SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Cirrhosis

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Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage associated molecular patterns (DAMPs), such as high mobility group box-1 (HMGB1), and dysregulated microRNAs (miRNAs) involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in over-expression of miR-21. These changes were found to be dependent on the IL-6/Stat3 signaling axis. Invasion and migration of HCC cells in vitro was inhibited by both Stat3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a post-transcriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL-6/Stat3-miR-21 axis.

Concepts: Inflammation, Gene expression, Cancer, Extracellular matrix, Cirrhosis, Anti-inflammatory, Matrix metalloproteinase, Tissue inhibitor of metalloproteinases

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To investigate the outcomes of living donor liver transplantation for advanced hepatocellular carcinoma in Child-Pugh A/B patients and the usefulness of our expanded selection criteria, the Kyoto criteria.

Concepts: Cancer, Cirrhosis, Liver, Liver transplantation

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Greenland remains a highly endemic area for hepatitis B virus (HBV) infection. This is in sharp contrast to other modern societies, such as Denmark. To address this discrepancy, we investigated the natural history of HBV infection in Greenland by estimating the age-specific incidence of HBV infection, the proportion of chronic carriers, and the rates of hepatitis B surface antigen seroclearance. In total, 8,879 Greenlanders (16% of the population) from population-based surveys conducted in 1987 and 1998 were followed through March 2010. Data on HBV status were supplemented by HBV test results from all available HBV registries in Greenland to determine changes in HBV status over time. Incidence rates of HBV infection and hepatitis B surface antigen seroclearance were estimated after taking into account interval censoring. The incidence of HBV infection in 5-14-year-old subjects was less than 1 per 100 person-years and peaked at 5 per 100 person-years in persons 15-24 years of age. Overall, 17.5% of persons infected in adulthood were estimated to become chronic carriers. HBV is primarily transmitted in adolescence and adulthood in Greenland. In contrast to what is observed in most other populations, HBV-infected adults in Greenland have a high risk of progressing to chronic HBV carriage. This phenomenon might explain how the high rate of infection is maintained in Greenland.

Concepts: Cohort study, Epidemiology, Cirrhosis, Hepatitis, Hepatitis B, Hepatitis B virus, Denmark, Greenland

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Daclatasvir (Daklinza(®)) is an inhibitor of hepatitis C virus (HCV) NS5A protein. It is a new, oral, direct-acting antiviral with potent pangenotypic activity. This article provides a narrative review of the efficacy and tolerability of daclatasvir in combination with other agents in the treatment of patients with chronic HCV infection and summarizes its pharmacological properties. Since daclatasvir has a different mechanism of action to other current direct-acting antivirals, it provides additive or synergistic antiviral activity when used in combination. It produces high sustained virological response rates when used in combination with peginterferon-α plus ribavirin in patients chronically infected with HCV genotypes 1-4, and provides even higher response rates when used in an interferon-free, all-oral combination with sofosbuvir, with or without ribavirin. Daclatasvir has a moderately high genetic barrier to resistance, is effective during short-term treatment over 12 weeks and has a tolerability profile similar to that of placebo. In conclusion, daclatasvir is a highly effective and well tolerated, oral, once-daily, direct-acting antiviral for use in combination therapy in adult patients chronically infected with HCV.

Concepts: Genetics, Virus, Cirrhosis, Hepatitis, Antiviral drug, Hepatitis C, Hepatitis B, Hepatitis C virus

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Adefovir dipivoxil (ADV) is recommended for patients infected with lamivudine-refractory hepatitis B virus (HBV). We report a case of low-dose ADV-induced hypophosphatemic osteomalacia that initially presented as diffuse musculoskeletal pain.

Concepts: Cirrhosis, Hepatitis, Hepatitis B, Viruses, Hepatitis B virus, Hepadnaviridae, Adefovir, Fanconi syndrome

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Liver transplantation is the treatment of choice for chronic liver failure, although it is complicated by donor shortage, surgery-related complications, and immunological rejection. Cell transplantation is an alternative, minimally invasive treatment option with potentially fewer complications. We used human palatine tonsil as a novel source of mesenchymal stem cells (T-MSCs) and examined their ability to differentiate into hepatocyte-like cells in vivo and in vitro. Carbon tetrachloride (CCl4) mouse model was used to investigate the ability of T-MSCs to home to the site of liver injury. T-MSCs were only detected in the damaged liver, suggesting that they are disease-responsive. Differentiation of T-MSCs into hepatocyte-like cells was confirmed in vitro as determined by expression of hepatocyte markers. Next, we showed resolution of liver fibrosis by T-MSCs via reduction of TGF-β expression and collagen deposition in the liver. We hypothesized that autophagy activation was a possible mechanism for T-MSC-mediated liver recovery. In this report, we demonstrate for the first time that T-MSCs can differentiate into hepatocyte-like cells and ameliorate liver fibrosis via autophagy activation and down-regulation of TGF-β. These findings suggest that T-MSCs could be used as a novel source for stem cell therapy targeting liver diseases.

