Pakistan journal of pharmaceutical sciencesLinhua Zhu, Yongfang Yue, Lili Cao
BACKGROUND: Intrauterine adhesion (IUA) is a common complication of endometrial injury. Bone marrow mesenchymal stem cells (BMSCs) have been implicated in endometrial repair, but strategies to enhance their therapeutic efficacy remain to be optimized. The C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis plays a pivotal role in BMSC homing. OBJECTIVE: This study aimed to test the hypothesis that ATI-2341, a functionally selective allosteric regulator of CXCR4, enhances the therapeutic efficacy of BMSCs in a rat IUA model. METHODS: After establishing the endometrial injury model, rat BMSCs were extracted and treated with ATI-2341 TFA (100 ng/mL). IUA model rats were randomly divided into model control group, BMSCs group, BMSCs+ATI-2341 TFA group, BMSCs+PBS group and Positive control group (n=10 each). Endometrial thickness was assessed by hematoxylin and eosin (HE) staining; cell proliferation by the methyl thiazolyl tetrazolium (MTT) assay; matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) protein expression by Western blot; and cytokeratin and vimentin expression by immunohistochemistry. RESULTS: ATI-2341 TFA-pre-treated BMSCs significantly increased endometrial thickness compared to untreated BMSCs (P < 0.05) or estrogen (P < 0.05). ATI-2341 TFA enhanced BMSC proliferation at 48 h (P < 0.05) and 72 h (P < 0.05). BMSCs exposed to ATI-2341 TFA or estrogen exhibited strong cytokeratin positivity and vimentin negativity. MMP-9 was downregulated (P < 0.05) and TIMP-1 upregulated (P < 0.05) in the ATI-2341 TFA group relative to controls. CONCLUSION: ATI-2341 TFA promotes acquisition of epithelial-like immunophenotype in BMSCs within the injured endometrial microenvironment and is associated with improved endometrial morphology in IUA rats. These findings provide preliminary evidence for the functional modulation of BMSCs by CXCR4-targeted therapy in endometrial repair.
BACKGROUND: Duo Nang Decoction (DND) is widely used for treating polycystic ovary syndrome (PCOS)-related infertility. However, the molecular mechanisms underlying its action remain unclear. In a previous study, downregulation of caveolin-1 (Cav-1) was shown to impair endometrial angiogenesis, a key determinant of endometrial receptivity. OBJECTIVES: This research study aimed to elucidate the influence and potential molecular mechanisms of DND on endometrial receptivity, specifically focusing on Cav-1 in PCOS rats. METHODS: Sprague Dawley (SD) rats (females, 3-week-old) were randomly categorized into the DND and aspirin cohorts. After successful PCOS modeling, the rats were orally administered DND or aspirin, respectively. Then, ovulation was induced and mating was performed. The rats were euthanized on the 2nd and 5th day of conception and the endometrium was extracted for histological evaluation via hematoxylin and eosin (HE) staining. Furthermore, immunohistochemistry (IHC) staining was carried out to assess Cav-1, vascular endothelial growth factor (VEGF) and β-catenin levels, as well as endometrial microvascular density (MVD). Moreover, reverse transcription polymerase chain reaction (RT-PCR) was used to measure the mRNA levels of VEGF and Cav-1 in the endometrium of both groups. RESULTS: The HE and IHC staining, as well as RT-PCR analysis of endometrial tissue slices, revealed that on the 2nd and 5th day of conception, both groups indicated significantly increased endometrial thickness, MVD and elevated levels of VEGF, Cav-1 and β-Catenin. However, the MVD in the DND group was substantially higher relative to the aspirin group. CONCLUSION: This study revealed that DND significantly enhanced endometrial angiogenesis and improved endometrial receptivity in PCOS rats. Mechanistically, the effects of DND on endometrial receptivity may be associated with the upregulation of Cav-1 and β-catenin. However, the specific mechanism of action warrants further research.
BACKGROUND: Cervical cancer (CC) remains a leading cause of cancer-related mortality worldwide and cisplatin resistance poses a major challenge to effective treatment. MicroRNA-135 (miR-135) has been implicated in tumor progression and drug resistance, but its role in cisplatin-resistant CC remains unclear. OBJECTIVES: To investigate whether miR-135 affects cisplatin resistance in CC cells by targeting CD44v6. METHODS: Bioinformatic analysis (TargetScan) was performed to predict the miR-135 binding site in CD44v6, followed by a dual-luciferase reporter assay. RT-qPCR and Western blot were used to measure miR-135 and CD44v6 expression in cisplatin-resistant HeLa/DDP cells, HeLa cells and normal Ect1/E6E7 cells. HeLa/DDP cells were transfected with miR-135 mimic or NC mimic and cell proliferation (CCK-8, colony formation), apoptosis (flow cytometry) and CD44v6 expression were assessed. RESULTS: miR-135 directly bound to the CD44v6 3'-UTR, reducing luciferase activity by 58% (*p* < 0.001). miR-135 expression was decreased by 68% in HeLa/DDP cells compared to Ect1/E6E7 cells, while CD44v6 expression was increased 3.5-fold. miR-135 mimic transfection reduced CD44v6 protein expression by 62%, decreased cell viability by 57.3%, increased the apoptosis rate from 12.4% to 35.8% (absolute increase of 23.4%) and lowered the cisplatin IC50 from 22.36 to 8.47 μmol/L (2.64-fold reversal, *p* < 0.001). CONCLUSIONS: miR-135 overexpression was associated with reduced CD44v6 expression, decreased proliferation, increased apoptosis and enhanced sensitivity to cisplatin in HeLa/DDP cells. These findings demonstrate an inverse association between miR-135 and CD44v6 in cisplatin-resistant CC cells; however, causal mechanistic evidence (e.g., via CD44v6-specific knockdown or rescue experiments) is not provided. Further studies are required to establish whether CD44v6 directly mediates the chemosensitizing effects of miR-135.
Sexual healthOurlad Alzeus G Tantengco, Mikayla Francesca N de Guzman, Amina C Kunting, Sheriah Laine M de Paz-Silava, Michele H Diwa, Ian Kim B Tabios
BACKGROUND: Self-collected vaginal sampling for human papillomavirus (HPV) DNA testing provides a promising alternative to physician-collected Pap smears, especially in low-resource settings. However, data on its acceptability and preferences among Filipino women remain limited. This study aimed to assess women's perceptions, experiences, willingness and preferences regarding self-collected vaginal sampling for HPV DNA testing compared with Pap smears. METHODS: A cross-sectional study was conducted among 592 women. Participants underwent both physician-collected Pap smears and self-collected vaginal sampling for HPV DNA testing. Perceptions were measured using five-point Likert scale questionnaires before and after self-collection. Descriptive statistics were used, and paired and independent Wilcoxon tests were used to compare Likert responses. Willingness to undergo screening was analyzed with Cochran's Q and McNemar tests. Participants' reasons for their preferred screening method were categorized thematically and displayed in stacked bar charts. RESULTS: Self-collection was generally viewed as painless, not uncomfortable, non-embarrassing, and easy and convenient. Acceptability significantly increased after participants performed self-collection (P < 0.001 for pain and discomfort). Compared with Pap smears, self-collection was seen as less embarrassing (P < 0.001), but rated as less easy (P = 0.01) and less convenient (P = 0.004). Most participants preferred physician-administered screening (84.8%) due to trust in medical expertise, and confidence in the procedure's accuracy, safety and cleanliness. CONCLUSIONS: Self-collected vaginal sampling was highly acceptable, yet physician-collected screening remained the preferred method. Improving education, demonstrations, and support for self-collection may enhance the uptake of HPV DNA testing and broaden access to cervical cancer screening in the Philippines.
Sexual healthAlfa Putri Meutia, Gita Nurul Hidayah, Fernandi Moegni, Muhammad Syah Nadir Chan, Budi Iman Santoso
BACKGROUND: Vaginal dilators are used to manage genito-pelvic pain/penetration disorder, but longer daily sessions may increase treatment burden. This study evaluated achievement of intercourse and sexual-function outcomes following a multicomponent protocol incorporating 1-min daily vaginal dilation (AM-1 protocol). METHODS: This retrospective multicentre observational study screened 156 consecutive women with genito-pelvic pain/penetration disorder treated at YPK Mandiri Hospital and Bunda General Hospital, Jakarta, Indonesia, between January 2021 and October 2024. Of these, 123 initiated the AM-1 protocol as sole treatment, and 113 had complete paired pre-treatment and post-treatment Female Sexual Function Index-6 (FSFI-6) data for analysis. The AM-1 protocol combined psychoeducation, pelvic floor relaxation, cognitive reframing and progressive 1-min daily dilation. Outcomes were patient-reported successful unassisted penile-vaginal intercourse and paired FSFI-6 scores assessed at least 4 weeks after successful intercourse. RESULTS: Successful intercourse was documented in 113 of 123 women who initiated the AM-1 protocol as sole treatment (91.9%; 95% CI 85.6-96.0%); 10 women had no documented follow up and their outcomes were unknown. Among 113 complete cases, median total FSFI-6 score increased from 14 (interquartile range 10-16) before treatment to 22 (IQR 20-26) after treatment, with a median within-participant increase of 10 points (IQR 8-12; P < 0.001). Probable female sexual dysfunction decreased from 100% to 23.9% (P < 0.001). CONCLUSIONS: In this study, the AM-1 protocol was associated with documented successful intercourse and improved FSFI-6 scores. Comparative studies are needed to determine whether the brief dilation duration improves adherence or outcomes.
