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Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A β loop and a C-terminal membrane–anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3′ terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site.

BackgroundAlthough balloon-occluded retrograde transvenous obliteration (BRTO) is often selected to treat gastric varices caused by portal hypertension, data comparing BRTO and splenectomy with gastric devascularization (Sp + Dev) are limited.MethodsFrom January 2009 to February 2018, 100 patients with gastric varices caused by portal hypertension who underwent Sp + Dev (n = 45) or BRTO (n = 55) were included. Overall survival (OS) and the rebleeding rate were calculated using the inverse probability of a treatment weighting-adjusted log-rank test. Independent risk factors were identified by Cox regression analysis. Changes in liver function and adverse events after the procedures were analyzed.ResultsPatients in the Sp + Dev group tended to have lower platelet counts than those in the BRTO group, but liver function did not differ between these groups. The 5-year OS rates for the Sp + Dev and BRTO groups were 73.4 and 50.0% (p = 0.005), respectively. There were no significant differences in rebleeding rates between the two groups. Multivariate analysis showed that serum albumin level ≤3.6 g/dL, prothrombin time% activity (PT%) ≤80%, and serum creatinine level ≥0.84 mg/dL were poor prognostic factors. Although the Sp + Dev group had more short-term complications after procedures, Sp + Dev tended to be more effective in improving liver function than BRTO.ConclusionsSp + Dev showed better OS and improvement of liver function compared with BRTO for the treatment of gastric varices caused by portal hypertension.

Purpose Previous reports suggest that contrast-enhanced ultrasonography (CEUS) is useful for predicting the efficacy of sorafenib and lenvatinib treatment. However, there are no reports on the utility of CEUS for predicting the efficacy of atezolizumab plus bevacizumab combination therapy (Atezo + Bev). This study aimed to identify CEUS parameters for predicting the efficacy of Atezo + Bev. Methods A total of 30 patients with hepatocellular carcinoma (HCC) treated with Atezo + Bev who underwent CEUS before and 5 weeks after treatment initiation were included. Results Post area under the curve (post AUC) was identified as a predictive factor for early progressive disease (PD). The optimal cut-off value of post AUC for predicting progression-free survival (PFS) was 61.3. Conclusion The results of this study suggest that CEUS at 5 weeks after initiation of Atezo + Bev may predict PFS in HCC patients. Changes to the treatment plan may need to be considered in patients with post AUC > 61.3.

Hepatitis B virus (HBV) particles containing HBV RNA are secreted into the blood; these RNA-containing particles are non-infectious byproducts of the replication cycle and are distinct from mature, DNA-containing virions. The proportion of these particles increases during nucleoside/nucleotide analog therapy, but the clinical significance of serum HBV RNA remains unclear. We evaluated longitudinal changes in serum HBV RNA and their association with the antiviral efficacy of nucleoside/nucleotide analog therapy. Eighty-six patients with chronic HBV infection (baseline HBV DNA ≥ 5.0 Log IU/mL and ALT < 500 U/L) treated with entecavir (ETV, N = 80) or tenofovir alafenamide (TAF, N = 6) were included. Serum HBV RNA was quantified using Cobas HBV RNA (RUO) at baseline, week 12, and week 48. Associations with clinical variables and treatment response were analyzed. Baseline HBV RNA correlated with HBsAg, HBV DNA, and hepatitis B core-related antigen. Both HBV DNA and RNA tended to decrease with advanced liver fibrosis. HBV DNA and RNA declines did not differ between HBeAg-positive and -negative patients, but the HBV RNA/DNA ratio at week 48 was significantly higher in HBeAg-positive cases (p < 0.001). Patients with baseline ALT ≥ 100 U/L showed significantly lower RNA levels at weeks 12 and 48 (p = 0.004, p < 0.001). While HBV DNA decline was similar between ETV and TAF (p = 0.076), RNA decline was significantly greater with TAF at week 12 (p = 0.027). Serum HBV RNA reflects intrahepatic viral replication and may not be influenced by fibrosis progression. HBV RNA decline during nucleoside/nucleotide analog therapy differed between ETV and TAF, suggesting drug-specific effects on viral RNA dynamics.

BackgroundThis study investigated time-course changes in skeletal muscle volume per year with tolvaptan in patients with refractory ascites that was unresponsive to loop diuretics and aldosterone antagonists.MethodsThis retrospective study included 42 patients who received tolvaptan for refractory ascites and/or hepatic edema and underwent computed tomography (CT) before and ≥ 3 months after initiating tolvaptan. The time-course changes in skeletal muscle index per year [ΔSMI (%)] was calculated as follows: ΔSMI (%) = (SMI at final CT scan − SMI at initial CT scan)/SMI at initial CT scan × 100/years between CT scans.ResultsEligible patients were 23 men and 19 women of median age of 71 years (range 21–94 years). The median follow-up period was 22.7 (range 3.5–54.6) months. ΔSMI (%) was significantly higher in the responders group than in the nonresponder group. Multivariate analysis showed the response to tolvaptan was an independent and significant factor associated with an increase in muscle mass [odds ratio (OR) 20.364; 95% CI 2.327–178.97; P = 0.006]. Overall survival with tolvaptan was significantly higher in the responder group than in the nonresponder group. Multivariate analysis showed that the response to tolvaptan treatment was a significant contributor to good prognosis (OR 3.884; 95% CI 1.264–11.931; P = 0.018). A significant negative correlation was observed between the dosage of furosemide and ΔSMI (%) (P = 0.014).ConclusionsTreatment of refractory ascites with tolvaptan may attenuate the progression of sarcopenia and improve the prognosis in patients with decompensated cirrhosis.

Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAF mean ) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAF mean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

This study investigated whether the progression of liver fibrosis affects the prevalence of sarcopenia and incidence of decreased gait speed in older patients with chronic liver disease (CLD). Patients with CLD aged ≥ 60 years were classified into low, intermediate, and high fibrosis 4 (FIB-4) index groups according to the degree of liver fibrosis. The prevalence of sarcopenia and incidence of decreased gait speed (< 1.0 m/s) were compared among the three groups. Logistic regression analysis was performed to investigate factors affecting the risk of decreased gait speed. No significant difference was observed in the prevalence of sarcopenia among the three groups, but the incidence of decreased gait speed significantly differed ( p  = 0.029). When analyzed individually, a significant difference in decreased gait speed incidence was observed between the high and low FIB-4 index groups ( p  = 0.014). In logistic regression analysis, the progression of liver fibrosis (odds ratio: 1.32, 95% confidence interval: 1.13–1.55) and lower extremity muscle strength (LEMS) (odds ratio: 0.92, 95% confidence interval: 0.88–0.97) were significantly associated with decreased gait speed. As liver fibrosis progresses in older patients with CLD, it becomes important to focus on not only skeletal muscle mass and grip strength, but also gait speed and LEMS.

Background/Objectives: Hepatitis B virus (HBV) infection is a worldwide health problem responsible for chronic liver disease and hepatocellular carcinoma. Both innate immunity and the adaptive immune response play central roles in the development of chronic hepatitis and liver cancer. We previously performed a comprehensive analysis of gene expression in the livers of HBV-infected chimeric mice and found that several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were upregulated by HBV infection. However, due to the absence of adaptive immunity in uPA/SCID chimeric mice, we were unable to analyze the effect of the host immune response. Methods: In this study, we compared gene expression profiles in the livers obtained from HBV-infected chimeric mice with those of HBV carriers. Results: After HBV infection, the expression of genes associated with inflammation and immune response, especially involving the Th1 and Th2 activation pathways, was altered as HBV-specific intracellular immune responses both in vivo and in clinical samples. Interestingly, the proinflammatory gene IL12A was induced by HBV infection in the chimeric mouse livers but not in the human livers, and associated genes, such as SRDA5A2, AR, and CCR3, showed differential alteration by HBV infection between the chimeric mouse and human livers. Conclusions: These results suggest that hepatocarcinogenesis may be suppressed by host immunity in HBV carriers. This study highlights potential new implications for inhibiting the progression of HBV-related liver diseases, including hepatocarcinogenesis.

Cross-sectional analyses using liver tissue from chronic hepatitis B patients make it difficult to exclude the influence of host immune responses. In this study, we performed next-generation sequencing using the livers of hepatitis B virus (HBV)-infected uPA/SCID mice with humanized livers before and after antiviral therapy (AVT) with entecavir and pegylated interferon, and then performed a comparative transcriptome analysis of gene expression alteration. After HBV infection, the expression of genes involved in multiple pathways was significantly altered in the HBV-infected livers. After AVT, the levels of 37 out of 89 genes downregulated by HBV infection were restored, and 54 of 157 genes upregulated by HBV infection were suppressed. Interestingly, genes associated with hypoxia and KRAS signaling were included among the 54 genes upregulated by HBV infection and downregulated by AVT. Several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were significantly downregulated by AVT, with a potential application for the suppression of hepato-carcinogenesis.

Background Portal hypertensive enteropathy (PHE) is a small-bowel lesion observed in patients with portal hypertension. The clinical significance of endoscopic findings in PHE remains unclear. We aimed to clarify the clinical significance and predictive factors of capsule endoscopic findings in patients with PHE based on long-term outcomes. Methods This retrospective study enrolled 55 patients with PHE (33 males and 22 females; median age, 64 years; range, 23–87) followed for > 3 years using capsule endoscopy (CE) between February 2009 and May 2023. We evaluated the clinical factors affecting PHE exacerbations and the effects of PHE exacerbations on gastrointestinal bleeding by comparing exacerbated and unchanged PHE groups. Results Overall, 3 (5%) patients showed improvement, 33 (60%) remained unchanged, and 19 (35%) showed exacerbation on follow-up CE. In the exacerbated group, the rates of worsened fibrosis-4 index, exacerbated esophageal varices, and exacerbated portal hypertensive gastropathy were significantly higher than those in the unchanged group (21%, 32%, and 42% vs. 3%, 6%, and 12%, respectively; P  < 0.05), and the rate of splenectomy was significantly lower in the exacerbated group than in the unchanged group (5% vs. 39%, respectively; P  < 0.01). In multivariate analysis, exacerbation of esophageal varices and absence of splenectomy were significantly associated with PHE exacerbation. The rate of gastrointestinal bleeding after follow-up CE was significantly high in the exacerbated group (log-rank, P  = 0.037). Conclusions Exacerbation of esophageal varices and splenectomy were significantly associated with exacerbation of PHE. Exacerbated PHE requires specific attention to prevent gastrointestinal bleeding.