bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2020‒12‒06
fifty-eight papers selected by
Ayesh Seneviratne
University of Toronto


  1. Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30598-2. [Epub ahead of print]32(6): 981-995.e7
    Corrado M, Edwards-Hicks J, Villa M, Flachsmann LJ, Sanin DE, Jacobs M, Baixauli F, Stanczak M, Anderson E, Azuma M, Quintana A, Curtis JD, Clapes T, Grzes KM, Kabat AM, Kyle R, Patterson AE, Geltink RK, Amulic B, Steward CG, Strathdee D, Trompouki E, O'Sullivan D, Pearce EJ, Pearce EL.
      Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.
    Keywords:  Barth Syndrome; CD8 T cells; PTPMT1; Tafazzin; cardiolipin; immune memory; immunometabolism; mitochodria
    DOI:  https://doi.org/10.1016/j.cmet.2020.11.003
  2. Haematologica. 2020 Jan 23. 105(12): 2746-2756
    Timo Rademakers , Marieke Goedhart , Mark Hoogenboezem , Alexander García Ponce , Jos van Rijssel , Maryna Samus , Michael Schnoor , Stefan Butz , Stephan Huveneers , Dietmar Vestweber , Martijn A Nolte , Carlijn Voermans , Jaap D van Buul .
      Bone marrow endothelium plays an important role in the homing of hematopoietic stem and progenitor cells upon transplantation, but surprisingly little is known on how the bone marrow endothelial cells regulate local permeability and hematopoietic stem and progenitor cells transmigration. We show that temporal loss of vascular endothelial-cadherin function promotes vascular permeability in BM, even upon low-dose irradiation. Loss of vascular endothelial-cadherin function also enhances homing of transplanted hematopoietic stem and progenitor cells to the bone marrow of irradiated mice although engraftment is not increased. Intriguingly, stabilizing junctional vascular endothelial-cadherin in vivo reduced bone marrow permeability, but did not prevent hematopoietic stem and progenitor cells migration into the bone marrow, suggesting that hematopoietic stem and progenitor cells use the transcellular migration route to enter the bone marrow. Indeed, using an in vitro migration assay, we show that human hematopoietic stem and progenitor cells predominantly cross bone marrow endothelium in a transcellular manner in homeostasis by inducing podosome-like structures. Taken together, vascular endothelial-cadherin is crucial for BM vascular homeostasis but dispensable for the homing of hematopoietic stem and progenitor cells. These findings are important in the development of potential therapeutic targets to improve hematopoietic stem and progenitor cell homing strategies.
    DOI:  https://doi.org/10.3324/haematol.2018.196329
  3. PLoS Biol. 2020 Nov 30. 18(11): e3000981
    Houston R, Sekine S, Calderon MJ, Seifuddin F, Wang G, Kawagishi H, Malide DA, Li Y, Gucek M, Pirooznia M, Nelson AJ, Stokes MP, Stewart-Ornstein J, Mullett SJ, Wendell SG, Watkins SC, Finkel T, Sekine Y.
      The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.
    DOI:  https://doi.org/10.1371/journal.pbio.3000981
  4. J Clin Invest. 2020 Dec 03. pii: 146391. [Epub ahead of print]
    Califf RM, Curtis LH, Harrington RA, Hernandez AF, Peterson ED.
      In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies work, particularly in light of the tremendous pressure on the government and biomedical research enterprise to quickly develop safe, effective therapies during the SARS-CoV-2 pandemic.
    DOI:  https://doi.org/10.1172/JCI146391
  5. PLoS One. 2020 ;15(12): e0243145
    Wang Y, Zhang K, Georgiev P, Wells S, Xu H, Lacey BM, Xu Z, Laskey J, Mcleod R, Methot JL, Bittinger M, Pasternak A, Ranganath S.
      Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.
    DOI:  https://doi.org/10.1371/journal.pone.0243145
  6. J Clin Invest. 2020 Dec 01. pii: 136655. [Epub ahead of print]
    Kahn BM, Lucas A, Alur R, Wengyn MD, Schwartz GW, Li J, Sun K, Maurer HC, Olive KP, Faryabi RB, Stanger B.
      Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis inhibitors. Whether anti-angiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the Endothelial Index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypo-vascular tumors, enabling the classification of human tumors into six vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular hub genes. EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Our studies thus provide an unbiased picture of human tumor vasculature which may enable more precise deployment of anti-angiogenesis therapy.
    Keywords:  Angiogenesis; Cancer; Oncology; endothelial cells
    DOI:  https://doi.org/10.1172/JCI136655
  7. Stem Cells. 2020 Nov 30.
    Chen YY, Liu YF, Liu YD, Deng XH, Zhou J.
      Hematopoietic stem cells (HSCs) maintain quiescence under steady state, however, they are compelled to proliferate and expand to replenish the blood system under stress. The molecular basis underlying stress hematopoiesis remains to be fully understood. In this study, we reported that IRF7 represents an important regulator of stress hematopoiesis. Interferon regulatory factor 7 (IRF7) was dispensable for normal hematopoiesis, whereas its deficiency significantly enhanced hematopoietic stem and progenitor cells (HSPCs) regeneration and improved long-term repopulation of HSCs under stress. Mechanistic studies showed that CXCR4 was identified as a downstream target of IRF7. Overexpression of CXCR4 abrogated the enhanced proliferation and regeneration of IRF7-deficient HSPCs under stress. Similar results were obtained in HSCs from human umbilical cord blood. These observations demonstrated that IRF7 plays an important role in hematopoietic regeneration under stress. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: This study demonstrated that IRF7 is dispensable for steady-state hematopoiesis, whereas its deficiency enhances regeneration of hematopoietic stem and progenitor cells (HSPCs) under stress. Mechanistic studies show that the effects of IRF7 in HSPCs under stress are mediated through CXCR4. Similar results were obtained in human HSCs. These observations demonstrated an essential role of IRF7 in stress hematopoiesis. Silencing of IRF7 may have therapeutic value to improve hematopoietic recovery after hematopoietic injury or transplantation.
    Keywords:  CXCR4; Interferon regulatory factor 7; hematopoietic stem and progenitor cells; hematopoietic stress; human umbilical cord blood; regeneration
    DOI:  https://doi.org/10.1002/stem.3308
  8. Crit Care Explor. 2020 Dec;2(12): e0290
    Khan SH, Lindroth H, Perkins AJ, Jamil Y, Wang S, Roberts S, Farber M, Rahman O, Gao S, Marcantonio ER, Boustani M, Machado R, Khan BA.
      Objectives: To determine delirium occurrence rate, duration, and severity in patients admitted to the ICU with coronavirus disease 2019.Design: Retrospective data extraction study from March 1, 2020, to June 7, 2020. Delirium outcomes were assessed for up to the first 14 days in ICU.
    Setting: Two large, academic centers serving the state of Indiana.
