EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells.

BACKGROUND: Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways. METHOD: The expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation. RESULT: EFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon. CONCLUSION: EFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells.

The mediating role of menstrual irregularity on obesity and sexual function in Chinese women with pelvic floor disorders: a cross-sectional study.

BACKGROUND: Sexual problems are common among women with pelvic floor disorders (PFD). Few studies have explored the relationship between obesity and sexual function in women with PFD. This study aimed to prove that obesity was a risk factor for worse sexual function in women with PFD, and to investigate the mediating role of menstrual irregularity. METHODS: This was a cross-sectional study involving 783 women with PFD from Shandong Province, China between June 2020 and February 2021. Female sexual function was assessed using the Pelvic Organ Prolapse/UI Sexual Questionnaire-12 (PISQ-12). Obesity was defined as BMI ≥ 28.0. Menstrual irregularity was defined as menstrual cycles ≥ 35 or menstrual cycles < 25 days. Logistic regression and multiple linear regression were employed to explore the association among obesity, menstrual irregularity and sexual function. RESULTS: Obesity was associated with worse PISQ-12 scores compared with normal- weight women (mean score 28.14 ± 7.03 versus 32.75 ± 5.66, p < 0.001). After adjusting for controlling variables, women with obesity (ß= -3.74, p < 0.001) and menstrual irregularity (ß= -3.41, p < 0.001) had a worse sexual function. Menstrual irregularity had a mediation effect on the association between obesity and sexual function. CONCLUSIONS: This study provided evidence that obesity was associated with worse sexual function in women with PFDs, and the effect of obesity on sexual function was partially mediated by menstrual irregularity. Weight control may have potential benefits for improving sexual function and preventing female sexual dysfunction. It's also important to pay attention to the menstrual cycle.

The number of metabolic syndrome risk factors predicts alterations in gut microbiota in Chinese children from the Huantai study.

BACKGROUND: Evidence on the effect of gut microbiota on the number of metabolic syndrome (MetS) risk factors among children is scarce. We aimed to examine the alterations of gut microbiota with different numbers of MetS risk factors among children. METHODS: Data were collected from a nested case-control study at the baseline of the Huantai Childhood Cardiovascular Health Cohort Study in Zibo, China. We compared the differences in gut microbiota based on 16S rRNA gene sequencing among 72 children with different numbers of MetS risk factors matched by age and sex (i.e., none, one, and two-or-more MetS risk factors; 24 children for each group). RESULTS: The community richness (i.e., the total number of species in the community) and diversity (i.e., the richness and evenness of species in the community) of gut microbiota decreased with an increased number of MetS risk factors in children (P for trend < 0.05). Among genera with a relative abundance greater than 0.01%, the relative abundance of Lachnoclostridium (PFDR = 0.009) increased in the MetS risk groups, whereas Alistipes (PFDR < 0.001) and Lachnospiraceae_NK4A136_group (PFDR = 0.043) decreased in the MetS risk groups compared to the non-risk group. The genus Christensenellaceae_R-7_group excelled at distinguishing one and two-or-more risk groups from the non-risk group (area under the ROC curve [AUC]: 0.84 - 0.92), while the genera Family_XIII_AD3011_group (AUC: 0.73 - 0.91) and Lachnoclostridium (AUC: 0.77 - 0.80) performed moderate abilities in identifying none, one, and two-or-more MetS risk factors in children. CONCLUSIONS: Based on the nested case-control study and the 16S rRNA gene sequencing technology, we found that dysbiosis of gut microbiota, particularly for the genera Christensenellaceae_R-7_group, Family_XIII_AD3011_group, and Lachnoclostridium may contribute to the early detection and the accumulation of MetS risk factors in childhood.

Association between gut microbiota and obesity combined with high carotid intima-media thickness among Chinese children.

BACKGROUND AND OBJECTIVES: Obesity and related target organ damage such as high carotid intima-media thickness (cIMT) in children is associated with cardiovascular disease (CVD) later in life. However, the asso-ciation between gut microbiota and obesity combined with high cIMT among children remains unclear. Therefore, we compared differences in composition, community diversity, and richness of gut microbiota among normal children and obesity combined with or without high cIMT to identify differential microbiota biomarkers. METHODS AND STUDY DESIGN: A total of 24 children with obesity combined with high cIMT (OB+high-cIMT), 24 with obesity but normal cIMT (OB+non-high cIMT), and 24 with normal weight and normal cIMT aged 10-11 years matched by age and sex from the "Huantai Childhood Cardiovascular Health Cohort Study" were included. All included fecal samples were tested using 16S rRNA gene sequencing. RESULTS: The community richness and diversity of gut microbiota in OB+high-cIMT children were decreased compared with OB+non-high cIMT children and normal children. At the genus level, the relative abundances of Christensenellaceae_R-7_group, UBA1819, Family_XIII_AD3011_group, and unclassi-fied_o_Bacteroidales were associated with reduced odds of OB+high-cIMT among children. Receiver operating characteristic (ROC) analysis showed that combined Christensenellaceae_R-7_group, UBA1819, Fami-ly_XIII_AD3011_group, and unclassified_o_Bacteroidales performed a high ability in identifying OB+high-cIMT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed that several pathways such as biosynthesis of amino acids and aminoacyl-tRNA pathways were lower in the OB+high-cIMT group compared with the normal group. CONCLUSIONS: We found that the alteration of gut microbiota was associated with OB+high-cIMT among children, which indicates that the gut microbiota may be a marker for obesity and related cardiovascular damage among children.