FASEB journal : official publication of the Federation of American Societies for Experimental BiologyHoujin Dongye, Yuxiu Wu, Jie Hu, Chen Lv, Yuqing Wang, Minxue Gai, Shawei Sa, Wencai Zhang, Ming Li, Xiaoqiang Zhu, Keke Wei, Rusong Zhao, Lei Yan
As the leading cause of uterine factor infertility, intrauterine adhesion (IUA) poses a severe threat to the fertility and mental health of women at childbearing age. However, the efficacy of the present clinical treatments is unsatisfactory. There remains an urgent need to develop a safe, effective, and clinically feasible therapeutic strategy to restore the damaged endometrium. Here, we fabricated a gelatin-based electrospun nanofibrous membrane (GENM) via electrospinning and chemical crosslinking technique and characterized its properties. The anti-fibrotic and pro-angiogenic effects of GENM were evaluated in cellular models. A rat IUA model induced by mechanical scraping was established to assess the therapeutic efficacy of GENM by histological staining. Additionally, bulk RNA sequencing was performed to explore the underlying mechanisms. Our results demonstrated GENM inhibited transforming growth factor beta 1 (TGF-β1) induced fibrosis in human endometrial stromal cells (HESCs) and promoted angiogenesis of human umbilical vein endothelial cells (HUVECs). Animal experiments also suggested that GENM significantly improved endometrial receptivity and neovascularization while reducing fibrosis in the rat IUA model. RNA sequencing further identified several signaling pathways contributing to uncovering its mechanism of action. These findings indicate that GENM holds significant potential for clinical application in the management of IUA.
Reproduction, fertility, and developmentAna Camacho Benítez, Rossana Vasconcellos, Helen Viotti, Paula Lombide, Nicolás Cazales, Graeme B Martin, Graciela Pedrana
CONTEXT: In mares, post-breeding endometritis is a major cause of embryo mortality. In other species, endometrial function and pathology seem to involve heat shock protein-90 (HSP90), a factor regulated by heat shock transcription factor-1 (HSF-1). AIMS: To study the relationships between HSP90 and HSF-1 and post-insemination endometritis. METHODS: Endometrium was sampled at oestrus without artificial insemination (AI) and at 2 h and 4 h after AI. Immunohistochemistry and image analysis were used to localise and quantify HSP90 and HSF-1 in luminal and glandular epithelium; in stroma, immuno-positive leucocytes and fibroblasts were counted. KEY RESULTS: Both HSP90 and HSF-1 were expressed in the cytoplasm and the nucleus of luminal epithelial and stromal cells. In the glandular epithelium, HSP90 immunoexpression increased above the control (no AI) values, 2 h and 4 h after AI. In contrast, HSF-1 immunoexpression decreased 2 h and 4 h after AI. At 2 and 4 h after AI, the numbers of HSP90- and HSF-1-positive leucocytes and fibroblasts exceeded control values. CONCLUSIONS: Changes in HSP90 and HSF-1 expression in endometrium after AI are associated with endometrial inflammation. Their presence in the cytoplasm and nucleus (luminal and glandular epithelial cells, fibroblasts, leucocytes) suggests roles in cytosolic protein interactions and DNA regulation. Their expression in luminal and glandular epithelium, and in stromal cells, suggests roles in the regulation of endometrial repair and remodelling. IMPLICATIONS: The relationships between HSP90 and HSF-1 and the development of post-insemination endometritis suggest that these proteins can be targets for prevention or treatment of persistent endometritis.
FASEB journal : official publication of the Federation of American Societies for Experimental BiologyHuihui Wang, Chaoying Wang, Shuaishuai Guo, Guang Yang, Junnan Fang, Jingyi Hu, Ran Jiang, Jun Zhai, Haixia Jin, Wenyan Song, Senlin Shi, Xianju Huang, Lin Qi,…
Obesity triggers ovarian dysfunction and female infertility accompanied by granulosa cell damage. Ferroptosis, iron-dependent lipid peroxidation-mediated cell death, participates in multiple reproductive diseases, yet the molecular cascade linking metabolic obesity to granulosa ferroptosis remains undefined. Using high-fat diet obese mice, primary human granulosa cells from obese infertile patients, and KGN cell lines, we identified the nuclear receptor NR4A1 as a key mediator of obesity-induced ferroptosis downstream of PI3K/AKT signaling. Elevated NR4A1 was associated with upregulated ACSL4 and suppressed GPX4, accompanied by iron overload, lipid peroxidation, and mitochondrial collapse, impairing folliculogenesis and oocyte quality. Metformin reduced NR4A1 activation in association with PI3K/AKT signaling modulation, thereby attenuating ferroptotic injury and contributing to the restoration of ovarian function. In vivo NR4A1 agonist administration attenuated the protective effects of metformin, while ovarian-specific NR4A1 knockdown alleviated HFD-triggered ovarian ferroptosis. Single-cell RNA-seq further suggested that metformin remodels oocyte redox and folliculogenic transcriptional networks. These findings support a role for the PI3K/AKT-NR4A1 signaling pathway in driving ferroptosis during obesity-related ovarian dysfunction and suggest a potential anti-ferroptotic mechanism of metformin in this context.
Embryo implantation is a critical and complex process that requires coordination between the embryo and the receptive endometrium for its success. However, a multitude of factors have the potential to contribute to implantation failure. Among these factors, bacterial infections in the uterine environment are of particular concern and are increasingly being considered as a contributing factor to implantation failure. The presence of pathogenic bacteria has been demonstrated to stimulate inflammatory responses, alter the endometrial microbiome, interfere with critical signaling pathways, and finally change the uterus microenvironments that are required for implantation. We aimed to review bacterial infection as an important potential etiology of chronic endometritis pathophysiology and its correlation with implantation failure.
Endometriosis and ovarian cancer share invasive, inflammatory, and pro-survival mechanisms in which CXCR4 signaling may play an important role, yet phytochemical modulators of this receptor remain insufficiently characterized. This study addressed that gap by integrating receptor reconstruction, ligand-guided docking, pharmacokinetic and toxicity prediction, pharmacophore mapping, density functional theory, replicated membrane-embedded molecular dynamics, and MM/GBSA analysis. A native human CXCR4 model was generated using SWISS-MODEL with 98.2% template coverage and 100% sequence identity, while the co-crystallized IT1t ligand defined the docking cavity. Eighteen phytochemicals were screened, and naringenin achieved the most favorable predicted docking score (-6.361 kcal/mol), exceeding apigenin (-5.927 kcal/mol) and IT1t (-5.155 kcal/mol). Naringenin formed predicted interactions with Tyr116, Arg188, and Tyr255, showed acceptable drug-likeness, solubility, and gastrointestinal absorption, and displayed a wider HOMO-LUMO gap than apigenin. Two independent 100 ns simulations of the CXCR4 complexes with naringenin, apigenin, and IT1t indicated comparatively consistent structural behavior for naringenin, supported by RMSD, SASA, radius of gyration, hydrogen-bond, PCA, FEL, and DCCM analyses. MM/GBSA estimates were also more favorable for naringenin than apigenin across both replicas. Its predicted LD50 was 2000 mg/kg (toxicity class 4), emphasizing that favorable receptor interactions do not establish safety and require experimental toxicological assessment during further preclinical development. Collectively, naringenin emerged as the most coherent in silico prioritized CXCR4-binding candidate. However, the absence of receptor-binding assays, functional validation, and in vivo confirmation remains a major limitation.
