Extracellular vesicles (EVs) play a vital role in ovarian carcinoma (OvCa) metastasis, yet the mechanisms regulating EV biogenesis remain unclear. Here, we identify CBX2 as a key driver of omental metastasis, with elevated expression in metastatic lesions and association with poor prognosis. CBX2 promotes tumor cell migration, invasion, and metastasis by enhancing EV secretion and pro-metastatic cargo loading through remodeling lipid rafts, cholesterol-rich membrane microdomains essential for EV formation. Deletion of the intrinsically disordered region abolishes lipid raft remodeling and multivesicular body redistribution, indicating dependence on liquid-liquid phase separation (LLPS). CBX2 also transcriptionally upregulates FLOT1 in an LLPS-dependent manner. Disruption of lipid rafts or inhibition of CBX2 phase separation markedly reduces EV production and metastatic potential. These findings reveal an LLPS-dependent mechanism linking CBX2 to lipid raft-mediated EV biogenesis and OvCa metastasis.

Background:The current standard-of-care chemotherapy for treatment-naïve epithelial ovarian cancer is paclitaxel plus carboplatin. Objectives:To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin versus paclitaxel plus carboplatin as first-line treatment in patients with epithelial ovarian cancer. Design:This was an investigator-initiated, multicenter, open-label, randomized, noninferiority trial. Methods:This trial with a prespecified noninferiority margin (HR0) of 1.2, was conducted in 20 clinic centers in China. Eligible patients were randomly assigned in a 1:1 ratio to receive either PLD (30 mg/m2 on day 1) plus carboplatin (area under the curve (AUC) 5 on day 1; experimental group) or paclitaxel (175 mg/m2 on day 1) plus carboplatin (AUC 5 on day 1; control group) for up to six cycles. The primary endpoint was progression-free survival (PFS). The key secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results:Between March 21, 2019, and December 8, 2021, 395 eligible patients were enrolled, of whom 195 were randomly assigned to receive PLD-carboplatin and 196 received paclitaxel-carboplatin. Median PFS was 35.3 months (95% confidence interval (CI), 23.7-46.9) in the experimental group and 35.0 months (95% CI, 26.9-43.1) in the control group (hazard ratio = 0.99, 95% CI, 0.73-1.35; p = 0.94). There were no statistically significant differences between the two groups in median ORR (80.5% vs 79.2%), DCR (90.2% vs 83.3%), 2-year OS rate (96.2% vs 92.4%), or 4-year OS rate (87.6% vs 82.4%; all p > 0.05). In the experimental and control groups, 165 (84.6%) and 169 (86.2%) patients experienced at least one adverse event (AEs). Alopecia (9.2% vs 28.1%, p < 0.001), peripheral sensory neuropathy (2.1% vs 17.9%, p < 0.001), and febrile neutropenia (1.0% vs 6.1%, p = 0.01) were less common in the PLD-carboplatin group compared to the paclitaxel-carboplatin group. Conclusion:The superior tolerability and comparable efficacy of PLD plus carboplatin over paclitaxel plus carboplatin as a first-line treatment for epithelial ovarian cancer suggest that substituting paclitaxel with PLD is both feasible and potentially more beneficial. Trial registration:This trial is registered with ClinicalTrials.gov, NCT03794778.

Background: Poly ADP ribose polymerase (PARP) inhibitor resistance has emerged as a new challenge in the treatment of ovarian cancer. Intervening in cellular senescence to increase the sensitivity of ovarian cancer to olaparib has emerged as a key area of research. Objective: To determine the molecular mechanism underlying the antitumor effects of PPAR-γ agonists in promoting sensitivity to olaparib in ovarian cancer cells that induce senescence. Materials and Methods: The tumor-inhibitory effects of different PPAR-γ agonists alone or in combination with olaparib were analyzed in a subcutaneous transplanted ovarian tumor model in nude mice. β-Galactosidase (SA-β-Gal) staining and real-time PCR were used to detect changes in the cellular expression of senescence and senescence-associated secretory phenotype factors. Network pharmacological analysis revealed that the molecular mechanism underlying PPAR-γ agonist-mediated enhancement of olaparib’s anti-tumor efficacy is mechanistically linked to the SIRT1 signaling pathway. Subsequent functional validation through Western blotting and immunohistochemical analyses elucidated the critical modulatory role of SIRT1 signaling in determining olaparib sensitivity. Results: In vivo experiments showed that different PPAR-γ agonists (rosiglitazone and pioglitazone) combined with olaparib significantly reduced the volume of subcutaneously transplanted tumors in the mice. Further studies found that the PPAR-γ agonists inhibited the expression of SIRT1, attenuated olaparib-induced cellular senescence in ovarian cancer cells, and consequently inhibited tumor cell proliferation. Importantly, the SIRT1 overexpression reversed these phenotypic changes. Conclusions: PPAR-γ agonists enhance olaparib sensitivity through suppression of the SIRT1 signaling pathway and attenuation of olaparib-induced cellular senescence.

