Staging and clinical characteristics of pregnant women with chronic hepatitis B virus infection: A retrospective cohort study from Nanjing, China.

AIM: To investigate the immune status of Chinese chronic hepatitis B (CHB) pregnant women and their clinical characteristics. METHODS: About 1544 CHB pregnant women without antiviral therapy from 2013 to 2018 were selected from the hospital records. The definition of immune status is based on American Association for the Study of Liver Diseases (AASLD) 2018 Hepatitis B Guidance, and those who did not meet any criteria of the immune status were referred to in the gray zones (GZ). RESULTS: There were 284 patients in the immune-tolerance phase, 72 patients in the HBeAg-positive immune active phase, 553 patients in the inactive phase, 61 patients in the HBeAg-negative immune active phase. Of note, 574 (37.18%) patients did not fit into any of the above phases were defined as the GZ. Patients with elevated ALT had a higher rate of intrahepatic cholestasis of pregnancy (ICP). Mother to child HBV transmission was rare (only two cases) and occurred in mothers in the immune-tolerant phase. CONCLUSIONS: Our data showed that more than one-third of CHB pregnant women were classified into the GZ. In standard stages, advanced age is associated with HBeAg-negative and a higher cesarean rate in the inactive phase. The incidence of ICP was higher in immune active phases, including GB and GD. The probability of mother-to-child transmission in gray zones is low.

The relationship of maternal hepatitis B e antigen and response to vaccination of infants born to women with chronic infection.

BACKGROUND: The relationship of maternal HBeAg and infants' response to hepatitis B vaccine remains controversial. This study aims to observe the dynamic changes in infant birth HBV markers and study the time-varying effects of maternal HBeAg on vaccination response of infants born to women with chronic HBV infection. METHODS: 3163 infants born to HBsAg positive mothers including 1737 with maternal HBeAg positive in group A and 1426 negative in group B were enrolled eventually. Demographic information and laboratory tests were collected at birth, 7-12th and 24th month. The dynamic changes of infant HBV markers and HBsAb titers at different time points were compared between the two groups. RESULTS: The infant HBV markers at birth displayed different modes. During the follow-up, we observed a significant downward trend in the positive rates of HBsAg, HBeAg, HBeAb and HBcAb. The HBsAg of two groups switched to negative at 7-12 months and HBeAg in Group A became negative at 24 months. The HBsAb titers of the infants in the two groups were 576.91(192.8-1000.0) vs 719.67(208.1-1000.0) at 7-12 months (Z = -3.049, P = 0.002) and 783.5(227.8-1000.0) vs 891.4(234.0-1000.0) at 24 months (Z = -0.853, P = 0.394). High HBV DNA viral load (OR 1.260, 95% CI 1.139-1.395, P < 0.001) and maternal HBeAg level (OR 1.003, 95% CI 1.002-1.003, P < 0.001) were associated with the higher HBeAg positive rate of infants. CONCLUSIONS: Maternal HBeAg did affect the infants' immune response to vaccination and reduce the anti-response at 7-12th month temporarily, but these influences were negligible by 24th months after birth, which proved that the maternal HBeAg would not induce immune tolerance of infants from a long-term perspective.

Efficacy and Long-term Safety of Telbivudine Usage During Second or Third Trimester in Hepatitis B Surface Antigen Positive Mothers With High Viral Load: A 10-year Prospective Study.

GOALS: The study is to evaluate the efficacy and long-term safety of telbivudine (LdT) usage for hepatitis B surface antigen (HBsAg) positive pregnant women with high viral load. BACKGROUND: The efficacy and safety of LdT during pregnancy were not assessed from a long-term perspective. STUDY: HBsAg-positive pregnant women were enrolled and grouped according to antiviral initiation time. Group A (n=100) and group B (n=100) were treated with LdT initiated in the second or third trimester. Group C (n=90) received no antiviral treatment. The efficacy and safety of LdT treatment were compared and infants were followed-up at 1, 5, and 10 years. Denver developmental screening test was conducted at 5 years. RESULTS: Viral loads before delivery in LdT-treated groups were lower than that in group C and group A was lower than that in group B ( P <0.001). No infants in LdT-treated groups were infected whereas 8.8% (8/90) infants in group C had positive HBsAg (χ 2 =23.20, P <0.001). All LdT-treated mothers were well tolerated and no LdT-related adverse events in infants were reported. Part of the physical growth index of infants was higher than Chinese standard values (SV) and showed significant differences. In groups A and B, the developmental screening test qualified rate of 100% (48/48) and 97.96% (48/49) showed no significant difference compared with 92% in normal Chinese children (χ 2 =5.72, P =0.06). CONCLUSIONS: Treatment initiated during the second trimester could strengthen the success of mother-to-child transmission blockage. LdT treatment during pregnancy is safe for both mothers and infants in the long term.

