerella, and Phascolarctobacterium was decreased in the AIS group. More remarkably, a positive correlation between the abundance of the fecal genera Prevotella and the Cobb angles of the AIS patients was observed. Moreover, the major differential plasma proteins related to AIS were Fibronectin 1 (FN1), voltage-dependent anion channel 1 (VDAC1), Ras homolog family member A (RHOA), and AHNAK nucleoprotein (AHNAK). Additionally, the positive correlations between fecal Prevotella and the expression of host plasma FN1 as well as the negative relationships between fecal Prevotella and the expression of host VDAC1 and AHNAK were confirmed. Elucidating these differences in the gut microbiota will provide a foundation to improve our understanding of the pathogenesis of AIS and to support potential therapeutic options based on modifying the gut microbiota.
    Keywords:  16S rRNA gene; Adolescent idiopathic scoliosis; Gut microbiome; Plasma proteome; Prevotella
    DOI:  https://doi.org/10.1016/j.bone.2018.11.017
  44. Biomedicines. 2018 Nov 25. pii: E110. [Epub ahead of print]6(4):
    Dissecting the Immune Landscape of Acute Myeloid Leukemia.
    Jan Davidson-Moncada, Elena Viboch, Sarah E Church, Sarah E Warren, Sergio Rutella.
      Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50⁻70% of AML cases harbor either normal or risk-indeterminate karyotypes. The discovery of better biomarkers of clinical success and failure is therefore necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1)-directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies. However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance. We will review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space. Multiplexed, spatially-resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials.
    Keywords:  acute myeloid leukemia; bispecific antibodies; immune checkpoint blockade; immunotherapy; tumor immunological microenvironment
    DOI:  https://doi.org/10.3390/biomedicines6040110
  45. Cell Mol Life Sci. 2018 Nov 29.
    Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complex.
    Charlotte Kawecki, Olivier Bocquet, Christian E H Schmelzer, Andrea Heinz, Christian Ihling, Amandine Wahart, Béatrice Romier, Amar Bennasroune, Sébastien Blaise, Christine Terryn, Kenneth J Linton, Laurent Martiny, Laurent Duca, Pascal Maurice.
      In addition to its critical role in lysosomes for catabolism of sialoglycoconjugates, NEU1 is expressed at the plasma membrane and regulates a myriad of receptors by desialylation, playing a key role in many pathophysiological processes. Here, we developed a proteomic approach dedicated to the purification and identification by LC-MS/MS of plasma membrane NEU1 interaction partners in human macrophages. Already known interaction partners were identified as well as several new candidates such as the class B scavenger receptor CD36. Interaction between NEU1 and CD36 was confirmed by complementary approaches. We showed that elastin-derived peptides (EDP) desialylate CD36 and that this effect was blocked by the V14 peptide, which blocks the interaction between bioactive EDP and the elastin receptor complex (ERC). Importantly, EDP also increased the uptake of oxidized LDL by macrophages that is blocked by both the V14 peptide and the sialidase inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA). These results demonstrate, for the first time, that binding of EDP to the ERC indirectly modulates CD36 sialylation level and regulates oxidized LDL uptake through this sialidase. These effects could contribute to the previously reported proatherogenic role of EDP and add a new dimension in the regulation of biological processes through NEU1.
    Keywords:  Atherosclerosis; CD36; Elastin-derived peptides; NEU1; Sialylation
    DOI:  https://doi.org/10.1007/s00018-018-2978-6
  46. J Alzheimers Dis Rep. 2017 Sep 28. 1(1): 125-157
    Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer's Disease.
    Chris J Carter.
      Diverse pathogens are detected in Alzheimer's disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy.
    Keywords:  Alzheimer’s disease; bacteria; blood-brain barrier; fungi; gene/environment; immune system; inflammation; microbes; virus
    DOI:  https://doi.org/10.3233/ADR-170017
  47. J Alzheimers Dis Rep. 2018 Apr 12. 2(1): 79-91
    Neonatal Neurodegeneration in Alzheimer's Disease Transgenic Mouse Model.
    Aise Rumeysa Mazi, Aysegul Sumeyye Arzuman, Busra Gurel, Betul Sahin, Mete Bora Tuzuner, Mehmet Ozansoy, Ahmet Tarik Baykal.
      Alzheimer's disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro. We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable.
    Keywords:  Alzheimer’s disease; cerebellum; cortex; hippocampus; neonatal neurodegeneration; proteomics
    DOI:  https://doi.org/10.3233/ADR-170049
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