BACKGROUND:Endometriosis is a debilitating gynaecological disorder with an elusive pathogenesis. While gut microbiota dysbiosis has been implicated, the causal role of gut-peritoneum microbial translocation and the specific mechanisms driving disease progression remain elusive. Notably, the role of peritoneal neutrophils and neutrophil extracellular traps (NETs) in the development of endometriosis remains unknown. OBJECTIVE:This study aims to delineate the pathogenic pathway linking gut microbiota to peritoneal neutrophil activation and the development of endometriosis. DESIGN:We combined single-cell RNA sequencing of clinical peritoneal fluid immune cells with functional validation in heterologous and homologous mice models. We further adopted microbial source-tracking analysis of patient cohorts and interventional strategies, including faecal microbiota transplantation (FMT) and administration of green fluorescent protein (GFP)-tagged Pseudomonas aeruginosa. RESULTS:We identified a unique membrane metalloendopeptidase (MME) positive neutrophil subset (Neu_MME) that is expanded in endometriosis and primed for NETs formation (NETosis). These Neu_MME released NETs in response to bacterial lipopolysaccharides (LPS), which directly captured endometrial cells and enhanced their proliferation and migration, driving lesion development. Accordingly, inhibiting NETosis or degrading NETs significantly suppressed endometriosis in mice. Furthermore, FMT from patients with endometriosis to mice disrupted the intestinal barrier, promoting the translocation of gut microbiota, particularly Pseudomonas, into the peritoneal cavity and the lesions. This translocated Pseudomonas was identified as a key driver of LPS-induced NETosis and disease progression. CONCLUSION:Our findings define a gut-peritoneum axis in endometriosis, where gut-derived Pseudomonas triggers NETosis in peritoneal Neu_MME to promote disease, suggesting that targeting this bacterium or NETosis represents a viable therapeutic strategy.

Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11ra1 reduces the proportion of activated fibroblasts. Furthermore, administration of siIl11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging.

Vaginal aging is a multifactorial biological process characterized by structural, functional, and molecular alterations driven primarily by estrogen decline. This review summarizes current evidence on potential biomarkers across five domains: physiological parameters, imaging features, histological changes, and molecular alterations. We further discuss methodological challenges and future research directions necessary to establish standardized and clinically applicable biomarkers. Understanding these biological indicators may facilitate earlier diagnosis, improve patient stratification, and enable personalized therapeutic interventions in women experiencing vaginal aging.

Purpose: To systematically conduct a retrospective summary of the optimal surgical strategies and techniques for managing various types of unilateral genital tract obstruction with ipsilateral renal anomaly (UGTOIRA) syndrome, and to establish a comprehensive postoperative follow - up protocol. Methods: The clinical data of patients diagnosed with UGTOIRA syndrome over the past 13 years, encompassing treatment protocols, follow-up assessments, and treatment outcomes, were retrospectively analyzed. Statistical analysis was performed utilizing the SPSS 26.0 statistical software package. Results: All 68 patients underwent reproductive system surgery, with three additionally receiving urological procedures. The age at surgery ranged from 5 to 52 years, with a median of 15 years (interquartile range, 12- 23 years). For Type I, the surgical approach consisted of vaginal oblique septectomy, yielding a 100% clinical cure rate (53/53). Type II-a and II-b were managed with vaginal oblique septectomy and combined vaginal oblique septectomy with ipsilateral cervical plasty, respectively, resulting in an overall 71.4% clinical cure rate (5/7) for Type II. Type III was treated with cervical plasty, achieving a 66.7% clinical cure rate (2/3). Types IV and V were addressed with unilateral hysterectomy and salpingectomy, respectively, both demonstrating 100% clinical cure rates (3/3 and 2/2). The overall cure and improvement rates among the 68 patients were 95.6% (65/68) and 4.4% (3/68), respectively. A one-stage surgical procedure alone was sufficient for cure in 56 cases (82.4%). Significant differences were observed in the distribution of surgical interventions across types and subtypes (P < 0.001), as well as in clinical cure rates among different types and subtypes (P = 0.013). Conclusion: The optimal surgical approach, determined through precise classification of UGTOIRA syndrome, ensures a high clinical cure rate, while systematic postoperative follow-up facilitates the early detection and management of recurrent obstruction.

