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      Interferon-stimulated gene 20 kDa protein serum levels and clinical outcome of hepatitis B virus-related liver diseases

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          Abstract

          Interferon-stimulated gene 20 kDa protein (ISG20) with 3’ to 5’ exonuclease activity mainly targeting single-stranded RNA plays an important role in immune responses against various infectious pathogens, including hepatitis viruses. ISG20 levels were measured by ELISA assays in sera of 339 hepatitis B-virus (HBV) infected patients and 71 healthy individuals and were correlated with clinical and laboratory parameters. ISG20 mRNA was quantified by qRT-PCR in 30 pairs of hepatocellular carcinoma (HCC) tumour and adjacent non-tumour liver tissues. ISG20 levels were significantly elevated in HBV patients compared to healthy controls ( P<0.0001). In the patient group, varying ISG20 levels were associated with different forms of HBV-related liver diseases. ISG20 levels were higher in patients with HCC compared to those without HCC ( P<0.0001), and increased according to the stages of HCC ( P<0.0001). ISG20 mRNA expression was up-regulated in tumour tissues compared to the expression in adjacent non-tumour tissues ( P=0.017). Importantly, ISG20 levels were strongly correlated with the levels of AST, ALT, total and direct bilirubin among HCC patients (Pearson’s r = 0.43, 0.35, 0.34, 0.3; P<0.0001, respectively). Although differences between liver cirrhosis (LC) and non-LC patients were not observed, ISG20 levels were elevated according to the progression of cirrhosis in patients with LC plus HCC ( P=0.005). In conclusions, ISG20 levels are induced by HBV infection and significantly associated with progression and clinical outcome of HBV-related liver diseases, especially in patients with HCC. ISG20 might be a potential indicator for liver injury and the clinical outcome in HBV-related HCC.

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          Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis?

          Prognosis in cirrhotic patients has had a resurgence of interest because of liver transplantation and new therapies for complications of end-stage cirrhosis. The model for end-stage liver disease score is now used for allocation in liver transplantation waiting lists, replacing Child-Turcotte-Pugh score. However, there is debate as whether it is better in other settings of cirrhosis. To review studies comparing the accuracy of model for end-stage liver disease score vs. Child-Turcotte-Pugh score in non-transplant settings. Transjugular intrahepatic portosystemic shunt studies (with 1360 cirrhotics) only one of five, showed model for end-stage liver disease to be superior to Child-Turcotte-Pugh to predict 3-month mortality, but not for 12-month mortality. Prognosis of cirrhosis studies (with 2569 patients) none of four showed significant differences between the two scores for either short- or long-term prognosis whereas no differences for variceal bleeding studies (with 411 cirrhotics). Modified Child-Turcotte-Pugh score, by adding creatinine, performed similarly to model for end-stage liver disease score. Hepatic encephalopathy and hyponatraemia (as an index of ascites), both components of Child-Turcotte-Pugh score, add to the prognostic performance of model for end-stage liver disease score. Based on current literature, model for end-stage liver disease score does not perform better than Child-Turcotte-Pugh score in non-transplant settings. Modified Child-Turcotte-Pugh and model for end-stage liver disease scores need further evaluation.
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            Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden.

            Worldwide, 350 million people are chronically infected with hepatitis B virus (HBV) who are at greater risk of hepatocellular carcinoma (HCC) compared with uninfected people. The relative risks of HCC among people infected with HBV ranges from 5 to 49 in case-control studies and from 7 to 98 in cohort studies. More than 50% of HCC cases worldwide and 70-80% of HCC cases in highly HBV endemic regions are attributable to HBV. Incidence of HCC (per 100,000 person/year) among people with chronic HBV infection ranges from 400 to 800 in male and from 120 to 180 in female. Factors associated with increased risk of HCC include demographic characteristics (male sex and older age), lifestyles (heavy alcohol consumption and smoking), viral factors (genotype C, D F, high level of HBV DNA, core/precore mutation) and clinical factors (cirrhosis, elevated alpha-fetoprotein (AFP) and alanine aminotransferase (ALT)). HBV-related HCC has extremely poor prognosis with median survival less than 16 months. Survival rates of HBV-related HCC ranged from 36% to 67% after 1 year and from 15% to 26% after 5 year of diagnosis. Older age, liver function impairment, vascular invasion, tumour aggressiveness and elevated AFP are associated with HCC survival. Global burden of HBV-related liver disease is still a major challenge for public health in the 21st century. While decreases in incidence of HBV infection have been observed in birth cohorts following the introduction of universal infant HBV vaccination programme, HBV-related HCC incidence in is projected to increase for at least two decades because of the high prevalence of chronic HBV infection and prolonged latency to HCC development. To reduce HBV-related HCC continued expansion of universal infant HBV vaccination is required along with antiviral therapy targeted to those individuals at highest risk of HCC. Broad public health strategies should include routine testing to identify chronic HBV infection, improved health infrastructures including human resource to provide diagnosis and treatment assessment.
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              Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus.

              Hepatitis C virus (HCV) infection is a common cause of chronic hepatitis and is currently treated with alpha interferon (IFN-alpha)-based therapies. However, the underlying mechanism of IFN-alpha therapy remains to be elucidated. To identify the cellular proteins that mediate the antiviral effects of IFN-alpha, we created a HEK293-based cell culture system to inducibly express individual interferon-stimulated genes (ISGs) and determined their antiviral effects against HCV. By screening 29 ISGs that are induced in Huh7 cells by IFN-alpha and/or up-regulated in HCV-infected livers, we discovered that viperin, ISG20, and double-stranded RNA-dependent protein kinase (PKR) noncytolytically inhibited the replication of HCV replicons. Mechanistically, inhibition of HCV replication by ISG20 and PKR depends on their 3'-5' exonuclease and protein kinase activities, respectively. Moreover, our work, for the first time, provides strong evidence suggesting that viperin is a putative radical S-adenosyl-l-methionine (SAM) enzyme. In addition to demonstrating that the antiviral activity of viperin depends on its radical SAM domain, which contains conserved motifs to coordinate [4Fe-4S] cluster and cofactor SAM and is essential for its enzymatic activity, mutagenesis studies also revealed that viperin requires an aromatic amino acid residue at its C terminus for proper antiviral function. Furthermore, although the N-terminal 70 amino acid residues of viperin are not absolutely required, deletion of this region significantly compromises its antiviral activity against HCV. Our findings suggest that viperin represents a novel antiviral pathway that works together with other antiviral proteins, such as ISG20 and PKR, to mediate the IFN response against HCV infection.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                12 June 2018
                12 June 2018
                : 9
                : 45
                : 27858-27871
                Affiliations
                1 Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, Hanoi, Vietnam
                2 Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
                3 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
                4 108 Military Central Hospital, Hanoi, Vietnam
                5 Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
                6 Duy Tan University, Da Nang, Vietnam
                Author notes
                Correspondence to: Hoang Van Tong, hoangvantong@ 123456vmmu.edu.vn
                Thirumalaisamy P. Velavan, velavan@ 123456medizin.uni-tuebingen.de
                Article
                25559
                10.18632/oncotarget.25559
                6021248
                90295126-b8cb-412b-ab33-6d0964e11b66
                Copyright: © 2018 Van Tong et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 April 2018
                : 21 May 2018
                Categories
                Clinical Research Paper

                Oncology & Radiotherapy
                interferon-stimulated gene,isg20 levels,isg20 expression,viral hepatitis,hepatocellular carcinoma

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