BMJ openYiran Han, Chenfeng Zhu, Jun Zhang, Wei Liu, Dongjian Yang, Feng Sun, Hong Xu
INTRODUCTION: Uterine fibroids represent the most common benign tumours in women of reproductive age and may impair reproductive function. Approximately 30% of infertile patients require myomectomy. However, evidence supporting the conventional postoperative interpregnancy interval (IPI) is not individualised, potentially resulting in unduly delayed childbearing for some women. Currently, no definitive clinical guidelines exist regarding the optimal IPI following myomectomy. After imaging confirmation at 6 months postoperatively showing no evidence of poor scar healing, this study will randomise patients who have undergone myomectomy to compare the safety and efficacy of a shortened pregnancy interval of 6 months with the conventional 12-month interval. METHODS AND ANALYSIS: This multicentre randomised controlled trial will be conducted in Shanghai from 24 November 2025 to 31 August 2028, with the recruitment period running concurrently. A total of 384 women of reproductive age with Federation of Gynecology and Obstetrics type I-VI uterine fibroids, who have undergone myomectomy and express a clear immediate desire for conception, will be enrolled. Following provision of informed consent, and postoperative imaging at 6 months confirming satisfactory scar healing, eligible participants will be randomly allocated in a 1:1 ratio to either the shortened IPI group or the conventional IPI group. The primary outcome is the incidence of adverse pregnancy outcomes associated with myomectomy. The secondary outcomes include cumulative live birth rate, fibroid recurrence rate and obstetric complications. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Review Boards of the Obstetrics and Gynecology Hospital of Fudan University, the Shanghai First Maternity and Infant Hospital and the China Welfare Institute International Peace Maternity and Child Health Hospital (approval number: GKLW-A-2025-108-01). Written informed consent will be obtained from all participants. The primary results of this trial will be submitted for publication in a peer-reviewed scientific journal. Following the publication, a lay summary of the main findings will be prepared and disseminated to all participants who request it. TRIAL REGISTRATION NUMBER: ChiCTR2500112650.
Human fertility (Cambridge, England)Raashi Shah, Jennifer Barcroft, Hannan Al-Lamee, Erna Bayar, Rana Al-Odetalah, Marius Zaharia, Kinjal Shah, Anamika Sakhuja, Danai Balfoussia, Emil Barsoum, Ra…
Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproductive technology (ART). Risk factors for OHSS include female age, polycystic ovarian morphology and high ovarian reserve. The use of a gonadotrophin-releasing hormone (GnRH) agonist trigger in a freeze-all cycle is an effective strategy for reducing the risk of OHSS in suspected high responders. Various GnRH agonist trigger preparations exist but their use is subject to manufacturer availability. The national shortage of Buserelin necessitated a switch to alternative GnRH agonist trigger preparations such as Modified-Release (MR) Triptorelin resulting in a spike in OHSS cases, prompting an urgent review of our local treatment protocols and an immediate switch to Nafarelin (nasal preparation). We performed a retrospective study of freeze-all GnRH antagonist treatment cycles treated with a GnRH agonist (Triptorelin-MR, Nafarelin, and Buserelin) trigger at a London fertility clinic. The high-risk cohort consisted of patients with ≥18 follicles >12mm on ultrasonography. The diagnosis of OHSS was based on the criteria outlined by the Royal College of Obstetricians and Gynaecologists (RCOG). Relevant clinical data were extracted from medical records including female age, antral follicle count (AFC), anti-Mullerian hormone (AMH), ovarian stimulation dose (international units; IU), trigger preparation, oestradiol level on trigger day (pmol/l), oocyte yield, and the diagnosis and management of OHSS. A total of 333 patients underwent a freeze-all GnRH antagonist cycle between January 2023 and September 2024, 224 due to a high-risk of OHSS (≥18 follicles >12mm). The GnRH agonist preparations used included: Triptorelin-MR only (0.75 mg subcutaneous injection, SC; n = 69), Triptorelin-MR (0.375 mg SC) plus Menopur (150 IU SC; n = 49), Buserelin (2 mg SC; n = 69), and Nafarelin (1.6 mg nasal spray; n = 37). Forty-three patients met the RCOG diagnostic criteria for OHSS (mild n = 5, moderate n = 25 and severe n = 13). Six patients required inpatient OHSS management; none required intensive care or a chest/abdominal drain. Of those that developed severe OHSS, 92.3% (n = 12/13) had received Triptorelin-MR only or in combination with Menopur. Based on this cohort, Triptorelin-MR containing triggers are associated with a 12-fold increased risk of severe OHSS compared with other preparations and should not be used as a GnRH agonist trigger in patients at high risk of OHSS.
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and GynaecologyJingjing Zhang, Juan Sun, Xiaohang Ye, Xiaolei Yang, Wei Jin, Le Bu
BACKGROUND: Chronic pelvic pain (CPP) remains a common and clinically challenging outcome after uterus-preserving surgery for adenomyosis. Identifying patients at higher risk of postoperative CPP may facilitate individualised postoperative management. METHODS: The clinical data of 150 patients with adenomyosis admitted to our hospital from January 2022 to January 2025 were prospectively collected for observation. Uterine volume, Pictorial Blood Loss Assessment Chart (PBAC) score, Cox Menstrual Symptom Scale (CMSS) score, cancer antigen 125 (CA125) level, haemoglobin (Hb) level, and three-level version of the EuroQol five-dimensional questionnaire (EQ-5D-3L) score were recorded preoperatively and at 3 and 6 months postoperatively. Patients were divided into CPP (n = 38) and non-CPP (n = 112) groups based on 6‑month CPP status. Independent risk factors were identified using logistic regression, and a predictive model was developed and validated. RESULTS: Significant improvements were observed in uterine volume, PBAC score, CMSS score, CA125 level, and Hb level postoperatively (P < 0.05). EQ-5D-3L scores improved in usual activities, pain/discomfort, and anxiety/depression (P < 0.05). Preoperative CMSS score, CA125 level, and diffuse-type adenomyosis were identified as independent factors associated with CPP, while preoperative hormonal pre-treatment and postoperative regular hormonal therapy showed significant associations in univariate analysis. The predictive model incorporating these variables showed good calibration (Hosmer-Lemeshow χ2 = 15.477, P = 0.051) and strong discrimination (AUC = 0.820, 95% CI: 0.743-0.897). At the maximum Youden's index (0.567), sensitivity was 76.30% and specificity was 80.40% (P < 0.001). CONCLUSION: High preoperative CMSS score, high CA125 level, and diffuse-type adenomyosis are independent risk factors for postoperative CPP, while preoperative hormonal pre-treatment and postoperative regular hormonal therapy may be associated with a lower risk of CPP. The predictive model effectively identifies high-risk patients, supporting targeted nursing interventions.
Gynecological endocrinology : the official journal of the International Society of Gynecological EndocrinologyXiangyan Ruan, Juan Du, Muqing Gu, Fengyu Jin, Jing Jin, Yanglu Li, Jiaojiao Cheng, Yanqiu Li, Weimin Kong, Qi Zhang, Zecheng Wang, Mingzhen Zhang, Anming Liu,…
OBJECTIVE: This article reports on the world's first live birth after ovarian tissue cryopreservation and transplantation (OTCT) in a patient with colon cancer. METHODS: A 29-year-old unmarried nulliparous patient underwent ovarian tissue cryopreservation before chemotherapy. After chemotherapy-induced premature ovarian insufficiency, she received the first transplantation of six thawed ovarian cortex strips. Despite normal ovarian function being maintained for over 2 years, she requested and underwent a second transplantation with another six strips to maximize her chances of pregnancy. RESULTS: After the first transplantation, she resumed spontaneous menstruation with restored ovarian function, which was remained functional for 28 months until the second transplantation. Following the second transplantation, she conceived spontaneously without assisted reproductive technology two months after grafting. Routine prenatal examinations showed normal fetal development without abnormalities. She delivered a healthy baby girl weighing 2785 g with Apgar scores of 8/9 at 1 and 5 min. CONCLUSIONS: This case demonstrates the feasibility and safety of OTCT for fertility and ovarian function preservation in patients with colon cancer.
Antonie van LeeuwenhoekYu Li, Tianshu Gu, Li Ma, Lan Yao, Minghui Li, Shuyan Han, Xingjiang Li, Weikuan Gu, Jiamin Ma
The potential relationship between fungal biology and cervical cancer remains poorly understood. This study aimed to assess the ability of ChatGPT-4o to generate research hypotheses concerning possible links between fungal factors, HPV persistence, and cervical carcinogenesis. ChatGPT-4o generated hypotheses in three prespecified domains: microbial dysbiosis, inflammation, and immune modulation. Three author-evaluators with expertise in pathology, oncology, and microbiology independently assigned overall evaluation scores and assessed the scientific reasonableness of experimental-plan components. Targeted literature searches identified publications directly addressing each proposed mechanism. Inter-rater reliability was quantified using a two-way random-effects, absolute-agreement intraclass correlation coefficient (ICC) and pairwise quadratic-weighted Cohen's kappa. No human-generated hypothesis set, alternative language model, or repeated independent AI session was included. ChatGPT-4o generated 55 hypotheses. No directly matching publication was identified for 48 hypotheses under the prespecified search framework; this finding was interpreted as indicating an underexplored direction, not proof of novelty. Based on the predefined composite evaluation rubric, 35 hypotheses (63.6%) received high mean evaluation scores and 20 (36.4%) received moderate mean evaluation scores. Agreement for hypothesis scores was high (ICC (2,1) = 0.975; pairwise weighted kappa = 0.963-1.000). Among 18 experimental-plan components, 12 received high mean scores and 6 received moderate mean scores; agreement was lower but still strong (ICC (2,1) = 0.821; weighted kappa = 0.727-0.914). Representative hypotheses concerned fungal metabolites and oxidative stress, fungal-associated inflammation and oxidative damage, and fungal modulation of immune-checkpoint pathways. This pilot study suggests that ChatGPT-4o can generate diverse and potentially testable hypotheses concerning fungal biology and cervical cancer. However, the generated hypotheses should be regarded as exploratory research directions rather than validated mechanisms and require independent literature verification and experimental validation.