This study aimed to compare laparoscopic peritoneal vaginoplasty and laparoscopic sigmoid colon vaginoplasty in patients with congenital absence of vagina, aiming to provide more robust guidance for clinicians and patients with congenital absence of vagina in choosing the most appropriate surgical approach. Patients with congenital absence of vagina who underwent laparoscopic vaginoplasty in our hospital from 2011 to 2023 were included in this study. Participants were divided into two groups: the laparoscopic peritoneal vaginoplasty group (peritoneal group, n = 20) and the laparoscopic sigmoid colon vaginoplasty group (sigmoid colon group, n = 30). Short-term outcomes (operative duration, intraoperative hemorrhage, postoperative ventilation time, time to resume oral intake, length of postoperative hospital stay,) and long-term outcomes (sexual satisfaction, vaginal discharge odor, complications, vaginal mold duration) were evaluated. Comparative analysis revealed that the peritoneal group demonstrated significantly reduced operative duration (p < 0.01), accelerated postoperative ventilation recovery (p < 0.01), and earlier resumption of oral intake (p < 0.01). No significant intergroup differences were observed in intraoperative blood loss (p = 0.10), length of postoperative hospital stay (p = 0.52), or vaginal discharge odor (p = 1). The peritoneal group had shorter vaginal mold use (p < 0.05) and higher sexual satisfaction (p < 0.01). While the peritoneal group showed a trend toward lower postoperative complication rates (3

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

Introduction: Recurrence signifies the primary mortality factor in patients suffering from endometrial cancer, with few efficacious treatments currently available for recurrent cases. This research investigates the anti-tumoral capacities of WEE1 inhibitors within the context of endometrial cancer, aiming to establish a novel therapeutic avenue for high recurrence-risk patients. Materials and methods: We evaluated WEE1 expression in endometrial cancer patients utilizing immunohistochemistry on paraffin-embedded tissue sections. The cytotoxic potential of WEE1 inhibitors on endometrial cancer cells was assessed by CCK8 assay. Assays to gauge the influence of WEE1 inhibitors on cell proliferation and migration included clonal proliferation, wound healing, and transwell assays. We determined the impacts on apoptosis and cell cycle stages by flow cytometry. Employing qRT-PCR and western blotting, we investigated the mechanistic pathways underlying the anti-tumoral activity of WEE1 inhibitors. In vivo evaluations were executed to ascertain the inhibitory effect of WEE1 inhibitors on tumor growth in mice. Results: WEE1 exhibited high-level expression in endometrial cancer tissues, particularly pronounced in recurrent compared with non-recurrent patients. WEE1 inhibitors effectively eliminated endometrial cancer cells while inhibiting their proliferation and migration. Flow cytometric analyses revealed a significant promotion of apoptosis and an increase in G2/M phase cell proportion upon WEE1 inhibitor treatment. qRT-PCR and western blotting elucidated that WEE1 inhibitors activated the innate immune signaling pathway in endometrial cancer cells. Furthermore, in vivo assessments demonstrated substantial tumor growth suppression due to WEE1 inhibitors. Conclusions: WEE1 inhibitors initiated an innate immune response in endometrial cancer, exhibiting considerable anti-tumoral effects, which was promising for postoperative treatment of endometrial cancer, especially recurrent endometrial cancer patients.

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies. Ovarian aging has an important role in health and fertility; however, the molecular mechanisms underlying it remain incompletely understood. Here the authors use single-cell and spatial transcriptomics in reproductively young, middle-aged and older human ovarian tissue to elucidate ovarian aging. They describe spatiotemporal changes in ovarian cells and highlight the important regulatory role of FOXP1.

Ovarian aging is marked by a reduction in the quantity and quality of ovarian follicles, leading to a decline in female fertility and ovarian endocrine function. While the biological characteristics of ovarian aging are well-established, the exact mechanisms underlying this process remain elusive. Recent studies underscore the vital role of trace elements (TEs) in maintaining ovarian function. Imbalances in TEs can lead to ovarian aging, characterized by reduced enzyme activity, hormonal imbalances, ovulatory disorders, and decreased fertility. A comprehensive understanding of the relationship between systemic and cellular TEs balance and ovarian aging is critical for developing treatments to delay aging and manage age-related conditions. This review consolidates current insights into TEs homeostasis and its impact on ovarian aging, assesses how altered TEs metabolism affects ovarian aging, and suggests future research directions to prolong ovarian reproductive life. These studies are expected to offer novel approaches for mitigating ovarian aging.