ECRG4 acts as a tumor suppressor in nasopharyngeal carcinoma by suppressing the AKT/GSK3ß/ß-catenin signaling pathway.

Nasopharyngeal carcinoma (NPC) is a malignant tumor with a poor prognosis. Studies have shown that esophageal carcinoma related gene 4 (ECRG4) is hypermethylated and significantly downregulated in NPC tissues. However, the role of ECRG4 in NPC, and in particular the underlying molecular mechanism, is largely unclear. In this study, using immunohistochemical staining of ECRG4 in NPC and normal specimens, we confirmed that ECRG4 was downregulated in human NPC tissues. In addition, various biological and molecular studies were carried out and the results showed that ECRG4 exerted anticancer effect in NPC, including inhibiting cell growth, migration, and invasion of NPC cells in vitro. Moreover, restoring ECRG4 expression suppressed the in vivo tumorigenesis of CNE2 cells. ECRG4 inhibited AKT/GSK3ß/ß-catenin signaling, as well as the downstream targets of ß-catenin. LiCl treatment, which reduced GSK3ß phosphorylation and upregulated ß-catenin expression, restored the invasive ability of ECRG4-overexpressing NPC cells. Furthermore, we showed that the DNA methylation inhibitor 5-aza-dC reduced ECRG4 methylation and the invasive ability of negative control cells, but not that of ECRG4-overexpressing cells, suggesting that the inhibitory effect of 5-aza-dC depends on low expression of ECRG4. Collectively, our results demonstrated that ECRG4 downregulation contributed to NPC growth and invasion by activating AKT/GSK3ß/ß-catenin signaling pathway. ECRG4 could be a promising therapeutic target for the treatment of NPC. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-022-00520-8.

The EZH2- H3K27me3-DNMT1 complex orchestrates epigenetic silencing of the wwc1 gene, a Hippo/YAP pathway upstream effector, in breast cancer epithelial cells.

It is well known that epithelial-mesenchymal transition (EMT) can confer cancer cells with invasive and migratory capabilities associated with distant metastasis. As a key upstream factor in the Hippo pathway, Kibra (wwc1 gene) has been shown to suppress EMT in breast cancer cells, and we have found that its expression is reduced or lost completely in both human breast cancer cell lines and clinical tissue samples, particularly in triple negative breast cancer (TNBC). Unfortunately, the molecular mechanisms underlying this progression-associated event remain to be elucidated. Epigenetic gene silencing is one of the most common causes of suppressed expression of tumor suppressor genes. Furthermore, recent studies have demonstrated that EZH2 can recruit DNA methyltransferases, resulting in DNA methylation and subsequent gene silencing in certain circumstances. Thus, we hypothesized that there may exist a link between EZH2 and DNA methylation in association with wwc1 silencing in breast cancer. To test this hypothesis, we performed bisulfite sequencing, shRNA, co-IP, ChIP, MeDIP and ChIP-qPCR. As expected, RG108 or 5-Aza treatment improved the wwc1 gene transcription and Kibra protein expression. Both bisulfite sequencing and MeDIP demonstrated higher CpG methylation of the wwc1 promoter the TNBC cells (MDA-MB-231) than in luminal breast cancer cells (MCF7). It is noteworthy that ChIP and co-IP assays showed that EZH2, H3K27me3 and DNMT1 are enriched at the wwc1 promoter, and there exist physiologically relevant protein-protein interactions between them. We also found that EZH2 knockdown leads to a partial increase in Kibra expression and a considerable reduction in H3K27 and DNMT1 trimethylation. Moreover, ChIP-qPCR revealed more DNA fragments containing the wwc1 promoter in MDA-MB-231 than in MCF7 cells after immunoprecipitation with EZH2, DNMT1 and H3K27me3 antibodies. Collectively, our results reveal crosstalk between H3K27me3 inhibition catalyzed by EZH2 and CpG island methylation mediated by DNMT1 within the wwc1 promoter, which synergistically silence wwc1 gene expression in TNBC. Based on these results, we conclude that EZH2 shows promise as a potential anti-tumor target.