BackgroundUltra-radical cytoreductive surgery is frequently performed for patients with advanced ovarian cancer (OC). However, anastomotic leakage (AL) is a serious complication of such surgeries and the risk factors remain unclear. This study identified early postoperative C-reactive protein (CRP) and albumin were the strongest predictors of leakage.MethodsThis multicenter retrospective study involved 305 patients with ovarian cancer who underwent primary anastomosis following enterectomy, spanning January 2018 to June 2023. Comprehensive clinical and demographic data were used to develop predictive models. Feature selection was performed using LASSO and univariate logistic regression. Machine learning algorithms were subsequently applied, with model interpretability assessed using SHapley Additive explanations (SHAP).ResultsThe study revealed an AL prevalence of 14.1%, with 46.5% of affected patients requiring reoperation. Five predictors were identified, including postoperative CRP, serum albumin levels, Eastern Cooperative Oncology Group score, N stage, and blood urea nitrogen. The Lasso-Logistic model demonstrated the best predictive performance with an area under the curve of 0.828 (0.119). SHAP analysis highlighted early postoperative CRP, albumin, and N stage as major contributing factors. Economic analysis revealed a significant correlation between AL and hospital stay, hospital costs, and time to chemotherapy.DiscussionEarly postoperative inflammatory and nutritional biomarkers, particularly CRP and albumin, demonstrated significant predictive value for anastomotic leakage, providing an early warning for risk stratification and intervention. The investigation also bolstered the evidence supporting the restrictive surgical scope approach advocated in clinical guidelines.

This study applied integrated multi-omics to explore the role of plasma elements, blood clinical indicators, and metabolome in cervical cancer (CC). Based on data from 436 subjects, untargeted/targeted metabolomics and ICP-MS analyses revealed significant plasma metabolome reprogramming in CC. This was characterized by upregulated levels of estrone glucuronide and cortisol, and downregulation of androstenedione. A random forest model constructed with four metabolites (androstenedione, calcitriol, paraxanthine, theobromine) achieved an AUC of 0.884, superior to conventional markers (CEA, CA125). Among nine metals linked to CC risk, Cd, Cr, Pb, Ba, and Li increased risk, while Mn, Cu, and Sn were protective; mixed metal exposure elevated risk dose-dependently. CC patients also showed abnormal blood parameters, including reduced RBC and lymphocyte counts, and higher TG, GLU, CEA, and CA125. Multi-omics network analysis indicated co-clustering of Li, Cr, and Co with estrone glucuronide, 5-HIAA, GLU, PCT, and CA125; Pb and Ba with L-valine; Mn with paraxanthine, androstenedione, A/G, and GLOB; cortisol, caffeine, and theobromine with RBC and LYM#. These integrated network highlights complex interactions among metals, clinical indicators, and metabolites, providing new insights for non-invasive diagnosis and environmental health interventions in CC.

Residual disease after cytoreductive surgery is a dominant, surgeon-modifiable determinant of outcome in advanced ovarian cancer, yet white-light inspection cannot reliably identify microscopic implants, plaque-like deposits, or therapy-altered fibrotic foci across complex peritoneal surfaces. Intraoperative molecular imaging aims to close this visibility gap by translating tumor-associated biology into real-time signal that can prompt additional resection, direct sampling, and support intraoperative decision-making. Across probe classes, folate receptor-α-targeted agents represent the most clinically mature approach, while activatable tracers and multimodal platforms are expanding capabilities beyond superficial visualization. However, improved detection alone does not establish patient benefit. We therefore frame molecular guidance as a workflow intervention and organize evidence along a clinically oriented hierarchy-lesion detection, decision impact, and patient outcomes-highlighting the need for standardized acquisition/quantification and pathology-linked validation. We propose pragmatic, trial-compatible definitions for pathology-confirmed completeness and prespecified molecular field clearance, and discuss how AI-assisted interpretation, multimodality, and radionuclide-enabled strategies could strengthen reproducibility and extend management toward microscopic residual disease.

