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      Correlation between IL28B/TLR4 genetic variants and HCC development with/without DAAs treatment in chronic HCV patients


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          In Egypt, Sofosbuvir (SOF) in combination with Dataclasvir (DCV) is the broadly used DAAs with excellent therapeutic profile. This study is designed to explore the relation between IL28B/TLR4 genetic variants and each of the followings; HCC development post SOF/DCV treatment, progression to HCC in naïve patients and SOF/DCV therapy outcome. A total of 493 blood samples were collected (controls ( n = 70); HCV patients treated with SOF/DCV ( n = 252) of whom 65 patients developed HCC, 187 patients didn't develop HCC (125 responders, 62 relapsers); naïve HCV patients ( n = 171) had early ( n = 48), late liver fibrosis ( n = 21) and HCC ( n = 102)). Both SNPs were genotyped using a TaqMan 5′ allelic discrimination assay. At IL28B rs12979860 SNP, the C allele was significantly correlating with the response rate more than T allele (OR 1.9, 95% CI 1.29–2.9, p = 0.004), while at TLR4 rs4986791 SNP, no association was found (OR 6.5, 95% 0.57–75.28, p = 0.09). Both SNPs couldn't detect the probability for HCC emergence after treatment. In naïve patients, the protective alleles were detected in their lowest frequency in HCC patients ( p = 0.1, for rs12979860 and, p = 0.001 for rs4986791). SOF/DCV combination improved SVR rates in HCV genotype 4a infected patients regardless of IL28B genotype, with the best rates in those lacking the T allele.

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          A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.

          Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
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            HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma

            Background and Aims It is unclear whether direct-acting antiviral (DAA) treatment-induced sustained virologic response (SVR) reduces the risk of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. We aimed to determine the impact of DAA-induced SVR on HCC risk. Methods We identified 62,354 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1/1/1999 to 12/31/2015, including 35,871 (58%) interferon-only regimens, 4535 (7.2%) DAA+interferon regimens and 21,948 (35%) DAA-only regimens. We retrospectively followed patients until 6/15/2017 to identify incident cases of HCC. We used Cox proportional hazards regression to determine the association between SVR and HCC risk or between type of antiviral regimen (DAA-only vs DAA+interferon vs Interferon-only) and HCC risk. Results We identified 3271 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 6.1 years. The incidence of HCC was highest in patients with cirrhosis and treatment failure (3.25 per 100 patient-years), followed by cirrhosis and SVR (1.97), no cirrhosis and treatment failure (0.87) and no cirrhosis and SVR (0.24). SVR was associated with a significantly decreased risk of HCC in multivariable models irrespective of whether the antiviral treatment was DAA-only (adjusted hazard ratio [AHR] 0.29, 95% CI 0.23–0.37), DAA+interferon (AHR 0.48, 95% CI 0.32–0.73) or interferon-only (AHR 0.32, 95% CI 0.28–0.37). Receipt of a DAA-only or DAA+interferon regimen was not associated with increased HCC risk compared to receipt of an interferon-only regimen. Conclusions DAA-induced SVR is associated with a 71% reduction in HCC risk. Treatment with DAAs is not associated with increased HCC risk compared to treatment with interferon. Kaplan-Meier curves of survival free of HCC by cirrhosis and SVR status after DAA-only antiviral treatment: SVR is associated with a reduction in HCC risk both among patients with cirrhosis and those without cirrhosis.
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              Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma.

              Because recent studies implicate Toll-like receptors (TLRs) in the pathogenesis of fibrosis, we sought to investigate the in vitro and in vivo role and mechanism of TLR4-mediated fibroblast responses in fibrogenesis. We found that TLR4 was constitutively expressed, and accumulation of endogenous TLR4 ligands significantly elevated, in lesional skin and lung tissues from patients with scleroderma. Activation of TLR4 signaling in explanted fibroblasts resulted in enhanced collagen synthesis and increased expression of multiple genes involved in tissue remodeling and extracellular matrix homeostasis. Moreover, TLR4 dramatically enhanced the sensitivity of fibroblasts to the stimulatory effect of transforming growth factor-β1. These profibrotic responses were abrogated by both genetic and pharmacological disruption of TLR4 signaling in vitro, and skin fibrosis induced by bleomycin in vivo was attenuated in mice harboring a mutated TLR4. Activation of TLR4 in fibroblasts augmented the intensity of canonical Smad signaling, and was accompanied by suppression of anti-fibrotic microRNA expression. Together, these results suggest a novel model to account for persistent fibrogenesis in scleroderma, in which activation of fibroblast TLR4 signaling, triggered by damage-associated endogenous TLR4 ligands, results in augmented transforming growth factor-β1 sensitivity with increased matrix production and progressive connective tissue remodeling. Under these conditions, fibroblast TLR4 serves as the switch for converting self-limited tissue repair into intractable fibrosis. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                27 May 2019
                September 2020
                27 May 2019
                : 7
                : 3
                : 392-400
                [a ]Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
                [b ]Department of Tropical Medicine, Faculty of Medicine, Cairo University, Giza, P.O. 12622, Egypt
                Author notes
                []Corresponding author. Microbial Biotechnology Department, Genetic Engineering Division, National Research Center, EL Bohouth St. (former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt. rmhaemd@ 123456hotmail.com
                © 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 4 April 2019
                : 13 May 2019
                : 20 May 2019

                daas,dcv,hcv,hcc,il28b,sof,tlr4,sof, sofosbuvir,dcv, dataclasvir,daas, direct acting antiviral agents,hcv, hepatitis c virus,hcc, hepatocellular carcinoma,ifnλ, type iii ifns,snp, single nucleotide polymorphism,svr, sustained virological response,pamps/damps, pathogen/damage associated molecular patterns,tlrs, toll like receptors,jak/stat, janus kinase/signal transducers and activators of transcription,isgs, interferon-stimulated genes


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