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ObjectiveTo screen and modify more accurate clinical and viral indicators for differentiating the different stages of chronic hepatitis B virus (HBV) infection based on liver histopathological changes.MethodsThe clinical and liver pathology data of chronic hepatitis B (CHB) patients undergoing liver biopsy were collected for retrospective analysis. The area under the curve (AUC) of the receiver operating characteristic (ROC) was used to evaluate the diagnostic value for differentiating the different stages of chronic HBV infection.ResultsA total of 118 patients who met the diagnostic and exclusion criteria were selected. There were significant differences among HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, HBcAb, and platelets (PLT) between the IT and IC stages. Platelets were significantly higher in patients with the IT stage of CHB than in patients with the IC stage, whereas HBcAb levels were directly reversed. Multivariate analysis showed that HBeAg independently correlated with the IT and IC stages. Univariate analysis showed that HBV DNA and HBsAg were quantified between the ICO and IR stages except for ALT. The cutoff value of HBeAg used to quantitatively differentiate between IT and IC was 1335 and the AUC was 0.921 (95% confidence interval (CI): 0.836 to 0.971).ConclusionsThe high levels of HBeAg rather than HBeAg positive might help to identify patients with the “true” IT stage. PLT and HBcAb are effective indicators for differentiating patients between the IT and IC stages of chronic HBV infection. HBV DNA of

Epithelial cell transformation (EMT) plays an important role in the pathogenesis and metastasis of hepatocellular carcinoma (HCC). We aimed to establish a genetic risk model to evaluate HCC prognosis based on the expression levels of EMT-related genes. The data of HCC patients were collected from TCGA and ICGC databases. Gene expression differential analysis, univariate analysis, and lasso combined with stepwise Cox regression were used to construct the prognostic model. Kaplan–Meier curve, receiver operating characteristic (ROC) curve, calibration analysis, Harrell’s concordance index (C-index), and decision curve analysis (DCA) were used to evaluate the predictive ability of the risk model or nomogram. GO and KEGG were used to analyze differently expressed EMT genes, or genes that directly or indirectly interact with the risk-associated genes. A 10-gene signature, including TSC2, ACTA2, SLC2A1, PGF, MYCN, PIK3R1, EOMES, BDNF, ZNF746, and TFDP3, was identified. Kaplan–Meier survival analysis showed a significant prognostic difference between high- and low-risk groups of patients. ROC curve analysis showed that the risk score model could effectively predict the 1-, 3-, and 5-year overall survival rates of patients with HCC. The nomogram showed a stronger predictive effect than clinical indicators. C-index, DCA, and calibration analysis demonstrated that the risk score and nomogram had high accuracy. The single sample gene set enrichment analysis results confirmed significant differences in the types of infiltrating immune cells between patients in the high- and low-risk groups. This study established a new prediction model of risk gene signature for predicting prognosis in patients with HCC, and provides a new molecular tool for the clinical evaluation of HCC prognosis.

Objective: This study aimed to investigate the role of microRNA (miRNA)-4804-3p in liver injury during chronic hepatitis B virus(HBV) infection through inhibit chemerin/chemokine-like receptor 1(CMKLR1) mediated NF-κB signal pathway. Methods: miRNA-4804-3p, CMKLR1, extracellular signal regulated kinase (ERK), and nuclear factor kappa B (NF-κB) mRNA expression were detected by qPCR, western blot or immunohistochemistry (IHC). A mouse model of liver injury induced by concanavalin A was established and used for experiments in vivo. Results: Pearson correlation analysis showed a significantly negative correlation between the expression level of miRNA-4804-3p and CMKLR1 in PBMCs of patients with CHB. The miRNA-4804-3p was significantly negatively correlated with the level of alanine transaminase in patients with CHB. Previous our study have showed that the cytokine secretion of human monocyte lines could be inhibited by miRNA-4804-3p. The level of CMKLR1 gene, phosphorylated ERK (p-ERK) and NF-κB protein in cells transfected with miRNA-4804-3p mimics was significantly decreased compared with that of the negative control group. The levels of IL-2, IL-10, TNF-α and IFN-γ in cell culture supernatant were no significant difference between miRNA-4804-3p mimics+CMKLR1 knocdown group and negative control group. The level of AST after injection with agomiRNA-4804-3p significantly decreased compared with that of pre-injection. The amount of inflammation in liver tissue of mice injected with agomiRNA-4804-3p was significantly lower compared with that of the negative control group, but the amount of fibrosis had no significant alteration. Conclusions: miRNA-4804-3p may inhibit chemerin/CMKLR1–mediated NF-κB signal pathway and be involved in regulating liver inflammatory injury in CHB. This study might not only provide a new explanation for the pathogenesis of CHB, but also provide new potential molecular markers for the prevention and treatment of CHB.