V-domain immunoglobulin suppressor of T-cell activation (VISTA), an immune checkpoint protein, is overexpressed in multiple cancers. However, its mechanistic role in ovarian cancer (OC) remains largely undefined. Transcriptomic analysis of OC cohorts (OCA and OCB) and single-cell RNA sequencing (GSE184880) were conducted to evaluate VISTA expression and associated pathway enrichment. Functional assays, including proliferation, migration, and epithelial-mesenchymal transition (EMT) analyses, along with in vivo models, were employed to determine the role of VISTA in OC progression. Mechanistic investigations, incorporating co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase, and dual-luciferase reporter assays, elucidated VISTA-mediated NF-κB activation. Immune profiling using CIBERSORT and flow cytometry was performed to characterize tumor microenvironment (TME) modulation. VISTA was significantly upregulated in OC tissues and associated with poor prognosis. Furthermore, VISTA promoted OC cell proliferation, migration, EMT, and cell cycle progression. Mechanistically, VISTA bound HSP90AB1 to stabilize the VISTA/HSP90AB1/IKK complex, facilitating IKKα/β phosphorylation, p65 nuclear translocation to active NF-κB pathway. In vivo VISTA knockdown suppressed tumor growth, whereas its overexpression accelerated tumor progression. Notably, VISTAhigh OC exhibited reduced CD8 + T cell infiltration and dendritic cell activation, fostering an immunosuppressive TME. Depleting CD8 + T cells depletion abrogated the anti-tumor effects of VISTA inhibition. VISTA promotes OC progression through dual mechanisms: activation of the NF-κB pathway and immunosuppression within the tumor microenvironment. Targeting the VISTA/HSP90AB1/NF-κB axis represents a promising therapeutic strategy to counteract OC immune evasion and tumor aggressiveness.

Accurate prediction of the binding specificity between T-cell receptors (TCRs) and epitopes, along with the elucidation of their molecular interaction mechanisms, is pivotal for advancing immunotherapy and vaccine development. In this study, we propose a negative dataset construction strategy based on region-directed random mutations as an effective complement to traditional negative sampling methods. This strategy preserves the conserved amino acid motifs encoded by the V and J gene segments of the CDR3$\beta$ sequence while introducing key residue mutations within the central junctional region. By constructing hard negatives, this approach encourages the model to capture more discriminative TCR-epitope binding features. Based on this optimized dataset, we developed TranTCR, a computational framework comprising two models: TranTCR-bind, which focuses on global sequence-level binding probability prediction, and TranTCR-map, which leverages transfer learning to translate global binding knowledge into fine-grained characterizations of residue-level interactions, such as inter-residue distances and contact scores. Experimental results demonstrate that TranTCR-bind exhibits superior predictive performance and generalization robustness across various negative sampling protocols. Furthermore, TranTCR-map utilizes attention mechanisms to deeply resolve complex inter-amino acid associations, enabling the identification of latent binding patterns and the revelation of TCR cross-reactivity characteristics. This study provides an efficient computational tool for the high-throughput screening of TCR repertoires and the digital characterization of immune recognition mechanisms.

BACKGROUND:Ovarian cancer remains a formidable therapeutic challenge due to late diagnosis, high recurrence rates, and limited treatment options. Mesothelin (MSLN) is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Given this target profile, the authors developed a novel T-cell receptor (TCR)-like chimeric antigen receptor (CAR) T-cell therapy targeting MSLN, designated KT127. METHODS:A first-in-human, dose-escalation trial of KT127 was conducted following preclinical evaluation in vitro and in vivo. A combination of rapid titration and a standard "3 + 3" dose-escalation design was implemented. Eleven patients received KT127 at doses ranging from 1 × 106 to 2 × 107 cells/kg following lymphodepletion. The primary objectives were to assess the safety and tolerability of KT127. Secondary objectives included overall survival, disease control rate (DCR), and progression-free survival as efficacy measures. Quality of life (QOL) was assessed using the European Organisation for Research and Treatment of Cancer QLQ-OV28 questionnaire. RESULTS:No dose-limiting toxicities, cytokine release syndrome, or immune effector cell-associated neurotoxicity syndrome were observed. The DCR was 80% (95% confidence interval, 44.4%-97.5%). QOL assessments indicated improvement in abdominal/gastrointestinal symptoms post-treatment (p = .037), with no significant deterioration in other domains. Proteomic analysis identified differential expression of kallikrein-related peptidases (KLK13, KLK14) and chemokine CXCL17 at baseline, potentially linked to treatment outcomes. CONCLUSIONS:This study highlights that KT127 has a manageable safety profile and shows preliminary biological activity in patients with advanced ovarian cancer, particularly those who have failed multiple lines of therapies.

