Ovarian endometriosis is a chronic inflammatory disease characterized by extensive tissue remodeling and fibrosis, which significantly impacts female reproductive health. This study demonstrates that ectopic endometrium (Ect) in patients with endometriosis exhibit pronounced fibrotic changes compared to normal (Norm) and eutopic endometrium (Eut), characterized by the upregulation of fibrosis-associated genes including α-SMA, Col-1α1, and CTGF. Using primary cell isolation and characterization, we identified that exosomes derived from ectopic endometrial stromal cells (EctESCs-exo) serve as critical mediators of this pathological process. Fluorescent tracking and functional assays revealed that EctESCs-exo are internalized by eutopic endometrial stromal cells (EutESCs), subsequently triggering a pro-fibrotic phenotype in vitro and promoting lesion growth and collagen deposition in a mouse model of endometriosis. Through bioinformatic and multi-cohort validation, miR-21-5p was found to be significantly enriched in both ectopic tissues and their secreted exosomes. Silencing miR-21-5p in donor ectopic endometrial stromal cells (EctESCs) effectively attenuated the fibrotic response in recipient cells, whereas miR-21-5p-enriched exosomes markedly accelerated disease progression and fibrosis in vivo. Mechanistically, dual-luciferase reporter assays and functional rescue experiments confirmed that miR-21-5p directly targets von Hippel-Lindau (VHL), a negative regulator of fibrosis that is downregulated in ectopic lesions. Collectively, our findings elucidate a novel mechanism of exosome-mediated intercellular communication where EctESCs drive fibrotic progression via the miR-21-5p/VHL axis, suggesting that targeting this pathway could offer a promising therapeutic strategy for endometriosis.

BACKGROUND:Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age, in which abnormal follicular development is a major contributor to ovulatory dysfunction and infertility. Studies have shown that granulosa cell dysfunction underlies this aberrant follicular development. Within the follicular microenvironment, exosomes serve as crucial mediators of intercellular communication. Notably, exosomal non-coding RNAs (ncRNAs) are dysregulated in PCOS and have been implicated in its pathogenesis. Nevertheless, the precise mechanisms by which these exosomal ncRNAs influence abnormal follicular development in PCOS remain to be elucidated. METHODS:A total of 40 PCOS patients and 45 non-PCOS controls undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment were included in this study. Exosomes and mural granulosa cells (mGCs) of those patients were isolated from follicular fluid. Cumulus granulosa cells (cGCs) were separated from the cumulus-oocyte complexes (COCs). High-throughput miRNA sequencing were performed to analyze the expression profile of miRNAs in follicular fluid exosomes from 3 PCOS patients and 3 controls, and an additional 37 PCOS and 42 control samples were used for validation. The diagnostic potential of exosomal miR-143-5p for PCOS was evaluated using receiver operating characteristic (ROC) curve analysis, and its correlation with clinical parameters was examined. Quantitative real-time PCR was used to confirm miR-143-5p expression in exosomes and granulosa cells. Functional assays in primary mural GCs (mGCs) and KGN cells investigated the effects of exosomal miR-143-5p on granulosa cell proliferation. Bioinformatic analysis combined with dual-luciferase reporter assays were performed to validate the target gene of miR-143-5p. In vivo, a letrozole-induced PCOS rat model was established to investigate the role of miR-143-5p in the pathogenesis of the disease. RESULTS:In this study, we identified exosomal miR-143-5p as significantly upregulated in follicular fluid from PCOS patients, in which it correlated with serum AMH levels and demonstrated strong diagnostic potential. Functional experiments in primary mGCs and KGN cells revealed that miR-143-5p promotes GC proliferation. Mechanistically, RASAL2 was identified and validated as a direct target of miR-143-5p. Exosomes derived from miR-143-5p-overexpressing cells enhanced recipient GC proliferation, confirming the role of exosomal mediation. In a letrozole-induced PCOS rat model, inhibition of miR-143-5p increased RASAL2 expression and ameliorated key pathological features, including ovarian weight, cystic follicle formation, and hormonal imbalances. CONCLUSIONS:These findings reveal a novel exosomal miR-143-5p/RASAL2 pathway driving GC proliferation and ovarian dysfunction in PCOS, highlighting its potential as both a diagnostic biomarker and therapeutic target.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder manifested by hyperandrogenism, ovulatory dysfunction, and systemic metabolic dysregulation. While the 'gut-diet' axis offers potential therapeutic avenues, the synergistic molecular mechanisms integrating dietary flavonoids and gut microbiota remain elusive. This study employed a comprehensive network pharmacology approach, coupled with molecular docking validation, to decode the tripartite interaction network of 'Dietary Flavonoids-Gut Microbiota-Host Targets.' Our analysis identified Luteolin and Quercetin as critical bioactive mediators that interact with specific gut microbial taxa. Topological network analysis revealed that these compounds exert the effects by targeting pivotal nodes-AKT Serine/Threonine Kinase 1 (AKT1), Epidermal Growth Factor Receptor (EGFR), and Insulin Receptor (INSR). Functional enrichment analysis further demonstrated that these targets converge on the Mitogen-Activated Protein Kinase (MAPK) signalling pathway. Conclusively, this study establishes a systematic theoretical framework for the integrated management of PCOS. Future research should prioritize experimental validation and clinical translation of the findings to develop personalized precision medicines targeting the gut-metabolic axis.