    Patients: Consecutive patients admitted to the ICU with positive severe acute respiratory syndrome coronavirus 2 nasopharyngeal swab polymerase chain reaction test from March 1, 2020, to June 7, 2020, were included. Individuals younger than 18 years of age, without any delirium assessments, or without discharge disposition were excluded.
    Measurements and Main Results: Primary outcomes were delirium rates and duration, and the secondary outcome was delirium severity. Two-hundred sixty-eight consecutive patients were included in the analysis with a mean age of 58.4 years (sd, 15.6 yr), 40.3% were female, 44.4% African American, 20.7% Hispanic, and a median Acute Physiology and Chronic Health Evaluation II score of 18 (interquartile range, 13-25). Delirium without coma occurred in 29.1% of patients, delirium prior to coma in 27.9%, and delirium after coma in 23.1%. The first Confusion Assessment Method for the ICU assessment was positive for delirium in 61.9%. Hypoactive delirium was the most common subtype (87.4%). By day 14, the median number of delirium/coma-free were 5 days (interquartile range, 4-11 d), and median Confusion Assessment Method for the ICU-7 score was 6.5 (interquartile range, 5-7) indicating severe delirium. Benzodiazepines were ordered for 78.4% of patients in the cohort. Mechanical ventilation was associated with greater odds of developing delirium (odds ratio, 5.0; 95% CI, 1.1-22.2; p = 0.033) even after adjusting for sedative medications. There were no between-group differences in mortality.
    Conclusions: Delirium without coma occurred in 29.1% of patients admitted to the ICU. Delirium persisted for a median of 5 days and was severe. Mechanical ventilation was significantly associated with odds of delirium even after adjustment for sedatives. Clinical attention to manage delirium duration and severity, and deeper understanding of the virus' neurologic effects is needed for patients with coronavirus disease 2019.
    Keywords:  brain diseases; coma; coronavirus disease 2019; critical illness; delirium; respiratory insufficiency
    DOI:  https://doi.org/10.1097/CCE.0000000000000290
  9. PLoS One. 2020 ;15(11): e0242809
    Yuan B, El Dana F, Ly S, Yan Y, Ruvolo V, Shpall EJ, Konopleva M, Andreeff M, Battula VL.
      The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) consists of various cell types that support the growth of AML cells and protect them from chemotherapy. Mesenchymal stromal cells (MSCs) in the BME have been shown to contribute immensely to leukemogenesis and chemotherapy resistance in AML cells. However, the mechanism of stroma-induced chemotherapy resistance is not known. Here, we hypothesized that stromal cells promote a stem-like phenotype in AML cells, thereby inducing tumorigenecity and therapy resistance. To test our hypothesis, we co-cultured AML cell lines and patient samples with BM-derived MSCs and determined aldehyde dehydrogenase (ALDH) activity and performed gene expression profiling by RNA sequencing. We found that the percentage of ALDH+ cells increased dramatically when AML cells were co-cultured with MSCs. However, among the 19 ALDH isoforms, ALDH2 and ALDH1L2 were the only two that were significantly upregulated in AML cells co-cultured with stromal cells compared to cells cultured alone. Mechanistic studies revealed that the transforming growth factor-β1 (TGF-β1)-regulated gene signature is activated in AML cells co-cultured with MSCs. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced the ALDH+ phenotype in AML cells. We also found that TGF-β1-induced ALDH2 expression in AML cells is mediated by the non-canonical pathway through the activation of p38. Interestingly, inhibition of ALDH2 with diadzin and CVT-10216 significantly inhibited MSC-induced ALDH activity in AML cells and sensitized them to chemotherapy, even in the presence of MSCs. Collectively, BM stroma induces ALDH2 activity in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.
    DOI:  https://doi.org/10.1371/journal.pone.0242809
  10. Exp Hematol. 2020 Dec 01. pii: S0301-472X(20)30619-6. [Epub ahead of print]
    Samuelson C, Radtke S, Cui M, Perez A, Kiem HP, Humbert O.
      AMD3100 (plerixafor) is a vital component of many clinical and pre-clinical transplant protocols, facilitating harvest of hematopoietic stem and progenitor cells through mobilization into the peripheral blood circulation. Repeat mobilization with AMD3100 is also necessary for many patients with suboptimal first stem cell collection or those requiring repeat transplantation. In this study we investigated the mobilization efficacy of repeated AMD3100 dosages in the non-human primate and humanized mouse models. In non-human primates we demonstrate effective mobilization after the first AMD3100 administration but significantly poorer response in CD34+ and hematopoietic stem cell-enriched CD90+ cells with subsequent doses of the drug. A similar loss of efficacy with repeated administration was found in immunodeficient mice engrafted with human CD34+ cells, in whom the total human white cell population and particularly human hematopoietic stem and progenitor cells mobilized significantly less effectively following a second AMD3100 administration when compared to first dose. Together, our results are expected to inform future mobilization protocols for the purposes of peripheral blood hematopoietic stem cell extraction or for applications in which hematopoietic stem cells must be made accessible for in vivo-delivered gene targeting agents.
    Keywords:  Anemia, Sickle Cell; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells
    DOI:  https://doi.org/10.1016/j.exphem.2020.11.001
  11. J Clin Invest. 2020 Dec 03. pii: 146392. [Epub ahead of print]
    Paneth N, Joyner M.
      Randomized controlled trials are the preferred design for the analysis of health-related interventions. In this Viewpoint, Nigel Paneth and Michael Joyner discuss circumstances when randomized controlled trials might not be feasible and the criteria that should be used when considering applying observational data medicine.
    DOI:  https://doi.org/10.1172/JCI146392
  12. Sci Adv. 2020 Dec;pii: eabc8482. [Epub ahead of print]6(49):
    Li M, Wang H, Li W, Xu XG, Yu Y.
      The activation of Toll-like receptor heterodimer 1/2 (TLR1/2) by microbial components plays a critical role in host immune responses against pathogens. TLR1/2 signaling is sensitive to the chemical structure of ligands, but its dependence on the spatial distribution of ligands on microbial surfaces remains unexplored. Here, we reveal the quantitative relationship between TLR1/2-triggered immune responses and the spacing of ligand clusters by designing an artificial "phagocytic synapse" nanoarray platform to mimic the cell-microbe interface. The ligand spacing dictates the proximity of receptor clusters on the cell surface and consequently the pro-inflammatory responses of macrophages. However, cell responses reach their maximum at small ligand spacings when the receptor nanoclusters become adjacent to one another. Our study demonstrates the feasibility of using spatially patterned ligands to modulate innate immunity. It shows that the receptor clusters of TLR1/2 act as a driver in integrating the spatial cues of ligands into cell-level activation events.
    DOI:  https://doi.org/10.1126/sciadv.abc8482
  13. Blood. 2020 Dec 04. pii: blood.2019004397. [Epub ahead of print]
    Stauber J, Greally J, Steidl U.