Annals of medicinePeixin Wang, Mengyu Zhang, Yucheng Lai, Tao Song, Yan Shen, Haiying Chen, Xiaoyan Chen
BACKGROUND: PAX1/JAM3 methylation are promising biomarkers for high-grade cervical intraepithelial neoplasia (CIN) detection, but menopausal status may affect diagnostic accuracy. This retrospective study compared their clinical performance between premenopausal and postmenopausal women undergoing colposcopy. METHODS: 705 women undergoing colposcopy for abnormal screening results and/or clinical symptoms were stratified by menopausal status, including 192 postmenopausal and 513 premenopausal women. Subjects were further classified into ≤CIN1 and CIN2+ groups according to histopathology. Diagnostic and triage utility of PAX1/JAM3 methylation for identifying CIN2+ lesions were compared between premenopausal and postmenopausal women. RESULTS: PAX1/JAM3 methylation demonstrated superior diagnostic performance for CIN2+ detection in postmenopausal women compared with premenopausal women, either alone or in combination. Sensitivities of PAX1m and JAM3m in postmenopausal women (90.00%, 95% CI: 76.34-97.21%; 82.50%, 95% CI: 67.22-92.66%) were higher than those in premenopausal women (61.98%, 95% CI: 52.71-70.65%; 60.33%, 95% CI: 51.04-69.11%) (all p < 0.05). The combination improved sensitivity to 72.73% in premenopausal women and maintained 92.50% in postmenopausal women. Besides, PAX1/JAM3 methylation outperformed cytology and HPV16/18 testing in both groups (p < 0.001). In HPV16/18-positive or cytology triage, methylation increased positive predictive values (PPVs) for CIN2+/CIN3+ and reduced colposcopy referrals . However, CIN2+ missed rates in premenopausal women (27.54% for HPV16/18-positive triage and 23.85% for cytology triage) were higher than those in postmenopausal counterparts. CONCLUSIONS: The diagnostic performance of PAX1/JAM3 methylation for high-grade cervical lesions differs distinctly between premenopausal and postmenopausal women undergoing colposcopy. Menopausal status should be considered when applying methylation biomarkers, particularly as a valuable auxiliary tool to improve diagnostic accuracy in elderly women.
Annals of medicineXinyun Tu, Youni Zhang, Li Wang, Yiyi Shan, Lihong Xie, Huafeng Shou, Yan Liang
BACKGROUND: Ovarian, cervical and endometrial cancers have been the leading cause of morbidity and mortality in women, often resulting from late diagnosis, resistance to therapies and off-target toxicity of conventional therapies. DISCUSSION: The review discusses recent progress in the development of dual-targeted nanocarrier systems in gynaecologic oncology, relying on peer-reviewed publications in scientific databases published within the past decade. Applications of these systems are also discussed in terms of the potential to improve the selectivity and therapeutic efficiency of tumour therapy. Major available evidence is based on preclinical in vitro and in vivo models. Clinical translation is in its early-phase trials, suggesting clinical validation in gynaecologic oncology remains in its infancy. The most important challenges in translation are scalable manufacturing, long-term safety, biological complexity and regulatory challenges. CONCLUSION: This review describes the prevailing situation and constraints of dual-targeted nanotechnology, focusing on possible applications in the development of more accurate and individualized therapies for gynaecologic cancers.
BACKGROUND: Evidence regarding repeated remimazolam administration remains limited. We hypothesized that remimazolam would be associated with fewer adverse events than propofol while maintaining stable sedative requirements across three repeated sedation sessions. METHODS: Patients with cervical cancer undergoing three fractions of interstitial brachytherapy were randomized to propofol or remimazolam. The primary outcome was the proportion of sedation episodes with at least one prespecified intraoperative adverse event across three sessions. Secondary outcomes included sedative dose, hemodynamics, and sleep quality assessed using the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale (AIS). RESULTS: A total of 100 participants were randomized, of whom 91 completed all three prespecified sedation sessions and were included in the primary per-protocol analysis (46 in the propofol group and 45 in the remimazolam group). Across 138 propofol and 135 remimazolam episodes, overall adverse events were less frequent with remimazolam (17.78% vs. 59.42%; RR, 0.30; 95% CI, 0.18-0.49; p < 0.001). Respiratory depression (3.70% vs. 26.09%; RR, 0.14; 95% CI, 0.04-0.53; p = 0.004) and hypotension (8.15% vs. 41.30%; RR, 0.20; 95% CI, 0.09-0.42; p < 0.001) were also lower with remimazolam. Remimazolam requirements remained stable across sessions (third vs. first: mean difference, 0.19 mg; 95% CI, -0.78 to 1.15; p = 0.846). No significant between-group differences were observed in PSQI or AIS scores. CONCLUSION: Across three consecutive sedation sessions for interstitial brachytherapy, remimazolam was associated with fewer respiratory and hemodynamic adverse events than propofol, while sedative requirements remained stable across the three sessions. TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR2500108294).
MedicineZiyad S Almalki, Ahmad A Alamer, Shaheed K Alhumaid, Abdulrahman A Alsuhibani, Bandar S Alghamdi, Meshal M Alqahtani, Nawaf S Alzahrani, Osama A Alghamdi, Hait…
BACKGROUND: Adding pembrolizumab to standard concurrent chemoradiotherapy (CCRT) has shown substantial survival benefits in newly diagnosed, high-risk locally advanced cervical cancer (LACC), but its economic value in Saudi Arabia has not been established. This study assessed the cost-effectiveness of pembrolizumab plus CCRT versus placebo plus CCRT as first-line treatment for high-risk LACC from the perspective of the Saudi Arabian healthcare payer. METHODS: A partitioned survival analysis model was developed to project lifetime costs and quality-adjusted life-years (QALYs) for a hypothetical cohort of women with high-risk LACC in the Saudi public healthcare sector, using resource use patterns consistent with major tertiary care and specialized cancer centers. Clinical efficacy data were obtained from the KEYNOTE-A18 trial. Costs were sourced from official Saudi price lists, local hospital data, and a formal Structured Expert Elicitation process, and were reported in 2025 United States dollars. Health state utilities were derived from the literature. The primary outcome was the incremental cost-effectiveness ratio. Future costs and QALYs were discounted at an annual rate of 3%. Comprehensive deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty. RESULTS: Adding pembrolizumab to CCRT resulted in an incremental gain of 3.51 life-years and 2.93 QALYs at an additional cost of $242,043 compared with placebo plus CCRT. At its current list price, the regimen yielded an incremental cost-effectiveness ratio of $82,626 per QALY. At a willingness-to-pay threshold of $90,000 per QALY, the probability of the pembrolizumab regimen being cost-effective was 67%. CONCLUSION: Pembrolizumab in combination with CCRT provides substantial clinical benefits in patients with high-risk LACC in Saudi Arabia. At the current price, this regimen is likely to be considered cost-effective. The analysis provides a strong, evidence-based rationale for significant price negotiations to ensure that the regimen delivers value to the Saudi healthcare system.
This study aimed to systematically investigate the epidemiological distribution characteristics and disease burden of cervical cancer (CC) in Asian populations, and to assess the causal relationship between smoking, a key modifiable risk factor, and the incidence of CC based on genetic evidence, thereby providing a scientific basis for targeted prevention and control strategies in Asia. This study first used the GBD 2021 database to analyze trends in CC incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021 across global, Asian, and East Asian regions, along with age distribution and attributable risk factors. It then applied 2-sample Mendelian randomization (MR) using genome-wide association study (GWAS) data from East Asian populations, with multiple smoking-related behaviors (e.g., current smoking, cigarettes per day, household smoking exposure) as exposures and CC as the outcome. GBD analysis revealed that in 2021, Asia accounted for over half of the global CC disease burden. Although point estimates suggested a potential upward trend in CC burden across Asia from 1990 to 2021, statistical significance was not reached for the overall Asian population. Despite a general decline in the global incidence rate, the incidence in Japan exhibited a statistically supported upward trend, while point estimates in several other East Asian countries also suggested an increase. The peak disease burden was concentrated among women aged 55 to 59 years. Risk attribution analysis indicated that unsafe sexual behavior was the primary attributable factor for CC-related DALYs, while the attributable burden of smoking was significantly higher in Japan than in other regions. However, MR analysis did not identify statistically significant causal associations between any smoking-related exposure factors and CC risk (P-FDR ≥ .05 after false discovery rate correction). Sensitivity analyses revealed no substantial heterogeneity or pleiotropy bias. Asia, particularly East Asia, faces a substantial and potentially growing burden of CC. Causal inference based on genetic data from East Asian populations did not confirm a direct causal relationship between smoking and the incidence of cervical cancer. Future studies with larger genetic samples are needed to further elucidate the precise role of smoking.
