These results suggest that P.g infection is an important risk factor for pathological progression in NAFLD. Increase in the monounsaturated/saturated fatty acid ratio may be an important change that facilitates progression of NAFLD.
CRISPR-Cas9-mediated genome-editing technology contributes not only to basic genomic studies but also to clinical studies such as genetic correction and virus inactivation. Hepatitis B virus (HBV) is a major target for potential application of CRISPR-Cas9 in eliminating viral DNA from human cells. However, the high stability of covalently closed circular DNA (cccDNA) makes it difficult to completely clear HBV infection. Here, we report highly multiplexed CRISPR-Cas9-nuclease and Cas9-nickase vector systems that simultaneously target three critical domains of the HBV genome. Co-transfection of an HBV-expressing plasmid and all-in-one CRISPR-Cas9 vectors resulted in significant reduction in viral replicative intermediates and extracellular hepatitis B surface and envelope antigens. In addition, successful fragmentation of the HBV genome was confirmed by DNA sequencing. Despite its high efficacy in suppressing HBV, no apparent off-target mutations were detected by genomic cleavage detection assay and the small number of observed mutations was extremely rare and could only be detected by deep sequencing analysis. Thus, our all-in-one CRISPR-Cas9-nuclease and Cas9-nickase vectors present a model for simultaneous targeting of multiple HBV domains, potentially contributing to a well-designed therapeutic approach for curing HBV patients.
Urokinase-type plasminogen activator/severe combined immunodeficiency (uPA/SCID) mice transplanted with human hepatocytes are permissive for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, one of the problems affecting uPA transgenic mice is the expansion of mouse hepatocyte colonies due to homologous recombination of the uPA gene. In this study, we attempted to infect HBV and HCV in humanized cDNA-uPA/SCID mice, a novel uPA transgenic mouse model designed to overcome this disadvantage. Three hundred and eighty-six uPA/SCID and 493 cDNA-uPA/SCID mice were transplanted with human hepatocytes and then injected with either HBV-or HCV-positive human serum samples or HBVtransfected cell culture medium. Twelve weeks after human hepatocyte transplantation, the mouse serum concentration of human albumin, which is correlated with the degree of repopulation by human hepatocytes, was significantly higher in cDNA-uPA/SCID mice compared with uPA/SCID mice. HBV-infected cDNA-uPA/SCID mice showed significantly greater and more persistent viraemia, and similar virological effects by entecavir treatment were achieved in both systems. HCV-infected cDNA-uPA/SCID mice developed more frequent and significantly higher viraemia compared with uPA/SCID mice. The present study using a large number of mice showed that cDNA-uPA/SCID mice transplanted with human hepatocytes developed high and long-term persistent viraemia following HBV and HCV infection, and a higher survival rate was observed in cDNA-uPA/ SCID compared with uPA/SCID mice. These mice may be a useful animal model for the study of HBV and HCV virology and the analysis of the effect of antiviral drugs.
Background: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. Methods: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. Results: Relative dose intensity (RDI) decreased significantly between weeks 1–2 and 3–4 ( p < 0.001), and RDI during weeks 3–4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18–0.96, p = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1–8.3, p = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0–8.3, p = 0.045) had higher risk of shorter PFS. Conclusion: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients.
These results suggest that monthly HBIG injection might benefit patients with chronic hepatitis B whose HBsAg titer becomes lower following long-term nucleotide/nucleoside analogue treatment.
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