Pengming Sun

BST2 Drives Epithelial Ovarian Cancer Progression via Macrophage M2 Polarization, Neural Remodeling, and Immunosuppressive Microenvironment Formation

Background Epithelial ovarian cancer (EOC) ranks as the most lethal of gynecological cancers. Despite advances in therapeutic interventions that have marginally extended survival rates, the early detection and management of EOC pose significant hurdles. Consequently, identifying novel therapeutic targets is imperative for enhancing the survival outcomes of patients afflicted with this malignancy. Purpose This research is aimed at exploring the functions of Bone Marrow Stromal Antigen 2 (BST2) in the pathogenesis of EOC and their influence on macrophage polarization, evaluating their viability as targets for immunotherapy. Methods Gene expression profiles and clinical data of EOC patients were retrieved from the TCGA repository to develop prognostic models centered on BST2. The expression patterns of BST2 in HGSOC cell lines were quantified via RT‐qPCR and Western blot analyses. The impact of BST2 on the proliferative, migratory, and invasive capacities of EOC cells was assessed through gene silencing and gene overexpression experiments. Results Elevated levels of BST2 expression were observed in EOC tissues, correlating with adverse prognostic indicators. Enhanced BST2 expression facilitated EOC cell growth, motility, and invasiveness, whereas BST2 suppression mitigated these oncogenic attributes. In vivo assessments revealed that BST2 augmentation modified the macrophage phenotypes within grafted ovarian tumors, with BST2 diminution reversing these effects. Conclusion The findings propose that BST2 acts as a pivotal facilitator in the progression of ovarian carcinoma. The expression metrics of BST2 may serve as prognostic markers for patient outcomes in EOC. These findings suggest that BST2 is a key promoter of ovarian cancer progression, and its expression may serve as a prognostic marker. The mechanisms uncovered, including the modulation of macrophage polarization and neural marker expression, indicate that targeting BST2 represents a potential future strategy for immunotherapy in EOC.

High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy–lysosomal pathway in endometrial cancer

Abstract Endometrial cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy–lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769HK2 vs. ARG 313HMGCS1) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy–lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy–lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and cholesterol metabolism.

Integrative Analysis of Glycine, Serine, and Threonine Metabolism and the Immune Microenvironment in Endometrial Cancer: A Prognostic Model and Metabolic-Immune Framework for Precision Oncology

Background: Metabolic reprogramming is a hallmark of the pathogenesis and progression of endometrial carcinoma (EC). This study comprehensively analyzed the expression profiles of glycine, serine, and threonine (Gly/Ser/Thr) metabolism–related genes in EC. We also established a robust prognostic model and developed a molecular subtyping framework that integrates metabolic and immune characteristics based on the identified prognostic genes. The aims of this work are to enhance diagnostic precision and improve clinical management strategies for patients with EC. Methods: Untargeted metabolomic analysis was performed on 35 EC and 15 normal tissues. The Cancer Genome Atlas (TCGA) transcriptomic data were integrated with weighted gene co-expression network analysis (WGCNA) to identify EC-related metabolic genes and construct a prognostic model using Cox proportional hazards and least absolute shrinkage and selection operator (LASSO) regression analyses. The model was validated using an independent proteomic and single-cell dataset from our institution. Consensus clustering classified patients into three molecular subtypes, which were further characterized by gene set variation analysis (GSVA) and profiling of immune infiltration. Finally, key prognostic genes were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in EC and normal endometrial epithelial cells. Results: Metabolomic analysis revealed significant enrichment of the Gly/Ser/Thr metabolic pathways. WGCNA identified a tumor-associated metabolic module among 1741 pathway-related genes. A prognostic model comprising methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), ribosomal protein S6 kinase A1 (RPS6KA1), and cyclin-dependent kinase inhibitor 2A (CDKN2A) was subsequently established. Consensus clustering based on risk scores stratified EC patients into three molecular subtypes: immunometabolic-suppressed (C1), proliferative-immunobalanced (C2), and immune-activated (C3). The C1 subtype had the poorest prognosis and was characterized by metabolic suppression and immune evasion. The C2 subtype showed a favorable prognosis and was defined by a “proliferation–immune balance” in which high proliferative activity coexisted with strong anti-tumor immunity. The C3 subtype was also associated with a favorable outcome, driven by upregulated DNA repair and oxidative phosphorylation pathways alongside infiltration of immune-active cells. RT-qPCR confirmed significant differences in the mRNA expression of MTHFD2, RPS6KA1, and CDKN2A between normal and EC cells (p < 0.05). Conclusion: This study developed a Gly/Ser/Thr pathway–based prognostic model for EC, based on the expression of MTHFD2, RPS6KA1, and CDKN2A as novel biomarkers. The resulting patient stratification framework holds significant clinical potential for guiding precise and personalized management of EC.

ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer

Abstract Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. Results Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. Conclusions ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.

EIF1AX Nucleolar Condensates Enhance Susceptibilities for the Management of Endometrial Cancer

Abstract Endometrial cancer harboring TP53 aberrations presents a significant therapeutic challenge due to the lack of druggable targets. A promising strategy involves inducing senescence in cancer cells followed by targeted elimination using senolytic agents. The preliminary findings indicated that the aberrant subcellular localization of EIF1AX in endometrial cancer is significantly correlated with a poor prognosis. In this study, a compound library is employed to screen for therapeutic agents that induce the nuclear localization of EIF1AX in endometrial cancer cells, followed by a CRISPR library screen to identify senolytic compounds. The results demonstrated that the combination of 2,5‐MeC and dacinostat effectively inhibited tumor growth. Mechanistically, co‐immunoprecipitation mass spectrometry and cleavage under targets and tagmentation sequencing analyses demonstrated that 2,5‐MeC acts as a potent inducer of EIF1AX nucleolar translocation. This translocation promoted senescence by recruiting DDX21 to form nucleolar aggregates, which suppressed rDNA transcription. Additionally, RNA sequencing and antibody array analyses revealed that the synthetic lethality of 2,5‐MeC and dacinostat is mediated through the activation of the JNK/MAPK signaling pathway. Collectively, these findings highlight a novel therapeutic strategy for TP53‐aberrant endometrial cancer.

Antagonism of estrogen-related receptor-α inhibits mitochondrial oxidative phosphorylation and reduces M2 macrophage infiltration in endometrial cancer

Objective Endometrial cancer (EC) is a female malignancy closely linked to metabolic dysregulation. Most patients with EC exhibit poor responses to immunotherapy, underscoring the need to identify novel therapeutic targets at the intersection of metabolism and immune regulation. Methods In vitro: integrated proteomics, CUT&Tag (cleavage under targets and tag mentation) sequencing, dual-luciferase reporter assays, lipidomic profiling, and macrophage-tumor co-culture systems collectively demonstrated estrogen-related receptor (ERR) α’s dual metabolic-immunomodulatory role in KLE and HEC-1A human cell lines. Patient-derived organoids were used to validate the therapeutic efficacy of ERRα targeting. In vivo, the KLE cell xenograft model was used to evaluate tumorigenicity and therapeutic efficacy in mice. In humans, a retrospective cohort of 166 patients with EC was analyzed by immunohistochemistry (IHC) to quantify ERRα expression and macrophage infiltration, establishing clinical correlations and therapeutic implications. Spatial analysis of M2 macrophages in EC progression was performed using multiplex IHC. Results In EC cells, ERRα transcriptionally upregulates protein tyrosine phosphatase mitochondrial 1 through direct promoter binding (-624 to −609 bp). This interaction promotes cardiolipin biosynthesis, thereby stabilizing mitochondrial inner membrane ultrastructure, enhancing oxidative phosphorylation activity, and elevating reactive oxygen species (ROS) levels. Subsequently, ROS activates the NF-κB signaling axis, inducing CCL2 secretion to recruit M2 macrophages into the tumor microenvironment. Importantly, combined inhibition of ERRα (using XCT790) and CCL2 (using carlumab) significantly enhanced antitumor efficacy in EC. Additionally, ERRα expression in EC tissues may serve as a clinical indicator for disease evaluation. Conclusions This study uncovers a pivotal role of the ERRα metabolic axis in reshaping the EC immune microenvironment, providing the mechanistic evidence linking mitochondrial lipid metabolism to macrophage-driven immunosuppression. Our findings establish a theoretical foundation for developing combination therapies targeting metabolic-immune crosstalk, offering a strategy to overcome immunotherapy resistance in EC.