      Hematological malignancies are an aggregate of diverse populations of cells that arise following a complex process of clonal evolution and selection. Recent approaches have facilitated the study of clonal populations and their evolution over time across multiple phenotypic cell populations. In this review, we present current concepts on the role of clonal evolution in leukemic initiation, disease progression, and relapse. We highlight recent advances and unanswered questions on the contribution of the hemopoietic stem cell population on these processes.
    DOI:  https://doi.org/10.1182/blood.2019004397
  14. PLoS One. 2020 ;15(12): e0233662
    Zou Y, Fineberg S, Pearlman A, Feinman RD, Fine EJ.
      BACKGROUND: The effects of diet in cancer, in general, and breast cancer in particular, are not well understood. Insulin inhibition in ketogenic, high fat diets, modulate downstream signaling molecules and are postulated to have therapeutic benefits. Obesity and diabetes have been associated with higher incidence of breast cancer. Addition of anti-cancer drugs together with diet is also not well studied.METHODS: Two diets, one ketogenic, the other standard mouse chow, were tested in a spontaneous breast cancer model in 34 mice. Subgroups of 3-9 mice were assigned, in which the diet were implemented either with or without added rapamycin, an mTOR inhibitor and potential anti-cancer drug.
    RESULTS: Blood glucose and insulin concentrations in mice ingesting the ketogenic diet (KD) were significantly lower, whereas beta hydroxybutyrate (BHB) levels were significantly higher, respectively, than in mice on the standard diet (SD). Growth of primary breast tumors and lung metastases were inhibited, and lifespans were longer in the KD mice compared to mice on the SD (p<0.005). Rapamycin improved survival in both mouse diet groups, but when combined with the KD was more effective than when combined with the SD.
    CONCLUSIONS: The study provides proof of principle that a ketogenic diet a) results in serum insulin reduction and ketosis in a spontaneous breast cancer mouse model; b) can serve as a therapeutic anti-cancer agent; and c) can enhance the effects of rapamycin, an anti-cancer drug, permitting dose reduction for comparable effect. Further, the ketogenic diet in this model produces superior cancer control than standard mouse chow whether with or without added rapamycin.
    DOI:  https://doi.org/10.1371/journal.pone.0233662
  15. PLoS One. 2020 ;15(12): e0242995
    Harber MP, Metz M, Peterman JE, Whaley MH, Fleenor BS, Kaminsky LA.
      INTRODUCTION: Cardiorespiratory fitness (CRF) is a strong independent predictor of cardiovascular disease (CVD) and CVD mortality. However, little is known in regards to how CRF has trended in apparently healthy adults over the past several decades.PURPOSE: To analyze trends in CRF and CVD risk factors over the last 50 years in a population of apparently healthy adult men and women.
    METHODS: Participants were 4,214 apparently healthy adults (2,390 men and 1,824 women) from the Ball State Adult Fitness Longitudinal Lifestyle STudy (BALL ST) that performed maximal cardiopulmonary exercise testing between 1970-2019 for the assessment of CRF defined as VO2max (ml/kg/min). Participants were self-referred either to a community-based exercise program, fitness testing, or were research subjects in exercise related studies and were placed into groups by decade based on testing date.
    RESULTS: CRF showed a general trend to decline (P<0.05) from the 1970s to the 2000s with an increase (P<0.05) from the 2000s to the 2010s for both men and women. This pattern persisted for age and sex-adjusted CRF level, determined by Fitness Registry and the Importance of Exercise: A National Data Base (FRIEND). For both women and men, CRF across the decades was associated (P<0.05) with the prevalence of physical inactivity, smoking, obesity, dyslipidemia and hypertension, and with diabetes in men only.
    CONCLUSION: CRF declined from 1970 through the 2000s in a cohort of apparently healthy men and women which was associated with worsening CVD risk profiles. However, the decline in CRF was attenuated over the past decade which may have a positive impact on future CVD in the population. Promoting physical activity to increase CRF should be a primary aspect of CVD prevention programs.
    DOI:  https://doi.org/10.1371/journal.pone.0242995
  16. Cell Signal. 2020 Nov 30. pii: S0898-6568(20)30343-0. [Epub ahead of print] 109866
    Jeon YH, He M, Austin J, Shin H, Pfleger J, Abdellatif M.
      Adiponectin is one of the most abundant circulating hormones, which through adenosine monophosphate-activated protein kinase (AMPK), enhances fatty acid and glucose oxidation, and exerts a cardioprotective effect. However, its effects on cellular bioenergetics have not been explored. We have previously reported that AMPK enhances mitochondrial respiration through a succinate dehydrogenase (SDH or complex II)-dependent mechanism in cardiac myocytes, leading us to predict that Adiponectin would exert a similar effect via activating AMPK. Our results show that Adiponectin enhances basal mitochondrial oxygen consumption rate (OCR), ATP production, and spare respiratory capacity (SRC), which were all abolished by the knockdown of AMPKγ1, inhibition of SDH complex assembly, via the knockdown of the SDH assembly factor 1 (Sdhaf1), or inhibition of SDH activity. Additionally, Adiponectin alleviated hypoxia-induced reductions in OCR and ATP production, in a Sdhaf1-dependent manner, whereas overexpression of Sdhaf1 confirmed its sufficiency for mediating these effects. Importantly, the levels of holoenzyme SDH under the various conditions correlated with OCR. We also show that the effects of Adiponectin, AMPK, Sdhaf1, as well as, SDH complex assembly all required sirtuin 3 (Sirt3). In conclusion, Adiponectin potentiates mitochondrial bioenergetics via promoting SDH complex assembly in an AMPK-, Sdhaf1-, and Sirt3-dependent fashion in cardiac myocytes.
    Keywords:  AMPK; Adiponectin; Bioenergetics; Complex II; Oxygen consumption rate; Prkag1; Sdhaf1; Sirt3; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.cellsig.2020.109866
  17. Sci Transl Med. 2020 Dec 02. pii: eaaz2253. [Epub ahead of print]12(572):
    Armstrong JPK, Keane TJ, Roques AC, Patrick PS, Mooney CM, Kuan WL, Pisupati V, Oreffo ROC, Stuckey DJ, Watt FM, Forbes SJ, Barker RA, Stevens MM.
      The past few decades have produced a large number of proof-of-concept studies in regenerative medicine. However, the route to clinical adoption is fraught with technical and translational obstacles that frequently consign promising academic solutions to the so-called "valley of death." Here, we present a proposed blueprint for translational regenerative medicine. We offer principles to help guide the selection of cells and materials, present key in vivo imaging modalities, and argue that the host immune response should be considered throughout design and development. Last, we suggest a pathway to navigate the often complex regulatory and manufacturing landscape of translational regenerative medicine.
    DOI:  https://doi.org/10.1126/scitranslmed.aaz2253
  18. Development. 2020 Dec 02. pii: dev.193870. [Epub ahead of print]
    Susila H, Nasim Z, Gawarecka K, Jung JY, Jin S, Youn G, Ahn JH.