Although neuromodulation has emerged as a critical factor in cancer biology, its involvement in cervical cancer remains largely unexplored. In this study, we identified the serotonin transporter (SERT), a marker of serotonergic neurons, as a potential tumor suppressor in cervical cancer. SERT expression was progressively reduced with increasing severity of cervical lesions and was negatively associated with patient survival. Functionally, SERT overexpression significantly inhibited cervical cancer cell viability and xenograft tumor growth in the presence of serotonin (5-Hydroxytryptamine, 5-HT), both in vitro and in vivo. Mechanistically, SERT promoted mitochondrial-mediated tumor cell apoptosis through upregulation of Bax and cleaved caspase-3, without affecting cell proliferation. This proapoptotic effect may be associated with inhibition of STAT3 pathway activation. Notably, these tumor-suppressive effects could be largely abolished by fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) widely used as a first-line antidepressant. Collectively, our findings reveal a direct suppressive function of the SERT-5-HT axis in cervical cancer cells and suggest a potential risk that FLX may interfere with this antitumor activity, warranting further investigation to assess its impact on cervical cancer progression.

PURPOSE:The biological function of p27Kip1 largely depends on its subcellular localization and phosphorylation status. Different subcellular localizations and phosphorylation statuses of p27Kip1 may represent distinct clinical values, which are unclear in ovarian cancer. This study aimed to elucidate different subcellular localizations of p27Kip1 and pSer10p27 in predicting prognosis and chemotherapy response in ovarian cancer. METHODS:Meta-analyses were executed to evaluate the association of p27Kip1 and phosphorylated p27Kip1 with the prognosis of ovarian cancer patients. The expression levels and patterns of p27Kip1 and pSer10p27 were evaluated by immunohistochemistry. The correlations between different p27Kip1 states, clinicopathological features, and prognosis were analyzed. p27Kip1 and pSer10p27 expression levels in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines were detected using WB. KEGG analysis and WB were performed to evaluate the pathways in which p27Kip1 was involved. RESULTS:Meta-analyses showed that p27Kip1 was associated with significantly better overall survival (OS) in ovarian cancer (HR=2.14; 95% CI [1.71-2.68]) and pSer10p27 was associated with significantly poor OS in mixed solid tumors (HR=2.56; 95% CI [1.76-3.73]). In our cohort of ovarian cancer patients, low total p27Kip1 remained independent risk factors of OS (HR=2.097; 95% CI [1.121-3.922], P=0.021) and PFS (HR=2.483; 95% CI [1.364-4.518], P=0.003), while low cytoplasmic pSer10p27 had independent protective effects in terms of OS (HR=0.472; 95% CI [0.248-0.898], P=0.022) and PFS (HR=0.488; 95% CI [0.261-0.910], P=0.024). Patients with low total p27Kip1/pSer10p27 and low nuclear p27Kip1 had worse chemotherapy responses, while patients with low cytoplasmic pSer10p27 expression had better chemotherapy responses. The protein levels of p27Kip1 and pSer10p27 were significantly reduced in the cisplatin-resistant cell lines SKOV3-cDDP and A2780-cDDP, and the level of p27Kip1/pSer10p27 was subjective to Akt activation. CONCLUSIONS:The present study demonstrates that p27Kip1 and cytoplasmic pSer10p27 are promising biomarkers for predicting prognosis and chemotherapy response in ovarian cancer.