An integrated approach of network pharmacology, molecular docking, and experimental verification uncovers kaempferol as the effective modulator of HSD17B1 for treatment of endometrial cancer

Abstract Background Endometrial cancer (EC) is one of the most common gynecological malignancies globally, and the development of innovative, effective drugs against EC remains a key issue. Phytoestrogen kaempferol exhibits anti-cancer effects, but the action mechanisms are still unclear. Method MTT assays, colony-forming assays, flow cytometry, scratch healing, and transwell assays were used to evaluate the proliferation, apoptosis, cell cycle, migration, and invasion of both ER-subtype EC cells. Xenograft experiments were used to assess the effects of kaempferol inhibition on tumor growth. Next-generation RNA sequencing was used to compare the gene expression levels in vehicle-treated versus kaempferol-treated Ishikawa and HEC-1-A cells. A network pharmacology and molecular docking technique were applied to identify the anti-cancer mechanism of kaempferol, including the building of target-pathway network. GO analysis and KEGG pathway enrichment analysis were used to identify cancer-related targets. Finally, the study validated the mRNA and protein expression using real-time quantitative PCR, western blotting, and immunohistochemical analysis. Results Kaempferol was found to suppress the proliferation, promote apoptosis, and limit the tumor-forming, scratch healing, invasion, and migration capacities of EC cells. Kaempferol inhibited tumor growth and promotes apoptosis in a human endometrial cancer xenograft mouse model. No significant toxicity of kaempferol was found in human monocytes and normal cell lines at non-cytotoxic concentrations. No adverse effects or significant changes in body weight or organ coefficients were observed in 3–7 weeks’ kaempferol-treated animals. The RNA sequencing, network pharmacology, and molecular docking approaches identified the overall survival-related differentially expressed gene HSD17B1. Interestingly, kaempferol upregulated HSD17B1 expression and sensitivity in ER-negative EC cells. Kaempferol differentially regulated PPARG expression in EC cells of different ER subtypes, independent of its effect on ESR1. HSD17B1 and HSD17B1-associated genes, such as ESR1, ESRRA, PPARG, AKT1, and AKR1C1\2\3, were involved in several estrogen metabolism pathways, such as steroid binding, 17-beta-hydroxysteroid dehydrogenase (NADP+) activity, steroid hormone biosynthesis, and regulation of hormone levels. The molecular basis of the effects of kaempferol treatment was evaluated. Conclusions Kaempferol is a novel therapeutic candidate for EC via HSD17B1-related estrogen metabolism pathways. These results provide new insights into the efficiency of the medical translation of phytoestrogens.

Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression

Abstract Background Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. The transcription factor EB (TFEB)-ERRα axis induces lipid reprogramming to promote progression of EC was explored in this study. Methods TFEB and ERRα were analyzed and validated by RNA-sequencing data from the Cancer Genome Atlas (TCGA). The TFEB-ERRα axis was assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the TFEB-ERRα-related lipid metabolism pathway. Pseudopods were observed by scanning electron microscope. Furthermore, immunohistochemistry and lipidomics were performed in clinical tissue samples to validate the ERRα-related lipids. Results TFEB and ERRα were highly expressed in EC patients and correlated to EC progression. ERRα is the direct target of TFEB to mediate EC lipid metabolism. TFEB-ERRα axis mainly affected glycerophospholipids (GPs) and significantly elevated the ratio of phosphatidylcholine (PC)/sphingomyelin (SM), which indicated the enhanced membrane fluidity. TFEB-ERRα axis induced the mitochondria specific phosphatidylglycerol (PG) (18:1/22:6) + H increasing. The lipid reprogramming was mainly related to mitochondrial function though combining lipidomics and proteomics. The maximum oxygen consumption rate (OCR), ATP and lipid-related genes acc, fasn, and acadm were found to be positively correlated with TFEB/ERRα. TFEB-ERRα axis enhanced generation of pseudopodia to increase the invasiveness. Mechanistically, our functional assays indicated that TFEB promoted EC cell migration in an ERRα-dependent manner via EMT signaling. Consistent with the in vitro, higher PC (18:1/18:2) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (18:1/18:2) + HCOO was an independent risk factor positively related to ERRα for lymph node metastasis. Conclusion Lipid reprogramming induced by the TFEB-ERRα axis increases unsaturated fatty acid (UFA)-containing PCs, PG, PC/SM and pseudopodia, which enhance membrane fluidity via EMT signaling to promote EC progression. PG (18:1/22:6) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.

