PRDM14 extinction enables the initiation of trophoblast stem cell formation.

Trophoblast stem cells (TSCs) can be chemically converted from embryonic stem cells (ESCs) in vitro. Although several transcription factors (TFs) have been recognized as essential for TSC formation, it remains unclear how differentiation cues link elimination of stemness with the establishment of TSC identity. Here, we show that PRDM14, a critical pluripotent circuitry component, is reduced during the formation of TSCs. The reduction is further shown to be due to the activation of Wnt/ß-catenin signaling. The extinction of PRDM14 results in the erasure of H3K27me3 marks and chromatin opening in the gene loci of TSC TFs, including GATA3 and TFAP2C, which enables their expression and thus the initiation of the TSC formation process. Accordingly, PRDM14 reduction is proposed here as a critical event that couples elimination of stemness with the initiation of TSC formation. The present study provides novel insights into how induction signals initiate TSC formation.

Comprehensive preimplantation genetic testing for balanced insertional translocation carriers.

BACKGROUND: Balanced insertional translocations (BITs) can increase the risk of infertility, recurrent miscarriages or neonatal birth defects due to chromosomal imbalances in gametes. However, studies on preimplantation genetic testing (PGT) for patients carrying BITs are inadequate. METHODS: A preimplantation genetic genotyping and haplotype analysis approach was developed and implemented in this study. Genome-wide SNP genotyping was performed, followed by core family-based haplotype analysis. The balanced insertion segments in euploid embryos were inferred from the haplotypes inherited from the carrier parent. RESULTS: A total of 10 BIT carrier couples were enrolled in our study. 15 in vitro fertilisation cycles were conducted, resulting in 73 blastocysts biopsied and subjected to PGT analysis. Among these, 20 blastocysts displayed rearrangement-related imbalances, 13 exhibited de novo aneuploidies, 15 presented a complex anomaly involving both imbalances and additional aneuploidies, while 25 were euploid. Within the euploid embryos, 12 were balanced carrier embryos and 13 were non-carrier embryos. To date, eight non-carrier and one carrier embryos have been transferred, resulting in seven clinical pregnancies. All pregnancies were recommended to perform prenatal diagnosis, our date revealed complete concordance between fetal genetic testing results and PGT results. Presently, five infants have been born from these pregnancies, and two pregnancies are still ongoing. CONCLUSION: The proposed method facilitates comprehensive chromosome screening and the concurrent identification of balanced insertions or normal karyotypes in embryos. This study offers an effective and universally applicable strategy for BIT carriers to achieve a healthy pregnancy and prevent the transmission of BITs to their offspring.

Sodium oligomannate's amelioration of reproductive and metabolic phenotypes in a letrozole-induced PCOS-like mouse model depends on the gut microbiome†.

It has been well established that there is a connection between polycystic ovary syndrome pathology and gut microbiome dysbiosis. A marine-derived oligosaccharide, GV-971, has been reported to alter gut microbiota and alleviate Aß amyloidosis. In this study, the effects of GV-971 on polycystic ovary syndrome-like mice were explored. Mice were randomly assigned into four groups: control, letrozole, letrozole + GV-971, and control + GV-971. Glucose metabolism in polycystic ovary syndrome-like mice was ameliorated by GV-971, while the reproductive endocrine disorder of polycystic ovary syndrome-like mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes in ovaries of polycystic ovary syndrome-like mice were improved. GV-971 restored the fertility of polycystic ovary syndrome-like mice and significantly increase the number of litters. Furthermore, GV-971 treatment effectively mitigated abnormal bile acid metabolism. Notably, after GV-971 intervention, gut microbiota alpha-diversity was considerably raised and the relative abundance of Firmicutes was reduced. In conclusion, the hyperinsulinemia and hyperandrogenemia of polycystic ovary syndrome-like mice were alleviated by GV-971 intervention, which was associated with mitigating bile acid metabolism and modulating gut microbiota.

Chronic Stress Blocks the Endometriosis Immune Response by Metabolic Reprogramming.

Studies have shown that the occurrence and development of endometriosis are closely linked to long-term psychological stress. The specific contribution of chronic stress to the metabolic adaptations in patients with endometriosis is still unknown. Lesions were removed from ten endometriosis patients during an operation, and the participants were divided into two groups using a psychological questionnaire. An mRNA Human Gene Expression Microarray analysis was applied to compare the mRNA expression profiles between the chronic stress group and the control group. In addition, the reliability of the mRNA Human Gene Expression Microarray analysis was verified by using research on metabolites based on both the liquid chromatography (LC-MS/MS) technique and quantitative reverse transcription polymerase chain reaction (RT-PCR). A microarray analysis of significantly up-regulated, differentially expressed genes between the chronic stress and the control groups showed genes that were principally related to metabolism-related processes and immune-related processes, such as the immune response process, negative regulation of T cell proliferation, the leucine metabolic process, and the L-cysteine metabolic process (p < 0.05). LC-MS showed that the differential metabolites were primarily concerned with arginine and proline metabolism, D-glutamine and D-glutamate metabolism, aspartate metabolism, glycine, serine metabolism, and tyrosine metabolism (p < 0.05). The possibility of chronic stress blocks the endometriosis immune response through metabolic reprogramming. Chronic stress reduces the supply of energy substrates such as arginine and serine, down-regulates T immune cell activation, and affects the anti-tumor immune response, thereby promoting the migration and invasion of endometriosis lesions in patients with chronic stress.