The mediating effect of the prolonged second stage of labor on delivery mode and urinary incontinence among postpartum women: evidence from Shandong, China.

INTRODUCTION AND HYPOTHESIS: This study was aimed at exploring the mediating role of the prolonged second stage of labor (PSSL) in the association between delivery mode and urinary incontinence (UI) among postpartum women in Shandong, China. METHODS: A cross-sectional study involving postnatal women from the Women's Pelvic Floor Functional Health Center in Shandong, China, was conducted. An electronic questionnaire was used to collect the data between June 2020 and February 2021. UI was assessed using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). Logistic regression and multiple linear regression were employed to explore the association among delivery mode, PSSL, and UI, and the mediating role of PSSL. RESULTS: Among the total of 5,586 postpartum women included in this study, the prevalence of UI was 13.3%. Among the 742 patients with UI, the prevalence of stress urinary incontinence (78.3%) was greater than urge urinary incontinence (8.6%), mixed urinary incontinence (9.3%), and others (3.8%). After adjusting for controlling variables, delivery mode was found to be significantly associated with PSSL, whereby women with vaginal delivery were more likely to be in PSSL, and women with PSSL had a higher probability of suffering from UI. PSSL played a partial mediating effect in delivery mode and UI. CONCLUSIONS: This study provided evidence that the effect of delivery mode on UI was partially mediated by PSSL among postpartum women in Shandong, China. Strategies to prevent PSSL should be actively adopted to reduce the risk of UI in women.

Clinical value of serum neuron-specific enolase in sepsis-associated encephalopathy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the serum levels of neuron-specific enolase (NSE) in sepsis-associated encephalopathy (SAE) and perform a meta-analysis to assess the diagnostic and prognostic potential of serum NSE in SAE patients. METHODS: We searched English and Chinese databases for studies related to SAE that reported serum NSE levels until November 2023. We extracted information from these studies including the first author and year of publication, the number of samples, the gender and age of patients, the collection time of blood samples in patients, the assay method of serum NSE, the study methods, and the levels of serum NSE with units of ng/mL. The quality assessment of diagnostic accuracy studies 2 (QUADAS-2) tool was used to evaluate the study quality. A meta-analysis was performed using Review Manager version 5.3, employing either a random effects model or a fixed effects model. RESULTS: A total of 17 studies were included in the final meta-analysis, including 682 SAE patients and 946 NE patients. The meta-analysis demonstrated significantly higher serum NSE levels in SAE patients compared to NE patients (Z = 5.97, P < 0.001, MD = 7.79, 95%CI 5.23-10.34), irrespective of the method used for serum NSE detection (Z = 6.15, P < 0.001, mean difference [MD] = 7.75, 95%CI 5.28-10.22) and the study methods (Z = 5.97, P < 0.001, MD = 7.79, 95%CI 5.23-10.34). Furthermore, sepsis patients with a favorable outcome showed significantly lower levels of serum NSE compared to those with an unfavorable outcome (death or adverse neurological outcomes) (Z = 5.44, P < 0.001, MD = - 5.34, 95%CI - 7.26-3.42). CONCLUSION: The Serum level of NSE in SAE patients was significantly higher than that in septic patients without encephalopathy. The higher the serum NSE level in SAE patients, the higher their mortality rate and incidence of adverse neurological outcomes.

Pregnancy Outcome Difference between Fresh and Frozen Embryos in Women without Polycystic Ovary Syndrome: a Systematic Review and Meta-Analysis.

The purpose of this study is to identify that the advantages of frozen embryos are not evident in ovulatory women or women with non-polycystic ovary syndrome (non-PCOS) by meta-analysis. An exhaustive literature search of PubMed (MEDLINE), Embase, and Cochrane Library databases was performed until March 20, 2020 (limited to articles published in English). We included randomized clinical trials comparing the results of frozen and fresh embryo transfers. The primary outcomes were live birth rate and birth weight. The fixed effect model was used when a significant heterogeneity was observed. Otherwise, a random effect model was used. In 511 identified studies, 4 were eligible and were included in this review. There was no difference in live birth rate, singleton birth weight, clinical pregnancy, ongoing pregnancy, gestational diabetes, and gestational hypertension between frozen and fresh embryos. In frozen embryos, the relative risk of moderate or severe ovarian hyperstimulation syndrome (OHSS) was lower, the incidence rate of pre-eclampsia higher, and the standardized mean difference of twin birth weight higher than in fresh embryos. There is no significant difference between frozen embryo transfer (FET) and fresh embryo transfer in ovulatory women or women with non-PCOS. We recommend that the transfer depends on the actual situation in the patient in clinical practice, rather than the "freeze all" policy and thawing FET.