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.

Exploring the Micro-Mosaic Landscape of FGFR3 Mutations in the Ageing Male Germline and Their Potential Implications in Meiotic Differentiation.

Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the FGFR3 mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis-expansion patterns, as well as the increases in mutations in sperm for two FGFR3 variants-c.1138G>A (p.G380R) and c.1948A>G (p.K650E)-which are associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase in mutant sperm with the donor's age, as also reported in other studies, the TDII mutation showed focal mutation pockets in the testis but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signalling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into the transmission risks of micro-mosaics associated with advanced paternal age in the male germline.

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.

The impact of poly-A microsatellite heterologies in meiotic recombination.

Meiotic recombination has strong, but poorly understood effects on short tandem repeat (STR) instability. Here, we screened thousands of single recombinant products with sperm typing to characterize the role of polymorphic poly-A repeats at a human recombination hotspot in terms of hotspot activity and STR evolution. We show that the length asymmetry between heterozygous poly-A's strongly influences the recombination outcome: a heterology of 10 A's (9A/19A) reduces the number of crossovers and elevates the frequency of non-crossovers, complex recombination products, and long conversion tracts. Moreover, the length of the heterology also influences the STR transmission during meiotic repair with a strong and significant insertion bias for the short heterology (6A/7A) and a deletion bias for the long heterology (9A/19A). In spite of this opposing insertion-/deletion-biased gene conversion, we find that poly-A's are enriched at human recombination hotspots that could have important consequences in hotspot activation.

Artifactual mutations resulting from DNA lesions limit detection levels in ultrasensitive sequencing applications.

The need in cancer research or evolutionary biology to detect rare mutations or variants present at very low frequencies (<10-5) poses an increasing demand on lowering the detection limits of available methods. Here we demonstrated that amplifiable DNA lesions introduce important error sources in ultrasensitive technologies such as single molecule PCR (smPCR) applications (e.g. droplet-digital PCR), or next-generation sequencing (NGS) based methods. Using templates with known amplifiable lesions (8-oxoguanine, deaminated 5-methylcytosine, uracil, and DNA heteroduplexes), we assessed with smPCR and duplex sequencing that templates with these lesions were amplified very efficiently by proofreading polymerases (except uracil), leading to G->T, and to a lesser extent, to unreported G->C substitutions at 8-oxoguanine lesions, and C->T transitions in amplified uracil containing templates. Long heat incubations common in many DNA extraction protocols significantly increased the number of G->T substitutions. Moreover, in ∼50-80% smPCR reactions we observed the random amplification preference of only one of both DNA strands explaining the known 'PCR jackpot effect', with the result that a lesion became indistinguishable from a true mutation or variant. Finally, we showed that artifactual mutations derived from uracil and 8-oxoguanine could be significantly reduced by DNA repair enzymes.

Aquaporin 5 expression in mouse mammary gland cells is not driven by promoter methylation.

Several studies have revealed that aquaporins play a role in tumor progression and invasion. In breast carcinomas, high levels of aquaporin 5 (AQP5), a membrane protein involved in water transport, have been linked to increased cell proliferation and migration, thus facilitating tumor progression. Despite the potential role of AQP5 in mammary oncogenesis, the mechanisms controlling mammary AQP5 expression are poorly understood. In other tissues, AQP5 expression has been correlated with its promoter methylation, yet, very little is known about AQP5 promoter methylation in the mammary gland. In this work, we used the mouse mammary gland cell line EpH4, in which we controlled AQP5 expression via the steroid hormone dexamethasone (Dex) to further investigate mechanisms regulating AQP5 expression. In this system, we observed a rapid drop of AQP5 mRNA levels with a delay of several hours in AQP5 protein, suggesting transcriptional control of AQP5 levels. Yet, AQP5 expression was independent of its promoter methylation, or to the presence of negative glucocorticoid receptor elements (nGREs) in its imminent promoter region, but was rather influenced by the cell proliferative state or cell density. We conclude that AQP5 promoter methylation is not a universal mechanism for AQP5 regulation and varies on cell and tissue type.