Ovarian endometriosis (OEMs) is a primary cause of female infertility and is driven primarily by fibrosis, which disrupts the ovarian follicular microenvironment. Pirfenidone (PFD), an FDA-approved antifibrotic drug, holds promise for treating OEMs, but its efficacy and underlying mechanisms in a relevant in vivo model remain unexplored. A novel mouse model of OEMs was surgically induced. Model mice were randomized to receive either PFD (200 mg/kg every 2 days, n = 20) or vehicle (n = 20) for 24 days. We assessed lesion size and weight, fibrosis via Masson’s trichrome staining and α-SMA immunohistochemistry (IHC), ovarian function through follicle-stimulating hormone receptor (Fshr) IHC and quantitative PCR, and granulosa cell status via Ki67 IHC and TUNEL assays. An unbiased label-free quantitative proteomic analysis was performed to elucidate the mechanism, with key pathways validated by Prussian blue staining and Western blotting. Statistical significance was determined via Student’s t test. The OEMs exhibited characteristic cysts, extensive fibrosis (increased α-SMA and collagen deposition, p < 0.05), impaired fertility, and disrupted ovarian function (downregulated Fshr, reduced granulosa cell proliferation, and increased apoptosis, p < 0.05). PFD treatment significantly reduced lesion size, weight, and fibrosis (p < 0.05) and restored the expression of markers of ovarian reserve and folliculogenesis (p < 0.05). Proteomics revealed 554 differentially expressed proteins. PFD downregulated pathways involved in extracellular matrix (ECM) organization and inflammation and upregulated proteins related to iron ion transport and ferroptosis. These findings were confirmed by a significant reduction in ferric iron deposition (p < 0.05) and collagen I protein expression (p < 0.05) in the PFD group. Pirfenidone has strong therapeutic potential for treating ovarian endometriosis by simultaneously alleviating fibrosis and restoring ovarian function. Its efficacy is mediated through a novel mechanism of modulating iron homeostasis and the ferroptosis pathway, alongside its known antifibrotic actions. Our findings provide a compelling rationale for repurposing pirfenidone as a disease-modifying treatment for OEMs.

