HOXA10 improves endometrial receptivity by upregulating E-cadherin†.

In the endometrium of women with recurrent implantation failure and unexplained recurrent miscarriage, the expression levels of homeobox A10 and E-cadherin were positively correlated. To explore whether homeobox A10 regulates E-cadherin during endometrial receptivity establishment, Ishikawa and RL95-2 cells were transfected with target-specific small interfering RNA (siRNA) and overexpression plasmid of homeobox A10. The expression levels of homeobox A10 and E-cadherin were measured by western blot and quantitative Real-time Polymerase Chain Reaction (qRT-PCR). Attachment assay of JEG-3 spheroids to endometrial cells were conducted to explore the adhesive functions after homeobox A10 interfered. Chromatin immunoprecipitation assays and dual luciferase reporter were used to investigate the regulatory mechanism of homeobox A10. The CD1 mice were transfected with si-homeobox A10 to confirm these results in vivo. In Ishikawa and RL95-2 cells, the expression of E-cadherin was positively correlated with homeobox A10 when it was silenced/overexpressed. Consistently, the adhesion of endometrial epithelium cells and trophoblast cells was inhibited after homeobox A10 was silenced, and exogenous restoration of E-cadherin expression reversed this effect to some extent. Homeobox A10 regulates the expression of E-cadherin by directly binding to a conserved motif (TGTACTAAAAA) located in the E-cadherin promoter region. In addition, after knockdown of homeobox A10 in CD1 mice, both the implantation and live birth rates were decreased. In conclusion, homeobox A10 can bind to the E-cadherin promoter region and directly regulate its expression, thereby improving endometrial receptivity and subsequently increasing the embryo adhesion and implantation.

A molecular-beacon-based asymmetric PCR assay for detecting polymorphisms related to folate metabolism.

BACKGROUND: Polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) of the MTHFR gene and rs1801394 (A66G) of the MTRR gene are important genetic determinants of folate metabolism. A convenient, sensitive, and reliable method is required to detect polymorphisms for the precise supplementation of folate. METHODS: A rapid detection method based on molecular beacon probes that can detect rs1801133, rs1801131, and rs1801394 simultaneously was developed in this study. Specific primers and probes were designed, and the amplification system and conditions were optimized. We applied our method to a group of 500 unrelated women of gestational age in the Dongguan region of Guangdong Province in China. The clinical performance of this assay was evaluated by testing 94 samples in comparison with Sanger sequencing. RESULTS: The molecular-beacon-based PCR assay we established is extremely sensitive, with a detection limit of 2 ng/µL of genomic DNA, and validated by direct sequencing in a blind study with 100% concordance. CONCLUSION: The results demonstrate that our molecular-beacon-based asymmetric PCR assay is an easy, reliable, high-yield, and cost-effective method for the simultaneous detection of three polymorphisms related to folate metabolism. It could help evaluate the risk of perinatal-neonatal neural tube malformation, pregnancy hypertension, and other diseases and guide the individualized supplementation of folic acid. Data on the spectrum of mutations in the Dongguan District in this study are beneficial for guiding the supplementation of folic acid.

G-CSF-mobilized peripheral blood mononuclear cells combined with platelet-rich plasma accelerate restoration of ovarian function in cyclophosphamide-induced POI rats†.

Peripheral blood mononuclear cells (PBMCs) are rich in hematopoietic cells and mesenchymal stem cells. Platelet-rich plasma (PRP) is rich in various growth factors. PBMCs and PRP have been suggested, individually, to restore ovarian function by improving the local microenvironment. The current study investigated the effect of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMCs combined with PRP on restoring ovarian function in rats with primary ovarian insufficiency (POI). Thirty adult female rats were randomly subdivided into five groups: normal control (control), cyclophosphamide (CTX) plus subsequent PBS (POI + PBS), CTX plus subsequent PRP (POI + PRP), CTX plus subsequent G-CSF-mobilized PBMCs (POI + PBMCs), and CTX plus subsequent G-CSF-mobilized PBMCs combined with PRP (POI + PBMCs + PRP). CTX exposure induced the typical POI phenotype with increased diestrus; shortened estrus; follicle arrest at all stages; decreased serum levels of estradiol-17ß (E2) and anti-Mullerian hormone (AMH); and increased levels of follicle-stimulating hormone (FSH). Transplantation of mobilized PBMCs with PRP resulted in a much earlier restoration of the estrous cycle, sex hormone levels, and preantral follicle growth in POI rats. Expression of the male-specific Sry gene in the ovarian tissues of POI + PBMCs + PRP female recipient rats was evident at 5, 10, and 20 days posttransplantation along with significant increases in the expression of angiogenesis markers CD34+ and VEGF and folliculogenesis markers AMH and FSHR. Additionally, PBMCs in combination with PRP mitigated granulosa cell apoptosis by downregulating BAX and upregulating BCL-2. These results demonstrate that G-CSF-mobilized PBMCs combined with PRP accelerate the restoration of ovarian function in POI rats by increasing ovarian neovascularization, reducing granulosa cell apoptosis, and promoting folliculogenesis.

