Identification of potential models for predicting progestin insensitivity in patients with endometrial atypical hyperplasia and endometrioid endometrial cancer based on ATAC-Seq and RNA-Seq integrated analysis.

Objective: The aim of this study was to establish predictive models based on the molecular profiles of endometrial lesions, which might help identify progestin-insensitive endometrial atypical hyperplasia (EAH) or endometrioid endometrial cancer (EEC) patients before progestin-based fertility-preserving treatment initiation. Methods: Endometrial lesions from progestin-sensitive (PS, n = 7) and progestin-insensitive (PIS, n = 7) patients were prospectively collected before progestin treatment and then analyzed by ATAC-Seq and RNA-Seq. Potential chromatin accessibility and expression profiles were compared between the PS and PIS groups. Candidate genes were identified by bioinformatics analyses and literature review. Then expanded samples (n = 35) were used for validating bioinformatics data and conducting model establishment. Results: ATAC-Seq and RNA-Seq data were separately analyzed and then integrated for the subsequent research. A total of 230 overlapping differentially expressed genes were acquired from ATAC-Seq and RNA-Seq integrated analysis. Further, based on GO analysis, REACTOME pathways, transcription factor prediction, motif enrichment, Cytoscape analysis and literature review, 25 candidate genes potentially associated with progestin insensitivity were identified. Finally, expanded samples were used for data verification, and based on these data, three predictive models comprising 9 genes (FOXO1, IRS2, PDGFC, DIO2, SOX9, BCL11A, APOE, FYN, and KLF4) were established with an overall predictive accuracy above 90%. Conclusion: This study provided potential predictive models that might help identify progestin-insensitive EAH and EEC patients before fertility-preserving treatment.

Increased TET1 Expression in Inflammatory Microenvironment of Hyperinsulinemia Enhances the Response of Endometrial Cancer to Estrogen by Epigenetic Modulation of GPER.

Background: Insulin resistance (IR) has been well studied in the initiation and development of endometrial endometrioid carcinoma (EEC). As yet, it has been largely neglected for estrogen sensitivity in local endometrium in hyperinsulinemia-induced systemic microenvironment. The aim of this study was to investigate the role of insulin in regulating estrogen sensitivity and explore the potential mechanisms in insulin-driven inflammatory microenvironment. Methods: We first investigated the effect of insulin on estradiol-driven endometrial cancer cells proliferation in vitro to address the roles of insulin in modulating estrogen sensitivity. Then GPER, ERα and TET1 in EEC samples with or without insulin resistance were screened by immunohistochemistry to confirm whether insulin resistance regulates estrogen receptors. Further mechanism analysis was carried out to address whether TET1 was mediated epigenetic modulation of GPER in insulin-induced microenvironment. Results: Insulin enhanced estradiol-driven endometrial cancer cells proliferation by up-regulating G-protein-coupled estrogen receptor (GPER) expression, but not ERα or ERß. Immunohistochemistry of EEC tissues showed that GPER expression was greatly increased in endometrial tissues from EEC subjects with insulin resistance and was positively correlated with Ten-eleven-translocation 1 (TET1) expression. Mechanistically, insulin up-regulates TET1 expression, and the latter, an important DNA hydroxymethylase, could up-regulate GPER expression through epigenetic modulation. Conclusion: This study identified TET1 as the upstream regulator of GPER expression and provides a possible mechanism that insulin-induced positive regulation of estrogen sensitivity in endometrial cancer cells. Increasing expression of GPER through TET1-mediated epigenetic modulation may emerge as the main regulator to enhance the response of endometrial cancer to estrogen in insulin-driven inflammatory microenvironment.

TET1-GPER-PI3K/AKT pathway is involved in insulin-driven endometrial cancer cell proliferation.

Large amount of clinical evidence has demonstrated that insulin resistance is closely related to oncogenesis of endometrial cancer (EC). Despite recent studies showed the up-regulatory role of insulin in G protein-coupled estrogen receptor (GPER/GPR30) expression, GPER expression was not decreased compared to control when insulin receptor was blocked even in insulin treatment. The purpose of this study was to explore the possible mechanism by which insulin up-regulates GPER that drives EC cell proliferation. For this purpose, we first investigated the GPER expression in tissues of endometrial lesions, further explored the effect of GPER on EC cell proliferation in insulin resistance context. Then we analyzed the role of Ten-Eleven Translocation 1 (TET1) in insulin-induced GEPR expression and EC cell proliferation. The results showed that GPER was highly expressed in endometrial atypical hyperplasia and EC tissues. Mechanistically, insulin up-regulated TET1 expression and the latter played an important role in up-regulating GPER expression and activating PI3K/AKT signaling pathway. TET1 mediated GPER up-regulation was another mechanism that insulin promotes EC cell proliferation.

Evaluation of the otolith function using c/oVEMPs in patients with Ménière's disease.

BACKGROUND: Cervical and ocular vestibular evoked myogenic potentials (c/oVEMPs) reflect otolith function. Up-to-date, there are no published reports on the systemic evaluation of otolith function in Ménière's Disease (MD) nor are there any reports on the differences in VEMPs between patients with early and late stage MD. The aim of this study was to evaluate the difference in c/oVEMPs between patients with MD and normal controls, as well as between patients with early and late stage MD. METHODS: Thirty patients with unilateral MD and thirty healthy subjects (as normal controls) were prospectively enrolled. c/oVEMPs using 500 Hz tone-burst stimuli were performed. VEMP tests were repeated 3 times on each subject to ensure reliability and reproducibility of responses. VEMPs were defined as present or absent. Abnormal VEMP was defined by lack of VEMP response. RESULTS: In the control group, abnormal cVEMPs and oVEMPs responses were detected in 6.67 and 3.34 % respectively. In MD patients (20 with early stage MD [ES-MD], 10 with late stage MD [LS-MD]), abnormal cVEMPs and oVEMPs responses were detected in 40 and 16.7 % respectively. More patients with MD showed abnormal responses in c/oVEMPs as compared to the control group (p < 0.05). cVEMPs was more often abnormal as compared to oVEMPs in MD patients (p < 0.05). There was a significant difference in abnormal cVEMP responses between ES-MD patients (25 %) and LS-MD patients (70 %) (p < 0.05). Difference in abnormal oVEMP responses (ES-MD, 5 %; LS-MD, 40 %) was significant (p < 0.05). CONCLUSION: An increased occurrence of abnormal c/oVEMP recordings appeared in MD patients, possibly as a result of hydrops of the otolith. cVEMPs were more often abnormal in MD patients as compared to oVEMPs, suggesting that saccular dysfunction may be more common than utricular dysfunction. Furthermore, o/cVEMP abnormalities in the LS-MD group were significantly higher than those in the ES-MD group, suggesting the trend that otolith damage is gradually increasing with the aggravation of cochlear injury in MD.

(5R,8R)-2-(3,8-Dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octa-hydro-azulen-5-yl)acrylic acid (rupestonic acid).

The title compound, C(15)H(20)O(3), crystallizes with two independent mol-ecules in the asymmetric unit. In both mol-ecules, the seven-membered ring adopts a chair conformation. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into chains extending in the [201] direction. The absolute configuration was assigned on the basis of the starting materials.