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Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21–5 p to inhibit miR-21–5 p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC–EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC–EMT and administration of miR-21–5 p could reverse this process and improve endometrial fibrosis. Our findings revealed that the dysfunction of circPTPN12/miR-21–5 p/∆Np63α pathway contributed to the pathogenesis of endometrial fibrosis.

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5p to inhibit miR-21-5p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT. Our findings reveal the novel mechanism in the pathogenesis of endometrium fibrosis and the potential therapeutic strategy for endometrium fibrosis via targeting circPTPN12/miR-21-5p/ΔNp63α pathway.

Intrauterine adhesions (IUAs), the leading cause of uterine infertility, are characterized by endometrial fibrosis. The management of IUA is challenging because the pathogenesis of the disease largely unknown. In this study, we demonstrate that the mRNA and protein levels of high mobility group AT-hook 2 (HMGA2) were increased by nearly 3-fold (P

Epithelial homeostasis plays an essential role in maintaining endometrial function. But the epithelial role in endometrial fibrosis has been less studied. Previously, we showed that ectopic expression of ΔNp63α is associated with fibrosis process and epithelial dysfunction in endometria of patients with intrauterine adhesions (IUAs). Since ΔNp63α is profoundly involved in maintaining the epithelial homeostasis, we hereby focused on its roles in regulating the function and phenotype of endometrial epithelial cells (EECs) in context of endometrial fibrosis. We identified a typical type 2 epithelial-to-mesenchymal transition (EMT) in EECs from IUA patients and this process was induced by the forced expression of ΔNp63α in EECs. In transcriptomic analysis, we found that diverse signaling pathways regulated by ΔNp63α were involved in pro-EMT. We demonstrated that the DUSP4/GSK-3β/SNAI1 pathway was critical in transducing the pro-EMT signals initiated by ΔNp63α, while bFGF reversed ΔNp63α-induced EMT and endometrial fibrosis both in vitro and in vivo by blocking DUSP4/GSK3β/SNAI1 pathway. Taken together, our findings are important to understand the molecular mechanisms of endometrial fibrosis and to provide potential therapeutic targets.

Assessing liver fibrosis with chronic hepatitis B (CHB) in patients is quite important. Some non-invasive approaches for evaluating liver fibrosis include blood tests and ultrasound elastography. How to effectively combine multiple methods to improve the diagnostic performance remains a challenging problem. The main goal of this paper is to assess and stage liver fibrosis in CHB using feature selection and machine learning methods based on multimodal data. Popular machine learning approaches (e.g., support vector machine (SVM)) and feature selection (FS) were explored to stage the CHB. 16 volunteers and 92 patients with CHB were investigated for liver fibrosis staging based on transient elastography (TE) and acoustical radiation force impulse imaging (ARFI) data. The accuracy of the staging result using FS and a SVM classifier was an accuracy of 90.68% for significant fibrosis (≥F2) and an accuracy of 93.52% for cirrhosis (F4), respectively. The proposed method also increased the sensitivity, specificity, and area under curve (AUC) values for both significant fibrosis and cirrhosis diagnosis, which is very promising for staging liver fibrosis from multimodal information. It outperforms any single method and their linear combination and also achieves a state-of-the-art performance.

Aim We aimed to investigate the efficacy and safety of telbivudine (LdT) on the intervention of mother-to-child transmission (MTCT) in different trimesters of pregnant women with high viral loads. Methods In this prospective cohort study, 160 cases of mothers with high viral loads were included. Eighty-two subjects received 600 mg/day LdT therapy. Fifty of them started LdT therapy before the third trimester of gestation, including 17 cases before pregnancy, nine and 24 cases in the first and second trimesters of pregnancy, respectively. The other 32 cases started LdT in the third trimester of gestation. Control pregnant women (78 cases) did not take LdT therapy. MTCT rate was determined by hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA data of infants at the 51st week post-partum. Adverse events were also evaluated throughout the study. Results One hundred and sixty infants were born from 160 pregnant women. Both LdT-treated groups displayed a marked decline in HBV DNA levels from the beginning to delivery. Positive rate of serum HBsAg in infants born from the above two groups of mothers were 0% and 3.1%, respectively, which was significantly lower than that in the untreated controls (24.4%). The incidence of detectable HBV DNA levels was significantly lower in infants born to LdT-treated mothers than in the controls (16.7%) at the 51st week post-partum. No infant had birth defects. No severe adverse event or complication were observed in LdT-treated mothers or infants followed until the 51st week post-partum. Conclusion The earlier application of LdT during pregnancy, the better preventive effects it offered on MTCT.

