Jun Zhang

Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers

The vasculogenic mimicry, CD146 + and CD105 + microvessel density in the prognosis of endometrioid endometrial adenocarcinoma: a single-centre immunohistochemical study

The microvessel compartment is crucial in the tumour microenvironment of endometrioid adenocarcinoma (EA). This study investigated the role of vasculogenic mimicry (VM), CD146, and CD105 microvessel density in the clinical prognosis of EA. A total of 188 EA cases were analyzed, with VM channels and microvessels detected using PAS/CD31, CD146, and CD105 staining. Mann-Whitney and Fisher exact tests were used to compare the study groups according to the evaluated criteria. ROC analysis included determination of the confidence interval (CI) and area under the ROC curve. The Mantel-Cox test was used to analyze progression-free survival. Multivariate Cox proportional hazard analysis was performed using stepwise regression. Results showed that VM channels and CD146 and CD105 microvessels were significantly higher (

UBE2C -mediated Autophagy Inhibition via Ubiquitination of SIRT1 Contributes to Endometrial Cancer Progression

Abstract Recent studies have shown that autophagy plays an important role in gynecologic tumors, and ubiquitin modification of autophagy regulatory components is essential to regulate autophagic flux. In this study, we found that the ubiquitin-conjugating enzyme E2C (UBE2C) affects endometrial cancer cell apoptosis and proliferation by inhibiting autophagy. Electron microscopy observation of cell ultrastructure and experimental biochemical analysis showed that endometrial cancer cells with UBE2C expression knocked down display typical autophagic characteristics. Cells were cotreated with the autophagy pharmacologic inhibitors chloroquine and/or bafilomycin A1, and mRFP-GFP-LC3 assays were performed to monitor autophagic flux and determine whether UBE2C suppresses the autophagy program. Investigation of the corresponding mechanism by which UBE2C inhibits autophagy revealed that UBE2C induces K48-linked SIRT1 ubiquitination and promotes ubiquitination-dependent degradation of SIRT1, subsequently reducing H4K16 deacetylation levels and epigenetically inhibiting the expression of autophagy-related genes. The results of cell counting kit-8, Hoechst staining, and immunofluorescence assays further indicated that deletion of the autophagy-related gene BECN1 significantly attenuates UBE2C knockdown–induced cell apoptosis. Moreover, overexpression of UBE2C promoted tumor growth in the xenograft mice model. While, the introduction of rapamycin, an agonist of autophagy, successfully reversed tumor growth and apoptosis inhibition mediated by UBE2C overexpression in vitro and in vivo. Taken together, our results suggested that UBE2C-mediated ubiquitination and degradation of SIRT1 contribute to the malignant progression of endometrial cancer through epigenetic inhibition of autophagy. Implications: Our study highlights the tumorigenic role and regulatory mechanism of UBE2C in endometrial cancer; UBE2C inhibits endometrial cancer cell apoptosis through autophagy-related mechanisms and our findings provide new insights into the treatment of endometrial cancer.

miR‐548ag functions as an oncogene by suppressing MOB1B in the development of obesity‐related endometrial cancer

AbstractObesity is a high‐risk factor in the development of endometrial cancer (EC). Our previous study observed that miR‐548ag was significantly overexpressed in the sera of obese individuals. Here, we report the function of miR‐548ag and its mechanism in promoting the obesity‐related progression of EC. The content of miR‐548ag was increased in the serum of obese EC individuals. Bioinformatics analysis indicated that the survival rate of EC patients with a higher expression of miR‐548ag was significantly reduced. The Mps One Binder Kinase Activator 1B (MOB1B, the core member of the Hippo signaling pathway) is a direct target gene of miR‐548ag, which is inversely correlated with the expression of miR‐548ag. The overexpression of miR‐548ag enhances the proliferation, invasion, and migration, and inhibits apoptosis by downregulating the expression of MOB1B, leading to the deactivation of the Hippo pathway in EC cell lines and contributing to tumor progression in vivo. Our study has established that miR‐548ag functions as an oncogene by suppressing MOB1B in the development of obesity‐related EC.