OBJECTIVE:To assess CIN3+ risk in a Chinese cohort of outpatients undergoing contesting screening and to evaluate the portability of the American Society for Colposcopy and Cervical Pathology (ASCCP) risk-based management, which was primarily developed using data from the Kaiser Permanente of Northern California (KPNC) cohort. METHODS:Females aged 25-65 years who were screened with cytology and high-risk human papillomavirus (hrHPV) co-testing between 2011 and 2020 at Wuhan Union Hospital (WHUH) were retrospectively studied. The risks of immediate and 3-year CIN3+ were estimated via prevalence-incidence mixture models. Portability was evaluated via the ratio of the observation risk in the WHUH cohort to the expected risk in the KPNC cohort (O/E) and its 95% CI. RESULTS:A total of 96 318 females were included, and 16.83% of the women tested hrHPV-positive at initial screening, who had a CIN3+ immediate risk of 14.14%. The CIN3+ immediate risk varied between subgroups of positive HPV16 (34.09%), HPV18 (13.38%), other HPV types (6.71%), and negative hrHPV (0.12%). Compared to the KPNC cohort, our cohort exhibited a significantly higher CIN3+ immediate risk (1.42% vs 0.46%; O/E, 3.09; 95% CI, 2.92-3.26) and disproportionately increased cancer immediate risks in most subgroups requiring immediate colposcopy or treatment, as well as higher 3-year CIN3+ risks in women with hrHPV-negative ASC-US/NILM. Yet, the action threshold suggested by ASCCP, a CIN3+ immediate risk of 4%, showed good portability to our cohort. CONCLUSIONS:Despite the higher risks in our cohort, the ASCCP clinical action threshold remains portable. For women with minimal abnormalities or normal results, shortened follow-up intervals should be considered.

Ovarian cancer is associated with the highest mortality rate among all malignant gynecological tumors. PolyADP-ribose polymerase (PARP) inhibitor maintenance therapy is the standard treatment strategy for this type of cancer, and olaparib is a widely used oral PARP inhibitor for tumors with BRCA mutations. The present study aimed to investigate the effects of olaparib in non-BRCA-mutated ovarian cancer and the potential mechanisms involved. The antitumor effect of cisplatin alone or in combination with olaparib was analyzed in an ovarian cancer subcutaneous transplantation tumor model in nude mice. Furthermore, the differences in microRNA (miRNA) expression levels were analyzed using miRNA arrays. In addition, the effects of miR-125a-3p on the proliferation of non-BRCA-mutated (A2780 and OVCAR-3) ovarian cancer cells were detected using A Cell Counting Kit-8 and changes in the cell cycle were detected using flow cytometry. Furthermore, SPiDER-βGal was used to detect expression changes in cellular senescence, and the expression of DNA damage repair proteins was detected using western blot analysis. The results revealed that cisplatin plus olaparib significantly reduced tumor volume in mice subjected to subcutaneous tumor transplantation, and the expression of miR-125a-3p significantly increased with this treatment combination. The overexpression of miR-125a-3p could inhibit cell migration, invasion and induces cell cycle arrest. On the whole, the present study demonstrates that the increased expression of miR-125a-3p induces DNA damage and senescence in ovarian cancer cells, which enhances the therapeutic sensitivity.

This retrospective study aimed to determine the risk factors for venous thromboembolism (VTE) in patients undergoing radical hysterectomy for cervical cancer. Data from 366 patients who underwent radical surgery between June 2020 and December 2021 were collected from medical records. The patients were divided into a thrombosis group and a nonthrombotic group based on the presence or absence of VTE. Multivariate analyses revealed that age greater than 45 years, open radical hysterectomy surgery, an operation time exceeding 4 hours, intraoperative blood transfusion, and postoperative plasma D-dimer levels greater than 2.0 mg/L were significant independent risk factors for postoperative VTE, which could be used to help identify patients at an increased risk of VTE.