      PHOSPHORYLETHANOLAMINE CYTIDYLYLTRANSFERASE 1 (PECT1) regulates phosphatidylethanolamine biosynthesis and controls the phosphatidylethanolamine: phosphatidylcholine ratio in Arabidopsis thaliana Previous studies suggested that PECT1 regulates flowering time by modulating the interaction between phosphatidylcholine and FLOWERING LOCUS T (FT), a florigen, in the shoot apical meristem (SAM). Here, we show that knock-down of PECT1 by artificial microRNA in the SAM (pFD::amiR-PECT1) accelerated flowering under inductive and even non-inductive conditions, where FT transcription is almost absent, and in ft-10 twin sister of ft-1 double mutants under both conditions. Transcriptome analyses suggested that PECT1 affects flowering by regulating SHORT VEGETATIVE PHASE (SVP) and GIBBERELLIN 20 OXIDASE 2 (GA20ox2). SVP mis-expression in the SAM suppressed the early flowering of pFD::amiR-PECT1 plants. pFD::amiR-PECT1 plants showed increased gibberellin (GA) levels in the SAM, concomitant with the reduction of REPRESSOR OF GA1-3 levels. Consistent with this, GA treatment had little effect on flowering time of pFD::amiR-PECT1 plants and the GA antagonist paclobutrazol strongly affected flowering in these plants. Together, these results suggest that PECT1 also regulates flowering time through a florigen-independent pathway, modulating SVP expression and thus regulating GA production.
    Keywords:  Florigen; Flowering; GA20ox2; Gibberellin; PECT1; SVP
    DOI:  https://doi.org/10.1242/dev.193870
  19. medRxiv. 2020 Nov 27. pii: 2020.11.25.20233163. [Epub ahead of print]
    Bolton KL, Koh Y, Foote MB, Im H, Jee J, Sun CH, Safonov A, Ptashkin R, Moon JH, Lee JY, Jung J, Kang CK, Song KH, Choe PG, Park WB, Kim HB, Oh MD, Song H, Kim S, Patel M, Derkach A, Gedvilaite E, Tkachuk KA, Braunstein LZ, Gao T, Papaemmanuil E, Babady NE, Pessin MS, Kamboj M, Diaz LA, Ladanyi M, Rauh MJ, Natarajan P, Machiela MJ, Awadalla P, Joseph V, Offit K, Norton L, Berger MF, Levine RL, Kim ES, Kim NJ, Zehir A.
      Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. 1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. 2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. 7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10 -3 ) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
    DOI:  https://doi.org/10.1101/2020.11.25.20233163
  20. Cell Rep. 2020 Dec 01. pii: S2211-1247(20)31454-6. [Epub ahead of print]33(9): 108465
    Qiu J, Nordling S, Vasavada HH, Butcher EC, Hirschi KK.
      Development of blood-forming (hemogenic) endothelial cells that give rise to hematopoietic stem and progenitor cells (HSPCs) is critical during embryogenesis to generate the embryonic and postnatal hematopoietic system. We previously demonstrated that the specification of murine hemogenic endothelial cells is promoted by retinoic acid (RA) signaling and requires downstream endothelial cell cycle control. Whether this mechanism is conserved in human hemogenic endothelial cell specification is unknown. Here, we present a protocol to derive primordial endothelial cells from human embryonic stem cells and promote their specification toward hemogenic endothelial cells. Furthermore, we demonstrate that RA treatment significantly increases human hemogenic endothelial cell specification. That is, RA promotes endothelial cell cycle arrest to enable RA-induced instructive signals to upregulate the genes needed for hematopoietic transition. These insights provide guidance for the ex vivo generation of autologous human hemogenic endothelial cells that are needed to produce human HSPCs for regenerative medicine applications.
    Keywords:  cell cycle regulation; human hemogenic endothelial cell specification; retinoic acid signaling
    DOI:  https://doi.org/10.1016/j.celrep.2020.108465
  21. Cell Stem Cell. 2020 Nov 24. pii: S1934-5909(20)30540-3. [Epub ahead of print]
    Ning W, Muroyama A, Li H, Lechler T.
      Basal stem cells fuel development, homeostasis, and regeneration of the epidermis. The proliferation and fate decisions of these cells are highly regulated by their microenvironment, including the basement membrane and underlying mesenchymal cells. Basal progenitors give rise to differentiated progeny that generate the epidermal barrier. Here, we present data that differentiated progeny also regulate the proliferation, differentiation, and migration of basal progenitor cells. Using two distinct mouse lines, we found that increasing contractility of differentiated cells resulted in non-cell-autonomous hyperproliferation of stem cells and prevented their commitment to a hair follicle lineage. This increased contractility also impaired movement of basal progenitors during hair placode morphogenesis and diminished migration of melanoblasts. These data suggest that intra-tissue tension regulates stem cell proliferation, fate decisions, and migration and that differentiated epidermal keratinocytes are a component of the stem cell niche that regulates development and homeostasis of the skin.
    Keywords:  cell fate; contractility; differentiation; epidermis; microtubule; proliferation; stem cell; tension
    DOI:  https://doi.org/10.1016/j.stem.2020.11.002
  22. Biomedicines. 2020 Nov 25. pii: E537. [Epub ahead of print]8(12):
    Sumi S.
      Diabetes mellitus (DM) is caused by insufficient insulin function [...].
    DOI:  https://doi.org/10.3390/biomedicines8120537
  23. J Pharmacol Exp Ther. 2020 Nov 30. pii: JPET-AR-2020-000277. [Epub ahead of print]
    Komiya T, Goda M, Shioya H, Katsumata S.
      ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator that exhibits selectivity for S1P receptors 1 and 5. Treatment with ONO-4641 leads to a reduction in magnetic resonance imaging disease measures in patients with relapsing-remitting multiple sclerosis. The objective of this study was to explore the potential impact of ONO-4641 treatment based on its immunomodulatory effects. Severe aplastic anemia is a bone marrow (BM) failure disease, typically caused by aberrant immune destruction of blood progenitors. Although the T helper type-1-mediated pathology is well described for aplastic anemia, the molecular mechanisms driving disease progression remain undefined. We evaluated the efficacy of ONO-4641 in a mouse model of aplastic anemia. ONO-4641 reduced the severity of BM failure in a dose-dependent manner, resulting in higher blood and BM cell counts. By evaluating the mode of action, we found that ONO-4641 inhibited the infiltration of donor-derived T lymphocytes to the BM. ONO-4641 also induced the accumulation of hematopoietic stem cells in the BM of mice. These observations indicate, for the first time, that S1P receptor modulators demonstrate efficacy in the mouse model of aplastic anemia and suggest that treatment with ONO-4641 might delay the progression of aplastic anemia. Significance Statement ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator selective for S1P receptors 1 and 5. In this study, we demonstrated that ONO-4641 regulates the trafficking of T lymphocytes along with hematopoietic stem and progenitor cells leading to alleviation of pancytopenia and destruction of bone marrow in a bone marrow failure-induced mouse model mimicking human aplastic anemia.