Cervical cancer is a malignant tumor that threatens women's health and radiotherapy represents a major therapeutic approach for its treatment; however, radioresistance frequently leads to treatment failure. The present study aimed to investigate whether loperamide (LOP), a µ‑opioid receptor agonist commonly used as an antidiarrheal agent, could enhance the radiosensitivity of cervical cancer cells by regulating ferroptosis. A Cell Counting Kit‑8 assay was used to evaluate the cytotoxicity of LOP in SiHa and HeLa cells, and EdU and colony formation assays were performed to assess cell proliferation. In addition, wound‑healing and Transwell assays were performed to detect cell migration. Flow cytometry was applied to measure cell apoptosis and intracellular reactive oxygen species (ROS) levels, and colorimetric assays were used to determine malondialdehyde (MDA) and glutathione (GSH) contents. The mRNA and protein expression levels of the ferroptosis‑related markers GSH peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) were analyzed using reverse transcription‑quantitative PCR and western blotting. The results showed that LOP significantly inhibited the viability of SiHa and HeLa cells, and exerted a synergistic effect with radiotherapy (combination index <1) to suppress cell proliferation and migration. Combined treatment with LOP and radiotherapy markedly increased apoptosis and ROS accumulation, elevated MDA levels and reduced GSH levels. Moreover, the combination treatment significantly downregulated the expression of GPX4 and SLC7A11. These findings indicated that LOP enhances the radiosensitivity of cervical cancer cells, with ferroptosis induction via inhibition of the GPX4/SLC7A11 axis as a contributing mechanism. Both apoptosis and ferroptosis were induced by the combination treatment, suggesting that the radiosensitizing effect may involve multiple cell death pathways. These observations provide a basis for further investigation into LOP as a potential radiosensitizing agent in cervical cancer.
Journal of applied clinical medical physicsHaiyan Jiang, Zengtai Yuan, Zihao Liu, Yuxiang Wang, Wei Hu, Bing Yan, Yidong Yang
BACKGROUND: Radiation therapy treatment planning is a time-consuming trial-and-error process, and the plan quality is heavily dependent on planners' experiences, resulting in a strong demand for automated planning methods that can rapidly generate uniformly high-quality plans. PURPOSE: This study aimed to develop a hybrid automated deep learning-based plan optimization (HALO) framework, integrating deep learning fluence prediction and optimization, multileaf collimator (MLC) sequencing, and GPU-accelerated Monte Carlo dose computation. HALO was designed to ensure robust plan generation for cervical cancer intensity-modulated radiation therapy (IMRT). METHODS: The proposed HALO framework incorporated several functional modules. First, a dose-guided Fluence Prediction Network (DG-FPN) was developed. A total of 120 cervical cancer clinical IMRT plans were collected to train the DG-FPN, of which 90 plans were assigned for training, 10 for validation, and 20 for testing. The neural network took patients' computed tomography (CT) anatomy as input and predicted the 3D dose distribution and fluence maps. Next, the predicted fluence maps were further optimized to meet dose-volume constraints (DVCs), and then the refined fluence maps were converted into deliverable segments using an MLC sequencing algorithm. Finally, dose calculation was performed using a GPU-accelerated Monte Carlo engine. The 20 patients in the testing set were used to evaluate the HALO method, and the plan deliverability was validated by patient-specific IMRT Quality Assurance (QA). RESULTS: The DG-FPN achieved superior fluence prediction accuracy compared to previous work, with a median mean absolute error (MAE) of 0.055 and a structural similarity index (SSIM) of 0.94. The automated framework generated high-quality plans and reduced dose to adjacent OARs, with V50Gy decreased from 46.5 ± 5.0% to 41.5 ± 4.8% (p = 0.008)for bladder, V35Gy decreased from 31.5 ± 8.2% to 29.2 ± 7.5% (p = 0.024) for small intestine, while preserving PTV homogeneity and conformity. Importantly, the entire treatment planning time was within 3 minutes, with fluence optimization time decreased by an average of 82.6% after using deep learning prediction. The mean gamma passing rate under the 2%/2 mm criterion for the patient-specific IMRT QA achieved 97.37 ± 1.01%. CONCLUSIONS: This study demonstrated the clinical feasibility of the proposed HALO framework for cervical cancer radiotherapy in producing high-quality and deliverable IMRT plans. The proposed automated paradigm can serve as a stand-alone platform for treatment planning.
Biomedical chromatography : BMCMengxue Feng, Yan Song, Xueqing Qian
Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is characterized by dysregulation of multiple steroid hormones. Accurate quantification of these analytes is essential for laboratory evaluation; however, currently may involve complex sample-preparation workflows or provide insufficient analytical coverage, particularly for dehydroepiandrosterone sulfate (DHEAS). A liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was established for the simultaneous measurement of six steroid hormones associated with PMOS. Sample preparation combined liquid-liquid extraction with protein precipitation. Chromatographic separation was completed within 6 min. Validation followed international recommendations and included linearity, sensitivity, precision, accuracy, matrix effects, selectivity, and specificity. All analytes showed excellent linearity (R = 0.9959-0.9995), with intra- and inter-day CVs ≤ 5.6%. Spike recovery ranged from 85.2% to 114.9%. Accuracy was further supported by third-party QC materials and successful participation in an external quality assessment program. The assay provided an expanded linear range for DHEAS (20-20,000 ng/mL). This validated LC-MS/MS assay provides rapid, sensitive, and reproducible quantification of six PCOS-related steroid hormones and is suitable for routine laboratory implementation.
The journal of obstetrics and gynaecology researchBurcu Dincgez, Gulten Ozgen, Nergis Kender Erturk, Hazel Cagın Kuzey, Esra Kartal Golcuk
AIM: Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, hyperandrogenism, and reproductive dysfunction. Myoinositol and coenzyme Q10 (CoQ10) have complementary metabolic and hormonal effects; however, the additive and dose-dependent effects of CoQ10 remain unclear. This study evaluated these effects in women with PCOS. METHODS: In this retrospective study, 200 women with PCOS were assigned to four groups: myoinositol plus CoQ10 100 mg (n = 55), myoinositol plus CoQ10 200 mg (n = 55), myoinositol alone (n = 45), and untreated controls (n = 45). Fasting insulin, HOMA-IR, total testosterone, and menstrual cycle regularity were assessed at baseline and 6 months. Between-group differences were evaluated using multivariable regression analyses and sensitivity analyses. RESULTS: All treatment groups showed improvements in metabolic and hormonal parameters, with the greatest effects observed in the combination therapy groups. Myoinositol alone was associated with significant reductions in HOMA-IR (β = -0.219; p < 0.001) and total testosterone (β = -3.145; p < 0.001) compared with untreated controls. The addition of CoQ10 resulted in dose-dependent improvements, with 100 and 200 mg doses demonstrating progressively greater reductions in HOMA-IR (β = -0.308 and -0.571, respectively) and total testosterone (β = -2.847 and -5.325, respectively) (all p < 0.001). Multivariable regression analyses confirmed that both CoQ10 doses remained significantly superior to myoinositol monotherapy. Menstrual cycle regularity improved most in the MI + CoQ10 200 mg group (36.4%). CONCLUSION: Adjunctive CoQ10 supplementation with myoinositol provides significant and dose-dependent improvements in insulin resistance and hyperandrogenism in PCOS. The magnitude of reduction observed with 200 mg CoQ10 suggests potential clinical relevance, particularly in metabolically compromised patients. Prospective randomized studies are warranted to confirm these findings.
Cancer medicineYufei Li, Runhua Li, Rufei Duan, Xiaofen Gu, Jia You, Hong Wang, Tingting Zuo, Zhe Wang, Weizhao Lin, Li Li, Bo Zhu, Shaokai Zhang, Wen Yang, Shuai Yuan, Hongp…
OBJECTIVE: Cervical cancer poses a significant burden globally, particularly in developing countries, with China accounting for 20% of the global incidence. This study aimed to examine temporal changes in the pathological distribution of cervical cancer, particularly squamous cell carcinoma (SCC) and adenocarcinoma (ADC), in China from 2013 to 2022. METHODS: A nationwide, multicenter, retrospective study analyzed 6645 cervical cancer cases diagnosed between 2013 and 2022 across seven tertiary hospitals in China. The study analyzed demographic, obstetric, and reproductive factors to identify trends in the proportions of SCC and ADC. Multivariable logistic regression was further performed among women with SCC or ADC to identify factors independently associated with histological type. RESULTS: SCC accounted for 86.9% and ADC for 10.4% of invasive cervical cancer (ICC) cases. Although no significant change in SCC proportion was observed overall, declines were observed in specific subgroups-unemployed women, premenopausal women, and those with a history of reproductive system disease (ptrend = 0.012, 0.021, and 0.011, respectively). In multivariable analysis, compared with Central China, the odds of ADC relative to SCC were significantly higher in North China, Southwest China, East China, and South China, whereas menopausal women, Uyghur women, and rural residents showed lower odds of ADC relative to SCC. CONCLUSIONS: Although the overall proportion of SCC among ICC cases remained statistically stable during 2013-2022, SCC showed a decreasing trend in several high-risk subpopulations. Compared with our 2005-2010 series, the present 2013-2022 study showed a higher ADC proportion and a lower SCC proportion. These findings suggest a gradual shift in the pathological landscape of ICC in China and provide up-to-date nationwide multicenter data that may help refine future screening and prevention strategies.