To characterize the hrHPV genotype distribution and attribution to cervical lesions in the cohort of women screened in Shanxi Province. Data from the records of cervical cancer screening programs for rural women in Shanxi Province were retrospectively collected. Women who underwent primary human papillomavirus (HPV) screening between January 2014 and December 2019 were included. The attribution proportion of specific hrHPV types for different grades of cervical lesions was calculated by using the type contribution weighting and the proportional attribution methods to estimate the potential impact of HPV vaccines on CIN II + lesions. CIN II + lesions were observed mainly with HPV16 (65.85%), HPV18 (10.20%), HPV58 (10.20%), HPV52 (7.98%), HPV31 (4.66%), HPV33 (4.43%), HPV51 (2.22%) and HPV56 (2.22%). A total of 97.42% of all CIN II + lesions were attributed to HPV16, HPV18, HPV52, HPV58, HPV31, HPV33 and HPV35. A total of 75.4% (95% CI, 71.4-79.3) of CIN II + lesions were attributable to HPV16/18, and 21.1% (95% CI, 17.4-25.1) were attributable to the 5 additional types (HPV31/33/45/52/58) covered by the 9-valent vaccine. The prevalence of hrHPV infection among women in Shanxi Province was high, and HPV16, HPV18, HPV58, HPV52, HPV31, HPV33 and HPV35 had the highest attributable proportion of CIN II + lesions. The type-specific HPV prevalence and attribution proportion of cervical precancerous lesions should be taken into consideration in both clinical management and the design of preventive strategies.

The frequent omental metastasis of ovarian cancer (OvCa) at initial diagnosis is due to the omental premetastatic microenvironment, which is rich in activated fibroblasts. However, the molecular events driving the phenotypic transformation of omental fibroblasts that favor metastasis remain largely unexplored. Previously, we found that tumoral enhancer of zest homolog 2 (EZH2), a key epigenetic regulator catalyzing trimethylation at H3K27, played a crucial role in OvCa metastasis. In this study, we revealed that extracellular vesicles (EVs) derived from EZH2-high OvCa cells induce the expression of Periostin (POSTN), but not α-SMA, in omental fibroblasts, facilitating tumor metastasis. Nude mice with intraperitoneal injection of EVs before tumor cell inoculation showed that EVs derived from EZH2-high ovarian cancer cells promote omental metastasis. Human primary omental fibroblasts cocultured with EVs, especially those derived from EZH2-high OvCa cells, exhibited boosted migration, invasion capacities and conditioned medium from EV-activated fibroblasts promotes cancer cell migration, invasion and proliferation. These results may provide novel insight into EZH2-targeted therapy for ovarian carcinoma with intraperitoneal dissemination.

Ovarian cancer exhibits striking metastatic tropism for the omentum, where lipid-laden macrophages are key mediators that fuel disease progression. However, the mechanisms governing their formation and pro-metastatic functions remain poorly understood. As extracellular vesicles (EVs) have as critical regulators of tumor-stroma crosstalk in metastatic niches, we sought to define how ovarian cancer-derived EVs orchestrate macrophages and adipocytes, and their impact on omental metastasis, aiming to explore potential therapeutic interventions. Single-cell transcriptomics of ovarian cancer revealed a distinct lipid-laden macrophage population in omentum, whose abundance correlated with metastatic burden and poor survival. Proteomics revealed that EVs from highly metastatic ovarian cancer cells were enriched in lipid metabolism regulators. In vivo experiments demonstrated that these tumor-derived vesicles mediated macrophage reprogramming, driving the acquisition of a pro-metastatic phenotype. Quantitative lipidomic profiling and lipid staining approaches confirmed the progressive lipid-laden in EV-treated macrophages. Using a patient-derived omentum-macrophage co-culture system, we demonstrated that tumor-derived EVs stimulate lipid release from omental adipocytes, which macrophages subsequently internalize through CD36-dependent uptake to drive lipid accumulation. This metabolic reprogramming culminated in cellular senescence, as evidenced by classical biomarkers including SA-β-galactosidase activity, elevated p16-INK4A and p53 levels, and the development of a matrix metalloproteinase-enriched senescence-associated secretory phenotype. Immunohistochemistry of clinical specimens demonstrated overexpression of CD36 correlated with omental metastasis and poor survival in ovarian cancer. In vivo experiments demonstrated that CD36 inhibition and senolytic therapy attenuated omental metastasis. This study unveils an EV-driven mechanism of adipose tropism in ovarian cancer metastasis, where EVs promote the formation of senescent lipid-laden macrophages via CD36-mediated lipid uptake, remodeling the metastatic niche. Targeting CD36 and senescent cells offers a promising therapeutic strategy against omental metastasis.

Ovarian carcinoma (OvCa) metastasis is initiated and boosted by tumor-stroma interactions mediated by small extracellular vesicles (sEVs) containing microRNAs (miRNAs). However, the mechanisms of sorting relevant miRNAs into tumoral sEVs remain elusive. In this study, among the RNA-binding proteins, hnRNPA2B1 was identified as the most significant factor associated with survival in OvCa patients, and its expression was higher in omental metastases compared to paired ovarian lesions. Based on the CRISPR-Cas9 technique, orthotopic xenograft mice revealed a remarkable metastasis-inhibiting effect of hnRNPA2B1-knockdown, accompanied by diminished myofibroblast signals in the omentum. Meanwhile, after hnRNPA2B1-knockdown, OvCa-sEVs largely lost the ability to promote omental metastasis and myofibroblast activation in vivo and in vitro. High-throughput miRNA sequencing of sEV cargoes revealed that UAG motif-containing miRNAs were significantly affected by hnRNPA2B1, and RNA immunoprecipitation (RIP) verified their direct binding to hnRNPA2B1. In pull down assays, the miRNAs with mutated UAG motif exhibited decreased binding capacity to hnRNPA2B1. The myofibroblasts activated by OvCa-sEVs could promote tumor metastasis, and this effect was notably impacted by manipulating hnRNPA2B1, related sEV-miRNAs, and PI3K/AKT signaling. These findings highlight the miRNA sorting to sEVs mediated by hnRNPA2B1 as an important mechanism involved in OvCa metastasis, which may illuminate new therapeutic strategies.

Aim: Cancer stem cells (CSCs) are pivotal in mediating platinum resistance in ovarian cancer. This study aimed to screen compounds sensitizing CSCs to cisplatin by using a small molecule inhibitor library. Methods: A library of 105 common drugs was screened in ovarian CSC model SK-3rd and ovarian cancer platinum-resistant cell model SKDDP to identify those that could enhance sensitivity to cisplatin by MTT assay. The antitumor effect was assessed in ovarian cancer cells using the MTT assay, colony formation assay, and apoptosis assay. The impact on cancer cell stemness was evaluated using qPCR and Sphere-forming assays. Finally, the effect of the combination regimen was evaluated in patient-derived organoids (PDOs) under different treatments by the CellTiter-Glo Luminescence Assay. Results: The results of the initial screening on SK-3rd identified five candidate compounds. Rescreening on SKDDP showed that Ivosidenib was the most effective in sensitizing cisplatin. MTT, colony formation, and apoptosis assays demonstrated that Ivosidenib enhanced the sensitivity to cisplatin, inhibited proliferation, and induced apoptosis in ovarian cancer cells, including SK-3rd and SKDDP. Furthermore, Ivosidenib lowered stemness marker expression and countered CSC enrichment caused by platinum-based chemotherapy in ovarian cancer cells. Finally, the synergistic effect of this combination was also confirmed in three ovarian cancer PDOs. Conclusion: Ivosidenib may increase cisplatin sensitivity in ovarian cancer cells by decreasing their stemness, providing a potential therapeutic method for ovarian cancer patients.

Peritoneal metastases prevalently occur in ovarian cancer, deteriorating patient prognosis. During the metastatic cascade, tumor plasticity enables cells to adapt to environmental changes, thereby facilitating dissemination. We previously found that epithelial splicing regulatory protein 1 (ESRP1) is linked to peritoneal metastasis and epithelial-mesenchymal plasticity in ovarian cancer. This study delves into the underlying mechanism. We found that ESRP1 preserves epithelial plasticity in ovarian cancer cells in vitro and in vivo. Functionally, ESRP1 enhances ovarian cancer cell growth and peritoneal dissemination. High-throughput sequencing revealed several ESRP1-related epithelial RNAs, encompassing both linear and circular forms. Specifically, ESRP1 triggers the cyclization of circPAFAH1B2 and circUBAP2 through binding to the GGU sequences in adjacent introns. The two ESRP1-induced circular RNAs stabilize DKK3 and AHR mRNAs, which are critical for epithelial plasticity, through interaction with IGF2BP2. Collectively, ESRP1 triggers the formation of circPAFAH1B2 and circUBAP2, which in turn stabilizes DKK3 and AHR through IGF2BP2 binding, thereby modulating the epithelial plasticity and aiding the peritoneal spread of ovarian cancer cells. The findings unveiled a biological network, orchestrated by ESRP1, that governs the epithelial-mesenchymal plasticity of ovarian cancer cells, emphasizing the therapeutic potential of ESRP1 and its induced circular RNAs for ovarian cancer treatment.

High-grade serous ovarian cancer (HGSOC) is the most common type of epithelial ovarian cancer with insidious onset, rapid growth, and invasive spread. Here, we reported the diagnosis and treatment of a 53-year-old patient with a history of hysterectomy aided by the 68Ga-FAPI PET/MR scan. The patient was first presented to the local hospital with a lump on the left side of the neck with a biopsy suggesting metastatic cancer. Pelvic ultrasonography revealed two irregular masses. After admission, tumor markers, pathology consultation of the biopsy, and the 68Ga-FAPI PET/MR scan were administered. The biopsy of the lump suggested poorly differentiated adenocarcinoma and CA125 was elevated at 530.6 U/ml. The 68Ga-FAPI PET/MR scan showed several abnormal lymph nodes and two soft tissue masses with borders of dispersed restriction displaying internally uneven signals depicted by slightly elongated T1 and T2 signals within the pelvic cavity suggesting that pelvic mass could be the primary lesion. The patient received cytoreductive surgery including bilateral adnexectomy, omentectomy, and appendectomy. Post-surgical pathology suggested left and right HGSOC with left fallopian tube invasion. The patient completed six courses of first-line chemotherapy and remained progression-free for 14 months up to date. To conclude, 68Ga-FAPI PET/MR aids in primary tumor determination and tumor burden assessment and provides a guide for the management of late-stage HGSOC patients.

BACKGROUND:Peritoneal dissemination of ovarian cancer (OvCa) can be largely attributed to the formation of a metastatic microenvironment driven by tumoral exosomes. Here, we aimed to elucidate the mechanisms through which exosomal annexin A2 (ANXA2) derived from OvCa cells induces an HPMC phenotypic shift in favour of peritoneal metastasis. METHODS:Immunohistochemistry and orthotopic and intraperitoneal OvCa xenograft mouse models were used to clarify the relationship between tumour ANXA2 expression and peritoneal metastasis. Exosomes were isolated from OvCa cell lines via ultracentrifugation. Functional experiments on cell proliferation and motility, and western blot were performed to investigate the activation of HPMCs and its impact on tumour cell in vitro. High-throughput transcriptional sequencing and rescue experiments in which ANXA2 inhibitor (LCKLSL) or the toll-like receptor 2 (TLR2) inhibitor (C29) was used to co-culture the HPMCs with exosome were employed to identify the crucial functional molecules through which exosomal ANXA2 activates HPMCs. The impact of exosomal ANXA2-activated HPMCs on tumour progression was assessed via functional experiments. RESULTS:Primary OvCa samples with high ANXA2 expression exhibited a stronger tendency to metastasize to the abdominal cavity. Tumoral ANXA2 promoted OvCa peritoneal metastasis through the secretion of exosomes carrying ANXA2. ANXA2-loaded exosomes activated HPMCs through exosomal ANXA2 binding to TLR2, shifting the phenotype of HPMCs towards mesenchymal cells, increasing their migration and invasion capacities, and elevating the expression of lipocalin 2 (LCN2). High LCN2 expression in HPMCs promoted OvCa cell adhesion, proliferation, motility, and lipid metabolism reprogramming. CONCLUSION:Exosomal ANXA2 secreted by tumour cells activates HPMCs and induces the expression of LCN2, which in turn promotes the peritoneal metastasis of OvCa.

We investigate the feasibility, safety, and clinical therapeutic effect of laparoscopic sigmoid vaginoplasty in women with Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome. We performed a retrospective case review cohort study of 56 patients with MRKHs undergoing laparoscopic sigmoid vaginoplasty in Wuhan Union Hospital between 2000 and 2020, and all patients were followed up. The median operating time was 165 min (120–420 min). The median hospital stay was 10 days (rang 7–15 days). A functional neovagina was created 11–15 cm in length and two fingers in breadth in all patients. No introitus stenosis was observed. No intra- or post-operative complications occurred. Two patients were lost to follow-up after 3 months of outpatient visits. Six patients had no intercourse and were required to wear a vaginal mold occasionally. None of the patients had complained of local irritation or dyspareunia. Patients who had post-surgery sexual intercourse were satisfied with their sexual life and the mean total Female Sexual Function Index (FSFI) score was 25.17 ± 0.63. The cosmetic results were excellent. The laparoscopic sigmoid vaginoplasty can achieve the goal of making a functional neovagina. The main advantage of this surgical technique is that it is minimally invasive and that there are fewer complications post-operation. It is an acceptable procedure for patients with MRKH syndrome.

Mounting evidence has highlighted the multifunctional characteristics of glutamine metabolism (GM) in cancer initiation, progression and therapeutic regimens. However, the overall role of GM in the tumour microenvironment (TME), clinical stratification and therapeutic efficacy in patients with ovarian cancer (OC) has not been fully elucidated. Here, three distinct GM clusters were identified and exhibited different prognostic values, biological functions and immune infiltration in TME. Subsequently, glutamine metabolism prognostic index (GMPI) was constructed as a new scoring model to quantify the GM subtypes and was verified as an independent predictor of OC. Patients with low-GMPI exhibited favourable survival outcomes, lower enrichment of several oncogenic pathways, less immunosuppressive cell infiltration and better immunotherapy responses. Single-cell sequencing analysis revealed a unique evolutionary trajectory of OC cells from high-GMPI to low-GMPI, and OC cells with different GMPI might communicate with distinct cell populations through ligand-receptor interactions. Critically, the therapeutic efficacy of several drug candidates was validated based on patient-derived organoids (PDOs). The proposed GMPI could serve as a reliable signature for predicting patient prognosis and contribute to optimising therapeutic strategies for OC.

Objective: To explore the genotype distribution of high-risk human papillomavirus (hrHPV) and the attribution of different grades of cervical lesions to the disease in Shanxi Province and estimate the potential impact of the HPV vaccine on CIN II+ lesions to direct the implementation of successful programs for cervical cancer prevention and management. Methods: Data from the records of cervical cancer screening programs for rural women in Shanxi Province wereretrospectively collected. Women who underwent primary HPV screeningbetween January 2014 and December 2019 were included. The attribution proportion of specific hrHPV types for different grades of cervical lesions was calculated by using the type contribution weighting and the proportional attribution methods to estimate the potential impact of HPV vaccines on CIN II+ lesions. Results: CIN II+ lesions were observed mainly with HPV16 (65.85%), HPV18 (10.20%), HPV58 (10.20%), HPV52 (7.98%), HPV31 (4.66%), HPV33 (4.43%), HPV51 (2.22%) and HPV56 (2.22%). A total of 97.42% of all CIN II+ lesions were attributed to HPV16, HPV18, HPV52, HPV58, HPV31, HPV33 and HPV35. A total of 75.4% (95% CI, 71.4-79.4) of CIN II+ lesions were attributable to HPV16/18, and 21.1% (95% CI, 17.4-25.1) were attributable to the 5 additional types (HPV31/33/45/52/58) covered by the 9-valent vaccine. Conclusions: The prevalence of hrHPV infection among women in Shanxi Province was high, and HPV16, HPV18, HPV58, HPV52, HPV31, HPV33 and HPV35 had the highest attributable fractions of CIN II+ lesions. The type-specific HPV prevalence and attribution proportion of cervical precancerous lesions should be taken into consideration in both clinical management and the design of preventive strategies.