Background: Portal vein thrombosis (PVT) is a relatively common complication of cirrhosis. However, the effect of PVT on the prognosis might not be unequivocal. A systematic review and meta-analysis were performed to investigate the effect of PVT on the prognosis of patients with cirrhosis who have not received a liver transplant. Methods: Three databases, including PubMed, EMBASE, and Cochrane Library, were searched for studies published up to March 2020. The survival or mortality rate of patients with PVT served as the main index to evaluate the prognosis of these patients. Hepatic decompensation served as the index of disease progression. Meta-analyses were conducted using Review Manager software 5.2. Results: Sixteen clinical studies were included and analyzed. PVT was associated with an increased risk of mortality in patients with decompensated cirrhosis. According to the meta-analysis, patients with cirrhosis presenting with PVT had a lower 1-year survival rate than patients without PVT (odds ratio (OR), 0.32; 95% confidence interval (CI), 0.14–0.75; P = .008). The cumulative survival rates were similar between the 2 groups at 3 years (OR, 1.04; 95% CI, 1.00–1.08; P = .06), 5 years (OR, 1.33; 95% CI, 0.71–2.48; P = .38) and 10 years (OR, 1.24; 95% CI, 0.79–1.93; P = .35). PVT was associated with a higher mortality rate in patients with Child-Pugh class B and C disease. A significantly increased risk of death was observed in patients with complete PVT. Patients with both PVT and cirrhosis had a higher rate of decompensation than patients without PVT. Conclusions: The presence of PVT might exert a slight effect on the overall prognosis of patients with cirrhosis. PVT might mainly affect the short-term prognosis by increasing hepatic decompensation events in patients with cirrhosis. However, PVT might not influence the long-term prognosis of patients with cirrhosis.

Aim Many studies have shown that some microRNAs (miRNAs) play an important role in the pathogenesis of chronic hepatitis B (CHB) infection. In this study, we aimed to explore the role and molecular mechanism of miRNA-548ah in the replication and expression of the hepatitis B virus (HBV). Main methods Overexpression and knockdown of miRNA-548ah were performed in three hepatoma cell lines with HBV replication and in a murine HBV model injected with adenovirus HBV vector. The effect of miRNA-548ah on its target gene, histone deacetylase (HDAC) 4, were confirmed in in vitro studies and further investigated in liver tissues from CHB patients. Key findings miRNA-548ah significantly increased the expression of HBV in hepatoma cell lines and in a HBV mouse model. The expression level of covalently closed circular DNA (cccDNA) in the miRNA-548ah mimics group was significantly higher than the negative control group and significantly lower in the miRNA-548ah inhibitor group. The HBV core antigen promotes the expression of miRNA-548ah in hepatocytes. Finally, we observed a negative correlation between the expression of miRNA-548ah and HDAC4 in the liver tissue of patients with CHB. Significance miRNA-548ah promoted the replication and expression of HBV through the regulation of the target gene, HDAC4. Inhibition of HDAC4 by miRNA-548ah might influence the deacetylation state of histones binding to cccDNA, thereby enhancing the replication of cccDNA. The HBV core antigen might increase the expression of miRNA-548ah. These results may provide new potential molecular targets for the prevention and treatment of CHB.

Background HBeAg seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B (CHB) patients. This study aimed to compare the effect of nucleos(t)ide analogs (NAs) on HBeAg seroconversion in treating CHB with lamivudine, adefovir, telbivudine, entecavir, and tenofovir. Methods Network meta-analysis of NA treatment-induced HBeAg seroconversion after 1-2 years of treatment was performed. In addition, NA treatment-induced HBeAg seroconversion after 3-5 years of treatment was systematically evaluated. Results A total of 31 articles were included in this study. Nine and five studies respectively reporting on 1- and 2-year treatment were included in our network meta-analysis. In addition, 6, 5, and 5 studies, respectively reporting on 3-, 4-, and 5-year treatment were included in our systematic evaluation. Telbivudine showed a significantly higher HBeAg seroconversion rate after a 1 year treatment period compared to the other NAs (odds ratio (OR) = 3.99, 95% CI 0.68-23.6). This was followed by tenofovir (OR = 3.36, 95% CI 0.70-16.75). Telbivudine also showed a higher seroconversion rate compared to the other NAs after a 2 year treatment period, (OR = 1.38, 95% CI 0.92-2.22). This was followed by entecavir (OR = 1.14, 95% CI 0.72-1.72). No significant difference was observed between spontaneous induction and long-term telbivudine treatment-induced HBeAg seroconversion. However, entecavir and tenofovir treatment-induced HBeAg seroconversions were significantly lower than spontaneous seroconversion. Conclusion Long-term treatment with potent anti-HBV drugs, especially tenofovir and entecavir, may reduce HBeAg seroconversion compared with spontaneous HBeAg seroconversion rate. Telbivudine treatment, whether short term or long term, is associated with higher HBeAg seroconversion compared with the other NAs. However, the high rates of drug resistance likely limit the application of telbivudine.

