High mobility group box 1 (HMGB1) plays an important role in the pathologic processes of endothelial permeability under oxidative stress. Trophoblast oxidative stress has been implicated in the pathophysiology of preeclampsia (PE). HMGB1 serum levels are increased in PE. However, the potential roles of HMGB1 in endothelial permeability in PE remain unclear. We assessed the effects of the hypoxic trophoblast on the permeability of the endothelial monolayer. Our results showed that the hypoxic trophoblast displayed higher HMGB1 mRNA, intracellular HMGB1 protein, and HMGB1 in conditioned medium than those of the normoxic trophoblast did. The hypoxic trophoblast conditioned medium increased the endothelial monolayer permeability and increased TLR 4 and caveolin-1 (CAV-1) protein expression in endothelial cells, which was inhibited by glycyrrhizic acid and HMGB1 small interfering RNA transfection to trophoblasts before hypoxia. The increased endothelial permeability induced by hypoxic trophoblast conditioned medium could be inhibited with TLR4 or CAV-1 gene silencing in endothelial cells. Immunoprecipitation showed that CAV-1 and TLR4 are colocalized in HUVECs and C57BL/6 mouse kidney. TLR4 small interfering RNA suppressed CAV-1 protein expression in endothelial cells upon stimulation of hypoxic trophoblast conditioned medium or HMGB1. We conclude that hypoxic trophoblasts play an important role in the mechanism of general edema (including protein urine) in PE via increasing endothelial monolayer permeability through the HMGB1/TLR4/CAV-1 pathway.

High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an “accomplice” of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the “don’t eat me” signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.

Shedding of STBMs into the maternal circulation occurs in greater amounts in early-onset pre-eclampsia than in late-onset pre-eclampsia.

Endometrial cancer (EC) is one of the most common female malignancies. The patients with high-risk factors may have poor prognosis. Therefore, there is an urgent need to find a new molecule to more accurately predict survival of patients. Leucine-rich-alpha-2-glycoprotein1 (LRG1), one of leucine-rich repeat family, was closely associated with cancer metastasis and poor prognosis. The biological functions and the expression level of LRG1 remain obscure in EC. In this study, by immunohistochemical analysis of 242 EC patient tissues, we found that LRG1 expression was associated with stage and lymphatic metastasis in both test cohort (133 patients) and validation cohort (109 patients). Furthermore, to investigate the prognostic value of LRG1 in endometrial carcinoma, we analyzed the correlation between variables and overall survival with Cox proportional hazard regression. The result showed that LRG1 was an independent prognostic factor for overall survival of endometrial carcinoma patients. To further evaluate the prognostic efficiency of LRG1 in endometrial carcinoma, we compared the sensitivity and specificity of LRG1 in endometrial carcinoma prognosis by logistic regression. The result showed that LRG1 combining with other clinicopathological risk factors was a stronger prognostic model than clinicopathological risk factors alone or their combination. Thus, LRG1 potentially offered clinical value in directing personal treatment for endometrial carcinoma patients.

BackgroundCardiovascular disease is the leading cause of mortality in postmenopausal women. Follicle‐stimulating hormone (FSH) shows negative associations with obesity and diabetes mellitus in postmenopausal women. We aimed to study the associations between FSH and 10‐year risk of atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women.Methods and Results SPECT‐China (the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors) is a 22‐site, population‐based study conducted during 2014–2015. This study included 2658 postmenopausal women. A newly developed effective tool for 10‐year ASCVD risk prediction among Chinese was adopted. Regression analyses were performed to assess the relationship among FSH, 10‐year ASCVD risk, and multiple cardiometabolic risk factors. With the increase in FSH quartiles, the mean 10‐year ASCVD risk in postmenopausal women decreased from 4.9% to 3.3%, and most metabolic parameters were significantly ameliorated (all P for trend <0.05). In regression analyses, a 1‐SD increment in ln‐FSH was negatively associated with continuous (B −0.12, 95% confidence interval, −0.16, −0.09, P<0.05) and categorical (odds ratio 0.65, 95% confidence interval, 0.49, 0.85, P<0.05) 10‐year ASCVD risk. These significant associations existed in subgroups with or without medication use, obesity, diabetes mellitus, hypertension, and dyslipidemia. Body mass index and waist circumference (both B −0.35, 95% confidence interval, −0.40, −0.30, P<0.05) had the largest associations of all metabolic measures, and blood pressure had the smallest association.ConclusionsSerum FSH levels were negatively associated with 10‐year ASCVD risk in postmenopausal women. Among cardiometabolic factors, obesity indices had the largest associations with FSH. These results indicated that a low FSH might be a risk factor or a biomarker for cardiovascular disease risk in postmenopausal women.

BackgroundThe severity of menopausal symptoms can vary according to ethnicity and geography. Two common menopausal symptom scales, the modified Kupperman Index (KI) and the Menopausal Rating Scale (MRS), are accepted internationally. In this study, we evaluated the correlation between these scales and their relevance to women in the People’s Republic of China.MethodsWe enrolled treatment-naïve women who visited the menopause outpatient department at a major teaching hospital in Shanghai, People’s Republic of China. The women were required to complete two questionnaires, ie, the modified KI and the MRS. We assessed the correlation between the tools using a correlation analysis.ResultsWe enrolled 277 women of average age 51.5 ± 4.8 years. There was a strong positive correlation between total scores on the modified KI and the MRS (0.74, 95% confidence interval 0.69–0.79) and subscores for the somatic and psychological domains (0.74 and 0.77, respectively), with a moderate correlation for urogenital symptoms. According to the modified KI, 15 (5.4%) women were categorized as asymptomatic, and when using the MRS, 33 (11.9%) were categorized as asymptomatic. Women categorized as having none/minimal symptoms by the MRS were diagnosed as having mild to severe symptoms using the modified KI. The highest agreement (74%) was found when symptoms were moderate.ConclusionThe modified KI and the MRS do correlate in Chinese women, but the modified KI is more likely to identify menopausal symptoms than the MRS in screening if there is doubt about the diagnosis of menopause.

Objective: To explore the knowledge and prevalence of menopausal symptoms as well as the use and attitude toward hormone replacement therapy (HRT) in Chinese women. Methods: A cross-sectional study was conducted between May 2011 and April 2012 in Shanghai, China. The structured questionnaire addressing sociodemographic characteristics, knowledge and prevalence of menopausal symptoms, and knowledge and attitude towards HRT and its use were investigated. Results: 3,619 women aged 40-65 years were included in the analysis. The majority of the women had knowledge of menopause. Symptoms were prevalent in 16.1% of premenopausal women and in 49.3% of peri-, post- and surgical-menopausal women. Back and joint pain, sleeplessness, fatigue and sweating/hot flushes were frequently reported. HRT awareness among women was 3.5% and was related to menopausal, working and marital status; 75 (2.1%) women had used or were using HRT, of which 57.3% used HRT with a doctor's prescription and 29.3% experienced side effects from the use of HRT. Conclusion: Most Chinese women had knowledge of menopause and thought menopausal symptoms should not be treated. The awareness of HRT was poor and influenced by menopausal, working and marital status. Chinese health care providers have to assume responsibility for educating women about menopause and HRT use.

3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.