Cancer-associated fibroblasts (CAFs) are key players in the tumor microenvironment (TME), but their roles in prognosis and immunotherapy response in mismatch repair-deficient endometrial cancer (dMMR EC) remain unclear. This study used single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to identify Wnt-related CAF subclusters and applied multi-algorithm machine learning to build a risk signature for predicting clinical outcomes and immunotherapy response. We obtained scRNA-seq data for dMMR EC and bulk RNA-seq data from public databases. The Seurat R package was used to define Wnt-related CAFs. We identified tumor and normal cells through copy number variation (CNV) and screened differentially expressed genes with the limma package, determining their correlation with CAF clusters via Pearson correlation analysis. Prognostic genes related to CAFs were first filtered using univariate Cox regression, followed by a machine learning framework comprising ten algorithms and 101 combinations, evaluated by the concordance index (C-index) to identify the optimal gene signature. A nomogram model was developed, combining clinicopathological features and risk score. We conducted SNV mutation risk analysis, immune landscape analysis, and validated the response to immune checkpoint modules. By using scRNA-seq data, we identified six CAF clusters in dMMR EC, five of which were related to prognosis. We distinguished 9,682 tumor cells and 5,476 normal cells using copykat methods. Gene Set Variation Analysis (GSVA) revealed significantly higher tumor-related pathway scores in the tumor group, with 1,329 upregulated and 2,726 downregulated DEGs, among which 1,319 were significantly related to prognosis. Based on the highest C-index and minimal gene number, the CoxBoost + Enet [alpha = 0.6] model was selected to construct the prognostic signature. Six significant genes were identified: HAPLN1, CIT, CDK16 (risk gene), RARRES2, LRRN4CL, and LTB (protective gene). Ten pathways were significantly associated with these genes, including cell cycle, focal adhesion, and vascular smooth muscle contraction. Kaplan-Meier analysis showed that high-risk patients had poorer survival. Protective genes correlated positively with immune infiltration, while risk genes showed a significant negative correlation. Mutation analysis found that LTB was positively correlated with Aneuploidy Score, whereas LRRN4CL was negatively correlated with the Number of Segments. The nomogram model, incorporating clinical characteristics (Stage, Age) and risk genes, identified the risk score as an independent prognostic factor for EC. TimeROC analysis highlighted the nomogram’s superior predictive performance, and survival analysis confirmed the Risk Score’s response to immune checkpoint modules. By systematically integrating 101 machine learning models derived from 10 algorithms, we constructed a Wnt-CAF-driven risk signature. Combined with clinicopathological features in a nomogram, this model effectively predicted prognosis and potential immunotherapy response in dMMR EC. These findings deepen the understanding of the EC microenvironment and provide valuable guidance for personalized treatment strategies and prognostic assessment in clinical practice.

Aims A high-salt diet (HSD) induced excessive sodium intake is a major risk factor for various diseases, including pregnancy disorder. We aim to explore the effects of HSD on uterine endothelial cell and remodeling of spiral artery during pregnancy in mice. Materials and methods Blood pressure was monitored during pregnancy in control and HSD treated mice. Uterine endothelial were RNA-seq was used to profile the molecular basis for the adaptation of vascular endothelial cell during pregnancy. Salt accumulation in decidual tissue was measured and in vitro cultured endothelial were treated with NaCl to investigate the mechanisms for cell junction change. Key findings HSD impairs the normal pregnancy-associated blood pressure adaptation. Cell junction in the endothelia undergo significant changes for the during the pregnancy adaptation. HSD induced more salt accumulation in the uteri and triggered the disturbed vascular endothelium cytoskeletal remodeling, which was associated impaired trophoblast cell invasion and incorporation into the vascular wall. Significance Our study identifies unique roles of decidual endothelium for pregnancy vascular remodeling, and demonstrates that HSD disrupts physiological spiral artery remodeling through endothelial maladaptation, which may concurrently induce systemic endothelial damage in maternal systemic vascular.

To evaluate the clinical impact of 18F-FDG PET/CT versus 68Ga-FAPI-46 PET/CT in patients with advanced epithelial ovarian cancer (EOC), this study aims to investigate preoperative scoring criteria and establish a basis for the formulation of treatment plans tailored to this patient population. A total of forty-one treatment-naive patients with advanced epithelial ovarian cancer were recruited for this study between July 2022 and February 2024. Each participant underwent both 18F-FDG and 68Ga-FAPI-46 PET/CT imaging. The study compared the diagnostic accuracy, PET/CT parameters, tumor staging, and the guidance provided for clinical treatment decisions by these two imaging modalities. Additionally, the tumor burden as assessed by both imaging techniques was evaluated to predict the likelihood of achieving R0 resection in subsequent surgical procedures. In the context of peritoneal metastasis, various PET/CT parameters were analyzed, including Gross Tumor Volume (GTV), SUVmax, Total Lesion Glycolysis (TLG(FDG)), and Total Lesion-FAPI (TL-FAPI). The comparative analysis of the two imaging modalities revealed statistically significant differences (P < 0.001). 68Ga-FAPI-46 PET/CT showed a higher PCI score and better sensitivity than 18F-FDG PET/CT (P = 0.03). Notably, the diagnostic accuracy of 68Ga-FAPI-46 PET/CT for detecting pelvic, para-aortic, and extra-abdominal lymph nodes was superior to that of 18F-FDG PET/CT, demonstrating enhanced sensitivity, specificity, and overall accuracy. Following the application of 68Ga-FAPI-46 PET/CT, tumor stages were upgraded in 22