In this study, we investigated the roles of T follicular helper (TFH) cells and related molecules in the pathogenesis of chronic hepatitis B virus (HBV) infection. The levels of circulating TFH cells and their surface CD40 ligand (CD40L), as well as CD19(+) B cells and their surface CD40 expression were detected by flow cytometry. Peripheral blood plasma interleukin (IL)-21 levels were detected by enzyme-linked immunosorbent assay (ELISA). Compared with hepatitis B surface antibody (HBsAb)(-) and HBsAb(+) healthy controls, the percentage of TFH cells and their surface CD40L expression significantly increased in patients with chronic HBV infection, particularly those with chronic hepatitis B (P0.05). The percentage of CD19(+) B cells significantly increased in chronic hepatitis B patients and CD40 expression levels on the CD19(+) B cell surface in chronic HBV infection decreased compared with those in the healthy controls (P0.05). Compared with the healthy controls, the plasma IL-21 level in chronic hepatitis B patients was significantly increased in chronic HBV carriers and decreased in inactive hepatitis B surface antigen (HBsAg) carriers (P0.05). The TFH cell percentage, B cell percentage and IL-21 expression did not significantly differ between the hepatitis B e-antigen (HBeAg)(-) and HBeAg(+) chronic hepatitis B groups (P0.05). The abnormal expression of TFH cells and IL-21 is related to the dysfunction of immune response during chronic HBV infection. The interaction of CD19(+) B cells with TFH cells via their CD40 and CD40L molecules may also play an important role in this process.

Objective: To study the expression profile and clinical significance of microRNAs (miRNAs) at different stages of chronic hepatitis B virus (HBV) infection. Methods: The miRNA expression profiles of peripheral blood mononuclear cells (PBMCs) at different stages of chronic HBV infection were screened using miRNA microarray and validated using real-time quantitative polymerase chain reaction (qPCR). Results: Significant differences in miRNA expression profiles of PBMCs were observed between patients in IA and IT phases of CHB. Expression was significantly down-regulated in the former but up-regulated in the latter group. No significant differences in inactive hepatitis B surface antigen carriers were observed. Changes in expression of six miRNAs determined by real-time qPCR were consistent with those determined by microarray. Areas under the receiver operation characteristic curve of the six miRNAs distinguishing immune tolerance and clearance of chronic HBV infection were 99.4%, 98.4%, 96.7%, 100%, 100%, and 99.6%. Positive correlation was found between the levels of hsa- miR-146a and ALT (r = 0.56, P < 0.01) while negative correlation was found between the levels of hsa-miR-548ah-5p and HBV DNA (r = -0.73, P < 0.01). Conclusions: Abnormal expression of miRNAs and the resulting gradual decline in the various immune states of patients with chronic HBV infection may play important roles in maintenance of the immune homeostatic mechanisms of chronic HBV infection. Hsa-miR-548ah-5p, hsa-miR-3191-5p and hsa-miR-4711-3p can be used as potential molecular markers to distinguish among different stages of chronic HBV infection.

To explore the effect of IFN-gamma and TNF-alpha on hepatitis B virus posttranscriptional regulatory elements.The objective eukaryotic expression vectors were constructed by molecular cloning and PCR-based site-directed mutagensis in vitro, and identification was performed using PCR and sequencing analysis. CAT assays were performed by using ELISA kit.The eukaryotic expression vectors containing HPRE segment and mutating point were constructed successfully as confirmed by sequencing analysis. The normalized CAT activity from recombinant pDM138 and control produced in transfected cells incubated in the absence of cytokine were 896 +/- 214 and 37 +/- 11 pg/ml, respectively. After incubation with IFN-gamma, TNF-alpha and IFN-gamma + TNF-alpha, the normalized CAT activity from recombinant pDM138 produced in transfected cells were 324 +/- 57, 396 +/- 82 and 175 +/- 36 pg/ml, respectively (t = 5.19,4.39, 6.68, P0.01). The effect of IFN-gamma and TNF-alpha were dose dependent over a range of 0 to 1,000 U/ml.The expression of HBV gene may be regulated by IFN-gamma and TNF-alpha through inhibiting the function of HPRE.