Ovarian cancer (OC) lethality is frequently associated with an immunosuppressive tumor immune microenvironment (TIME). While monocytes appear to function as notable regulators within the TIME, their causal involvement in OC pathogenesis remains poorly defined. To investigate the causal involvement of monocytes in OC, we integrated single-cell RNA sequencing datasets from the GEO and TISCH databases. Comparative cell proportion analysis was conducted using Fisher’s exact test. Cell–cell communication networks were mapped with CellChat to characterize tumor-specific interactions via ligand–receptor pairs (e.g., MIF, MDK). Causal associations were identified through Summary-data-based Mendelian randomization (MR) and two-sample MR, integrating eQTLGen statistics (n = 31,684) with OC GWAS data (1,588 cases). Instrumental variables were prioritized based on F-statistics > 10 and LD clumping. Bayesian colocalization and the HEIDI test (P > 0.05) were employed to rule out linkage disequilibrium. Finally, functional roles of candidate genes were validated via qRT-PCR, Western blot, and in vitro polarization assays. Quantitative analysis revealed a significant enrichment of monocytes in the OC group (24.58

This study investigates the association between exposure to the PFOS alternative F-53B (6:2 Cl-PFESA) and cervical cancer risk in Chinese women, and elucidates its dual mechanisms of cervical toxicity and malignant progression. A case-control study (181 patients, 164 controls) measured plasma concentrations of 8 PFAS by UPLC-MS/MS, and logistic regression, WQS, and BKMR models were used to assess PFAS-cervical cancer associations. Human cervical epithelial cells (HcerEpic, HeLa, SiHa) were exposed to acute (425 μM) or long-term low-dose (1 μM) F-53B, followed by transcriptomics, ferroptosis phenotyping, functional assays, and protein/gene expression analyses. In vivo validation was performed using C57BL/6 mice (subacute exposure, metabolomics) and BALB/c nude mice (xenograft model). Epidemiological analysis identified F-53B as the predominant driver of cervical cancer risk within PFAS mixture exposure. Acute high-dose F-53B induced ferroptosis in cervical epithelial cells. At a concentration relevant to occupational exposure (1 μM), F-53B promoted malignant phenotypes by driving cell cycle progression, inhibiting apoptosis, enhancing migration/invasion, and inducing EMT. In vivo, F-53B caused cervical ferroptosis and systemic lipid metabolic reprogramming in C57BL/6 mice, and promoted xenograft growth and lymphatic metastasis in nude mice. This first multi-level evidence identifies F-53B, a widely used PFOS substitute, as an environmental risk factor for cervical cancer. It exerts acute toxicity via ferroptosis and drives malignant progression over the long term through multiple oncogenic phenotypes, underscoring the need for stringent risk assessment of emerging PFAS alternatives.

The increasing global use of organophosphate esters (OPEs) has raised concerns about their environmental and health impacts, with evidence suggesting adverse effects on reproductive system health. As a widely used OPE, triphenyl phosphate (TPHP) has drawn attention for its endocrine-disrupting properties; however, its effects on cervical epithelial cells and association with cervical diseases remain unclear. In this study, analysis of 12 urinary OPE metabolites (mOPEs) in 116 cervical cancer (CC) cases and 116 controls revealed that multiple exposure biomarkers, particularly those related to TPHP exposure, were significantly positively associated with CC risk, suggesting a potential link between OPE exposure and disease development. In toxicological experiments, acute exposure to TPHP (50 μM, 24 h) induced significant cytotoxicity in human cervical epithelial cells (HcerEpic), characterized by reduced cell viability, cell cycle disruption, apoptosis, and oxidative stress. Conversely, chronic low-dose exposure (100 nM, 30 weeks) conferred a survival advantage to HcerEpic cells and enhanced their epithelial-mesenchymal transition (EMT) capacity, with enhanced tumor formation ability observed in a nude mouse xenograft model. Transcriptomic analysis revealed that ferroptosis was a significantly enriched pathway in both exposure models. Furthermore, experimental validation confirmed that acute TPHP exposure induced ferroptosis in HcerEpic cells, whereas chronically exposed cells exhibited ferroptosis resistance. Collectively, our findings highlight the critical role of ferroptosis dysregulation in TPHP-induced acute and chronic toxicities in HcerEpic cells, suggesting that TPHP may be a potential risk factor for CC and underscoring the need for further attention to the health risks associated with OPE exposure.

