Obstetrics and Gynaecology - Research Publications
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ItemEpithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin(AMER ASSOC CANCER RESEARCH, 2022-12-01)UNLABELLED: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
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ItemInhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium(HINDAWI LTD, 2020-04-15)RESULTS: GPR91 mRNA expression was significantly higher in myometrium from women during term spontaneous labor compared to no labor. Likewise, in mice, GPR91 mRNA expression was significantly upregulated in myometrium during inflammation-induced preterm labor compared to preterm no labor. In myometrial cells, IL1B and TNF significantly increased GPR91 mRNA expression. Knockdown of GPR91 by siRNA in myometrial cells significantly suppressed the secretion and/or expression of IL1B- and TNF-induced proinflammatory cytokines (GM-CSF, IL1A, IL1B, and IL6) and chemokines (CXCL8 and CCL2), myometrial contractility (expression of the contraction-associated proteins PTGFR and CX43, secretion of the uterotonic PGF2α , and in situ collagen gel contraction), and the transcription factor NF-κB. CONCLUSION: Our findings demonstrate that GPR91 is involved in the genesis of proinflammatory and prolabor mediators induced by IL1B or TNF and collectively suggest that GPR91 may contribute to augmentation of the labor processes.
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ItemExploring the Relationship Between Maternal Circulating Hormones and Gestational Weight Gain in Women Without Obesity: A Cross-Sectional Study(DOVE MEDICAL PRESS LTD, 2020)BACKGROUND: Central homeostatic regulation of fat stores is attenuated during pregnancy, to allow for adequate fat deposition to support fetal development and lactation. What factors particular to pregnancy facilitate fat accumulation, and why gestational weight gain (GWG) is so variable, are not clear. The aim of this cross-sectional study was to examine the associations between GWG and circulating hormones with known effects on appetite and growth. METHODS: Women without obesity (body mass index, BMI <30 kg/m2), with a healthy singleton pregnancy, were recruited at the time of delivery by elective Caesarean section at a tertiary obstetric hospital. Women with preterm (<37 weeks) delivery and smokers were excluded. Maternal blood was collected at the time of delivery for measurement of fasting oestradiol, progesterone, prolactin, insulin, leptin, insulin-like growth factor 1 and insulin-like growth factor binding protein 3. Comparisons were made between women who gained weight within the range recommended by Institute of Medicine guidelines for normal weight women (11.5-16 kg; n=34) and those who gained excessive weight (>16 kg; n=35) during pregnancy. Analysis of covariance was carried out using multiple linear regression to test the effect of GWG group on biochemical parameters, accounting for pre-pregnancy BMI. RESULTS: The 69 participants had a mean age of 34.6 ± 4.3 years, and pre-pregnancy BMI of (23.3 ± 1.8 kg/m2), with no significant differences between groups in pre-pregnancy weight, BMI, age, birthweight or parity. Mean GWG was 14.0 ± 1.3 kg in the "recommended" group and 19.6 ± 3.2 kg in the "excessive" group. Leptin was significantly higher (43.4 ± 21.6 vs 33.4 ± 15.0 ng/mL, p=0.03) and prolactin tended to be lower (159.5 ± 66.1 vs 194.0 ± 85.6 ng/mL, p=0.07) at delivery in women with excessive (vs recommended) GWG. No other circulating factors were found to differ between groups. The between-group difference in leptin remained after adjustment for pre-pregnancy BMI in multiple linear regression and quantile regression analyses. CONCLUSION: In women without obesity, leptin remains a marker of adiposity during pregnancy. GWG was not associated with other circulating hormones with effects on appetite and growth.