Targeting metabolism to influence cellular senescence a promising anti-cancer therapeutic strategy.

Metabolic disorders are considered the hallmarks of cancer and metabolic reprogramming is emerging as a new strategy for cancer treatment. Exogenous and endogenous stressors can induce cellular senescence; the interactions between cellular senescence and systemic metabolism are dynamic. Cellular senescence disrupts metabolic homeostasis in various tissues, which further promotes senescence, creating a vicious cycle facilitating tumor occurrence, recurrence, and altered outcomes of anticancer treatments. Therefore, the regulation of cellular senescence and related secretory phenotypes is considered a breakthrough in cancer therapy; moreover, proteins involved in the associated pathways are prospective therapeutic targets. Although studies on the association between cellular senescence and tumors have emerged in recent years, further elucidation of this complex correlation is required for comprehensive knowledge. In this paper, we review the research progress on the correlation between cell aging and metabolism, focusing on the strategies of targeting metabolism to modulate cellular senescence and the progress of relevant research in the context of anti-tumor therapy. Finally, we discuss the significance of improving the specificity and safety of anti-senescence drugs, which is a potential challenge in cancer therapy.

Clinical characteristics and status of treatment of small-cell carcinoma of the ovary, hypercalcemic type in the Chinese population: a meta-analysis.

OBJECTIVE: This study aimed to comprehensively analyze the clinical characteristics and treatment status of Chinese small cell carcinoma of the ovary hypercalcemic type (SCCOHT) patients, providing insights into this unique population and comparing findings with international literature. METHODS: Through a meta-analysis, we collected data from published case reports and records from the Obstetrics & Gynecology Hospital of Fudan University. Demographic information, clinical presentations, tumor attributes, treatment modalities, and survival outcomes were extracted and examined alongside relevant global studies. RESULTS: The analysis encompassed 80 Chinese SCCOHT patients, of which 62 from 33 previously reported literatures, and the other 18 were from Obstetrics & Gynecology Hospital of Fudan University. In 62 cases with stage information, A total of 25 tumors were International Federation of Gynecology and Obstetrics stage I, 3 were stage II, 19 were stage III, and 15 were stage IV. Most patients received surgery and chemotherapy, but regimens were varied. Median follow-up was 10 months (range=4-120). Elevated carbohydrate antigen 125 and serum calcium levels were consistent findings. Recurrence rates were notable, especially among stage I patients. Platinum-based chemotherapy, paclitaxel and carboplatin (n=11, 13.4%), constituted common treatment regimens. CONCLUSION: This study observed demographic and clinical similarities with international datasets. And the findings emphasize the urgency for innovative therapeutic approaches to improve outcomes in SCCOHT patients. Continued research efforts are essential to enhance the knowledge surrounding this rare malignancy and to optimize its clinical management.

Biomarkers identification in follicular fluid in relation to live birth in in vitro fertilization of women with polycystic ovary syndrome in different subtypes by using UPLC-MS method.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common infertility disorder which affects reproductive-aged women. However, metabolic change profiles of follicular fluid (FF) in lean and obese women diagnosed with and without PCOS remains unclear. METHODS: 95 infertile women were divided into four subgroups: LC (lean control), OC (overweight control), LP (lean PCOS), and OP (overweight PCOS). The FF samples were collected during oocyte retrieval and assayed by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) metabolomics. RESULTS: A total of 236 metabolites were identified by metabolic analysis. The pathway enrichment analysis revealed that the glycerophospholipid metabolism (impact = 0.11182), ether lipid metabolism (impact = 0.14458), and primary bile acid biosynthesis (impact = 0.03267) were related to metabolic pathway between PCOS and control. Correlation analyses showed that epitestosterone sulfate was found positively correlated with fertilization rate in PCOS, while falcarindione, lucidone C. and notoginsenoside I was found to be negatively correlated. The combined four biomarkers including lucidone C, epitestosterone sulfate, falcarindione, and notoginsenoside I was better in predicting live birth rate, with AUC of 0.779. CONCLUSION: The follicular fluid of women with PCOS showed unique metabolic characteristics. Our study provides better identification of PCOS follicular fluid metabolic dynamics, which may serve as potential biomarkers of live birth.

IL-18BP Therapy Ameliorates Reproductive and Metabolic Phenotypes in a PCOS Mouse Model by Relieving Inflammation, Fibrosis and Endoplasmic Reticulum Stress.