Pakistan journal of pharmaceutical sciencesPeipei Li, Tuo He, Jiajia Pan, Jie Yang, Jiwen Peng
BACKGROUND: Adenomyosis is commonly associated with dysmenorrhea and heavy menstrual bleeding. Although the levonorgestrel-releasing intrauterine system (Mirena, LNG-IUS) is recommended as a first-line conservative treatment, device displacement or expulsion remains a major limitation, especially in patients with enlarged uteri or deep uterine cavities. OBJECTIVES: To evaluate the clinical efficacy and safety of the Indomethacin-GyneFix IUD (GyneFix IUD) combined with LNG-IUS in patients with adenomyosis and to assess whether uterine cavity depth influences device stability. METHODS: In this single-center prospective randomized controlled trial, 270 patients with adenomyosis were randomly assigned in a 1:1:1 ratio to the GyneFix IUD + LNG-IUS group, the ring IUD + LNG-IUS group, or the LNG-IUS-alone group (90 patients each). The primary endpoint was the rate of device displacement/expulsion at 6 months. Secondary endpoints included changes in visual analogue scale (VAS) scores, pictorial blood loss assessment chart (PBAC) scores, uterine volume, hemoglobin (Hb), serum CA125, adverse events and patient acceptance. Subgroup analysis was performed according to uterine cavity depth (≤ 9cm vs. >9 cm). RESULTS: At 6 months, the displacement/expulsion rate was significantly lower in the GyneFix IUD + LNG-IUS group (2.22%) than in the ring IUD + LNG-IUS group (10.00%) and the LNG-IUS-alone group (18.89%) (χ2=13.468, P<0.001). All three groups showed significant improvement in dysmenorrhea, menstrual blood loss, Hb and CA125 compared with baseline, without significant between-group differences (all P>0.05). Adverse event rates were comparable among groups (all P>0.05). Patient willingness to choose the same treatment again (95.12%) and willingness to recommend it (90.24%) were significantly higher in the GyneFix IUD + LNG-IUS group. In patients with uterine cavity depth >9 cm, the stability advantage of this strategy was more pronounced. CONCLUSION: GyneFix IUD combined with LNG-IUS significantly reduces device displacement/expulsion in adenomyosis, particularly in patients with deeper uterine cavities, while maintaining comparable symptom relief and safety. It may represent a more stable and acceptable long-term conservative treatment option.
Health expectations : an international journal of public participation in health care and health policyOcéane Pittet, Marion Delvallée, Nicola Pluchino, Kevin Selby, Glyn Elwyn, Marie-Anne Durand
BACKGROUND: Endometriosis treatment requires women to navigate complex, preference-sensitive decisions. Patient Decision Aids (PtDAs) help patients make value-aligned choices. However, the scope and quality of digital PtDAs for endometriosis, and the cap acity of conversational AI platforms to act as PtDAs, remain unclear. OBJECTIVES: Systematically map digital PtDAs for women of reproductive age with endometriosis, describe their content, development, and evaluation, and assess quality and replicability. SEARCH STRATEGY: Electronic databases, Google Scholar, grey literature, and web searches were conducted from inception to July 2025. SELECTION CRITERIA: We included digital PtDAs for women aged 18-49 with a clinical diagnosis of endometriosis that met the minimum criteria established to qualify as a PtDA. Additionally, we developed a prompt to generate five PtDAs using conversational AI platforms, mirroring patient or clinician decision-support queries. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data per Joanna Briggs Institute (JBI) scoping reviews methodology. IPDAS criteria (requirements for PtDAs) and TIDieR items (intervention reporting) were applied; data were summarised descriptively and qualitatively. RESULTS: Ten PtDAs were included (five expert-developed; five AI-generated). Overall, most addressed pharmacological and surgical options, while AI-generated PtDAs included more complementary therapies. All described the health condition, decision, and options with balanced pros/cons, but most failed on important IPDAS criteria for high-quality PtDAs. Most expert-developed PtDAs also lacked transparent development reporting and had not been formally evaluated. CONCLUSIONS: Few digital PtDAs for endometriosis were identified; most showed limited adherence to IPDAS criteria, poor reporting transparency, and absent formal evaluation.
Journal of neuroendocrinologyLillian Rose, Alexander S Kauffman
The hypothalamic-pituitary-gonadal (HPG) axis coordinates reproductive function and incorporates gonadal sex steroid feedback to regulate gonadotropin secretion in a homeostatic manner. In females, ovarian estrogens and progestins act as the primary negative feedback signals to suppress luteinizing hormone (LH) release, whereas in males, androgens, such as testosterone (T), typically provide this feedback. However, androgens can also exert feedback effects on the female HPG axis, particularly in conditions where circulating T levels exceed that of the normal female physiological range. Three clinically relevant examples are anabolic substance abuse, testosterone therapy, and polycystic ovary syndrome (PCOS; recently renamed polyendocrine metabolic ovarian syndrome [PMOS]). Despite shared exposure to "androgen excess," these different hyperandrogenic states are associated with strikingly different neuroendocrine phenotypes. In testosterone therapy and anabolic substance abuse, high exogenous androgen exposure in or above the male physiological range typically suppresses LH secretion and disrupts ovulatory cycling, mimicking enhanced negative feedback on the HPG axis. Conversely, in PMOS, endogenous elevations in T, high for a female but below the male physiological range, are associated with increased LH secretion, acyclicity, and anovulation. The mechanisms underlying these divergent LH outcomes remain unclear but may reflect, in part, differences in the source of androgens (exogenous vs. endogenous), circulating androgen concentrations, and development timing and/or duration of androgen exposure. This review synthesizes current clinical and preclinical evidence to compare distinct models of hyperandrogenemia with respect to the female HPG axis and aims to illuminate how endogenous and exogenous androgens with different features differentially alter female neuroendocrine function.
Journal of applied clinical medical physicsAmritpal Singh, Raffi Karshafian, Ananth Ravi, Moti Raj Paudel
BACKGROUND: The knowledge of the dosimetric impact of systematic source position uncertainty and the use of a methodology for robust treatment planning against such uncertainty can help improve the quality of treatment plans, during MR-only cervical brachytherapy treatment. PURPOSE: To assess the dosimetric impact of systematic source position uncertainty along the source path and evaluate strategies to minimize it during MRI-only cervical high-dose-rate (HDR) brachytherapy treatment planning. METHODS: Treatment plans from 22 cervical cancer patients (FIGO stages IB2-IVA; 11 intracavitary brachytherapy (ICBT), 11 interstitial brachytherapy (ISBT)) were retrospectively analyzed. Positional uncertainty was modeled by systematically shifting the source position (± 1 to ± 5 mm with 0 mm as the reference position) within applicators along the source path in the original plans. Dosimetric parameters, HRCTV_D90 and D2cc for organs at risk (OARs), were computed for each source position. Statistical significance was assessed via paired t-test and Wilcoxon signed-rank test. Targeted plans exceeding dosimetric limits for OARs were re-optimized by modifying dwell times or gradients within 1 cm of the targeted OAR to improve the variability and overall OAR dosimetry. RESULTS: Significant dosimetric changes were observed for bladder, sigmoid (all shift positions; p ≤ 0.001) and rectum (1 to 5 mm; p ≤ 0.04) in ICBT, and for all OARs (all shift positions; p ≤ 0.003) in ISBT. HRCTV_D90 was significantly affected in ICBT from -2 to -5 mm (p ≤ 0.042) and at all shifts (p ≤ 0.033) except at -1 and -2 mm in ISBT. Within ± 5 mm shift range, the mean (maximum) drop in HRCTV_D90 and increase in OARs (bladder, bowel, rectum and sigmoid) D2cc were up to -2.0 ± 1.9(-5.4)% and (6.0 ± 3.4(13.6)%, 0.5 ± 2.5(5.5)%, 2.2 ± 2.7(7.4)% and 1.8 ± 1.2(4.2)%) for ICBT, and -6.2 ± 1.4(-11.9)% and (5.2 ± 4.6(17.2)%, 1.3 ± 0.9(3.0)%, 4.6 ± 2.5(7.6)% and 6.6 ± 3.6(13.8)%) for ISBT, respectively. Re-optimized plans showed improved robustness of dosimetry against source positional uncertainty for the targeted OAR with the same or better dosimetry for other OARs and HRCTV. The strategies to obtain this robustness were patient and applicator-type dependent. CONCLUSION: Systematic source position uncertainty significantly influences dosimetry in MRI-only cervical HDR brachytherapy. Adjusting dwell times and gradients near the targeted OAR could minimize this effect.