Obesity is associated with both high and low levels of hypoglycemia, and impairment of counterregulatory hormones may predispose individuals to hypoglycemia. This study aimed to explore differences in the responsiveness of insulin counterregulatory hormones to hypoglycemia between men with or without obesity who have been newly diagnosed with type 2 diabetes mellitus (T2DM). This study enrolled 25 men newly diagnosed with T2DM who were hospitalized in the Department of Endocrinology and Metabolism between January 2022 and December 2022. All participants were treated with intensive insulin pump therapy to achieve glycemic control within one week, then a hyperinsulinemic-hypoglycemic clamp was used to evaluate insulin counter-regulatory hormones for hypoglycemia. Based on the body mass index, 10 and 15 patients were included in the obese and nonobese groups, respectively. During the hyperinsulinemic-hypoglycemic clamp test, the obese group showed a significant lower multiple of adrenocorticotropic hormone elevation than the nonobese group (P = 0.040). Regarding the proportion of hormone response multiples reaching the target, those who reached the reaction multiple were lower in the obese group than those in the non-obese group, although the differences were not statistically significant (all P > 0.05). The responses of insulin counterregulatory hormones to hypoglycemia in men with obesity and newly diagnosed T2DM were significantly lower than those in men with T2DM but without obesity.

Chimeric antigen receptor (CAR) T cells have demonstrated promising therapeutic outcomes in hematologic malignancies, but efficacy against most solid tumors, including ovarian cancer (OC). To address CAR-T challenges, we generated CAR-T cells (B4M3 CAR-T) targeting two tumor-associated antigens, B7H3 and MSLN, simultaneously. Immunohistochemistry and proteomics technologies, were employed to analyze the xenograft tumor tissues and key organ tissues at the end of the treatment in vivo assays. B4M3 CAR-T cells demonstrated rapid antitumor effects under in vivo stress conditions, protected against organ damage, and exhibited favorable safety and tolerability. Molecular and signaling studies indicated that B4M3 CAR-T promoted tumor cell death by activating the NF-κB and TNF signaling pathways. Furthermore, B4M3 CAR-T cells enhancing the innate immune response and altering the metabolic profile. Collectively, our study successfully developed B4M3 CAR-T cells, which exhibited significant antitumor effects in ovarian cancer and it provide a novel strategy for the immunotherapy of OC.

Ovarian cancer brain metastases (OCBM) are rare and have poor prognosis, with limited clinical management guidelines. This study aimed to identify prognostic factors and optimal treatment approaches for patients with OCBM. We conducted a retrospective multicenter analysis of patients with OCBM from 12 hospitals in China from May 2010 to May 2022. The primary outcomes were overall survival (OS) and brain metastasis–specific survival (BMSS). Kaplan–Meier and Cox regression analyses were used to assess treatment outcomes and identify prognostic risk factors. In total, 129 patients with OCBM were included. The median interval from ovarian cancer diagnosis to brain metastasis (BM) was 25.74 (range: 0–103.1) months. Headache attributed to BM was the most common presenting symptom, reported in 64 (49.6