There is a chronic inflammation in PCOS patients, which is correlated with the pathogenesis of PCOS. IL-18 and IL-18BP are related with some inflammatory diseases, while less explored in PCOS. Whether IL-18BP could be a potential drug of PCOS remains unknown.IL-18 and testosterone levels were evaluated in serum of 10 non-PCOS control patients and 20 PCOS patients. Female C57/BL6 mice were gavaged with letrozole to induce PCOS mouse model and IL-18 level was evaluated in the serum of PCOS mouse model, and IL-18 is intraperitoneally injected in female mice, IL-18BP is intraperitoneally injected in the PCOS mice models. Then the body weights, estrous cycles, reproductive hormones and morphology of ovaries were analyzed. The level of ovarian chronic inflammation, fibrosis and endoplasmic reticulum (ER) stress are evaluated.IL-18 levels are increased in the serum of PCOS patients and PCOS mice models respectively. The serum DHEAS, iWAT weight and adipocyte size were increased in IL-18 group compared to the control group (P < 0.05). In the PCOS mouse model treated with IL-18BP, the body weight and serum LH/FSH ratio was decreased compared to the PCOS group (P < 0.05). The expression levels of inflammatory factors and fibrosis-related genes, the expression level of endoplasmic reticulum stress-related genes, and the ROS positive area of ovarian tissue was decreased (P < 0.05).IL-18 is involved in inducing PCOS phenotypes, while IL-18BP relieves PCOS phenotypes by alleviating ovarian chronic inflammation, fibrosis and ER stress in PCOS mice.

A follicle-stimulating hormone receptor-targeted near-infrared fluorescent probe for tumor-selective imaging and photothermal therapy.

Late detection, peritoneal dissemination, chemoresistance and weak response to targeted therapeutics lead to high mortality in ovarian cancer. More efficient and specific tumor imaging and therapeutic agents are needed to improve the resection rate of surgery and to eliminate residual disease. The expression patterns of follicle-stimulating hormone (FSH) receptor make it a suitable target for ovarian cancer. Here, we report a strategy to develop an organic near-infrared probe for FSH receptor-targeted tumor imaging and photothermal therapy. The FSH-Rh760 probe was conjugated from the Rh760 fluorophore with the FSH ß subunit 33-53 peptide. FSH-Rh760 specifically distinguished peritoneal metastatic ovarian cancerous foci from surrounding normal tissues with a high tumor-to-background ratio. The fluorescence signals in tumors peaked at 2 h and were cleared at 120 h postinjection. FSH-Rh760 treatment rapidly increased the abdomen temperature of mice up to ∼43 °C upon exposure to a near-infrared laser and effectively suppressed peritoneal tumor growth with tumor specificity. No significant systemic toxicities were observed. This study demonstrates the targeting ability and biocompatibility of FSH receptor-targeted theranostics and highlights its potential for clinical application in imaging-guided precision tumor resection and photothermal therapy to eliminate cancer lesions intraoperatively and postoperatively.

Immunotherapy combined with targeted therapy in advanced small cell carcinoma of the ovary of hypercalcemic type: A case of overall survival lasting for over 5 years.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT.

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit the rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH, and ASK1-JNK pathway are targetable to alleviate PCOS.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

Prospective prenatal cell-free DNA screening for genetic conditions of heterogenous etiologies.

Prenatal cell-free DNA (cfDNA) screening uses extracellular fetal DNA circulating in the peripheral blood of pregnant women to detect prevalent fetal chromosomal anomalies. However, numerous severe conditions with underlying single-gene defects are not included in current prenatal cfDNA screening. In this prospective, multicenter and observational study, pregnant women at elevated risk for fetal genetic conditions were enrolled for a cfDNA screening test based on coordinative allele-aware target enrichment sequencing. This test encompasses the following three of the most frequent pathogenic genetic variations: aneuploidies, microdeletions and monogenic variants. The cfDNA screening results were compared to invasive prenatal or postnatal diagnostic test results for 1,090 qualified participants. The comprehensive cfDNA screening detected a genetic alteration in 135 pregnancies with 98.5% sensitivity and 99.3% specificity relative to standard diagnostics. Of 876 fetuses with suspected structural anomalies on ultrasound examination, comprehensive cfDNA screening identified 55 (56.1%) aneuploidies, 6 (6.1%) microdeletions and 37 (37.8%) single-gene pathogenic variants. The inclusion of targeted monogenic conditions alongside chromosomal aberrations led to a 60.7% increase (from 61 to 98) in the detection rate. Overall, these data provide preliminary evidence that a comprehensive cfDNA screening test can accurately identify fetal pathogenic variants at both the chromosome and single-gene levels in high-risk pregnancies through a noninvasive approach, which has the potential to improve prenatal evaluation of fetal risks for severe genetic conditions arising from heterogenous molecular etiologies. ClinicalTrials.gov registration: ChiCTR2100045739 .