Research Question Neonatal exposure to bisphenol A (BPA) of female rats have been reported to cause polycystic ovary syndrome (PCOS)-like symptom at adulthood. However, it is still unknown whether adolescent exposure to BPA induces PCOS-like phenotype in female rats and its specific characteristics. Design Adolescent Sprague-Dawley (SD) rats (6∼8 weeks) were administered daily for 10 weeks via gastric gavage with BPA (50 mg/kg body weight) in corn oil or corn oil vehicle alone. Estrous cycle of rats was consistently evaluated from the initiation of BPA exposure and continued observation for 21 days following the cessation of exposure. Serum sexual hormone levels, metabolism of blood glucose, ovarian morphology and fertility were investigated. Results Adolescent exposure to BPA could result in irregular estrus cycles and abnormal ovulation in female rats. Comparing with the control group, BPA exposure increased the serum levels of testosterone, luteinizing hormone (LH), insulin and glucagon, whereas reduced serum levels of estradiol, prolactin, sex hormone-binding globulin (SHBG) and anti-Müllerian hormone (AMH) were observed after BPA treatment. BPA exposure during adolescence of rats caused ovarian atrophy in adulthood, but it did not lead to polycystic changes in the ovaries. Moreover, female rats exposed to BPA showed a significant decreased in fertility. Conclusions Adolescent female rat exposure to BPA could induce a PCOS-like syndrome that is similar to clinical subtype B of PCOS in adulthood and lead to a marked decline in fertility. Our findings further extend the endocrine disrupting chemicals (EDCs) research in reproduction, which would help to shed light on the pathogenesis of PCOS.

Cervical cancer remains the fourth most common cancer among women globally and the second leading cause of cancer-related deaths. Radical hysterectomy (RH), combined with bilateral pelvic lymphadenectomy, is the recommended treatment for early-stage cervical cancer. The Laparoscopic Approach to Cervical Cancer (LACC) trial revealed inferior oncological outcomes with minimally invasive surgery (MIS) compared with open surgery, prompting many professional societies to recommend laparotomy as the standard approach. However, the relatively recent development of MIS and the lack of standardised protocols during the LACC trial suggest that dismissing MIS entirely may be premature. MIS techniques face challenges in achieving optimal radical resection, particularly in defining and standardising the dissection of sub-peritoneal avascular spaces. Advances in embryologically based anatomical surgeries, such as total mesometrial resection (TMMR), have shown promise but require reproducible anatomical markers and refined dissection methods to become practical and widely adopted.Recent anatomical studies have identified natural pelvic spaces and vascular landmarks, providing a foundation for standardised TMMR. Techniques such as uterine manipulator-free surgery have been introduced to improve MIS outcomes. Despite concerns raised by the LACC trial, MIS continues to evolve, offering benefits such as reduced bleeding, faster recovery and enhanced visualisation. By leveraging high-definition laparoscopy and adhering to tumour-free principles, MIS for cervical cancer can achieve improved oncological outcomes while maintaining functional preservation, marking a new phase of innovation and refinement in cervical cancer surgery.