Gaussian Belief Propagation for Solving Network Utility Maximization with Delivery Contracts.

Classical network utility maximization (NUM) models fail to capture network dynamics, which are of increasing importance for modeling network behaviors. In this paper, we consider the NUM with delivery contracts, which are constraints to the classical model to describe network dynamics. This paper investigates a method to distributively solve the given problem. We first transform the problem into an equivalent model of linear equations by dual decomposition theory, and then use Gaussian belief propagation algorithm to solve the equivalent issue distributively. The proposed algorithm has faster convergence speed than the existing first-order methods and distributed Newton method. Experimental results have demonstrated the effectiveness of our proposed approach.

Talin1 regulates endometrial adhesive capacity through the Ras signaling pathway.

AIMS: Blastocyst implantation is mainly depended on the adhesion between cells and cell matrix. Endometrial adhesion plays an important role in establishing embryo implantation, but the underlying mechanisms are remains unclear. Talin1 is a local adhesion complex protein that is necessary for cell adhesion and movement. However, the role and mechanisms of Talin1 in embryo implantation are still unclear. MAIN METHODS: The expression of Talin1 and Integrin αvß3 was measured in the receptive endometrium from the RIF (Recurrent implantation failure) cohort and NC (normal fertile control group) cohort. A JEG-3 trophoblast and endometrial epithelial cell adhesion model and pregnant mouse model were established. The molecular mechanism of Talin1-mediated cell adhesion was explored by RNA sequencing, RT-qPCR, as well as western blotting assays. KEY FINDINGS: Talin1 enhances endometrial cell adhesion by regulating the Ras signaling pathway, and ultimately facilitates embryo implantation. SIGNIFICANCE: This study revealed the molecular mechanisms of regarding the pathogenesis of RIF caused by endometrial receptivity insufficiency. Further pharmacological research on the Ras signaling pathway would be valuable and might provide new therapeutic targets for RIF patients.

Preoperative serum levels of HE4 and CA125 predict primary optimal cytoreduction in advanced epithelial ovarian cancer: a preliminary model study.

OBJECTIVE: The aim of this study is to establish a noninvasive preoperative model for predicting primary optimal cytoreduction in advanced epithelial ovarian cancer by HE4 and CA125 combined with clinicopathological parameters. METHODS: Clinical data including preoperative serum HE4 and CA125 level of 83 patients with advanced epithelial ovarian cancer were collected. The sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy of each clinical parameter were calculated. The Predictive Index score model and the logistic model were constructed to predict the primary optimal cytoreduction. RESULTS: Optimal surgical cytoreduction was achieved in 62.65% (52/83) patients. Cutoff values of preoperative serum HE4 and CA125 were 777.10 pmol/L and 313.60 U/ml. (1) Patients with PIV ≥ 6 may not be able to achieve optimal surgical cytoreduction. The diagnostic accuracy, NPV, PPV and specificity for diagnosing suboptimal cytoreduction were 71, 100, 68, and 100%, respectively. (2) The logistic model was: logit p = 0.12 age - 2.38 preoperative serum CA125 level - 1.86 preoperative serum HE4 level-2.74 histological type-3.37. AUC of the logistic model in the validation group was 0.71(95%CI 0.54-0.88, P = 0.025). Sensitivity and specificity were 1.00 and 0.44, respectively. CONCLUSION: Age, preoperative serum CA125 level and preoperative serum HE4 level are important non-invasive predictors of primary optimal surgical cytoreduction in advanced epithelial ovarian cancer. Our PIV and logistic model can be used for assessment before expensive and complex predictive methods including laparoscopy and diagnostic imaging. Further future clinical validation is needed.

IL-24 inhibits endometrial cancer cell proliferation by promoting apoptosis through the mitochondrial intrinsic signaling pathway.

BACKGROUND: Endometrial cancer is a type of malignant tumor of the female reproductive system. Preserving fertility in endometrial cancer patients is currently a formidable challenge. Interleukin-24 (IL-24) is a unique cytokine tumor suppressor gene belonging to the IL-10 cytokine family. IL-24 has broad-spectrum antitumor activity through different signaling pathways but does not affect normal cells. IL-24 gene therapy may provide a new method for the treatment of endometrial cancer. METHODS: Transfection was used for gene transfer. The expression of IL-24 and related pathway proteins in endometrial cancer tissue and the Ishikawa cell line was detected by immunohistochemistry and Western blotting, respectively. The antitumor function of IL-24 was examined in vitro and in vivo. Cell proliferation was determined by CCK-8 assay, cell migration was shown by wound-healing assay, and cell invasion was detected by Transwell assay. Apoptosis was analyzed by TUNEL assay, and HE staining was performed to observe the morphology of the samples. RESULTS: Immunohistochemical analysis showed different expression levels of IL-24 in human endometrial cancer tissues and normal endometrial tissues. IL-24 increased protein expression of BAX and Cytochrome C, while BCL-2, MMP-3, VEGF, Caspase-9 and Caspase-3 expression was decreased. Overexpression of IL-24 inhibited cell proliferation, migration and invasion, but increased cell apoptosis in endometrial cancer. Mechanistically, we demonstrated that IL-24 inhibited endometrial cancer cell growth by inducing cell apoptosis through the mitochondrial intrinsic signaling pathway. In addition, IL-24 inhibited tumor development by inducing cell apoptosis and inhibiting angiogenesis, as shown in xenograft tumor experiments. CONCLUSIONS: Our study demonstrates the antitumor effect of IL-24 on endometrial cancer and shows that IL-24 may be a promising therapeutic gene for endometrial cancer gene therapy.