Ovarian cancer (OC) remains a lethal malignancy with limited treatment options owing to antigen heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, we designed a unique chimeric Antigen Receptor T-Cell (CAR-T) construct (B4M3) that integrates an anti-MSLN scFv linked to the CD3ζ activation domain and an anti-B7H3 scFv linked to the 4-1BB co-stimulatory domain. In vitro, B4M3 CAR-T cells exhibited robust cytotoxicity against OC cell lines with enhanced degranulation (CD107a) and efficient tumor cell killing, even at low effector-to-target ratios. In vivo, B4M3 CAR-T cells significantly inhibited tumor growth and prolonged survival and demonstrated superior tumor infiltration and persistence in OC xenograft models. Imaging mass cytometry (IMC) revealed that B4M3 treatment reshaped the TME, increased cytotoxic T lymphocyte (CTL) infiltration, and reduced regulatory T cells (Tregs). Mechanistically, B4M3 therapy upregulated TGF-β, promoting Th17 differentiation and CTL recruitment, thereby enhancing anti-tumor immunity. Our findings demonstrate that B4M3 CAR-T cells effectively address antigen heterogeneity and enhance therapeutic efficacy in OC, thereby offering a promising strategy for solid tumor immunotherapy.

The transition from HPV infection to cervical cancer (CC) remains unclear, especially concerning small extracellular vesicles (sEVs). We analyzed plasma-sEVs from HPV-negative individuals (HPVN-sEVs), HPV-positive individuals (HPVP-sEVs), and HPV-positive CC patients (HPVC-sEVs) via proteomics (n = 5/5/9) and transcriptomics (n = 3/3/4). Multiomics revealed HPVP-sEVs harbor antiviral and pro-inflammatory signals early in infection, whereas HPVC-sEVs shift toward immunosuppression to sustain persistent infection. Specifically, IFITM2─an antiviral gene─was markedly enriched in HPVP-sEVs versus HPVN-sEVs (P < 0.001) and HPVC-sEVs (P = 0.014). Both HPVP-sEVs (P = 0.004) and HPVC-sEVs (P < 0.001) suppressed M2 macrophages, with HPVC-sEVs further reducing IL-6 (HPVN-sEVs, P = 0.005; HPVP-sEVs, P = 0.015). Notably, IFITM2 mRNA and protein levels in plasma-sEVs distinguished HPVP from HPVC patients, showing superior diagnostic accuracy (AUC = 0.833 and 0.822, respectively) over CA-125. These findings underscore sEVs' dynamic role in HPV-driven carcinogenesis and their potential as noninvasive biomarkers for CC diagnosis.

Dibutyl phthalate (DBP), a widespread phthalate with reproductive toxicity and potential carcinogenicity, its cervical effects remain unclear. This study explored DBP's cervical toxicity and mechanisms via epidemiological analysis, network toxicology, and in vivo/in vitro models. Urinary 6 phthalate metabolites in 104 cervical cancer (CC) patients and 104 controls (detected by UPLC-MS/MS) showed elevated levels of MBP, MEHP, MEOHP, MEHHP, MECPP, and ΣDEHP in CC patients; MBP had the strongest CC risk association (adjusted OR = 2.54, P < 0.001). Network toxicology identified 9 core targets of DBP (e.g., CASP3, MAPK8/14, ESR1) and key pathways involved (TNF, MAPK, apoptosis, oxidative stress, etc.). Short-term DBP exposure (mice: 10-50 mg/kg/day; HcerEpic cells: 100-400 μM) induced cervical injury/oxidative stress, suppressed NRF2, and activated MAPK/NF-κB; N-acetylcysteine (NAC) supplementation mitigated damages. Long-term exposure to environmentally relevant DBP concentrations (10-7 M) promoted HcerEpic cell malignant transformation (e.g., enhanced proliferation, migration, invasion, epithelial-mesenchymal transition) via activation of the TGF-β/Smad2/3 and MAPK pathways, with in vivo tumorigenicity validated in nude mice. In conclusion, our findings not only elucidate the molecular mechanisms underlying DBP-induced cervical injury and malignant transformation, but also provide theoretical evidence for evaluating the health risks of phthalates (PAEs) and guiding prevention strategies for environmental pollutant-related female reproductive malignancies.