Background:Disturbances in the endometrial immune microenvironment, particularly uterine natural killer (uNK) cell polarization, are linked to chronic endometritis (CE) and recurrent implantation failure (RIF). However, the underlying mechanisms and a lack of reliable biomarkers hinder effective clinical diagnosis and treatment. Methods:We integrated public single-cell RNA sequencing (scRNA-seq) datasets to characterize endometrial immune cell dynamics. Single-cell regulatory network inference identified key transcription factors (TFs) regulating uNK subtypes, and their functions were explored via pathway enrichment. A diagnostic model was subsequently developed and validated using bulk RNA-seq data from CE and RIF cohorts. Results:Our analysis identified two functionally distinct uNK subtypes: cytotoxic uNK2 cells regulated by TFs EOMES and ELF4, and uNK3 cells involved in platelet activation and tight junctions, driven by ELK4 and IRF1. The abundance of these TFs correlated with their respective uNK subtype proportions moderately (p< 0.001). Key marker genes-AFAP1L2, KLRC1, and SOCS1 for uNK2, and SAMD3 for uNK3-were identified and demonstrated altered expression patterns in samples from patients with CE and RIF. In a bulk RNA-seq dataset comprising 51 endometrial samples (18 CE and 33 normal), the ratio of uNK2/uNK3 signature expression was notably upregulated in CE samples. This finding was corroborated in an independent RIF dataset. The diagnostic model based on these markers demonstrated strong predictive power. For CE, the AUC for SDC1 was 0.48, the uNK2/uNK3 ratio was 0.675, and the logistic model reached 0.822. For RIF, the uNK2/uNK3 ratio had an AUC of 0.823, while the logistic model achieved 0.83. Conclusion:Our findings suggested that an imbalance in uNK cell polarization was a key feature of immune dysregulation in CE and RIF, with the uNK2/uNK3 signature ratio emerging as a potential biomarker. Extensive validation in prospective clinical cohorts and through functional experiments is essential to confirm the clinical utility and therapeutic potential of targeting these uNK subtypes to improve reproductive health.

Endometrial cancer (EC) is one of the most common malignancies in women. In recent years, immunotherapy has gradually become a significant treatment option. However, the mechanisms underlying immune checkpoint inhibitor (ICI)-related Adverse Events (AEs) remain poorly understood, posing significant challenges for optimizing clinical treatment strategies. This study aims to integrate the FAERS database and single-cell transcriptomic data to investigate potential mechanisms underlying PD-1 inhibitor-related AEs in EC immunotherapy, with a focus on exploring the PD-1-associated cell communication network and its potential compensatory activation pathways. Data related to AEs were extracted from the FAERS database. Disproportionality analyses, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), were used to quantify signals of immune-related AEs (irAEs) associated with ICIs. We compared the occurrence timing and characteristics of AEs across different drugs. Subsequently, scRNA-seq was performed to analyze the tumor microenvironment of EC, focusing on PD-1-high expressing cell populations. Cell Communication was analyzed and key receptor-ligand pairs were identified. From Q1 2004 to Q3 2024, 21,838,627 drug-related reports were retrieved from FAERS, including 2,202 related to ICIs. ICI-associated irAEs involved 26 organ systems, with general disorders, gastrointestinal disorders, and injury/poisoning as the top System Organ Class (SOC). Fatigue, product use issues, and diarrhea were the most reported Preferred Terms (PTs). PD-1 inhibitors were associated with faster onset of AEs compared to PD-L1 inhibitors and Weibull modeling indicated an early failure-type AE pattern for both treatments. Single-cell analysis further demonstrated that PD-1 was highly expressed in CD8 + cytotoxic T cells and Tfh cells, which communicated with other cells within the tumor microenvironment through key receptor-ligand pairs such as CXCL12-CXCR4 and CXCL16-CXCR6. These findings suggested that PD-1 inhibitors may induce AEs through compensatory activation of the CXCR4 and CXCR6 pathways. This study suggested that PD-1 inhibitors may contribute to irAEs in EC, potentially through compensatory activation of the CXCR4 and CXCR6 pathways. By integrating FAERS and scRNA-seq data, key receptor-ligand interactions were identified, providing preliminary insights that could inform future efforts to optimize immunotherapy efficacy and mitigate AEs. However, further validation through clinical studies and mechanistic research is needed to confirm these findings.