    Keywords:  animal models; aplastic anemia; cell trafficking; lymphocytes; multiple sclerosis; sphingosine 1-phosphate; stem cells
    DOI:  https://doi.org/10.1124/jpet.120.000277
  24. Trends Mol Med. 2020 Nov 30. pii: S1471-4914(20)30285-9. [Epub ahead of print]
      
    DOI:  https://doi.org/10.1016/j.molmed.2020.11.002
  25. Epilepsy Res. 2020 Nov 21. pii: S0920-1211(20)30557-X. [Epub ahead of print]169 106506
    Eor JY, Tan PL, Son YJ, Kwak MJ, Kim SH.
      PURPOSE: Seizures are a threat to the host brain and body and can even cause death in epileptic children. Ketogenic diet (KD) is suggested for children suffering from epileptic seizures and has been investigated for its anti-seizure effect. However, the relationships between KD and gut microbiota (GM) is not yet been deeply understood. Herein, we investigated the anti-seizure effect by administering KD and a lactic acid bacteria (LAB) in murine model of chemically induced seizures. We hypothesized that a single Lactobacillus fermentum MSK 408 (MSK 408) strain with or without KD may exert a neuroprotection by modulating host gut microbiota.METHOD: We performed animal study using pentylenetetrazole (PTZ) to induce seizure. Thirty 3-week-old male Institute of Cancer research (ICR) mice were divided in six groups, Normal diet (ND), ND + PTZ, ND + PTZ + LAB, KD, KD + PTZ, and KD + PTZ. Based on our previous study, 4:1 KD and selected MSK 408 strain was orally gavaged (4 × 109 CFU/mL) with both diets for 4 weeks. PTZ (40 mg/kg) was injected intraperitoneally 30 min before euthanization.
    RESULTS: Compared to ND, KD significantly reduced the seizure frequency. Administration of MSK 408 with both ND and KD for 4 weeks restored serum lipid profile and tight junction protein mRNA expression of the gut and brain. Additionally, PCoA revealed that MSK 408 independently affected fecal short chain fatty acid (SCFA) content via gut microbiota (GM) modulation. PICRUSt suggested that the modulation of microbiota by KD and MSK 408 led to increased GABA (gamma-aminobutyric acid) metabolism.
    SIGNIFICANCE: Our findings suggest that MSK 408 strain can be consumed with KD as supplement without interfering the anti-seizure action of KD, and may improve the serum lipid profile, and brain barrier function via gut microbiota and SCFA modulation.
    Keywords:  Epilepsy; Gut microbiota; Lactobacillus; Mice; Seizure
    DOI:  https://doi.org/10.1016/j.eplepsyres.2020.106506
  26. Eur J Haematol. 2020 Nov 29.
    Klyuchnikov E, Christopeit M, Badbaran A, Bacher U, Fritsche-Friedland U, von Pein UM, Wolschke C, Kröger N.
      OBJECTIVES AND METHODS: We analyzed the impact of pre-transplant MRD level in bone marrow measured by flow cytometry using "different from normal" method on outcomes for 189 AML patients (108 males; median age, 58 (21-80) years). All patients were subdivided into negative (n=96), "low" (0.1-0.5%, n=32) and "high" MRD (>0.5%, n=61) groups.RESULTS: In multivariate analysis, the hazard ratios for "high" and "low" MRD levels related to MRD negativity were 7.9 (95% CI 3.5-18.1, p<0.001) and 5.4 (95% CI 2.1-14, p=0.0058) for relapse; 2.3 (95% CI 1.3-4.1, p=0.006) and 1.6 (95% CI 0.82-3.3, p=0.16) for OS; 2.8 (95% CI 1.7-4.7, p<0.001) and 2.2 (95% CI 1.1-4.2, p=0.02) for LFS, respectively. We found no significant impact of "low" MRD level on relapses (0.68, 95% CI 0.33-1.4, p=0.30), OS (0.72, 95% CI: 0.36-1.5, p=0.36) and LFS (0.79, 95% CI: 0.42-1.5, p=0.46) related to "high" MRD group.
    CONCLUSIONS: Presence of detectable MRD was indicative for a high relapse risk, low LFS and OS. "Low" MRD level showed no significant impact on relapse, LFS and OS related to "high" MRD group.
    Keywords:  acute myeloid leukemia (AML); allogeneic stem cell transplantation; minimal residual disease (MRD); multicolor flow cytometry (MFC); relapse
    DOI:  https://doi.org/10.1111/ejh.13557
  27. Int J Mol Sci. 2020 Nov 27. pii: E9006. [Epub ahead of print]21(23):
    Kazi JU.
      Despite incredible progress in anticancer therapy development, resistance to therapy is the major factor limiting the cure of cancer patients [...].
    DOI:  https://doi.org/10.3390/ijms21239006
  28. Front Oncol. 2020 ;10 562558
    Samra B, Konopleva M, Isidori A, Daver N, DiNardo C.
      The past decade has witnessed major advances in our understanding of molecular biology, which led to breakthrough novel therapies, importantly including the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax. Notably, venetoclax-based combinations have improved outcomes, including both remission rates and overall survival, of older patients with acute myeloid leukemia (AML) deemed "unfit" for intensive chemotherapy due to age or comorbidities. This has translated into a rapid and widespread use of venetoclax-based combinations in both academic and community-based settings. Other venetoclax-based combinations are being investigated in AML with the ultimate goal of improving cure rates across many subgroups; frontline and relapsed/refractory, in combination with intensive chemotherapy, in the post-transplant setting, or as maintenance strategy. In this article, we summarize the current available data on venetoclax-based combinations. We also highlight areas of unmet medical need, and we offer practical clinical pearls for management of patients receiving such therapy.
    Keywords:  acute myeloid leukemia; acute myeloid leukemia combination therapy; relapsed acute leukemia; venetoclax; venetoclax-based combinations
    DOI:  https://doi.org/10.3389/fonc.2020.562558
  29. J Bone Miner Res. 2020 Nov 30.
    Stegen S, Devignes CS, Torrekens S, Van Looveren R, Carmeliet P, Carmeliet G.
      Skeletal homeostasis critically depends on the proper anabolic functioning of osteolineage cells. Proliferation and matrix synthesis are highly demanding in terms of biosynthesis and bioenergetics, but the nutritional requirements that support these processes in bone-forming cells are not fully understood. Here, we show that glutamine metabolism is a major determinant of osteoprogenitor function during bone mass accrual. Genetic inactivation of the rate-limiting enzyme glutaminase 1 (GLS1) results in decreased postnatal bone mass, caused by impaired biosynthesis and cell survival. Mechanistically, we uncovered that GLS1-mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production. In addition, glutamine-derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability. The pro-anabolic role of glutamine metabolism was further underscored in a model of parathyroid hormone (PTH)-induced bone formation. PTH administration increases glutamine uptake and catabolism, and GLS1 deletion fully blunts the PTH-induced osteoanabolic response. Taken together, our findings indicate that glutamine metabolism in osteoprogenitors is indispensable for bone formation. This article is protected by copyright. All rights reserved.
