Tongjing Xing

To identify clinical and viral indicators for the development of a new model to accurately differentiate the stages of chronic hepatitis B virus (HBV) infection based on histopathological changes in the liver. Clinical and liver pathology data from chronic hepatitis B (CHB) patients who underwent liver biopsy were retrospectively collected. The patients were allocated into test and validation groups. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated to idneitfy the optimal diagnostic value for differentiating the stages of chronic HBV infection. A total of 118 patients and 73 patients who met the diagnostic and inclusion criteria were selected as the test group and validation group, respectively. Multivariate analysis revealed that HBeAg was independently correlated with the IT and IC stages. The cutoff value of HBeAg used to quantitatively differentiate between IT and IC was 1335 S/CO. The AUC values were 0.921 (95% confidence interval (CI): 0.836–0.971) and 0.846 (95% CI: 0.726–0.967) in the test and validation groups, respectively. A new prediction model of the IT stage was established by using three indicators, namely, HBeAg, HBsAg and HBV DNA. The AUC values were 0.923 (95% CI: 0.864–0.982, p < 0.001) and 0.89 (95% CI: 0.787–0.994, p < 0.01) in the test and validation groups, respectively, when this prediction model was used. For the new model, CMA guidelines (2019 version), EASL guidelines (2017 version) and AASLD guidelines (2018 version), the error rates in the test group were 4.65%, 11.62%, 23.26%, and 46.51%, respectively, while the errors rates in the validation group were 20.0%, 25.0%, 40.0%, and 45.0%, respectively. High levels of HBeAg, rather than HBeAg positivity, may serve as a predictor of the IT stage. A predictive model for the immune tolerance stage was established by combining three indicators. Compared with the recommended standards from multiple current guidelines, the new prediction model has a significantly lower error rate.

Corrigendum: High expression of nectin-1 indicates a poor prognosis and promotes metastasis in hepatocellular carcinoma

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.

Objectives: Nectins 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).Methods: The 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.Results: The 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.Conclusions: Abnormal 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.

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.

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.

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. 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. 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. 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.

Liver failure (LF) is a clinical syndrome with complex clinical manifestations. The clinical diagnosis and classification of LF are still considerably different internationally. Based on the pace of the disease progression and its possible reversibility, LF can be divided into two categories: acute and chronic LF. However, a great difference exists in the diagnostic criteria between China, Europe, and the United States. These differences might be related to the various causes of LF, the complexity of clinical manifestations, and different experiences of experts from different centers. The main source of differences lies in the varied understanding of LF diagnostic standards. The pathologic basis of various types of LF is different also. This article discusses the clinical diagnosis and classification of LF internationally and suggests new recommendations for classification of LF. According to this classification, ALF is divided into fulminant type and subacute type, and CLF is divided into acute exacerbative type and slowly progressive type. This classification, if adopted worldwide, could help achieve uniformity in the classification and therapeutic guidelines for liver failure. However, the validity of the classification should be further tested in clinical practice.

To study the expression profile and clinical significance of microRNAs (miRNAs) at different stages of chronic hepatitis B virus (HBV) infection. 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). 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). 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.

Aims: Clinical diagnosis and classification of liver failure (LF) vary in different parts of the world. In this study, novel methods of the clinical classification of hepatitis B virus (HBV)-related LF were investigated. Methods: Clinical data from 153 HBV-related LF patients were analyzed by a retrospective study. Clinical classifications of LF were assigned according to the new proposal. Results: Among the 153 HBV-related LF patients, 20 (13.1%) were fulminant type, 53 (34.6%) were sub-acute type, 39 (25.5%) were acute exacerbative type, and 41 (26.7%) were slow progressive type. TBil, ALB, and PT levels were significantly different among the different types of patients with LF. Death or invalidity rate was significantly higher in acute exacerbative and fulminant type patients than in sub-acute type and slow progressive type patients. Conclusion: The proposed clinical classification of LF based on the complications of hepatic encephalopathy and/or HRS is simple and practical. This scheme may help establish uniformity in diagnostic and classified criteria of LF worldwide.