Objective To explore the neddylation pathway, found to be highly activated in various cancers, as a potential therapeutic target in endometrial carcinoma, one of the three most frequent malignant tumours in the female reproductive system. Methods Data from The Cancer Genome Atlas were analysed using online servers. Expression levels of key neddylation genes were validated by reverse-transcription polymerase chain reaction and western blots of tumour and adjacent tissues. Underlying mechanisms and the effects on cell activities of the neddylation pathway-specific inhibitor, MLN4924, were investigated in endometrial cancer cell lines. Results Key neddylation enzymes, ubiquitin conjugating enzyme E2 M ( UBC12), ubiquitin conjugating enzyme E2 F ( UBE2F), ring-box 1 ( RBX1) and ring finger protein 7 ( RBX2), were significantly overexpressed in endometrial carcinoma tissues versus normal tissues, but only UBE2F and RBX2 positively correlated with patient survival. MLN4924 significantly suppressed proliferation and colony formation in EC cells by inducing DNA re-replication, cell cycle arrest and apoptosis. Mechanism study revealed that MLN4924 induced the accumulation of cullin-RING ligase substrates in vitro. Conclusions The neddylation pathway was identified to play an important role in endometrial cancer. The neddylation specific inhibitor, MLN4924, may be a potential therapeutic drug for endometrial carcinoma.

Epithelial ovarian cancer has a low response rate to immunotherapy and a complex immune microenvironment that regulates its treatment outcomes. Understanding the immune microenvironment and its molecular basis is of great clinical significance in the effort to improve immunotherapy response and outcomes. To determine the characteristics of the immune microenvironment in ovarian cancer, we stratified ovarian cancer patients into three immune subtypes (C1, C2, and C3) using immune-related genes based on gene expression data from The Cancer Genome Atlas and found that these three subtypes had significant differences in immune characteristics and prognosis. Methylation and copy number variant analysis showed that the immune checkpoint genes that influenced immune response were significantly hypermethylated and highly deleted in the immunosuppressive C3 subtype, suggesting that epigenetic therapy may be able to reverse the efficacy of immunotherapy. In addition, the mutation frequencies of BRCA2 and CDK12 were significantly higher in the C2 subtype than in the other two subtypes, suggesting that mutation of DNA repair-related genes significantly affects the prognosis of ovarian cancer patients. Our study further elucidated the molecular characteristics of the immune microenvironment of ovarian cancer, which providing an effective hierarchical method for the immunotherapy of ovarian cancer patients, and has clinical relevance to the design of new immunotherapies and a reasonable combination strategies.

Background: Heterotopic pregnancy is rare in natural pregnancy. In recent years, with the development of assisted reproductive technology, the incidence of heterotopic pregnancy is increasing. Heterotopic pregnancy not only affects the development of intrauterine embryo, but also threatens the life of patients. There is no unified standard for the treatment of heterotopic pregnancy until now. So we research the clinical features and the effect of different intervention time on pregnancy outcome in patients with heterotopic pregnancy (HP) after assisted reproductive technology (ART).Methods: A retrospective analysis was conducted on the patients who were diagnosed as HP in Shanghai first maternal and infant hospital after conception through ART from January 2014 to June 2019. We analyzed the clinical characteristics, therapeutic method and intervention time to explore their impact on the outcome of HP.Results：47 patients with HP after ART were treated in our hospital and have complete clinical data. Among them, 18 cases treated with conservative therapy and 29 cases treated with operation. 29 cases delivered (including 3 cases of pre-term birth and 26 cases of full-term birth) and 18 cases aborted. In HP patients, β Human chorionic gonadotropin (β-HCG, 0.617) and extrauterine mass size (0.242) are not much guiding significance for the treatment. Transvaginal ultrasonography (TVS) examination on admission found that different conditions of ectopic (anechoic area, adnexal mass, heart beat, yolk sac) was independent risk factors of different treatment methods (P=0.005). And the intervention time before six weeks can get better pregnancy outcome (p=0.034).Conclusions：Patients with ART should be examined by TVS as early as possible. If abnormal TVS (anechoic area, adnexal mass, heart beat, yolk sac) results are found, patients should be operated by laparoscopy. And the best intervention time of laparoscopy is before 6 weeks.