Pakistan journal of pharmaceutical sciencesJun Gao, Yawen Liu, Guifang Sun
BACKGROUND: SJAMP, a natural polysaccharide compound, has demonstrated significant inhibitory effects on various tumor models. Whether it plays a role in cervical cancer is unclear. OBJECTIVES: To explore the effects of SJAMP on the mTOR/p70S6K signaling pathway and the invasion and migration abilities of cervical cancer HeLa cells. METHODS: The HeLa cells were divided into blank/solvent/polymer control groups and 1.2, 3.2 and 6.4 g/L SJAMP treatment groups. The cell proliferation, migration, invasion abilities, as well as the expression of mTOR/p70S6K protein and mRNA were detected. RESULTS: As the concentration of SJAMP increased, the proliferation, migration and invasion abilities of HeLa cells were significantly reduced (all P < 0.05) and the protein and mRNA expressions of mTOR and p70S6K also decreased in a concentration-dependent manner (all P < 0.05). CONCLUSION: SJAMP can effectively inhibit the proliferation, migration and invasion of cervical cancer HeLa cells and this inhibitory effect is strongly dose-dependent and correlates with the downregulation of the mTOR/p70S6K signaling pathway.
Journal of biochemical and molecular toxicologyXiuwen Wang, Haofei Sun, Xin Wen, Weiwei Xin, Zhandong Hu, Zhongwei Zhao, Lizhi Zhang
Endometrial cancer (EC) is the most common gynecological malignancy in postmenopausal women. Patients with low estrogen receptor alpha (ERα) expression frequently develop aggressive pathological subtypes and have poor prognosis. The role of estradiol (E2) in ERα-low EC remains poorly understood. This study investigated the tumor-promoting effects of E2 using clinical data, in vitro functional assays, and a mouse xenograft model. We found that serum E2 levels were elevated in ERα-low patients, of whom 67.7% showed high tumor expression of G protein-coupled estrogen receptor (GPER). High GPER expression correlated with increased E2 levels, enhanced sphingosine kinase 1 (SphK1) activity, and higher Ki67 proliferation index. In vitro, E2 promoted proliferation, migration, and invasion of HEC-1A cells (low ERα, high GPER). These effects were suppressed by pharmacological inhibition or siRNA knockdown of GPER or SphK1. Mechanistically, E2 activated the ERK1/2 pathway via the GPER/SphK1 axis, leading to upregulation of Cyclin D1, Cyclin E1, and MMP-9. In vivo, E2 stimulated xenograft tumor growth, an effect mitigated by inhibitors of GPER, SphK1, and ERK. Our findings demonstrate that E2 drives progression of ERα-low endometrial cancer through the GPER/SphK1 signaling pathway, revealing potential therapeutic targets for this high-risk subgroup.
MicrobiologyOpenGuojiao Wang, Xiaotong Liu, Zimo Wang, Huadong Tian, Yan Li, Yuexi Luo
Although the etiology of cervical cancer has been partially established, its pathogenesis remains a key research focus. Specific studies on the genital tract microbiota of cervical cancer patients in Southern China are still scarce. To address this research gap, the present study collected genital tract microbial samples from 16 cervical cancer patients and 16 healthy women. Analysis of cervical cancer-specific microbiota was conducted via 16S rRNA gene sequencing. The study included 32 women (16 cervical cancer patients and 16 healthy controls) aged 45-65 at enrollment. Total genome DNA from samples was extracted using the hexadecyltrimethylammonium bromide (CTAB) CTAB method. The vaginal and cervical microbiota composition was determined by sequencing barcoded 16S rDNA gene fragments (V3-V4), and a comparative bioinformatics analysis of the microbiome was performed. The study revealed a homogeneous microbial composition dominated by Lactobacillus in healthy women, whereas cervical cancer patients exhibited increased diversity with reduced Lactobacillus and enriched Prevotella. No significant differences were observed between sampling sites within each group. Functional predictions linked the cancer-associated microbiota to metabolic pathways and the AEROBACTIN-SYN-PWY pathway. In conclusion, our findings suggest that these specific key microbial taxa and their related metabolic pathways contribute to the pathogenesis of cervical cancer and may serve as promising targets for clinical treatment and intervention.
Journal of applied clinical medical physicsCarolyn Eckrich, Kristin Bradley, Bethany Anderson, Diego Hernando, Jessica Miller, Jainil Shah, Patrick Wohlfahrt, Michael Lawless
BACKGROUND: Pelvic external beam radiation therapy (EBRT), frequently exposes a substantial fraction of active bone marrow (ABM), leading to radiation-induced marrow suppression and associated hematologic toxicity. Accurate delineation and quantitative assessment of ABM are therefore essential to enable marrow-sparing radiotherapy strategies. PURPOSE: To identify and quantify changes in ABM after EBRT using multi-energy CT (MECT) and fat fraction MRI (FFMRI). METHODS: Patients with gynecological malignancies underwent MECT and FFMRI pre- and post-radiation therapy. ABM was delineated on both imaging modalities using thresholding where ABM was defined as voxels with CT numbers above the mean in MECT-derived virtual non-calcium (VNCa) datasets and voxels with percent fat fraction (%FF) below the mean on the FFMRI. ABM volumes and mean HU/%FF values were evaluated before and after treatment. A Wilcoxon-signed rank test was computed to compare paired MECT versus FFMRI ABM volume percent changes. Changes in ABM as a function of dose were also evaluated. A paired t-test was computed for each dose gradient (significant p < 0.05). RESULTS: The average Dice Similarity Coefficient (DSC) between the MECT and FFMRI pre-treatment ABM volumes was 0.57 (range: 0.50-0.68). The mean volumetric change in ABM volume between pre- and post-treatment scans was -37% ± 15% (range -57% to -12%) and -66% ± 27% (range 8% to -94%) for MECT and FFMRI, respectively. All paired patients demonstrated greater ABM volume reduction with FFMRI than with MECT, and this difference was statistically significant (p = 0.0078). ABM changes were observed as a function of dose: A decrease in mean CT numbers and an increase in %FF corresponds to an increase in dose. CT number decreased significantly at doses ≥10 Gy (p ≤ 0.005), while %FF increased significantly across all dose gradients (p ≤ 0.0017), with both metrics showing strong dose‑response behavior at higher doses (p < 10- 6). CONCLUSIONS: This feasibility study demonstrates the utility of using MECT and FFMRI for delineating ABM in patients receiving pelvic EBRT. These imaging modalities showed good agreement in characterizing ABM volumes changes and radiation-induced marrow suppression. These findings support further investigation of ABM segmentation into the RT-planning workflow to facilitate marrow-sparing strategies.
The Australian & New Zealand journal of obstetrics & gynaecologyHarrison Odgers, Rhonda Farrell
BACKGROUND: Endometrial cancer is the most common gynaecological malignancy in Australia. Patients diagnosed in their reproductive window may desire a fertility-sparing approach, opposed to standard surgical care. International guidelines on fertility-sparing management exist; however, these highlight the lack of high-level evidence to support the recommendations. There are no Australian-specific guidelines or registries, leading to uncertainty as to how patients are managed locally. AIM: To survey clinicians in Australia regarding fertility-sparing management of endometrial cancer, to identify areas of consensus and variation, barriers to care and research priorities. MATERIALS AND METHODS: A 47-item online survey was distributed to clinicians who manage patients with endometrial cancer in Australia between November 2024 and January 2025. Responses were analysed descriptively. RESULTS: Of 70 eligible clinicians, 56% responded. There was agreement on appropriate candidate selection for FIGO grade 1 disease with absent/focal myoinvasion, use of hysteroscopy for diagnosis, and preference for levonorgestrel intra-uterine device as initial therapy. Opinions were divided on management of patients with Lynch syndrome or more extensive myoinvasion, the diagnostic utility of endometrial pipelle, and treatment of recurrences. POLE mutation testing and hysteroscopic resection were uncommon practices. Most respondents referred patients to fertility specialists, while other members of the multi-disciplinary team were less frequently utilised. The most frequent research priorities were weight-loss strategies (31%) and molecular profiling (27%). CONCLUSIONS: Clinicians in Australia have common approaches to diagnosis and first-line therapy, but there is variation in patient selection, surveillance and engagement with a multi-disciplinary team. These discrepancies highlight the potential benefits of local guidelines and further research.
