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Thin endometrium has been widely recognized as a critical cause of infertility, recurrent pregnancy loss, and placental abnormalities; however, access to effective treatment is a formidable challenge due to the rudimentary understanding of the pathogenesis of thin endometrium. Here, we profiled the transcriptomes of human endometrial cells at single-cell resolution to characterize cell types, their communications, and the underlying mechanism of endometrial growth in normal and thin endometrium during the proliferative phase. Stromal cells were the most abundant cell type in the endometrium, with a subpopulation of proliferating stromal cells whose cell cycle signaling pathways were compromised in thin endometrium. Both single-cell RNA sequencing and experimental verification revealed cellular senescence in the stroma and epithelium accompanied by collagen overdeposition around blood vessels. Moreover, decreased numbers of macrophages and natural killer cells further exacerbated endometrial thinness. In addition, our results uncovered aberrant SEMA3, EGF, PTN, and TWEAK signaling pathways as causes for the insufficient proliferation of the endometrium. Together, these data provide insight into therapeutic strategies for endometrial regeneration and growth to treat thin endometrium.

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.

Background: A comprehensive geriatric assessment (CGA) of elderly patients is useful for detecting the patients' vulnerabilities. Exercise and early rehabilitation, nutritional intervention, traditional Chinese medicine (TCM), standardized medication guidance and patient education can, separately, improve and even reverse the physical frailty status. However, the effect of combining a CGA and multi-disciplinary management on frailty in elderly patients remains unclear. The present study assessed the effects of a CGA and multi-disciplinary management on elderly patients with frailty in China.Methods: In this study, 320 inpatients with frailty ≥70 years old will be randomly divided into an intervention group and a control group. The intervention group will be given routine management, a CGA and multi-disciplinary management involving rehabilitation exercise, diet adjustment, multi-drug evaluation, acupoint massage in TCM and patient education for 12 months, and the control group will be followed up with routine management for basic diseases. The primary outcomes are the Fried phenotype and short physical performance battery (SPPB). The secondary outcomes are the clinical frailty scale (CFS), non-elective hospital readmission, basic activities of daily living (BADL), 5­level european quality of life 5 dimensions index (EQ-5D), nutrition risk screening-2002 (NRS-2002), medical insurance expenses, fall events and all-cause mortality. In addition, a cost-effectiveness study will be carried out. Discussion: This paper outlines the protocol for a randomized, single-blind, parallel multi-center clinical study. This protocol, if beneficial, will demonstrate the interaction of various intervention strategies, will help improve elderly frailty patients, and will be useful for clinicians, nurses, policymakers, public health authorities and the general population.Trial registration: Chinese Clinical Trials Register, ChiCTR1900022623. Registered on 19 April 2019, http://www.chictr.org.cn/showproj.aspx?proj=38141.

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.

Background: No prior studies have assessed the role of cognitive impairment and physical frailty in elderly inpatients with cardiovascular disease (CVD). We aimed to assess the utility of a combination developed using the mini-mental state examination (MMSE) + clock drawing test (CDT) and the Fried phenotype for predicting non-elective hospital readmission or death within 6-month in elderly inpatients with CVD. Methods : A single center prospective cohort was conducted between September 2018 and February 2019. Inpatients aged 65 years or older were recruited. All enrolled patients received a comprehensive geriatric assessment during hospitalization. The Kaplan-Meier curves were used to estimate the cumulative incidence of events. The multivariate Cox regression model was used to analyze the association between frailty and cognitive status and the non-elective hospital readmission or death. Results : A total of 542 patients were included; and a total of 113 patients (20.9%) died or were readmitted at 6-month. Overall 20% screened positive for cognitive impairment, including 8% were cognitive impairment combined with physical frailty, which were more older, more common in women and non-married group, had a lower education and a higher risk of malnutrition. Frail participants with normal (hazard ratio [HR]:1.73, 95% confidence intervals [CI]:1.06-2.82, P=0.028) and impaired cognition (HR:2.50, 95% CI:1.27-4.91, P=0.008) had a higher risk of non-elective hospital readmission or death than robust patients, after adjustment for age, sex, education level, marital status, the presence of diabetes mellitus, heart failure, and previous stroke. Conclusions : The presence of physical frailty and cognitive frailty were powerful predictors of non-elective hospital readmission or death in elderly inpatients with CVD, and taking cognitive impairment into account in the frailty model may allow better prediction of adverse outcomes of frailty in the short time. Trial registration: ChiCTR1800017204; date of registration: 07/18/2018.

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.

Objective Various immune cells in patients with CHB have been demonstrated to play critical roles in HBV infection. The goal of this study is to observe changes in Th17, Treg, Th1 and B lymphocytes from peripheral blood and to evaluate immune status of CHB patients undergoing antiviral treatment. Methods Total of 49 CHB patients, 19 asymptomatic carriers and 29 healthy donors were included in our present study. The frequencies of peripheral Th17 cells (CD3+CD4+IL-17+Tcells), Treg cells (CD3+CD4+CD25+CD127- T cells), Th1 cells (CD3+CD4+IFN-γ T cells) and B lymphocytes in chronic hepatitis B (CHB) were analyzed by flow cytometry. Results The frequency of Th17 cells increased after treatment for 6 months, but there was no statistically significant difference of IL-17 expression between baseline and 6 months after treatment. The frequencies of Treg cells, momory B cells and total CD19+ B cells decreased after antiviral treatment. The frequencies of Th1 cells and plasma cells increased after antiviral treatment. Conclusions This study highlights that the reestablishment of immune function during antiviral treatment in CHB patients, which caused by the antiviral drugs or the patients themselves. CHB patients may exhibit varied responses to these antiviral drugs. It is essential to supplement immune therapy during the antiviral treatment, but Th17 may play a limited role in inflammation during antiviral treatment, targeting Th17 therapy may not be useful for CHB treatment. More time and more experiments are critical to explain it.

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