Exposure to airborne fine particulate matter (PM 2.5 ) is strongly associated with poor fertility and ovarian damage. However, the mechanism underlying this remains largely unclear. Here, we found that PM 2.5 markedly impaired murine ovarian reserve, decreased hormone levels, and aggravated ovarian inflammation. Circulating interleukin-6 (IL-6) was elevated in PM 2.5 -exposed mice and was further confirmed to mediate this damage by IL-6 recombinant protein intervention. PM 2.5 exposure led to increased alveolar macrophage infiltration in the lungs. However, alveolar macrophage clearance with clodronate liposomes could not fully reverse the elevated IL-6 levels and ovarian injury, suggesting that alveolar macrophages were probably not the only source of circulating IL-6. Further experiments indicated that IL-6 mainly targeted ovarian theca–interstitial cells and impaired testosterone synthesis via suppressing the peroxisome proliferator-activated receptor γ (PPARγ) pathway. In addition, apoptosis of granulosa cells and restriction of follicular growth were observed in co-cultures with IL-6-treated theca–interstitial cells, which could be further reversed by the PPARγ agonist. Moreover, IL-6-neutralizing antibodies ameliorated PM 2.5 -induced ovarian damage. Notably, increased levels of circulating IL-6 were observed in premature ovarian aging patients and were inversely associated with their ovarian function. In summary, our findings offer a mechanistic explanation for PM 2.5 -induced ovarian dysfunction and verify IL-6 as a biomarker and potential therapeutic target.

Purpose: To recommend the classification of unilateral genital tract obstruction with ipsilateral renal anomaly (UGTOIRA) syndrome into five types based on the site of obstruction, and to analyze the clinical manifestations and precise diagnosis of the syndrome. Methods: The data, including demographic characteristics, symptoms, and precise diagnoses from 59 patients over the last decade, were retrospectively analyzed. Data analysis was conducted using the statistical software package SPSS 26.0. Results: All 59 patients diagnosed with UGTOIRA syndrome were classified into five types based on the site of obstruction: Type I (vaginal obstruction) (45, 76.3%), Type II (cervicovaginal obstruction) (7, 11.9%), Type III (cervical obstruction) (3, 5.1%), Type IV (unilateral partial cervical aplasia) (3, 5.1%), and Type V (Unilateral isthmus atresia) (1, 1.7%). Of these cases, there were 34 cases (57.6%) with communication and 25 cases (42.4%) without communication between the left and right genital tracts. The chief complaints included dysmenorrhea alone in 28 cases (47.5%), dysmenorrhea accompanied by blood dripping after menstruation in 12 cases (20.3%), blood dripping after menstruation alone in 14 cases (23.7%), purulent vaginal secretions in one case (1.7%), vaginal pain in one case (1.7%), irregular menstruation in one case (l.7%), and infertility in two cases (3.4%). The precise diagnostic criteria include the affected side, abnormalities in the kidney and ureter, the site of obstruction, the location of blood accumulation, the size of the ipsilateral genital tract, whether there is communication and its site, the type based on the site of obstruction, and the presence and type of complications. Conclusion: This classification of UGTOIRA syndrome encompasses the anatomical features of all cases reported in our study. Only by fully understanding the anatomical characteristics of this syndrome and identifying its clinical manifestations can clinicians make precise diagnoses as early as possible and provide individualized management.