To explore the efficacy and safety of continuous subcutaneous glucagon-like peptide-1 receptor agonist infusion (CSGI) combined with continuous subcutaneous insulin infusion (CSII) on body weight, glycemic control and β-cell function in newly diagnosed type 2 diabetes (T2D) patients. From May 2018 to November 2021, 30 newly diagnosed T2D patients at Nanjing First Hospital were recruited then randomized 1:1 to receive either CSGI add-on to CSII or CSII for 4 weeks. The oral glucose tolerance test (OGTT) and 3-day continuous glucose monitoring (CGM) were performed at the baseline and endpoint. The primary outcome was body weight change from baseline to endpoint. After treatment for 4 weeks, the CSGI add-on group achieved greater weight reduction (− 8.8 ± 4.5 kg vs. 0.0 ± 1.8 kg; P < 0.001) and BMI decrease (3.0 ± 1.3 vs. 0.0 ± 0.7 kg/m²; P < 0.001) versus CSII alone, with 80

BACKGROUND:Effective and tolerable treatment for patients with platinum-resistant recurrent ovarian cancer remains a great challenge in clinical practice. This study aimed to evaluate the efficacy and safety of envafolimab, the first subcutaneously administered programmed death ligand 1 (PD-L1) inhibitor, combined with lenvatinib and etoposide in patients with platinum-resistant recurrent ovarian cancer. METHODS:This was an open-label, single-arm, phase 2 trial (ENLEN-OC-001). Patients with platinum-resistant recurrent ovarian cancer were eligible for inclusion who were administered envafolimab subcutaneously on day 1 and lenvatinib and etoposide orally on days 1-14, with 21 days as a cycle. After 6-10 cycles, envafolimab and lenvatinib were taken as maintenance therapy until intolerable toxicity, disease progression, withdrawal of consent, or finishing 24 months of treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:Of the screened 28 patients, 21 were included, with 18 being assessed for the efficacy and safety. The ORR was 44.4% (95% CI 21.5%-69.2%), and the DCR was 83.3% (95% CI 58.6%-96.4%). The median PFS was 10.2 months (95% CI 5.6-not applicable [NA]), and the median OS was 21.3 months (95% CI 6.8-NA). The most common grade 3/4 adverse events were leukopenia (27.8%) and thrombocytopenia (16.7%). No serious adverse events or treatment-related deaths were reported. No changes were observed in the depression, anxiety, and quality of life following treatment. CONCLUSION:Envafolimab combined with lenvatinib and etoposide showed promising efficacy and tolerable safety for patients with platinum-resistant recurrent ovarian cancer. CLINICALTRIALS.GOV IDENTIFIER:NCT05422183.

Background Hypoglycemia remains a major barrier to optimal glycemic control in diabetes. Counter-regulatory hormonal responses, particularly those involving the pituitary and adrenal systems, play a central role in mitigating hypoglycemia, yet differences between diabetes subtypes are not well characterized. We aimed to investigate pituitary-target gland responses to hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM). Methods We enrolled drug-naive patients with newly diagnosed T2DM or T1DM, along with controls who did not have diabetes. Participants with diabetes received insulin pump therapy until normoglycemia was achieved. Hyperinsulinemic euglycemic-hypoglycemic clamps were then performed in all participants. Hormonal profiles of the pituitary-adrenal axis and C-peptide were serially measured during the clamps. Results During hypoglycemic clamps, C-peptide, thyroid-stimulating hormone, estradiol, and testosterone decreased, whereas prolactin, adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) increased significantly according to repeatedmeasures analysis of variance (ANOVA) (P<0.05 for all). Compared to controls and T2DM, patients with T1DM exhibited elevated basal GH (P=0.002) and an exaggerated GH response to hypoglycemia (P=0.002), with earlier onset and sustained elevation. In contrast, patients with T2DM showed higher ACTH (P=0.024) and cortisol (P=0.043) levels during hypoglycemia compared to controls and T1DM. Relative to the T1DM group, the T2DM group demonstrated lower testosterone and higher estradiol levels during hypoglycemia (P<0.001 for both). Conclusion Distinct diabetes subtypes demonstrate divergent pituitary-adrenal counter-regulatory responses to hypoglycemia, suggesting unique pathogenic mechanisms contributing to glycemic variability. The exaggerated GH response in T1DM may aggravate glucose fluctuations, whereas elevated ACTH and cortisol in T2DM could perpetuate insulin resistance.