BACKGROUND:Endometriosis (EMs) is a condition characterized by the growth of endometrial tissue outside the uterine cavity. Although this condition is benign, it has cancer-like features. N6-methyladenosine (m6A) is a common RNA modification involved in diverse biological processes, but its role in EMs remains unclear. METHODS:A human endometrial stromal cell line (HESCs), primary eutopic endometrial stromal cells (Eu-ESCs), primary ectopic endometrial stromal cells (Ec-ESCs), and clinical samples were used in this study. A colorimetric assay was used to measure methylation levels in clinical and mouse EMs samples. Functional assays (CCK-8, EdU, Transwell, and wound healing) were used to evaluate phenotypic changes. m6A immunoprecipitation sequencing (MeRIP-seq) identified downstream targets. Mechanistic studies were conducted via qRT‒PCR, Western blot, RNA immunoprecipitation (RIP), dual-luciferase reporter, and RNA stability assays. RESULTS:We detected aberrantly low levels of m6A within endometriotic lesions, which was attributed to increased expression of the m6A eraser fat mass and obesity-associated protein (FTO). Notably, estrogen and inflammatory factors, which are recognized as pathogenic agents in EMs amplify FTO expression while suppressing m6A levels. In vitro experiments demonstrated that overexpression of FTO in endometrial stromal cells leads to a reduction in m6A levels and concomitantly promotes their proliferation, migration, and invasion. Furthermore, both genetic deletion of Fto and chemical inhibition of FTO impeded the growth of ectopic endometrial lesions in vivo. By utilizing m6A-seq, we identified GEF-H1 (a Rho guanine nucleotide exchange factor) as a pivotal downstream target of FTO. Specifically, diminished m6A methylation at a certain site within the 3'UTR of GEF-H1 promotes its expression in a YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1)-dependent manner, thereby activating the RhoA pathway. Subsequent experiments revealed that GEF-H1 mediates the effects of FTO in promoting migration and invasion. CONCLUSIONS:This study revealed that FTO decreases the m6A level of GEF-H1, thereby increasing its stability, which in turn activates the GEF-H1-RhoA pathway to promote the migration and invasion of endometrial stromal cells, thereby inducing EMs. Our findings suggest potential therapeutic avenues for targeting FTO to alleviate EMs progression.

Ovarian cancer (OC) is a highly lethal gynecological cancer. Olaparib maintenance therapy was effective and well-tolerated in pivotal RCTs. However, nationwide real-world safety information is limited in China. This multicenter, prospective, observational drug intensive monitoring study monitored the safety of olaparib in a largest-to-date, real-world Chinese OC cohort. Eligible OC patients had received ≥ 1 dose of olaparib. Follow-up extended up to 30 days post-olaparib discontinuation or maximally for six months post-enrolment. Primary and secondary endpoints were adverse events (AEs) in all OC patients and in special populations (hepatically/renally impaired before olaparib treatment; aged > 65 years), respectively. By Jun 30, 2023, 799 patients from 33 sites were enrolled. By data cut-off (Dec 29, 2023), 796 patients treated with olaparib were analyzed. The median age was 55 years (range, 25–85). Of 796 patients, 490 (61.6

Background:The tumor microenvironment (TME) is a complex network driving endometrioid endometrial cancer (EC) progression. Previous analyses of the EC TME were often limited by a lack of detailed cellular annotations. Integrating single-cell RNA sequencing (scRNA-seq) data offers a comprehensive approach to reconstruct the TME, aiming to uncover novel mechanisms and therapeutic targets. Methods:We integrated public scRNA-seq data from 15 EC and 5 normal endometrium samples. Through detailed cell annotation, we performed comprehensive bioinformatic analyses, including pseudotime trajectories, copy number variation, and cell communication, to investigate mechanisms of EC development. Results:We identified nine cell types and characterized subpopulations of epithelial, macrophage, lymphocyte, and stromal fibroblast cells. The SOX9+LGR5- epithelial subtype showed elevated malignancy and NFKB pathway enrichment. The M2_like2 macrophage subtype played a critical role, engaging in robust MIF-(CD74+CD44) mediated communication with SOX9+LGR5- cells. Experimental validation confirmed MIF co-expression with E-cadherin in EC tissues. Furthermore, the transcription factor NFKB2 was found to mediate MIF's effect on the CD44 receptor in malignant epithelial cells. A pericyte-to-fibroblast transition in stromal cells may also support tumor growth, while an increase in CD8 exhausted/Treg cells and a decrease in cytotoxic CD8 cells suggest potential immune evasion. Conclusion:Our single-cell analysis details the EC TME landscape, revealing robust communication between M2_like2 macrophages and SOX9+LGR5- epithelial cells. We highlight a key mechanism where NFKB2 mediates MIF's pro-tumorigenic effects via the CD44 receptor, offering new insights into EC progression and potential therapeutic targets.