5549 Background: The efficacy of PARP inhibitors as neoadjuvant therapy and its clear association with tumor microenvironment (TME) status remain enigmatic. Here, for the first time, we reported the efficacy and safety of niraparib monotherapy, an oral low-toxicity PARP inhibitor, as the neoadjuvant therapy in patients (pts) with HRD high-grade serous ovarian cancer (HGSOC), and directly linked pre-treatment TME components with response using cutting-edge technologies. Methods: Treatment-naïve pts with newly diagnosed advanced unresectable HGSOC and those who could not endure primary debulking surgery were enrolled to receive laparoscopic biopsies. TME landscape was profiled by single-cell RNA sequencing and multiplex immunohistochemistry. Pts with HRD ( BRCA1/2 mutations and/or genomic instability score ≥ 42) HGSOC received daily oral niraparib for two 28-day cycles. Pts with complete response, partial response (PR), or stable disease (SD) received interval debulking surgery (IDS). The co-primary endpoints were objective response rate (ORR) and R0 resection rate. Results: Between January 18, 2021 and July 18, 2023, 127 pts from six centers were screened for eligibility. Totally, 67 HRD pts received neoadjuvant niraparib monotherapy, 48 pts completed response evaluations, and 40 pts underwent IDS. Thirty pts achieved PR and 12 pts reached SD, resulting in an ORR of 62.5% and a disease control rate (DCR) of 87.5%. BRCAm pts exhibited improved responses with increased ORR (77.3%) and DCR (100.0%). For surgical outcomes, 80.0% of pts achieved R0 resection and 95.0% of pts accomplished optimal debulking. Treatment-related adverse events (TRAEs) of grade ≥3 were observed in 61.2% of pts and hematological toxicities were the most common. No fatal TRAEs were reported. Co-enrichment of MRC1 + macrophages, effector regulatory T cells, and myofibroblastic cancer-associated fibroblasts were associated with lack of response. Conclusions: Neoadjuvant niraparib monotherapy regimen achieved encouraging ORR and R0 resection rate with tolerable toxicities in pts with HRD unresectable HGSOC, offering an alternative option for those pts unwilling to receive or unable to tolerate neoadjuvant chemotherapy. Pre-treatment TME factors were correlated with clinical response to PARP inhibitors. Clinical trial information: NCT04507841 . [Table: see text]

Cancer has long been a major threat to human health. Recent advancements in molecular imaging have revolutionized cancer research by enabling early and precise disease localization, essential for effective management. In particular, optical molecular imaging is an invaluable cancer detection tool in preoperative planning, intraoperative guidance, and postoperative monitoring owing to its noninvasive nature,rapid turnover, safety, and ease of use. The tumor microenvironment and cells within it express distinct biomarkers. Optical imaging technology leverages these markers to differentiate tumor tissues from surrounding tissues and capture real-time images with high resolution.Nevertheless, a robust understanding of these cancer-related molecules and their dynamic changes is crucial for effectively managing cancer. Recent advancements in optical molecular imaging technologies offer novel approaches for cancer investigation in research and practice. This review investigates the modern optical molecular imaging techniques employed in both preclinical and clinical research, including bioluminescence, fluorescence, chemiluminescence, photoacoustic imaging, and Raman spectroscopy. We explore the current paradigm of optical molecular imaging modalities, their current status in preclinical cancer research and clinical applications, and future perspectives in the fields of cancer research and treatment.

Pelvic organ prolapse (POP) is a benign disease characterized by the descent of pelvic organs due to weakened pelvic floor muscles and fascial tissues. Primarily affecting elderly women, POP can lead to various urinary and gastrointestinal tract symptoms, significantly impacting their quality of life. The pathogenesis of POP predominantly involves nerve–muscle damage and disorders in the extracellular matrix metabolism within the pelvic floor. Recent studies have indicated that genetic factors may play a crucial role in this condition. Focusing on linkage analyses, single-nucleotide polymorphisms, genome-wide association studies, and whole exome sequencing studies, this review consolidates current research on the genetic predisposition to POP. Advances in epigenetics are also summarized and highlighted, aiming to provide theoretical recommendations for risk assessments, diagnoses, and the personalized treatment for patients with POP.

The ovary holds a significant role as a reproductive endocrine organ in women, and its aging process bears implications such as menopause, decreased fertility, and long-term health risks including osteoporosis, cardiovascular disorders, and cognitive decline. The phenomenon of oxidative stress is tightly linked to the aging metabolic processes. More and more studies have demonstrated that oxidative stress impacts both physiologic and pathologic ovarian aging, and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating the antioxidant response. Furthermore, various therapeutic approaches have been identified to ameliorate ovarian aging by modulating the Nrf2 pathway. This review summarizes the important role of the Nrf2/ Kelch-like ECH-associated protein 1 (Keap1) signaling pathway in regulating oxidative stress and influencing ovarian aging. Additionally, it highlights the therapeutic strategies aimed at targeting the Nrf2/Keap1 pathway.

