Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility in 8.8 -61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a two-dimensional polyacrylamide gel electrophoresis/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial to mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial to mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a ␤-catenin/T-cell factor (Tcf) signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1␣/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis, and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients.

Advanced and recurrent gynecological cancers are associated with poor prognosis and lack of effective treatment. The developments of the molecular mechanisms on cancer progression provide insight into novel targeted therapies, which are emerging as groundbreaking and promising cancer treatment strategies. In gynecologic malignancies, potential therapeutic targeted agents include antiangiogenic agents, poly (ADP-ribose) polymerase (PARP) inhibitors, tumor-intrinsic signaling pathway inhibitors, selective estrogen receptor downregulators, and immune checkpoint inhibitors. In this article, we provide a comprehensive review of the clinical evidence of targeted agents in gynecological cancers and discuss the future implication.

Objectives: Neutrophils are thought to release neutrophil extracellular traps (NETs) to form in response to exogenous bacteria, viruses and other pathogens. However, the mechanisms underlying NET formation during sterile inflammation are still unclear. In this study, we would like to identify neutrophil extracellular traps formation during sterile inflammation and tissue injury and associated pathways and its mechanism. Materials and methods:We identified different injuries such as chemical-induced and trauma-induced formation of NETs and investigated mechanism of the formation of NETs in vitro and in vivo during the treatment of mtDNA. Results:Here, we find the release of mitochondrial DNA (mtDNA) and oxidized mtDNA in acute peripheral tissue trauma models or other chemically induced lung injury, and moreover, endogenous mtDNA and oxidized mtDNA induce the formation of NETs and sterile inflammation. Oxidized mtDNA is a more potent inducer of NETs.Mitochondrial DNA activates neutrophils via cyclic GMP-AMP synthase (cGAS)-STING and the Toll-like receptor 9 (TLR9) pathways and increases the production of neutrophil elastase and extracellular neutrophil-derived DNA in NETs. Mitochondrial DNA also increases the production of reactive oxygen species (ROS) and expression of the NET-associated proteins Rac 2 and peptidylarginine deiminase 4 (PAD4). Conclusions:Altogether, these findings highlight that endogenous mitochondrial DNA inducted NETs formation and subsequent sterile inflammation and the mechanism associated with NET formation.

The present findings suggest that Lipo-HNK may provide an effective approach to inhibit tumor growth in both cisplatin sensitive and -resistant human ovarian cancer with minimal side effects.

Background Lipid metabolism plays an important role in the pathogenesis of diabetes. There is little evidence regarding the prospective association of the maternal lipidome with gestational diabetes mellitus (GDM), especially in Chinese populations. Objectives We aimed to identify novel lipid species associated with GDM risk in Chinese women, and assess the incremental predictive capacity of the lipids for GDM. Methods We conducted a nested case–control study using the Tongji-Shuangliu Birth Cohort with 336 GDM cases and 672 controls, 1:2 matched on age and week of gestation. Maternal blood samples were collected at 6–15 wk, and lipidomes were profiled by targeted ultra-HPLC–tandem MS. GDM was diagnosed by oral-glucose-tolerance test at 24–28 wk. The least absolute shrinkage and selection operator is a regression analysis method that was used to select novel biomarkers. Multivariable conditional logistic regression was used to estimate the associations. Results Of 366 detected lipids, 10 were selected and found to be significantly associated with GDM independently of confounders: there were positive associations with phosphatidylinositol 40:6, alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, and alkylphosphatidylethanolamine 40:5 (adjusted ORs per 1 log-SD increment range: 1.34–2.86), whereas there were inverse associations with sphingomyelin 34:1, dihexosyl ceramide 24:0, mono hexosyl ceramide 18:0, dihexosyl ceramide 24:1, and phosphatidylcholine 40:7 (adjusted ORs range: 0.48–0.68). Addition of these novel lipids to the classical GDM prediction model resulted in a significant improvement in the C-statistic (discriminatory power of the model) to 0.801 (95% CI: 0.772, 0.829). For every 1-point increase in the lipid risk score of the 10 lipids, the OR of GDM was 1.66 (95% CI: 1.50, 1.85). Mediation analysis suggested the associations between specific lipid species and GDM were partially explained by glycemic and insulin-related indicators. Conclusions Specific plasma lipid biomarkers in early pregnancy were associated with GDM in Chinese women, and significantly improved the prediction for GDM.