The global incidence of asthma, a leading respiratory disorder affecting more than 235 million people, has dramatically increased in recent years. Characterized by chronic airway inflammation and an imbalanced response to airborne irritants, this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea, cough, wheezing, and chest tightness. Conventional asthma therapies, such as corticosteroids, long-acting β-agonists, and anti-inflammatory agents, often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively. These limitations have prompted researchers to explore innovative therapeutic strategies, including stem cell-related interventions, offering hope to those afflicted with this incurable disease. In this review, we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.

RESEARCH QUESTION:Does adolescent exposure to bisphenol A (BPA) induce polycystic ovary syndrome (PCOS)-like phenotypes in female rats? DESIGN:Adolescent Sprague-Dawley rats (6-8 weeks old) were administered BPA (50 mg/kg body weight) in corn oil, or corn oil vehicle alone, daily for 10 weeks via gastric gavage. The rats' oestrous cycle was consistently evaluated from the initiation of BPA exposure, and observation was continued for 21 days after the exposure had ended. Serum sex hormone concentrations, blood glucose metabolism, ovarian morphology and fertility were investigated. RESULTS:Adolescent exposure to BPA resulted in irregular oestrous cycles and abnormal ovulation in female rats. Compared with the control group, BPA exposure increased the serum concentrations of testosterone, LH, insulin and glucagon, but reduced the serum concentrations of oestradiol, prolactin, sex hormone-binding globulin and anti-Müllerian hormone. BPA exposure during adolescence caused ovarian atrophy in the rats in adulthood but did not lead to polycystic changes in the ovaries. Moreover, female rats exposed to BPA showed a significant decrease in terms of litter number and weight. CONCLUSIONS:Exposure of adolescent female rats to BPA induced a PCOS-like syndrome that was similar to clinical subtype B of PCOS in adulthood and led to a marked decline in fertility. The findings further extend the research on endocrine-disrupting chemicals in reproduction, which would help to shed light on the pathogenesis of PCOS.

Recurrent implantation failure (RIF) remains a significant barrier in assisted reproductive technology (ART), where multiple transfers of high-quality embryos fail to achieve pregnancy. While embryo-related factors have been extensively investigated, the contribution of endometrial dysfunction to RIF remains poorly characterized. This study aimed to determine whether biologically distinct molecular subtypes of endometrial dysfunction exist in RIF and whether such subtypes could guide more personalized and effective treatment strategies. We conducted a comprehensive computational analysis integrating publicly available endometrial transcriptomic datasets with prospectively collected samples. Multi-platform data were harmonized using a random-effects model. Differentially expressed genes (DEGs) between RIF and normal samples were identified using MetaDE. Clinical and hormonal correlations were used to assess heterogeneity among RIF samples. Unsupervised clustering (ConsensusClusterPlus) identified RIF subtypes, and their biological characteristics were analyzed using Gene Set Enrichment Analysis (GSEA). Immunohistochemistry (IHC) was used to evaluate the protein-level expression of selected subtype-associated genes. A molecular classifier (MetaRIF) was developed using the optimal F-score from 64 combinations of machine learning algorithms. Candidate therapeutic compounds were predicted using the Connectivity Map (CMap) database. A total of 1,776 robust DEGs were identified between RIF and normal samples. Clustering analysis revealed two reproducible RIF subtypes: an immune-driven subtype (RIF-I) and a metabolic-driven subtype (RIF-M). RIF-I was enriched for immune and inflammatory pathways (e.g., IL-17 and TNF signaling, p < 0.01) and showed increased infiltration of effector immune cells. RIF-M was characterized by dysregulation of oxidative phosphorylation, fatty acid metabolism, steroid hormone biosynthesis, and altered expression of the circadian clock gene PER1. Immunohistochemical analysis showed that the T-bet/GATA3 expression ratio mirrored the expected subtype distribution, with higher values in RIF-I and lower values in RIF-M. The MetaRIF classifier accurately distinguished subtypes in independent validation cohorts (AUC: 0.94 and 0.85) and outperformed previously published models (AUC: MetaRIF = 0.88; koot_sig = 0.48; Wang_sig = 0.54; OSR_score = 0.72). CMap-based drug predictions identified sirolimus as a candidate for RIF-I and prostaglandins for RIF-M. Our findings reveal two biologically distinct endometrial subtypes of RIF, highlighting the heterogeneous nature of its pathogenesis. By addressing immune and metabolic dysregulation through subtype-specific approaches, our findings provide a foundation for improving diagnosis and tailoring treatment in RIF, potentially enhancing implantation outcomes in ART.