Background: Unilateral genital tract obstruction with ipsilateral renal anomaly (UGTOIRA) syndrome is a rare congenital urogenital anomaly, characterized by different combinations of uterine abnormalities, unilateral cervical-vaginal obstruction, and ipsilateral renal abnormalities. Timely and correct diagnosis is critical. In this study, we analyzed the diverse ultrasound image features of UGTOIRA syndrome on genitourinary system segmental sequential ultrasound screening (SSUS) and the accuracy of ultrasonic diagnosis. Methods: The data from 59 patients with UGTOIRA syndrome over the last decade were analyzed retrospectively, which included ultrasound presentations and diagnoses of abnormalities of the uterus, cervix, and vagina, as well as the conditions associated with the bilateral fallopian tubes, ovaries, pelvis, kidneys and ureters, bladder, and urethra. Results: All 59 patients (100%) were found to have ipsilateral renal agenesis,and the diagnostic accuracy of ultrasound was 100%. The uterus was correctively diagnosed as complete bicorporal uterus in 42 cases (71.2%), bicorporal septate uterus in 7 cases (11.9%), complete uterus septate in 8 cases (13.6%), partial uterus septate in 1 case (1.7%), and unilateral isthmus atresia in 1 case (1.7%). The cervix was correctively diagnosed as septate cervix in 28 cases (47.5%), double cervix in 17 cases (28.8%), unilateral small cervix in 5 cases (8.5%), unilateral obliterated cervical orifice in 5 cases (8.5%), partial development of the unilateral cervix with a blind end in 3 cases (5.1%), and unilateral completely undeveloped cervix appearing as a normal cervix in 1 case (1.7%). The vagina was correctively diagnosed as oblique vaginal septum (OVS) in 45 cases (76.3%), and normal vagina in 13 cases (22.0%) via preoperative ultrasound. In 1 case (1/59, 1.7%) of high OVS with ipsilateral obliterated external cervical orifice, the OVS was missed by preoperative ultrasound. The ultrasound diagnostic accuracy rates of uterine malformation, cervical malformation, vaginal malformation, hematoma location and volume, uterine communication, and cervical communication were respectively 100%, 100%, 98.3%, 100%, 100%, and 100%. The ultrasonic detection rate for a hole on the OVS was 0%, and the missed diagnosis rate was 100%. Conclusions: SSUS can be used to accurately evaluate uterine, cervical, and vaginal malformation, obstruction site, location and volume of keratocele, cervical or uterine communication, and ovarian endometriosis cyst in patients with UGTOIRA syndrome and ipsilateral urinary system malformation. However, ultrasound is unable to identify a hole on the OVS.

ObjectivesTo provide clinical guidance for early diagnosis and effective management of primary cesarean scar choriocarcinoma, which is an extremely rare but highly malignant trophoblastic tumor. MethodsThis retrospective case series summarized the clinical courses of seven patients diagnosed with cesarean scar choriocarcinoma. ResultsWe identified two patients in our institution with cesarean scar choriocarcinoma. In addition, details of the previous five patients were extracted from databases and analyzed to provide more clinical information. The seven patients had an average age of 31.14 years, their tumor sizes ranged from 2.0 to 6.5 cm, and their pretreatment serum beta-human chorionic gonadotropin (beta-hCG) levels ranged from 3664 to 312 468 mIU/mL. All the patients were categorized as having FIGO Stage I disease, with four patients at low risk and three at high risk. Six of the seven were misdiagnosed with ectopic pregnancy before pathologic examination. ConclusionsClinicians should pay attention to masses in cesarean scar and to continuous elevation of serum beta-hCG levels after treatment. When cesarean scar choriocarcinoma is suspected, diagnostic surgery can be chosen for tentative treatment and pathologic sampling. Salvage EMA-CO chemotherapy (etoposide, actinomycin D, methotrexate, cyclophosphamide and vincristine) should be performed as early as possible to prevent metastasis and recurrence after pathologic diagnosis.

Although previous studies have shed light on the etiology of cervical cancer, metastasis of advanced cervical cancer remains the main reason for the poor outcome and high cancer-related mortality rate. Cervical cancer cells closely communicate with immune cells recruited to the tumor microenvironment (TME), such as lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells. The crosstalk between tumors and immune cells has been clearly shown to foster metastatic dissemination. Therefore, unraveling the mechanisms of tumor metastasis is crucial to develop more effective therapies. In this review, we interpret several characteristics of the TME that promote the lymphatic metastasis of cervical cancer, such as immune suppression and premetastatic niche formation. Furthermore, we summarize the complex interactions between tumor cells and immune cells within the TME, as well as potential therapeutic strategies to target the TME.