Integrative Analysis of Shared Pathogenic Genes and Potential Mechanisms in Gardnerella vaginalis and Persistent HPV16 Infection

Bacterial vaginosis, often accompanied by Gardnerella vaginalis (GV) overgrowth, is associated with persistent high‐risk human papillomavirus (HR‐HPV) infection, particularly HPV16. This study integrated transcriptomic data from in vitro GV infection experiments and a GEO dataset (GSE75132) of HPV16 persistence to elucidate shared pathogenic mechanisms. Differential expression analysis identified 4115 genes modulated by GV infection and 861 by HPV16 persistence, with 74 common differentially expressed genes (DEGs) displaying consistent trends. Enrichment analyses revealed that these DEGs participate in metabolic pathways, immune defense, host–pathogen interactions, and carcinogenesis. Protein–protein interaction networks and Random Forest (RF) feature selection pinpointed radical S‐adenosyl methionine domain containing 2 (RSAD2) and Interferon‐induced protein with tetratricopeptide repeats 1 (IFIT1) as central hub genes. Upstream transcription analysis identified the homer_AGTTTCAGTTTC_ISRE motif and established a ceRNA network involving hsa‐miR‐654‐5p, IFIT1/RSAD2, and lncRNAs. Mendelian randomization (MR) and colocalization analyses linked RSAD2 downregulation to an increased risk of cervical carcinoma in situ (rs2595163, PPH4 = 0.62), while ROC analysis demonstrated strong diagnostic potential for the combined hub gene expression. Notably, single‐cell transcriptomics revealed distinct RSAD2 and IFIT1 expression patterns in immune and epithelial cells during the progression from HPV infection to cervical cancer. Collectively, these findings support RSAD2 and IFIT1 as promising biomarkers and therapeutic targets for HPV‐related cervical lesions.

Colorimetric aptasensor based on temporally controllable light-stimulated oxidase-mimicking fluorescein for the sensitive detection of exosomes in mild conditions

A colorimetric aptasensor for exosome detection under LED light.

Characteristics of Human Papillomavirus Prevalence and Infection Patterns Among Women Aged 35–65 in Fujian Province, China: A Nine‐Year Retrospective Observational Study

ABSTRACTThe assessment of human papillomavirus (HPV) genotype distribution could inform targeted cervical cancer prevention strategies. The epidemiology of HPV genotypes in terms of age and cervical lesions in Fujian Province, China has not been well described. This 9‐year retrospective study aimed to delineate the prevalence pattern and trend of HPV genotypes among a large‐scale community‐based population. Deidentified data were retrieved from the national cervical cancer screening program in China. We included eligible women aged 35–65 years who underwent cervical cancer screening between 2014 and 2022 in Fujian Province. The HPV prevalence within distinct subpopulations was calculated, and trends in HPV prevalence over the years and across age groups were examined using the Cochran‐Armitage trend test. A total of 551 604 women (median age 49 years [42, 54]; 0.10% with cervical cancer) were included in this study. The overall HPV prevalence was 11.72% (95% CI: 11.63%–11.80%), with HR‐HPV (high‐risk HPV) and HPV 16/18 prevalence at 10.02% (9.94%–10.10%) and 1.74% (1.71%–1.78%), respectively. HPV‐52, 58, 16, 39, 51, and 68 were the most predominant genotypes in the general population. Nearly all genotypes, except for HPV‐39 and 66, showed a decreasing trend in prevalence over the years, while a relatively high prevalence of HR‐HPV was observed across all age groups. As lesion severity increased, HR‐HPV and 9v‐HPV prevalence also increased. Our study underscores the importance of ongoing surveillance of HPV prevalence in China. While the overall decline in HPV infections over the years is encouraging, the relatively high prevalence of HR‐HPV warrants continued attention. Strengthening public health strategies—including prioritizing and promoting the current 9‐valent vaccination, extending HPV testing and cervical cancer screening to older women where feasible, and developing future vaccines targeting more HR‐HPV genotypes—will be crucial in eliminating cervical cancer and HPV‐related disease in China and beyond.

ERRα expression in ovarian cancer and promotes ovarian cancer cells migration in vitro

Ovarian cancer is the leading cause of death from a gynaecological malignancy in the developed world, and is characterized by invasion and metastasis and thus causes a high fatality rate. Estrogen-related receptor alpha (ERRα) has been demonstrated to play a widespread and pathophysiological relevant role in tumourigenesis and development. The aim of this study was to investigate the effect of ERRα expression on the progression of ovarian cancer. The correlation between ERRα expression level and clinical pathological parameters in ovarian cancer tissues were analysed via cancer public database CPTAC. The expression level of ERRα in ovarian cancer cells were confirmed by RT-qPCR and Western blot methods. The cellular ERRα expression was up-regulated by lentivirus transfection and down-regulated by specific antagonist. The invasion and metastasis capabilities of ovarian cancer cells were characterized by wound healing assay and trans-well chamber assay. The CPTAC database showed that the ERRα expression levels were higher in the late-stage and high-grade ovarian cancer tissues than in early-stage and low-grade tissues. Ovarian cancer cells with higher-expression ERRα exhibited stronger invasion and metastasis capabilities in vitro. After up-regulating the ERRα expression level, the invasion and metastasis capabilities of ovarian cancer cells were enhanced, while down-regulation weakened. Moreover, the wound sealing rate was positively correlated with the expression of ERRα mRNA expression level (r = 0.921, P < 0.01), and the cell invasiveness was also positively correlated with the cellular ERRα mRNA expression level (r = 0.926, P < 0.01). Our results suggest that ERRα may promote the progression of ovarian cancer, and may serve as a promising predictive biomarker.

HR-HPV viral load quality detection provide more accurate prediction for residual lesions after treatment: a prospective cohort study in patients with high-grade squamous lesions or worse

The relationship between high-risk-human-papillomavirus (HR-HPV) viral loads and residual/recurrence lesion is uncertain. This study aimed to evaluate the clinical value of HR-HPV viral loads to predict the residual/recurrence lesions among women with high-grade squamous lesions or worse (≥ HSIL) after surgery. Finally, 301 women who underwent primary screening of cervical cancer using polymerase-chain-reaction-(PCR)-reverse-dot-blot-(RDB) human papillomavirus (HPV) genotyping and cytology assays were enrolled. They received surgery and took HR-HPV viral loads with a BioPerfectus Multiplex Real-Time PCR assay. Colposcopy biopsies were performed in patients with HPV-16/18(+) and/or TCT ≥ ASCUS with HR-HPV(+). The risk of HR-HPV viral loads and potentials factors for residual/recurrence lesions were analyzed and the optimal cut-off values of HR-HPV viral loads were calculated. The significant differences were found in residual/recurrence lesions among patients with different ages, margin status, cytology and HR-HPV at 6 months (all P < 0.05). Interestingly, HPV viral loads were observed significant differences in the group of residual lesions, not recurrence group. Furthermore, except for HPV-31/33, the viral loads of HP-16/52/58 were significant differences in residual lesions. The cut-off level of HR-HPV viral loads was 5.22 copies/10,000 cells, providing viable triage for the risk of residual lesions. Compared with different follow-up methods, the HR-HPV viral loads ≥ 5.22copies/10,000 cells (HR 3.39, 95% CI 1.57-7.35) had a higher risk for developing residual lesions. HR-HPV viral loads can be a reliable predictor of residual lesions. Furthermore, women with viral loads ≥ 5.22 copies/10,000 cells may have higher risk for residual disease and should be give a more aggressive treatment and follow-up strategy.

The prevalence of human papillomavirus and bacterial vaginosis among young women in China: a cross-sectional study

Abstract Background The natural history of human papillomavirus (HPV) is influenced by vaginal microenvironment disorders, such as bacterial vaginosis (BV). The objective of this study was to assess the epidemiology of HPV combined with BV prevalence among Chinese women aged 20–35 years. Methods A total of 2000 sexually active women aged 20–35 years voluntarily enrolled in this study and underwent a ThinPrep cytologic test and PCR-reverse dot blot human papillomavirus genotyping (PCR-RDB HPV test). BV was diagnosed if clue cells were observed (20% more than epithelial cells). Results The overall HPV infection rate in this population was 16.2% (324/2000). Compared with HPV-negative individuals, BV prevalence was higher in the High-risk human papillomavirus (HR-HPV) (5.9% vs. 3.1%, P &lt; 0.001). BV and HPV-51, -52 infection were more commonly associated with each other. In patients with cervical lesions (≥ CIN 1), the BV prevalence rate was higher than in patients with negative for intraepithelial lesion or malignancy (NILM) (11.9% vs. 3.8%, P = 0.002). Conclusion BV was found to be related to HPV-51, -52 infections and cervical lesions. To better manage HPV infected population, more attention should be paid to the prevention and proper treatment of BV.

Prevotella as the hub of the cervicovaginal microbiota affects the occurrence of persistent human papillomavirus infection and cervical lesions in women of childbearing age via host NF‐κB/C‐myc

AbstractThere is evidence that coinfection of cervicovaginal high‐risk human papillomavirus (HR‐HPV) and bacteria is common in women of childbearing age. However, the relationship between bacterial vaginosis (BV) and persistent HR‐HPV infection in women of childbearing age and the underlying mechanisms remain unclear. In this study, we determined whether BV affects persistent HR‐HPV infection in women aged 20–45 years and explored the possible mechanisms of their interactions. From January 1 to April 30, 2020, we recruited women aged 20–45 years with and without BV at a ratio of 1:2 from Fujian Maternity and Child Health Hospital. All women were followed up at 0, 12, and 24 months. A BV assay, HR‐HPV genotyping and cervical cytology were performed at each follow‐up. At 0 months, additional vaginal secretions and cervical exfoliated cells were collected for 16S ribosomal RNA sequencing, bacterial metabolite determination, and POU5F1B, C‐myc, TLR4, NF‐κB, and hTERT quantification. A total of 920 women were included. The abundance of Prevotella (p = 0.016) and Gardnerella (p = 0.027) were higher, whereas the abundance of Lactobacillus was lower (p = 0.001) in women with persistent HR‐HPV infection and high‐grade squamous intraepithelial lesions (HSIL). The abundance of Prevotella (p = 0.025) and Gardnerella (p = 0.018) increased in the vaginas of women with persistent HPV16 infection, whereas only the abundance of Prevotella (p = 0.026) was increased in women with persistent HPV18 infection. The abundance of Prevotella in the vagina was significantly positively correlated with the expression levels of TLR4, NF‐κB, C‐myc, and hTERT in host cervical cells (p &lt; 0.05). Our findings suggest that overgrowth of Prevotella in the vagina may influence the occurrence of persistent HR‐HPV infection‐related cervical lesions through host NF‐κB and C‐myc signaling.

Recently urodynamic and quality of life assessment in the non-menopausal women with cervical cancer after radical hysterectomy

The aim of this study was to evaluate the pre- and postoperative changes in the recently urodynamic and quality of life (QoL) in nonmenopausal women diagnosed with cervical cancer and treated with radical hysterectomy (RH). Twenty-eight nonmenopausal women (28-49 years) with cervical carcinoma (FIGO stage Ia2-IIa) underwent a radical hysterectomy. Urodynamic studies were performed 1 week before (U0) and 3-6 months (U1) after surgery. A self-administered condition-specific QoL questionnaire (PFDI-20, PFIQ-7) was applied at U0 and U1. Data from the urodynamics analysis performed at U1 showed that the average first sensation volume (119.39 ± 12.28 ml vs 150.43 ± 31.45 ml, P < 0.001), the residual urine volume (6.39 ± 10.44 ml vs. 42.32 ± 33.72 ml, P < 0.001), and the time of urination (46.10 ± 16.65 s vs. 74.31 ± 23.94 s, P < 0.001) were increased, while the bladder volume at a strong desire to void (448.89 ± 86.62 ml vs. 322.82 ± 50.89 ml, P < 0.001), the bladder compliance (82.63 ± 58.06 ml/cmH Radical hysterectomy results in urodynamic changes, and 3-6 months postoperation may be an important period for changes in bladder dysfunction after RH. Urodynamic and QoL analyses may provide methods for assessing symptoms.

HPV positivity status in males is related to the acquisition of HPV infection in females in heterosexual couples

Abstract Purpose Few studies have focused on the impact of human papillomavirus (HPV) positivity in male partners on female HPV infection and cervical lesions. The purpose of this study was to evaluate the impact of the HPV infection status of husbands on wives’ cervical HPV infection and lesions. Methods We surveyed 251 monogamous couples who attended the outpatient department of Fujian Maternity and Child Health Hospital from 2013 to 2021. HPV type analysis was performed on exfoliated cells of the females’ cervix and males’ urethra by the PCR-reverse dot blot method. We analyzed the prevalence and consistency of HPV types in 251 couples. Subsequently, the risk of HPV infection in females with HPV-positive male partners was analyzed. SPSS version 26 (IBM, Chicago, USA) was used for statistical analysis. Results In 251 couples, the most commonly detected high-risk HPV (HR-HPV) genotypes were 52, 51, 16, and 58 for males and 16, 52, 18, and 58 for females. Wives with HPV-positive husbands had higher infection rates for most HR-HPV genotypes. HR-HPV positivity in husbands was a risk factor for the development of cervical lesions in wives (OR = 2.250, P = 0.014). Both single-type (OR = 2.085, P = 0.040) and multiple-type (OR = 2.751, P = 0.036) infection in husbands will contributed to an increased risk of non-HR-HPV infection and cervical lesions in wives. Conclusion Husbands’ HPV positivity increases the burden of non-HR-HPV infection and increases the risk of cervical lesions developing in wives. It is hoped to provide a reference value for cervical cancer prevention in females and HPV vaccination in males.

Identifying Data-Driven Clinical Subgroups for Cervical Cancer Prevention With Machine Learning: Population-Based, External, and Diagnostic Validation Study

Abstract Background Cervical cancer remains a major global health issue. Personalized, data-driven cervical cancer prevention (CCP) strategies tailored to phenotypic profiles may improve prevention and reduce disease burden. Objective This study aimed to identify subgroups with differential cervical precancer or cancer risks using machine learning, validate subgroup predictions across datasets, and propose a computational phenomapping strategy to enhance global CCP efforts. Methods We explored the data-driven CCP subgroups by applying unsupervised machine learning to a deeply phenotyped, population-based discovery cohort. We extracted CCP-specific risks of cervical intraepithelial neoplasia (CIN) and cervical cancer through weighted logistic regression analyses providing odds ratio (OR) estimates and 95% CIs. We trained a supervised machine learning model and developed pathways to classify individuals before evaluating its diagnostic validity and usability on an external cohort. Results This study included 551,934 women (median age, 49 years) in the discovery cohort and 47,130 women (median age, 37 years) in the external cohort. Phenotyping identified 5 CCP subgroups, with CCP4 showing the highest carcinoma prevalence. CCP2–4 had significantly higher risks of CIN2+ (CCP2: OR 2.07 [95% CI: 2.03‐2.12], CCP3: 3.88 [3.78‐3.97], and CCP4: 4.47 [4.33‐4.63]) and CIN3+ (CCP2: 2.10 [2.05‐2.14], CCP3: 3.92 [3.82‐4.02], and CCP4: 4.45 [4.31‐4.61]) compared to CCP1 (P&lt;.001), consistent with the direction of results observed in the external cohort. The proposed triple strategy was validated as clinically relevant, prioritizing high-risk subgroups (CCP3-4) for colposcopies and scaling human papillomavirus screening for CCP1-2. Conclusions This study underscores the potential of leveraging machine learning algorithms and large-scale routine electronic health records to enhance CCP strategies. By identifying key determinants of CIN2+/CIN3+ risk and classifying 5 distinct subgroups, our study provides a robust, data-driven foundation for the proposed triple strategy. This approach prioritizes tailored prevention efforts for subgroups with varying risks, offering a novel and scalable tool to complement existing cervical cancer screening guidelines. Future work should focus on independent external and prospective validation to maximize the global impact of this strategy.

Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1low/CAMSAP3low, emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer

AbstractThe clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.