The journal of obstetrics and gynaecology researchTuangsit Wataganara, Eiko Yamamoto, Somsook Santibenchakul, Ninlapa Pruksanusak, Jitti Hanprasertpong, Suthee Panichkul, Supitchaya Surasereewong
AIM: Obstetricians and gynecologists (OBGYNs) are high-risk, surgically intensive, and emergency-driven specialists. Women are the majority of OBGYNs, but their representation in decision-making roles remains disproportionately low. This narrative review explores the empirical evidence and aims to narrow gender gaps among OBGYNs. METHODS: We included 154 publications from 2000 to 2025 on gender inequity, career progression, women physicians, OBGYNs, academic promotion, leadership, workforce, and regional variation from Asia, Europe, North America, Africa, South America, and the Caribbean. Eligible studies either (1) focused on OBGYNs or female surgeons, (2) reported gender disparities in academic, administrative, or service domains, or (3) provided regional data. Qualitative and quantitative studies, policy reports, and professional society publications were included. RESULTS: There were insufficient data from South America and the Caribbean. For the other regions, we identified cultures, societal norms, and the structures of health systems as contributors to gender barriers in OBGYNs. These barriers are not at the entry levels, but rather in career ascension. In high-income countries, implicit biases persist despite established work-life policies and legislative protections. In low and middle-income countries, disparities are shaped by sociocultural expectations, fewer institutional supports, and rigid hierarchical structures. Men also face distinct barriers, such as limited patient acceptance and unequal distribution of out-of-hours duties. CONCLUSIONS: There is an urgent need to acquire high-quality data on stereotypic biases, structural, and cultural barriers to gender inequities among OBGYNs. Without timely intervention, gender gaps within the OBGYN workforce will likely be widened over time.
Japan journal of nursing science : JJNSSarina Enami, Yui Shimoyama, Hiroshige Matsumoto, Chikako Honda, Akari Maeda-Suzuki, Mari Ikeda, Kyoko Yoshioka-Maeda
AIM: This study aimed to investigate these aspects in female community-dwelling cancer survivors. METHODS: This secondary analysis of a community-based cancer survey was conducted in Tokyo, Japan. Emotional well-being (EWB) and functional well-being (FWB) were measured using two subdomains of the Functional Assessment of Cancer Therapy-General. The sample comprised 163 survivors of breast and gynecological cancers. We used descriptive statistics and multivariate regression analyses to explore the association between the challenges and EWB and FWB. RESULTS: All participants were women, of whom 118 and 45 were breast and gynecological cancer survivors, respectively. The most frequent challenges experienced but not addressed (referred to as "unaddressed challenges") were "anxieties about progression and prognosis", followed by "balancing hobbies and treatments", and "depressed mood". Although initial analyses suggested that the presence of challenges related to "depressed mood" and "balancing hobbies and treatments" was associated with lower EWB, these associations did not maintain statistical significance after adjusting for multiple testing. Conversely, excluding challenges related to "fertility preservation," all unaddressed challenges related to diagnosis and medical treatment and finances remained robustly associated with lower scores in EWB and FWB. Among unaddressed challenges related to balancing daily life and treatment, "balancing housework and treatment" and "balancing hobbies and treatments" remained associated with lower scores in EWB and FWB. CONCLUSIONS: Female community-dwelling survivors of breast and gynecological cancers face various unaddressed challenges that diminish EWB and FWB. Early identification and targeted public health interventions are required to address survivors' daily life challenges and improve well-being.
The journal of obstetrics and gynaecology researchTaro Miyake, Hidenori Sasa, Tsubasa Ito, Takanori Watanabe, Takako Sato, Sho Ogata, Masashi Takano
Metastasis of invasive ductal carcinoma of the breast to the uterine cervix is rare, with only one report of a case occurring more than 20 years after the primary surgery. A 69-year-old woman presented with abnormal uterine cervical cytology (atypical glandular cells without tumor diathesis) 30 years after undergoing breast cancer surgery. Magnetic resonance imaging revealed a 38-mm cervical mass. Modified radical hysterectomy was performed. The resected specimen exhibited an immunohistochemical profile of GATA3(+)/mammaglobin(+)/PAX8(-), which definitively excluded primary cervical adenocarcinoma and confirmed the diagnosis of metastatic invasive ductal carcinoma. Crucially, although the primary tumor was hormone receptor-positive, cervical metastasis exhibited receptor conversion to HER2-positive status. This case underscores the importance of considering metastatic breast cancer in the differential diagnosis of cervical masses in breast cancer survivors regardless of the disease-free interval. This further highlights the necessity for receptor re-evaluation in metastatic lesions to guide appropriate targeted therapy.
Rhode Island medical journal (2013)Tanin Zadeh, Komeil Mirzaei Baboli, Sara Salehiazar, Truc Tran
Malignant transformation of a mature cystic teratoma (MCT) is rare, with mucinous adenocarcinoma being an even more uncommon subtype. Accurate diagnosis requires distinction from metastatic gastrointestinal tumors. A woman in her 30s presented with a 19 cm right ovarian mass. She underwent exploratory laparotomy with right salpingo-oophorectomy, left ovarian cystectomy, omentectomy, peritoneal biopsies, and bilateral pelvic and para-aortic lymphadenectomy with intraoperative rupture of the mass. Frozen section suggested immature teratoma, but final pathology revealed mucinous adenocarcinoma arising within a mature teratoma. The tumor showed CK20, CDX2, SATB2 positivity, patchy CK7, and loss of PAX8. All lymph nodes and staging biopsies were negative for carcinoma. Final stage: FIGO IC1. This case highlights the diagnostic and staging challenges in malignant transformation (MT) of a MCT. Thorough sampling, immunohistochemistry (IHC), and clinical correlation are critical to differentiate primary ovarian neoplasms from metastatic disease. Accurate classification is essential to guide appropriate management.
Biometrical journal. Biometrische ZeitschriftFan Liu, Juan Liu, Hong Wang
While randomized controlled trials remain the gold standard for estimating causal effects in medical research, they are not always practical. Consequently, observational data become a necessary alternative, though it introduces confounding bias due to the lack of randomization. Propensity score modeling mitigates this bias but is highly sensitive to covariate selection. To address this critical limitation in survival analysis, we propose the outcome-adaptive Lasso (OAL)-Cox model-a novel variable selection framework for causal inference for right-censored data. The proposed method integrates the OAL with the Cox proportional hazards model by constructing penalty weights from coefficients estimated through the Cox partial likelihood. This design enables OAL-Cox to effectively identify outcome-related confounders while excluding irrelevant covariates, including instrumental and spurious variables, even under censoring and correlated covariate structures. Simulation studies demonstrate that OAL-Cox achieves stable variable selection across different censoring rates and correlation settings. Compared with the L-Cox and AL-Cox methods considered in this study, OAL-Cox more effectively reduces the inclusion of instrumental and spurious covariates while retaining outcome-related covariates, and it generally yields more stable restricted mean survival time-based causal effect estimates in the examined settings. We further illustrate the practical applicability of the proposed method by applying it to ovarian cancer recurrence time data to evaluate the effect of surgical sophistication on recurrence time.
The journal of obstetrics and gynaecology researchFajrin Mammadova Bahitli, Levent Akman, Gurdeniz Serin, Mert Acar, Nuri Yildirim, Osman Zekioglu, Mustafa Cosan Terek, Erdem Goker, Ahmet Aydin Ozsaran
OBJECTIVE: To evaluate and compare programmed cell death-ligand 1 (PD-L1) expression across benign and malignant uterine mesenchymal tumors using immunohistochemical analysis. METHODS: This retrospective study included 100 patients who underwent hysterectomy for uterine mesenchymal tumors at a single tertiary center between 2000 and 2022. Cases included leiomyoma (LM; n = 20), leiomyosarcoma (LMS; n = 20), low-grade endometrial stromal sarcoma (LG-ESS; n = 20), high-grade endometrial stromal sarcoma (HG-ESS; n = 20), and endometrial stromal nodule (ESN; n = 20). Immunohistochemical staining was performed using the PD-L1 (22C3) antibody, and PD-L1 expression was evaluated using the combined positive score. Clinicopathological parameters and PD-L1 expression were compared among tumor subtypes. RESULTS: Patients with HG-ESS demonstrated a significantly higher mean age at diagnosis compared with the other histopathological subtypes. PD-L1 expression was detected in 9 (45%) LMS, 10 (50%) HG-ESS, 3 (15%) LG-ESS, and 1 (5%) ESN cases, whereas no LM cases demonstrated positivity. PD-L1 expression rates were significantly higher in LMS and HG-ESS than in LM, LG-ESS, and ESN cases (p < 0.0001). Combined group analyses also demonstrated significantly higher PD-L1 expression rates in the combined LMS/HG-ESS group compared with the LG-ESS group and the combined LM/ESN group (p < 0.0001). CONCLUSION: These findings demonstrate increased PD-L1 expression in aggressive uterine mesenchymal tumors; however, the clinical and therapeutic significance of these immunohistochemical findings remains unclear. Further studies integrating PD-L1 expression with clinical findings and treatment outcomes are needed to determine the potential therapeutic relevance of PD-L1 in these neoplasms.