Browsing by Subject "hepatitis"

Now showing 1 - 4 of 4
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    Development of a Modified Lymphocyte Transformation Test for Diagnosing Drug Induced Liver Injury Associated with an Adaptive Immune Response
    (Taylor & Francis, 2017-12) Whritenour, Jessica; Ko, Mira; Zong, Qing; Wang, Jianying; Tartaro, Karrie; Schneider, Patricia; Olson, Ellen; Van Volkenburg, Maria; Serrano, Jose; Hayashi, Paul; Fontana, Robert; Chalasani, Naga; Bonkovsky, Herbert L.; Medicine, School of Medicine
    Drug induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals, and/or dietary supplements (polypharmacy) have not yet been established. The lymphocyte transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: 1) develop and optimize a modified version of the LTT (mLTT) and 2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive immune response and identifying the responsible drug. PBMC collected from donors with a history of drug hypersensitivity reactions to specific drugs (manifested as skin rash) were used as positive controls for assay optimization. Following optimization, samples collected from 24 subjects enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) were tested in the mLTT. Using cytokine and granzyme B production as the primary endpoints to demonstrate lymphocyte sensitization to a specific drug, most samples from the DILIN subjects failed to respond. However, robust positive mLTT responses were observed for two of four samples from three DILIN subjects with hepatitis due to isoniazid (INH). We conclude that the mLTT, as performed here on frozen and thawed PBMC, is not a reliable test for diagnosing DILI caused by all drugs, but that it may be useful for confirming the role of the adaptive immune response in DILI ascribed to INH.
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    Non-coding RNA crosstalk with nuclear receptors in liver disease
    (Elsevier, 2021-05) Wu, Jianguo; Nagy, Laura E.; Liangpunsakul, Suthat; Wang, Li; Medicine, School of Medicine
    The dysregulation of nuclear receptors (NRs) underlies the pathogenesis of a variety of liver disorders. Non-coding RNAs (ncRNAs) are defined as RNA molecules transcribed from DNA but not translated into proteins. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two types of ncRNAs that have been extensively studied for regulating gene expression during diverse cellular processes. NRs as therapeutic targets in liver disease have been exemplified by the successful application of their pharmacological ligands in clinics. MiRNA-based reagents or drugs are emerging as flagship products in clinical trials. Advancing our understanding of the crosstalk between NRs and ncRNAs is critical to the development of diagnostic and therapeutic strategies. This review summarizes recent findings on the reciprocal regulation between NRs and ncRNAs (mainly on miRNAs and lncRNAs) and their implication in liver pathophysiology, which might be informative to the translational medicine of targeting NRs and ncRNAs in liver disease.
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    Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody
    (AACR, 2017) Segal, Neil H.; Logan, Theodore F.; Hodi, F. Stephen; McDermott, David; Melero, Ignacio; Hamid, Omid; Schmidt, Henrik; Robert, Caroline; Chiarion-Sileni, Vanna; Ascierto, Paolo A.; Maio, Michele; Urba, Walter J.; Gandadhar, Tara C.; Suryawanshi, Satyendra; Neely, Jaclyn; Jure-Kunkel, Maria; Krishnan, Suba; Kohrt, Holbrook; Sznol, Mario; Levy, Ronald; Medicine, School of Medicine
    Purpose: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma. Experimental Design: A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose–escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatment-related and serious adverse events (AEs), as well as treatment-related AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs. Results: Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses ≥1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines. Conclusions: Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of ≥1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents.
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    Transcriptomic analysis reveals the miRNAs responsible for liver regeneration associated with mortality in alcoholic hepatitis
    (Wiley, 2021-11) Yang, Zhihong; Zhang, Ting; Kusumanchi, Praveen; Tang, Qing; Sun, Zhaoli; Radaeva, Svetlana; Peiffer, Brandon; Shah, Vijay H.; Kamath, Patrick; Gores, Greg J.; Sanyal, Arun; Chalasani, Naga; Jiang, Yanchao; Huda, Nazmul; Ma, Jing; Liangpunsakul, Suthat; Medicine, School of Medicine
    We conducted a comprehensive serum transcriptomic analysis to explore the roles of miRNAs in alcoholic hepatitis (AH) pathogenesis and their prognostic significance. Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, the expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell cycle progression pathways, including RRM2, CCND1, CCND2, MYC, and PMAIP1. We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1 in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3’-UTR luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3’-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher BMI, MELD, serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted the mortality. Conclusion: Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and upregulating genes responsible for DNA synthesis and cell cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients.