Targeting ferroptosis in ovarian cancer: Novel strategies to overcome chemotherapy resistance.

AIMS: This review investigates the role of ferroptosis in combating chemotherapy resistance in ovarian cancer, with a focus on its underlying mechanisms and therapeutic implications. MAIN METHODS: A database search was conducted up to December 2023 using PubMed, Scopus, Google Scholar, Web of Science, and the Cochrane Library. The keywords "ovarian cancer," "ferroptosis," "cisplatin," and "cisplatin resistance" were employed. We included studies that offered original data on the application of ferroptosis in platinum-based chemotherapy, focusing on both in-vitro and in-vivo research models. KEY FINDINGS: Our review reveals that ferroptosis significantly influences drug resistance in ovarian cancer. It investigates the existing studies to understand the role of ferroptosis in platinum resistance and explores its underlying mechanisms and assesses potential therapeutic strategies that uses ferroptosis to improve outcomes. The findings underscore the importance of ferroptosis in enhancing the effectiveness of platinum-based treatments and improving patient prognosis. SIGNIFICANCE: The potential of ferroptosis induction to develop novel therapeutic strategies against ovarian cancer, especially in cisplatin-resistant cases, is promising. The preliminary nature of these findings highlights the necessity for further research to bring these insights into clinical practice. This would not only improve treatment outcomes and prognosis but also encourage ongoing studies into ferroptosis as a viable therapeutic approach.

Effects of age on the diagnostic value of the soluble fms-like tyrosine kinase-1/ placental growth factor ratio in preeclampsia: a retrospective cohort study.

OBJECTIVE: Measurement of the ratio between soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) supports the diagnosis of preeclampsia. sFlt-1/PlGF ratios of at least 85 and at least 110 have previously been suggested for diagnosis of early-onset and late-onset preeclampsia, respectively. However, angiogenic and antiangiogenic factors change throughout the process of aging, potentially influencing preeclampsia diagnosis. In this study, we therefore evaluated in detail the effect of maternal age on sFlt-1/PlGF ratios. METHODS: A total of 2775 pregnant female patients were included in this retrospective cohort study, spread across three maternal age groups: 18-25 years, 26-35 years, and more than 35 years at delivery. Receiver-operating characteristic (ROC) curve analysis was employed to evaluate sFlt-1/PlGF ratio cutoffs for use in preeclampsia diagnosis. RESULTS: Controls (2462 pregnant women) showed a significant difference in sFlt-1/PlGF ratios between the youngest and oldest age groups, which resulted in differences in the best-performing sFlt-1/PlGF ratio cutoffs: optimized cutoffs were 143.4 (52.9%, 98.2%), 8.6 (84.4%, 75.3%), and 22.9 (78.6%, 82.3%) in early-onset preeclampsia, and 46.4 (67.5%, 81.5%), 40.8 (77.3%, 73%), and 44.1 (65.1%, 74.5%) in late-onset preeclampsia in age groups, 1, 2, and 3, respectively. CONCLUSION: sFlt-1/PlGF ratios change with maternal age, which has important clinical implications for their use in the diagnosis of preeclampsia: Better differentiated sFlt-1/PlGF cutoffs should be used that take maternal and gestational age into account.

TNF-α Regulated Endometrial Stroma Secretome Promotes Trophoblast Invasion.

Successful implantation requires the coordinated migration and invasion of trophoblast cells from out of the blastocyst and into the endometrium. This process relies on signals produced by cells in the maternal endometrium. However, the relative contribution of stroma cells remains unclear. The study of human implantation has major technical limitations, therefore the need of in vitro models to elucidate the molecular mechanisms. Using a recently described 3D in vitro models we evaluated the interaction between trophoblasts and human endometrial stroma cells (hESC), we assessed the process of trophoblast migration and invasion in the presence of stroma derived factors. We demonstrate that hESC promotes trophoblast invasion through the generation of an inflammatory environment modulated by TNF-α. We also show the role of stromal derived IL-17 as a promoter of trophoblast migration through the induction of essential genes that confer invasive capacity to cells of the trophectoderm. In conclusion, we describe the characterization of a cellular inflammatory network that may be important for blastocyst implantation. Our findings provide a new insight into the complexity of the implantation process and reveal the importance of inflammation for embryo implantation.

Maintenance tocolysis: a reappraisal of clinical evidence.

INTRODUCTION: Maintenance tocolysis, mostly defined as the continuation of tocolytic treatment beyond 48 h, remains a matter of debate. There is no sufficient evidence from randomized controlled trials, that maintenance tocolysis is able to prolong pregnancy significantly and to reduce severe neonatal morbidity and mortality. Hence, it is not recommended in current guidelines. On the contrary, maintenance tocolysis is commonly used in clinical practice and subject of current clinical-scientific investigations. TOCOLYTICS FOR MAINTENANCE TREATMENT: None of the conventional tocolytics (beta-sympathomimetics, calcium-channel blockers, magnesium, cyclooxygenase inhibitors, and oxytocin receptor antagonists) have proven to be appropriate for maintenance treatment. Progesterone and 17-α-hydroxyprogesterone caproate have shown promising results in low-quality randomized trials, but not in high-quality studies. DISCUSSION: Basically, the value of studies regarding maintenance tocolysis is limited by a considerable heterogeneity, its mostly low quality, significant differences in methodology as well as the inadequate statistical power due to the small number of women studied. So far, maintenance tocolysis is a case-by-case decision outweighing the benefits and harms of tocolytic treatment.

Novel 3D in vitro models to evaluate trophoblast migration and invasion.

PROBLEM: Embryo implantation depends on the interactions between the developing embryo and the maternal endometrium. Signals originating from the decidua play a critical role in the process of implantation and trophoblast invasion; however, the molecular mechanisms mediating this interaction are poorly understood. The objective of this study was to develop in vitro models that would mimic the processes of attachment, migration, and early invasion of the trophoblast. METHODS OF STUDY: First trimester trophoblast cells (Sw.71 cells) were cultured in low attachment plates to form blastocyst-like spheroids (BLS). Epithelial-mesenchymal transition (EMT) characterization during BLS formation was determined by RT-PCR and Western Blot. The two 3D in vitro culture models consist of (a) trophoblast migration: BLS cultured in suspension (b) trophoblast invasion: human endometrium stromal cells (HESC) plated in the bottom of a 96-well plate, covered by Matrigel and BLS transferred on top. Matrigel was used to mimic the human endometrial extracellular matrix. RESULTS: Using 3D cell culture systems and real-time imaging, we are able to determine the impact of endometrial factors on trophoblast cell function. Endometrial stromal cells promote blastocyst-like spheroid migration of trophoblast cells and invasion of the extracellular matrix. CONCLUSION: We report the characterization of 3D in vitro models to evaluate the interaction between endometrial cells and trophoblast during the process of migration and invasion. The models are useful tools in order to further study the molecular mechanism of embryo-maternal uterine cells interactions.