    Keywords:  PTH; biosynthesis; glutamine metabolism; osteoprogenitor; redox homeostasis
    DOI:  https://doi.org/10.1002/jbmr.4219
  30. Aging Dis. 2020 Dec;11(6): 1640-1653
    Wu Q, Chen X, Li J, Sun S.
      As one of the nonessential amino acids (NEAAs), serine is involved in the anabolism of multiple macromolecular substances by participating in one-carbon unit metabolism. Thus, rapidly proliferating cells such as tumor cells and activated immune cells are highly dependent on serine. Serine supports the proliferation of various immune cells through multiple pathways to enhance the antitumor immune response. Moreover, serine influences aging specificity in an epigenetic and metabolic manner. In this review, we focus on recent advances in the relationship between serine metabolism, antitumor immunity, and senescence. The metabolic regulation of serine seems to be a key point of intervention in antitumor immunity and aging-related disease, providing an opportunity for several novel therapeutics.
    Keywords:  Serine; antitumor immunity and senescence; metabolism
    DOI:  https://doi.org/10.14336/AD.2020.0314
  31. Cells. 2020 Nov 24. pii: E2536. [Epub ahead of print]9(12):
    Aquila G, Re Cecconi AD, Brault JJ, Corli O, Piccirillo R.
      Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction.
    Keywords:  bimodal approach; cancer cachexia; exercise; lifestyle interventions; muscle atrophy; muscle wasting; myokine; nutraceutical; nutrition
    DOI:  https://doi.org/10.3390/cells9122536
  32. Mol Cell. 2020 Dec 03. pii: S1097-2765(20)30801-7. [Epub ahead of print]80(5): 762-763
    Wilde BR, Christofk HR.
      Lactate initiates Mg2+ release from the ER and subsequent uptake by the mitochondria.
    DOI:  https://doi.org/10.1016/j.molcel.2020.11.023
  33. Science. 2020 Dec 04. 370(6521): 1186-1191
    Kasper DM, Hintzen J, Wu Y, Ghersi JJ, Mandl HK, Salinas KE, Armero W, He Z, Sheng Y, Xie Y, Heindel DW, Park EJ, Sessa WC, Mahal LK, Lebrilla C, Hirschi KK, Nicoli S.
      Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition (EHT) are poorly understood. We show that microRNA-223 (miR-223)-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid-myeloid lineages by suppressing the mannosyltransferase alg2 and sialyltransferase st3gal2, two enzymes involved in protein N-glycosylation. ECs that lack miR-223 showed a decrease of high mannose versus sialylated sugars on N-glycoproteins such as the metalloprotease Adam10. EC-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied miR-223 mutant defects. Thus, the N-glycome is an intrinsic regulator of EHT, serving as a key determinant of the hematopoietic fate.
    DOI:  https://doi.org/10.1126/science.aaz2121
  34. Clin Immunol. 2020 Nov 28. pii: S1521-6616(20)30799-3. [Epub ahead of print] 108639
    Wildermann C, Alosaimi M, Liebenehm S, Jacobsen E, Barth TFE, Möller P, Debatin KM, Schulz A, Sirin M, Abosoudah IF, Alkuraya FS, Geha RS, Hönig M.
      Complete remission from recurrent EBV-positive lymphoma is not mandatory before HSCT to achieve long-term cure in a patient suffering from a recently described immunodeficiency affecting the T-cell coactivation molecule 4-1BB.
    Keywords:  4-1BB; Epstein Barr virus; HSCT; Recurrent lymphoproliferation
    DOI:  https://doi.org/10.1016/j.clim.2020.108639
  35. Elife. 2020 Dec 01. pii: e60226. [Epub ahead of print]9
    Dumoulin PC, Vollrath J, Tomko SS, Wang JX, Burleigh B.
      The mechanisms underlying resistance of the Chagas disease parasite, Trypanosoma cruzi, to current therapies are not well understood, including the role of metabolic heterogeneity. We found that limiting exogenous glutamine protects actively dividing amastigotes from ergosterol biosynthesis inhibitors (azoles), independent of parasite growth rate. The antiparasitic properties of azoles are derived from inhibition of lanosterol 14α-demethylase (CYP51) in the endogenous sterol synthesis pathway. We find that carbons from 13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Incorporation of 13C-glutamine into endogenously synthesized sterols is increased with BPTES treatment, an inhibitor of host glutamine metabolism that sensitizes amastigotes to azoles. Similarly, amastigotes are re-sensitized to azoles following addition of metabolites upstream of CYP51, raising the possibility that flux through the sterol synthesis pathway is a determinant of sensitivity to azoles and highlighting the potential role for metabolic heterogeneity in recalcitrant T. cruzi infection.
    Keywords:  Trypanosoma cruzi; drug resistance; infectious disease; metabolism; microbiology; sterol biosynthesis
    DOI:  https://doi.org/10.7554/eLife.60226
  36. Clin Immunol. 2020 Nov 30. pii: S1521-6616(20)30801-9. [Epub ahead of print] 108641
    Wang W, Xu Z, Zhang J, Wang S, Ge W, Li X, Mou W, Wang X, Chai W, Zhao J, Wang G, Xi Y, Qiu Y, Ji T, Gui J, Tai J, Ni X.
      The mechanism of the characteristic intermittent hypoxia (IH) of obstructive sleep apnea syndrome (OSAS) on monocyte remain unclear. Our study found that OSAS children had a significantly upregulated expression in circulating proinflammatory cytokines IL-6 and IL-12, and endothelial injury markers VEGF and ICAM1. Association analysis revealed that the plasma TNFα, IL-1β, IL-6, IL-10 and IL-12 concentration were negatively associated with the minimal SpO2, a negative index for disease severity. OSAS monocytes presented an inflammatory phenotype with higher mRNA levels of inflammatory cytokines. Importantly, we noted a significant decrease in T-cell immunoglobulin and mucin domain (Tim)-3 expression in OSAS monocytes with the increase of the plasma proinflammatory cytokines. In vitro assay demonstrated that IH induced THP-1 cell overactivation via NF-κB dependent pathway was inhibited by the Tim-3 signal. Our results indicated that activation of monocyte inflammatory responses is closely related to OSAS-induced IH, and negatively mediated by a Tim-3 signaling pathway.
    Keywords:  Inflammation; Intermittent hypoxia (IH); Monocytes; OSAS; Tim-3
    DOI:  https://doi.org/10.1016/j.clim.2020.108641
  37. Medicina (Kaunas). 2020 Nov 24. pii: E637. [Epub ahead of print]56(12):
    Pasca S, Jurj A, Tomuleasa C, Zdrenghea M.