Differentiation antagonizing non‐protein coding RNA (DANCR) is a newly identified oncogenic long noncoding RNA found in various cancers. However, the functional role of DANCR in tumor angiogenesis and the underlying mechanisms are still unclear. The expression of DANCR was determined in ovarian malignant tissues and cell lines. The functional role of DANCR in tumor angiogenesis was revealed by the following methods: CD31 staining of ovarian tumor tissues, matrigel‐plug assay tissues, HUVEC‐related tube formation assay, and invasion assay. Enzyme‐linked immunosorbent assay, Western blotting, luciferase assay, and rescue experiments were used to investigate the underlying mechanisms of DANCR‐regulating angiogenesis. DANCR was upregulated in ovarian malignant tissues and ovarian cancer cells. Knockdown of DANCR efficiently impaired ovarian tumor growth through inhibition of tumor angiogenesis. Furthermore, the conditional culture medium from DANCR‐knockdown ovarian cells significantly inhibited tube formation and invasion of HUVEC in vitro. Mechanistic investigation indicated that vascular endothelial growth factor A (VEGF‐A, VEGF) plays a crucial role during DANCR inhibition of tumor angiogenesis in ovarian cancer. Further results demonstrated that miR‐145 is the direct binding target of DANCR during regulation of VEGF expression and tumor angiogenesis in ovarian cancer cells. Collectively, DANCR plays a promotional role in tumor angiogenesis in ovarian cancer through regulation of miR‐145/VEGF axis. Therefore, DANCR may be a novel therapy target for ovarian cancer.

Human papillomavirus (HPV) is the most common sexually transmitted infection, exhibiting a tropism for the epidermis and mucosae. The link between persistent HPV infection and malignancies involving the anogenital tract as well as the head and neck has been well-established, and it is estimated that HPV-related cancers involving various anatomical sites account for 4.5% of all human cancers. Current prophylactic vaccines against HPV have enabled the prevention of associated malignancies. However, the sizeable population base of current infection in whom prophylactic vaccines are not applicable, certain high-risk HPV types not included in vaccines, and the vast susceptible population in developing countries who do not have access to the costly prophylactic vaccines, put forward an imperative need for effective therapies targeting persistent infection. In this article, the life cycle of HPV, the mechanisms facilitating HPV evasion of recognition and clearance by the host immune system, and the promising therapeutic strategies currently under investigation, particularly antiviral drugs and therapeutic vaccines, are reviewed.

Objective We aimed to examine prospective associations between circulating fatty acids in early pregnancy and incident gestational diabetes mellitus (GDM) among Chinese pregnant women. Methods Analyses were based on two prospective nested case-control studies conducted in western China (336 GDM cases and 672 matched controls) and central China (305 cases and 305 matched controls). Fasting plasma fatty acids in early pregnancy (gestational age at enrollment: 10.4 weeks [standard deviation, 2.0]) and 13.2 weeks [1.0], respectively) were determined by gas chromatography-mass spectrometry, and GDM was diagnosed based on the International Association of Diabetes in Pregnancy Study Groups criteria during 24-28 weeks of gestation. Multiple metabolic biomarkers (HOMA-IR [homeostatic model assessment for insulin resistance], HbA1c, c-peptide, high-sensitivity C-reactive protein, adiponectin, leptin, and blood lipids) were additionally measured among 672 non-GDM controls at enrollment. Results Higher levels of saturated fatty acids (SFAs) 14:0 (pooled odds ratio, 1.41 for each 1-standard deviation increase; 95% confidence interval, 1.25, 1.59) and 16:0 (1.19; 1.05, 1.35) were associated with higher odds of GDM. Higher levels of n-6 polyunsaturated fatty acid (PUFA) 18:2n-6 was strongly associated with lower odds of GDM (0.69; 0.60, 0.80). In non-GDM pregnant women, higher SFAs 14:0 and 16:0 but lower n-6 PUFA 18:2n-6 were generally correlated with unfavorable metabolic profiles. Conclusions We documented adverse associations of 14:0 and 16:0 but a protective association of 18:2n-6 with GDM among Chinese pregnant women. Our findings highlight the distinct roles of specific fatty acids in the onset of GDM.