AIM In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. METHODS A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated. RESULTS Seventy-six out of 115 patients had drug-resistance mutations (R(+) ), including 27 with adefovir (ADV)-associated mutations (35.5%) and 49 with lamivudine (LMV)-associated mutations (64.5%). For all included patients, complete viral response (CVR) of HBV DNA (

To investigate the combined diagnostic accuracy of acoustic radiation force impulse (ARFI), aspartate aminotransferase to platelet ratio index (APRI) and Forns index for a non-invasive assessment of liver fibrosis in patients with chronic hepatitis B (CHB).In this prospective study, 206 patients had CHB with liver fibrosis stages F0-F4 classified by METAVIR and 40 were healthy volunteers were measured by ARFI, APRI and Forns index separately or combined as indicated.ARFI, APRI or Forns index demonstrated a significant correlation with the histological stage (all P0.001). According to the AUROC of ARFI and APRI for evaluating fibrotic stages more than F2, ARFI showed an enhanced diagnostic accuracy than APRI (P0.05). The combined measurement of ARFI and APRI exhibited better accuracy than ARFI alone when evaluating ≥ F2 fibrotic stage (Z = 2.77, P = 0.006). Combination of ARFI, APRI and Forns index did not obviously improve the diagnostic accuracy compared to the combination of ARFI and APRI (Z = 0.958, P = 0.338).ARFI + APRI showed enhanced diagnostic accuracy than ARFI or APRI alone for significant liver fibrosis and ARFI + APRI + Forns index shows the same effect with ARFI + APRI.

Background & Aims Accurate assessment of liver fibrosis in patients with chronic hepatitis B (CHB) is necessary not only to predict the long-term clinical course but also to determine an appropriate antiviral therapy scheme. Several noninvasive approaches – serum markers and elastography – have been proposed as alternatives for the histopathological analysis of liver biopsies. The aim of this study was to evaluate two ultrasound elastography methods (ARFI and TE) and one biochemical test (APRI), as well as their optimal linear combination, in the assessment of liver fibrosis in CHB. Methods Ninety five patients with CHB and 16 volunteers underwent ARFI, TE and APRI; and liver fibrosis was staged in the patients by a liver biopsy. An optimal linear combination of the three methods was developed, and its diagnostic performance was evaluated by a 10-fold cross-validation. Results The accuracy of the linear combination was 83.86% and 91.88% for significant fibrosis (≥F2) and cirrhosis (F4), respectively, higher than those obtained for ARFI (83.50%, 88.76%), TE (75.27%, 87.61%) and APRI (73.29% and 81.67%). The combination also increased the sensitivity and the negative predictive values for the diagnosis of significant fibrosis and cirrhosis. Conclusions The optimal linear combination algorithm is effective for noninvasive staging of liver fibrosis in CHB. However, linear combination has its own limitations; nonlinear methods may eventually reveal even clearer diagnostic results.

Background Increased numbers of Interleukin-17-producing CD4+ T cells (Th17) have been found in association with hepatitis B virus (HBV)-induced liver injury. However, the mechanism underlying the increase of Th17 responses in patients with HBV infection remains unclear. In this study, we investigate the possible regulatory mechanisms of increased Th17 responses in patients with chronic hepatitis B(CHB). Methods Th17 response and IL-6R expression on CD4+ T cells in peripheral blood samples were determined by flow cytometry. Cytokines TGF-β, IL-1β, IL-6 and IL-17 in plasma and/or supernatant samples were determined by ELISA and the IL-17 and IL-6R mRNA levels were quantified by quantitative real-time reverse polymerase chain reaction. Results All these data indicated that the frequency of periphery Th17 cells is significantly correlated with the percentage of CD4 + T cells expressing IL-6R in CHB patients. CD4+ T cells from patients with CHB, but not those from healthy donors, produced higher levels of IL-17 and had more IL-6R expression upon stimulation with the HBV core antigen (HBcAg) in vitro. The PMA/ionomycin and HBcAg -stimulated up-regulation of IL-17 production by CD4+ T cells could be reversed by a neutralizing antibody against IL-6R. Conclusion we showed that enhancement of IL-6R expression on CD4+ T cells upon HBV infection contributes to increased Th17 response in patients with CHB.

SummaryObjectivesThe objective of this study was to investigate the potential clinical roles of circulating soluble interleukin (IL)-6 receptor (sIL-6R) and IL-6R expression on CD4+ T cells (CD4+ IL-6R+ T cells) in chronic hepatitis B (CHB) patients.MethodsOne hundred and thirty-three subjects, including 72 CHB patients, 27 asymptomatic carriers, eight acute hepatitis B (AHB) patients, and 26 healthy donors were included in this study. Plasma IL-6 and sIL-6R levels were measured by enzyme-linked immunosorbent assay (ELISA); the frequency of CD4+ IL-6R+ T cells was detected by flow cytometry analysis.ResultsOur data showed a significant increase in plasma sIL-6R levels and the frequency of CD4+ IL-6R+ T cells in peripheral blood in CHB patients compared to asymptomatic carriers and healthy controls (both p1.0×106 copies/ml had a lower level of plasma sIL-6R than those with an HBV DNA load