      Background and objectives: Mutational analysis has led to a better understanding of acute myeloid leukemia (AML) biology and to an improvement in clinical management. Some of the most important mutations that affect AML biology are represented by mutations in genes related to methylation, more specifically: TET2, IDH1, IDH2 and WT1. Because it has been shown in numerous studies that mutations in these genes lead to similar expression profiles and phenotypes in AML, we decided to assess if mutations in any of those genes interact with other genes important for AML. Materials and Methods: We downloaded the clinical data, mutational profile and expression profile from the TCGA LAML dataset via cBioPortal. Data were analyzed using classical statistical methods and functional enrichment analysis software represented by STRING and GOrilla. Results: The first step we took was to assess the 196 AML cases that had a mutational profile available and observe the mutations that overlapped with TET2/IDH1/2/WT1 mutations. We observed that RUNX1 mutations significantly overlap with TET2/IDH1/2/WT1 mutations. Because of this, we decided to further investigate the role of RUNX1 mutations in modulating the level of RUNX1 mRNA and observed that RUNX1 mutant cases presented higher levels of RUNX1 mRNA. Because there were only 16 cases of RUNX1 mutant samples and that mutations in this gene determined a change in mRNA expression, we further observed the correlation between RUNX1 and other mRNAs in subgroups regarding the presence of hypermethylating mutations and NPM1. Here, we observed that both TET2/IDH1/2/WT1 and NPM1 mutations increase the number of genes negatively correlated with RUNX1 and that these genes were significantly linked to myeloid activation. Conclusions: In the current study, we have shown that NPM1 and TET2/IDH1/2/WT1 mutations increase the number of negative correlations of RUNX1 with other transcripts involved in myeloid differentiation.
    Keywords:  NPM1; RUNX1; TET2; acute myeloid leukemia
    DOI:  https://doi.org/10.3390/medicina56120637
  38. BJU Int. 2020 Dec;126(6): 754-755
    Dinneen E, Shaw G.
      
    DOI:  https://doi.org/10.1111/bju.15292
  39. Cancer Res. 2020 Dec 04. pii: canres.1346.2020. [Epub ahead of print]
    Oravecz-Wilson K, Rossi C, Zajac C, Sun Y, Li L, Decoville T, Fujiwara H, Kim S, Peltier D, Reddy P.
      Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T cell allo-immunity, we generated T cell specific ATG5 knock-out mice. Deficiency of ATG5 dependent autophagy reduced T cell proliferation, increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5 dependent autophagy uncouples T cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1346
  40. Viruses. 2020 Dec 01. pii: E1377. [Epub ahead of print]12(12):
    Pei Y, Robertson ES.
      Epigenetics is a versatile player in manipulating viral infection and a potential therapeutic target for the treatment of viral-induced diseases. Both epigenetics and metabolism are crucial in establishing a highly specific transcriptional network, which may promote or suppress virus infection. Human herpesvirus infection can induce a broad range of human malignancies and is largely dependent on the status of cellular epigenetics as well as its related metabolism. However, the crosstalk between epigenetics and metabolism during herpesvirus infection has not been fully explored. Here, we describe how epigenetic regulation of cellular metabolism affects herpesvirus infection and induces viral diseases. This further highlights the importance of epigenetics and metabolism during viral infection and provides novel insights into the development of targeted therapies.
    Keywords:  epigenetics; herpesvirus infection; metabolism
    DOI:  https://doi.org/10.3390/v12121377
  41. Hematology Am Soc Hematol Educ Program. 2020 Dec 04. 2020(1): 590-597
    Chong EA, Porter DL.
      Both older and newer cell therapies have demonstrated impressive responses in otherwise poor-prognosis lymphomas. Consequently, cellular therapy now plays a major role in the management of many non-Hodgkin lymphomas. In this article, we examine the role of chimeric antigen receptor (CAR) T cells, allogeneic stem cell transplantation, and virus-directed T cells for treatment of lymphomas. We review the current indications for CAR T cells and discuss our clinical approach to selecting and treating patients with aggressive B-cell lymphomas to receive CD19-directed CAR T cells. In addition, we highlight newer cell therapies and provide an overview of promising future approaches that have the potential to transform immunotherapy with cells to treat lymphomas.
    DOI:  https://doi.org/10.1182/hematology.2020000174
  42. Can J Cardiol. 2020 Dec 01. pii: S0828-282X(20)31115-6. [Epub ahead of print]
    Randhawa VK, Dhanvantari S, Connelly K.
      Heart failure (HF) and diabetes mellitus (DM) confer considerable burden on the healthcare system. Although these often occur together, DM can increase HF risk, while HF can accelerate DM complications. HF is a clinical syndrome resulting from systolic and/or diastolic impairment caused by ischemic, non-ischemic (e.g., DM) or other etiologies. HF exists along a spectrum, from stage A (i.e., at-risk DM persons) to stage D (i.e., refractory HF from end-stage DM cardiomyopathy (DMCM)). HF is further categorized by reduced, midrange and preserved ejection fraction (EF). In type 2 DM, the most prevalent form of DM, several pathophysiological mechanisms (e.g., insulin resistance, hyperglycemia, etc) can contribute to myocardial damage leading to DMCM. HF and DM management and patient outcomes are guided by EF and drug efficacy. In this review, we focus on the interplay between HF and DM on disease pathophysiology, management, and patient outcomes. Specifically, we highlight the role of novel anti-hyperglycemic (e.g., sodium glucose co-transporter 2 inhibitors) and HF therapies (e.g., renin-angiotensin-aldosterone system inhibitors) on HF outcomes in DM and HF patients.
    Keywords:  SGLT2 inhibitors; anti- hyperglycemic therapy; diabetes; diabetic cardiomyopathy; heart failure
    DOI:  https://doi.org/10.1016/j.cjca.2020.11.014
  43. Sci Rep. 2020 Dec 01. 10(1): 20912
    Jang HH, Lee J, Lee SH, Lee YM.
      Metabolic syndrome (MetS) has increasingly gained importance as the main risk factor for cardiovascular diseases and type II diabetes mellitus. Various natural compounds derived from plants are associated with beneficial effects on the incidence and progression of MetS. This study aimed to evaluate the effects of Capsicum annuum on factors related to MetS by assessing randomized controlled trials (written in English). We searched the online databases of PubMed, Embase, Google scholar, and Cochrane Library up to April 2020. 'Patient/Population, Intervention, Comparison and Outcomes' format was used to determine whether intervention with C. annuum supplementation compared with placebo supplementation had any effect on the components of MetS among participants. We considered standardized mean differences (SMD) with 95% confidence intervals (CI) as effect size measures using random-effects model. Analysis of the included 11 studies (n = 609) showed that C. annuum supplementation had significant effect on low density lipoprotein-cholesterol [SMD = - 0.39; 95% CI - 0.72, - 0.07; P = 0.02; prediction interval, - 1.28 to 0.50] and marginally significant effect on body weight [SMD = - 0.19; 95% CI - 0.40, 0.03; P = 0.09]. However, larger and well-designed clinical trials are needed to investigate the effects of C. annuum on MetS.
