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Abstract The natural stages of chronic hepatitis B can be divided into four stages according to changes in virology, biochemistry, and pathology. However, there have been significant differences in the recommended stage criteria in the several major guidelines for chronic hepatitis B, especially regarding the immune tolerance phase. Inconsistent standards of indicators for different stages resulted in some problems, such as incorrect stage, uncertain stages and poor comparation of related studies. We propose suggestions for revisions to the stage criteria for CHB based on recent researches, including three stages: immune tolerance stage, immune clearance stage, and immune control stage. These revision suggestions rationalize some of the existing problems with the stage criteria for CHB and can significantly reduce the number of patients in the “uncertain stage” or “gray zone,” which is particularly valuable in guiding clinical practice. However, further clinical studies with large samples are needed to confirm these suggestions.

ObjectiveThis study aimed to explore the potential causal relationship between the gut microbiota and/or its metabolites and the progression of chronic hepatitis B (CHB).MethodThe gut microbiota was used as the exposure factor. The training set exposure data were obtained from the China Nucleotide Sequence Archive (CNSA). Genome-wide association study (GWAS) data from Asia were used as the outcome variables. Outcome data for both the training and validation sets were sourced from the GWAS Catalog database. A dual-sample Mendelian randomization approach was used to analyze the causal relationships, with the inverse variance-weighted method serving as the main analytical strategy. Sensitivity analysis was conducted to assess the robustness of Mendelian randomization analysis results.ResultIn the training set database, analysis using the inverse variance-weighted method revealed a positive correlation between Fusobacterium varium and chronic hepatitis B [OR = 1.122, 95% CI (1.016, 1.240), p = 0.022]. Conversely, Veillonella parvula exhibited a negative correlation with chronic hepatitis B [OR = 0.917, 95% CI (0.852, 0.987), p = 0.021]. Sensitivity analysis revealed no evidence of pleiotropy and heterogeneity. No gut microbiota metabolites with a causal effect on chronic hepatitis B were identified. Additionally, no associations between the gut microbiota and the progression of chronic hepatitis B were found in the validation data from the European cohort.ConclusionThis study suggests that F. varium may facilitate the progression of chronic hepatitis B, whereas V. parvula may impede it. No causal relationships between gut microbiota metabolites and chronic hepatitis B were established.

ObjectivesNectins are a new class of cell-adhesion molecules that play an important role in tumorigenesis and disease progression. The aim of this study was to investigate the prognostic and pathogenetic roles of nectins in hepatocellular carcinoma (HCC).MethodsThe expression levels of the nectin family in HCC and their role in prognosis were analyzed by bioinformatics analysis based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma database. The correlations between nectins and immune cells were analyzed using TIMER. The functional enrichment of the nectin-1 coexpression network was evaluated in TCGA cohort, and the expression levels of nectin-1 were detected by immunohistochemistry and Western blot analysis. A Transwell kit was used for cell migration experiments. Cell proliferation was analyzed using Cell Counting Kit-8.ResultsThe expression levels of nectin-1 protein in the cancer tissues of 28 patients with HCC were higher than those in paracancerous tissues. The Kaplan–Meier plotter analysis showed that the high expression of all nectin family numbers was related to the poor prognosis of HCC patients. The abnormal expression of nectin-1 effectively distinguished the prognosis at different stages and grades of HCC. The high expression of 17 methylation sites of the nectin-1 gene was related to the high overall survival of HCC patients. Kyoto Encyclopedia of Genes and Genomes analysis of genes negatively correlated with nectin-1, revealing their close relation to the regulation of the immune-effector process. Pearson’s correlation analysis showed that nectin-1 was significantly positively correlated with multiple immune genes and B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cell infiltration. Cell proliferation of the knockdown (KD) group decreased significantly compared to the NC-KD group. The number of metastatic cells in the KD group decreased significantly compared to that in the NC-KD group.ConclusionsAbnormal expression of nectins and multiple methylation sites closely correlates with poor prognosis in HCC patients. Nectins are related to immune cell infiltration and immune-related genes. In particular, nectin-1 can promote the proliferation and migration of liver cancer cells and distinguish the prognosis at different stages and grades of HCC. Nectin-1 might be a new potential molecular marker for prognostic evaluation and also a therapeutic target for HCC.