Concepts: Stem cell, Mesenchymal stem cell, Bone marrow, Stem cells, Cirrhosis, Liver, Cellular differentiation, Hepatology

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Treatment with an all-oral interferon-free antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF) with/without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events (AEs) in non-liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3-F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV-based regimens) received treatment and were followed for a median of 30 weeks (range: 12-53 weeks). The median time from LT to treatment was 32 months (range: 2-317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval: 84%-96%). In patients with genotype 1a infection, SVR12 rate was significantly lower in those with METAVIR F3-F4 (71%), compared to those with F0-F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4 and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA level (83%). Treatment was very well tolerated with mild degrees of AEs, except 1 death possibly due to drug-induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. Conclusion: An all-oral interferon-free antiviral regimen using SMV and SOF with/without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. This article is protected by copyright. All rights reserved.

Concepts: Virus, Cirrhosis, Interferon, Organ transplant, Hepatitis C, Hepatitis B, Hepatitis C virus, Copyright

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The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) co-infection.

Concepts: Microbiology, Cirrhosis, Liver, Alanine transaminase, Bilirubin, Hepatitis C, Hepatitis A, Hepatitis C virus

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In clinical practice, establishing a subsequent optimum treatment for chronic hepatitis B patients with a history of multiple NAs treatment failures, including a suboptimal response to a final therapy with combined ETV and ADV, is a complicated but crucial challenge. This study investigated the efficacy and safety of a tenofovir rescue regimen in these patients. A total of six eligible patients were enrolled and were switched to a tenofovir rescue regimen. At baseline, the genotypes and genotypic mutations of the reverse transcriptase and surface gene were determined by ultra-deep pyrosequencing, and further clonal analyses of the reverse transcriptase domain were performed to identify multidrug-resistant HBV strains. In addition, HBV DNA levels, serology, and biochemistry parameters were monitored at baseline and every 3 months, and abdominal ultrasonography was performed at baseline and every 6 months. All patients were confirmed to harbor LAM-related resistant HBV strains. After switching to the tenofovir rescue treatment, all patients had an undetectable level of HBV DNA within 6 months and achieved normalization of the ALT level within 9 months. These virological and biochemical responses persisted until the end of the observation period. None of the patients developed clinical deterioration or any adverse events related to the tenofovir therapy during the median 16.5-month follow-up. In conclusion, the tenofovir rescue regimen can be employed confidently as a highly effective and safe treatment choice following a suboptimal response to ETV plus ADV therapy for a subset of chronic hepatitis B patients with a history of multiple unsuccessful antiviral treatments. J. Med. Virol. 00: 1-9, 2015. © 2015 Wiley Periodicals, Inc.

Concepts: Antiretroviral drug, DNA, Genetics, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B, Hepatitis A

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The objectives of this study were to establish a simple model based on quantitative serum markers of hepatitis B virus (HBV) infection to understand the complex immune response to HBV. Patients samples were obtained from individuals with active HBV infection (alanine transaminase [ALT]-positive, aspartate aminotransferase [AST]-positive and HBsAg-positive), or patients who had recovered from infection (ALT-negative, AST-negative, anti-HBs-positive and either HBsAg, HBeAg, anti-HBe or anti-HBc positive). HBV quantitative markers, including HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc, were measured using a chemiluminescent microparticle immunoassay. Based on cut-off values, anti-HBs levels were converted to a ratio (sample value/cut-off value, RV). Anti-HBe and anti-HBc levels were determined using a competition method, resulting in the use of a ratio (cut-off value/sample value, RV) for determination of anti-HBe and anti-HBc values. The greater RV value in a patient was considered as a trait marker for HBV infection (TMHB) of this patient. Patients with TMHB including HBsAg or HBeAg were defined as TMHB-Ag; and patients with TMHB including anti-HBs, anti-HBe, or anti-HBc TMHB were defined as TMHB-Ab. The percentage of patients determined to be TMHB-Ag was 96.3% in the HBV group. The percentage of patients determined to be TMHB-Ab was 94.7% in recovery group. TMHBs could be used to analyze different status of HBV infection. J. Med. Virol. © 2015 Wiley Periodicals, Inc.

Concepts: Cirrhosis, Hepatitis, Sociology, Aspartate transaminase, Alanine transaminase, Hepatitis B, Hepatitis B virus, Hepadnaviridae