Efficacy and safety of laparoscopy versus local injection with absolute ethanol in the management of tubal ectopic pregnancy.

OBJECTIVE: To compare the efficacy and safety between laparoscopy and local injection with absolute ethanol (AE) for treating tubal ectopic pregnancy (EP). STUDY DESIGN: Retrospective cohort study of ectopic pregnancies in the fallopian tube from two tertiary hospitals between January 2015 and December 2017. Clinical information such as presenting symptoms, reproductive history, possible risk factors, initial diagnosis, serum beta-human chor-ionic gonadotropin (ß-HCG) level, transvaginal ultrasonography findings, methods of treatment and outcomes were reviewed and analyzed. RESULTS: A total of 119 patients were identified for this study. The diagnosis was based on clinical manifestations, ultrasonography scan and dynamic serum ß-HCG. 71.4% of women (85/119) had at least one risk factor for ectopic pregnancy, with the most common risk factors being a history of induced labor, uterine curettage, spontaneous abortion or tubal pregnancy. 64 patients were managed by laparoscopic surgery (Group A) and 2 subjects were failure and followed by a systemic methotrexate (MTX) prescription. The other 55 patients had local injection with absolute ethanol, of which 9 cases failed, followed by a second local injection and intramuscular MTX. The HCG decrease rate post absolute ethanol injection was a value predictive factor for prognosis. Moreover, the pregnancy rate one-year post treatment in local injection subjects (10/55, 18.2%) was higher than that of surgical subjects (5/64, 7.8%). CONCLUSION: Local injection of absolute ethanol and laparoscopic surgery for tubal ectopic pregnancy are both effective and relatively safe, but laparoscopic surgery has better efficacy and shorten hospitalization day. Local injection may be less invasiveness and thus beneficial to fertility preservation.

Simultaneous Bayesian Clustering and Feature Selection Through Student's ${t}$ Mixtures Model.

In this paper, we proposed a generative model for feature selection under the unsupervised learning context. The model assumes that data are independently and identically sampled from a finite mixture of Student's distributions, which can reduce the sensitiveness to outliers. Latent random variables that represent the features' salience are included in the model for the indication of the relevance of features. As a result, the model is expected to simultaneously realize clustering, feature selection, and outlier detection. Inference is carried out by a tree-structured variational Bayes algorithm. Full Bayesian treatment is adopted in the model to realize automatic model selection. Controlled experimental studies showed that the developed model is capable of modeling the data set with outliers accurately. Furthermore, experiment results showed that the developed algorithm compares favorably against existing unsupervised probability model-based Bayesian feature selection algorithms on artificial and real data sets. Moreover, the application of the developed algorithm on real leukemia gene expression data indicated that it is able to identify the discriminating genes successfully.

FOLR1 increases sensitivity to cisplatin treatment in ovarian cancer cells.

BACKGROUND: Whether there is a mechanistic link between FOLR1 and response to cisplatin has not been extensively examined. In this study, we determine the expression of FOLR1 in ovarian cancer and examine if FOLR1 levels influence response to cisplatin. RESULTS: (1) FOLR1 protein expression was lowest in normal ovarian tissue, higher in benign ovarian tumors, and highest in malignant tumors (P < 0.01). (2) FOLR1 expression was decreased in platinum drug-resistant ovarian tumors compared to sensitive tumors (P < 0.01). Consistent with this, FOLR1 expression in tumors progressing following cisplatin treatment was lower than levels in tumors in remission (P < 0.01). (3) FOLR1 was successfully overexpressed at both the mRNA and protein levels following transfection in SKOV3 cells. (4) SKOV3 cells with FOLR1 overexpression were the most sensitive to cisplatin treatment (IC50 = 3.60 µg/ml) and exhibited the highest inhibition rates in the presence of the drug (P < 0.05). (5) The rate of apoptosis of SKOV3 cells increased with cisplatin treatment in a dose- and time-dependent manner (P < 0.05). Cisplatin also induced S phase arrest in a concentration-dependent manner (P < 0.05). Apoptosis and S phase proportion were significantly altered by FOLR1 overexpression (P < 0.05). CONCLUSION: FOLR1 may be a useful biomarker for ovarian cancer, and it may be useful as a therapeutic application to improve sensitivity to cisplatin treatment.