OBJECTIVE:To investigate risk factors associated with severe acute asthma attacks in children with asthma over six years of age. METHODS:This retrospective study enrolled children aged over six years diagnosed with acute asthma exacerbation at the Department of Pulmonology, Quanzhou Children's Hospital, from January 2012 to September 2024. Data on the patients' clinical manifestations were compared between the mild to moderate and severe asthma attack groups. RESULTS:The average age of the 261 patients was 8.03 ± 1.88 years. The patients were categorized into two groups based on attack severity: mild to moderate (n = 209) and severe (n = 52). Univariate analysis revealed significant differences between the two groups in terms of malnutrition, breastfeeding duration (over three and six months), eosinophil and neutrophil percentages, human rhinovirus (HRV) infection, mediastinal emphysema, and subcutaneous emphysema (p < 0.05). Logistic regression analysis revealed that children over six years of age hospitalized for asthma attacks were more likely to experience severe exacerbations if they had an elevated neutrophil % (OR = 1.040), HRV infection (OR = 5.655), malnutrition (OR = 5.051), or mediastinal emphysema (OR = 9.205). ROC analysis revealed that a neutrophil percentage threshold of 69.35 (the threshold value of neutrophil count over 6 years old is 1.6-8.3 × 109/L) was diagnostically useful for severe asthma, with a sensitivity of 0.750, specificity of 0.617, and an area under the curve of 0.73. CONCLUSION:The level of neutrophils, history of HRV infection, malnutrition, and mediastinal emphysema are all independent risk factors for a severe acute asthma attack in children aged over six years. Management strategies for asthma should be expanded to focus on high-risk children in order to avoid severe attacks.

PURPOSE:Endometriosis is characterized by the ectopic growth of endometrial-like tissue outside the uterus and altered energy metabolism, but the specific mechanisms involved remain unclear. This study aimed to investigate the impact of Sirtuins7 (SIRT7) on metabolic homeostasis to better understand the metabolic alterations underlying endometriosis. METHODS:Integrated metabolomic, transcriptomic, and proteomic analyses revealed metabolic dysregulation in endometriosis. Seahorse XF technology was used to assess metabolic rates. The effects of SIRT7 on endometriosis were validated both in vitro and in vivo. Immunoprecipitation and mass spectrometry were used to identify the interaction between SIRT7 and Tu translation elongation factor, mitochondrial (TUFM). Cellular phenotypes, including proliferation, migration, and apoptosis, were evaluated by CCK-8 assays, Transwell and scratch assays, and flow cytometry. RESULTS:Multiomics analyses and Seahorse XF tests revealed a metabolic shift from mitochondrial respiration to glycolysis in ectopic tissues. SIRT7 was found to be upregulated in ectopic lesions and significantly influenced the progression of endometriosis. In addition, an interaction between SIRT7 and TUFM has been observed. The metabolic reprogramming, proliferation and migration ability of endometrial stromal cells were greatly reduced by SIRT7 knockdown and TUFM overexpression. The effects of TUFM deficiency were reversed by SIRT7 knockdown. The results also demonstrated that SIRT7 promoted the glycolytic enzymes GBE1 and PYGL, suppressed the mitochondrial enzymes IDH1 and SDHB, and activated the RhoA/ROCK/AKT pathway and the EMT process, thereby facilitating the progression of endometriosis. CONCLUSIONS:These findings underscore the critical involvement of SIRT7 in the energy metabolism reprogramming of ectopic cells. Our research provides valuable insights for the development of nonsurgical treatment strategies for endometriosis.