    DOI:  https://doi.org/10.1038/s41598-020-77983-2
  44. Acad Emerg Med. 2020 Nov 28.
    Hunold KM, Schwaderer AL, Exline M, Hebert C, Lampert BC, Southerland LT, Stephens JA, Bischof JJ, Caterino JM.
      Dyspnea is the second leading cause of US emergency department (ED) visits and an independent predictor of morbidity and mortality1 in older adult patients aged ≥65 years. Unfortunately, the diagnosis of the cause of dyspnea presents diagnostic challenges to emergency physicians2-4 that disproportionately affects older adults.5 One in 5 dyspneic older adults experience missed diagnosis in the ED2 and 21% are treated for ≥1 pneumonia, acute exacerbation of chronic obstructive pulmonary disease [COPD], and acute exacerbation of heart failure [HF].5 Importantly, some may have multiple causes of their dyspnea but accurate diagnosis remains critical.
    DOI:  https://doi.org/10.1111/acem.14183
  45. Biomedicines. 2020 Dec 02. pii: E561. [Epub ahead of print]8(12):
    Shin TH, Ahn JS, Oh SJ, Shin YY, Yang JW, Kang MJ, Kim JM, Lee BJ, Seo Y, Kim HS.
      Mesenchymal stem cells (MSCs) have been spotlighted in the field of cell therapies as a promising tool for the treatment of intractable inflammatory diseases. However, their therapeutic potency still shows a gap between preclinical and clinical settings, and distinctive characteristics of specific tissue-derived MSCs and definitive ways to maximize their beneficial functions have not been fully elucidated yet. We previously identified the unique MSCs population from human palatine tonsil (TMSCs) and revealed their superior properties in proliferation and ROS regulation. Based on these findings, we explored further characteristics of TMSCs particularly focused on immunomodulatory function. We found the merit of TMSCs as a therapeutic agent that retains favorable MSCs properties until relatively late passages and revealed that pre-treatment of TNF-α can enhance the immunomodulatory abilities of TMSCs through the upregulation of the PTGS2/PGE2 axis. TMSCs primed with TNF-α effectively restrained the proliferation and differentiation of T lymphocytes and macrophages in vitro, and more interestingly, these TNF-α-licensed TMSCs exhibited significant prophylactic and therapeutic efficacy in a murine model of autoimmune-mediated acute colitis via clinical and histopathological assessment compared to unprimed naïve TMSCs. These findings provide novel insight into the optimization and standardization of MSCs-based anti-inflammatory therapies, especially targeting inflammatory bowel disease (IBD).
    Keywords:  colitis; cyclooxygenase-2; immunomodulation; mesenchymal stem cell; palatine tonsil; prostaglandin E2; tumor necrosis factor alpha
    DOI:  https://doi.org/10.3390/biomedicines8120561
  46. Oncogene. 2020 Dec 01.
    Lin WH, Chang YW, Hong MX, Hsu TC, Lee KC, Lin C, Lee JL.
      Epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET) processes are proposed to be a driving force of cancer metastasis. By studying metastasis in bone marrow-derived mesenchymal stem cell (BM-MSC)-driven lung cancer models, microarray time-series data analysis by systems biology approaches revealed BM-MSC-induced signaling triggers early dissemination of CD133+/CD83+ cancer stem cells (CSCs) from primary sites shortly after STAT3 activation but promotes proliferation towards secondary sites. The switch from migration to proliferation was regulated by BM-MSC-secreted LIF and activated LIFR/p-ERK/pS727-STAT3 signaling to promote early disseminated cancer cells MET and premetastatic niche formation. Then, tumor-tropic BM-MSCs circulated to primary sites and triggered CD151+/CD38+ cells acquiring EMT-associated CSC properties through IL6R/pY705-STAT3 signaling to promote tumor initiation and were also attracted by and migrated towards the premetastatic niche. In summary, STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates the EMT-MET switch within the distinct molecular subtypes of CSCs to complete the metastatic process.
    DOI:  https://doi.org/10.1038/s41388-020-01566-8
  47. Glia. 2020 Nov 29.
    Bhusal A, Rahman MH, Lee WH, Lee IK, Suk K.
      Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin-2 (LCN2) is a pro-inflammatory acute-phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes-induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus-mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate-keeping regulator pyruvate dehydrogenase kinase-2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2-PPARβ/δ-PDK2-lactic acid axis in progression of DPN. Our results establish a link between pro-inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia-based mechanism and drug target for therapy of DPN. MAIN POINTS: Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase-2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2-PDK2-lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.
    Keywords:  diabetes; dorsal root ganglion; lipocalin-2; neuropathy; pyruvate dehydrogenase kinase; satellite glial cells
    DOI:  https://doi.org/10.1002/glia.23942
  48. Blood. 2020 Dec 03. pii: blood.2019004108. [Epub ahead of print]
    Soares F, Chen B, Lee JB, Ahmed M, Ly D, Tin E, Kang H, Zeng Y, Akhtar N, Minden MD, He H, Zhang L.
      Acute myeloid leukemia (AML) remains a devastating disease in need of new therapies to improve patient survival. Targeted, adoptive T cell therapies have achieved impressive clinical outcomes in some B-cell leukemias and lymphomas but not in AML. Double negative T cells (DNTs) effectively kill blast cells from the majority of AML patients and are now being tested in clinical trials. However, AML blasts obtained from ~30% of patients show resistance to DNT cell-mediated cytotoxicity; the markers or mechanisms underlying this resistance have not been elucidated. Here, we used a targeted CRISPR/Cas9 screen to identify genes that confer susceptibility of AML cells to DNT cell therapy. Inactivation of the SAGA deubiquitinating complex components sensitized AML cells to DNT-mediated cytotoxicity. In contrast, CD64 inactivation resulted in resistance to DNT-mediated cytotoxicity. Importantly, the level of CD64 expression strongly correlated with the sensitivity of AML cells to DNT cell treatment. Furthermore, the ectopic expression of CD64 overcame AML resistance to DNTs both in vitro and in vivo. Altogether, our data demonstrate the utility of CRISPR/Cas9 screens to uncover mechanisms underlying the sensitivity to DNT cell therapy and suggest CD64 as a predictive marker for response in AML patients.
    DOI:  https://doi.org/10.1182/blood.2019004108
  49. Stem Cells. 2020 Nov 30.
    Jiao H, Walczak BE, Lee MS, Lemieux ME, Li WJ.
      Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells but how molecular mechanisms through which reprogrammed cells alter aging-related cellular activities still remain largely unclear. In this study, we reprogrammed human synovial fluid-derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging-related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 (FOXP1), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and FOXP1 pathway to modulate cellular senescence and aging-related activities.
    Keywords:  aging; cell signaling; mesenchymal stem cells; reprogramming; transcription factors
    DOI:  https://doi.org/10.1002/stem.3297