STAT3 Genotypic Variant rs744166 and Increased Tyrosine Phosphorylation of STAT3 in IL-23 Responsive Innate Lymphoid Cells during Pathogenesis of Crohn\u27s Disease

Crohn\u27s disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele A with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 A risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse

ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia

Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-beta (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies

A Novel Unsupervised Method to Identify Genes Important in the Anti-viral Response: Application to Interferon/Ribavirin in Hepatitis C Patients

Background: Treating hepatitis C with interferon/ribavirin results in a varied response in terms of decrease in viral titer and ultimate outcome. Marked responders have a sharp decline in viral titer within a few days of treatment initiation, whereas in other patients there is no effect on the virus (poor responders). Previous studies have shown that combination therapy modifies expression of hundreds of genes in vitro and in vivo. However, identifying which, if any, of these genes have a role in viral clearance remains challenging. Aims: The goal of this paper is to link viral levels with gene expression and thereby identify genes that may be responsible for early decrease in viral titer. Methods: Microarrays were performed on RNA isolated from PBMC of patients undergoing interferon/ribavirin therapy. Samples were collected at pre-treatment (day 0), and 1, 2, 7, 14 and 28 days after initiating treatment. A novel method was applied to identify genes that are linked to a decrease in viral titer during interferon/ribavirin treatment. The method uses the relationship between inter-patient gene expression based proximities and inter-patient viral titer based proximities to define the association between microarray gene expression measurements of each gene and viral-titer measurements. Results: We detected 36 unique genes whose expressions provide a clustering of patients that resembles viral titer based clustering of patients. These genes include IRF7, MX1, OASL and OAS2, viperin and many ISG's of unknown function. Conclusion: The genes identified by this method appear to play a major role in the reduction of hepatitis C virus during the early phase of treatment. The method has broad utility and can be used to analyze response to any group of factors influencing biological outcome such as antiviral drugs or anti-cancer agents where microarray data are available. © 2007 Brodsky et al

Understanding Eating Disorders in Elite Gymnastics

Eating disorders and disordered eating are more common in high performance sports than the general population, and particularly so in high performance aesthetic sports. This paper presents some of the conceptual difficulties in understanding and diagnosing eating disorders in high performance gymnasts. It presents qualitative and quantitative data from a study designed to ascertain the pattern of eating disorder symptoms, depressive symptoms and levels of self-esteem amongst national and international level gymnasts from the UK in the gymnastic disciplines of sport acrobatics, tumbling and rhythmic gymnastics

Influenza A Virus Inhibits Type I IFN Signaling via NF-κB-Dependent Induction of SOCS-3 Expression

The type I interferon (IFN) system is a first line of defense against viral infections. Viruses have developed various mechanisms to counteract this response. So far, the interferon antagonistic activity of influenza A viruses was mainly observed on the level of IFNβ gene induction via action of the viral non-structural protein 1 (NS1). Here we present data indicating that influenza A viruses not only suppress IFNβ gene induction but also inhibit type I IFN signaling through a mechanism involving induction of the suppressor of cytokine signaling-3 (SOCS-3) protein. Our study was based on the observation that in cells that were infected with influenza A virus and subsequently stimulated with IFNα/β, phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) was strongly reduced. This impaired STAT1 activation was not due to the action of viral proteins but rather appeared to be induced by accumulation of viral 5′ triphosphate RNA in the cell. SOCS proteins are potent endogenous inhibitors of Janus kinase (JAK)/STAT signaling. Closer examination revealed that SOCS-3 but not SOCS-1 mRNA levels increase in an RNA- and nuclear factor kappa B (NF-κB)-dependent but type I IFN-independent manner early in the viral replication cycle. This direct viral induction of SOCS-3 mRNA and protein expression appears to be relevant for suppression of the antiviral response since in SOCS-3 deficient cells a sustained phosphorylation of STAT1 correlated with elevated expression of type I IFN-dependent genes. As a consequence, progeny virus titers were reduced in SOCS-3 deficient cells or in cells were SOCS-3 expression was knocked-down by siRNA. These data provide the first evidence that influenza A viruses suppress type I IFN signaling on the level of JAK/STAT activation. The inhibitory effect is at least in part due to the induction of SOCS-3 gene expression, which results in an impaired antiviral response

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.Funding/Support: The Institute for Health Metrics and Evaluation received funding from the Bill & Melinda Gates Foundation and the American Lebanese Syrian Associated Charities. Dr Aljunid acknowledges the Department of Health Policy and Management of Kuwait University and the International Centre for Casemix and Clinical Coding, National University of Malaysia for the approval and support to participate in this research project. Dr Bhaskar acknowledges institutional support from the NSW Ministry of Health and NSW Health Pathology. Dr Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, which is funded by the German Federal Ministry of Education and Research. Dr Braithwaite acknowledges funding from the National Institutes of Health/ National Cancer Institute. Dr Conde acknowledges financial support from the European Research Council ERC Starting Grant agreement No 848325. Dr Costa acknowledges her grant (SFRH/BHD/110001/2015), received by Portuguese national funds through Fundação para a Ciência e Tecnologia, IP under the Norma Transitória grant DL57/2016/CP1334/CT0006. Dr Ghith acknowledges support from a grant from Novo Nordisk Foundation (NNF16OC0021856). Dr Glasbey is supported by a National Institute of Health Research Doctoral Research Fellowship. Dr Vivek Kumar Gupta acknowledges funding support from National Health and Medical Research Council Australia. Dr Haque thanks Jazan University, Saudi Arabia for providing access to the Saudi Digital Library for this research study. Drs Herteliu, Pana, and Ausloos are partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. Dr Hugo received support from the Higher Education Improvement Coordination of the Brazilian Ministry of Education for a sabbatical period at the Institute for Health Metrics and Evaluation, between September 2019 and August 2020. Dr Sheikh Mohammed Shariful Islam acknowledges funding by a National Heart Foundation of Australia Fellowship and National Health and Medical Research Council Emerging Leadership Fellowship. Dr Jakovljevic acknowledges support through grant OI 175014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. Dr Katikireddi acknowledges funding from a NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). Dr Md Nuruzzaman Khan acknowledges the support of Jatiya Kabi Kazi Nazrul Islam University, Bangladesh. Dr Yun Jin Kim was supported by the Research Management Centre, Xiamen University Malaysia (XMUMRF/2020-C6/ITCM/0004). Dr Koulmane Laxminarayana acknowledges institutional support from Manipal Academy of Higher Education. Dr Landires is a member of the Sistema Nacional de Investigación, which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación. Dr Loureiro was supported by national funds through Fundação para a Ciência e Tecnologia under the Scientific Employment Stimulus–Institutional Call (CEECINST/00049/2018). Dr Molokhia is supported by the National Institute for Health Research Biomedical Research Center at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London. Dr Moosavi appreciates NIGEB's support. Dr Pati acknowledges support from the SIAN Institute, Association for Biodiversity Conservation & Research. Dr Rakovac acknowledges a grant from the government of the Russian Federation in the context of World Health Organization Noncommunicable Diseases Office. Dr Samy was supported by a fellowship from the Egyptian Fulbright Mission Program. Dr Sheikh acknowledges support from Health Data Research UK. Drs Adithi Shetty and Unnikrishnan acknowledge support given by Kasturba Medical College, Mangalore, Manipal Academy of Higher Education. Dr Pavanchand H. Shetty acknowledges Manipal Academy of Higher Education for their research support. Dr Diego Augusto Santos Silva was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil Finance Code 001 and is supported in part by CNPq (302028/2018-8). Dr Zhu acknowledges the Cancer Prevention and Research Institute of Texas grant RP210042