Variations in the Natural History of High-Risk HPV Types Following HPV-16/18 Bivalent Vaccination in Females Aged 18-45 Years

Existing evidence regarding the impact of vaccination on the natural history of high-risk human papillomavirus (HPV) infections remains limited, understanding such effects is essential for optimizing cervical cancer screening in post-vaccination era. Using 10-year follow-up data from a phase 3 randomized trial of the Escherichia coli-produced HPV-16/18 bivalent vaccine (NCT01735006) and its extension study (NCT05045755, NCT04969445), we compared the spectra and natural history (persistence, clearance, and progression) of high-risk HPV infections between vaccinated and unvaccinated females aged 18-45 years. Data was analyzed using the Cox regression and the competing risk model. Our findings indicate that vaccination reduces the burden of HPV-16/18-associated lesions (HR = 0.12, p = 0.0041) primarily by preventing incident infections (HR = 0.45, p < 0.0001) and modifying the natural history of breakthrough infections (enhancing clearance: 98.5% vs. 93.8%, p < 0.0001; and attenuating progression: 1.5% vs. 6.2%, p = 0.0420). Conversely, the elevated burden of HPV-52-associated lesions (HR = 3.06, p = 0.0303) observed in the vaccine group stems mainly from altered natural history (reduced clearance: 90.3% vs. 97.9%, p = 0.0144; and increased progression: 9.7% vs. 2.1%, p = 0.0421), rather than an increase in incidence (HR = 1.09, p = 0.2669). In this work, the observed shifts in HPV infection profiles and natural history between vaccinated and unvaccinated populations suggest that cervical cancer screening recommendations may warrant adjustment for vaccinated individuals.

Imaging-Based AI for Predicting Lymphovascular Space Invasion in Cervical Cancer: Systematic Review and Meta-Analysis

Abstract Background The role of artificial intelligence (AI) in enhancing the accuracy of lymphovascular space invasion (LVSI) detection in cervical cancer remains debated. Objective This meta-analysis aimed to evaluate the diagnostic accuracy of imaging-based AI for predicting LVSI in cervical cancer. Methods We conducted a comprehensive literature search across multiple databases, including PubMed, Embase, and Web of Science, identifying studies published up to November 9, 2024. Studies were included if they evaluated the diagnostic performance of imaging-based AI models in detecting LVSI in cervical cancer. We used a bivariate random-effects model to calculate pooled sensitivity and specificity with corresponding 95% confidence intervals. Study heterogeneity was assessed using the I2 statistic. Results Of 403 studies identified, 16 studies (2514 patients) were included. For the interval validation set, the pooled sensitivity, specificity, and area under the curve (AUC) for detecting LVSI were 0.84 (95% CI 0.79-0.87), 0.78 (95% CI 0.75-0.81), and 0.87 (95% CI 0.84-0.90). For the external validation set, the pooled sensitivity, specificity, and AUC for detecting LVSI were 0.79 (95% CI 0.70-0.86), 0.76 (95% CI 0.67-0.83), and 0.84 (95% CI 0.81-0.87). Using the likelihood ratio test for subgroup analysis, deep learning demonstrated significantly higher sensitivity compared to machine learning (P=.01). Moreover, AI models based on positron emission tomography/computed tomography exhibited superior sensitivity relative to those based on magnetic resonance imaging (P=.01). Conclusions Imaging-based AI, particularly deep learning algorithms, demonstrates promising diagnostic performance in predicting LVSI in cervical cancer. However, the limited external validation datasets and the retrospective nature of the research may introduce potential biases. These findings underscore AI’s potential as an auxiliary diagnostic tool, necessitating further large-scale prospective validation.

The variations in the natural history of high‐risk human papillomavirus infections in Chinese healthy women aged 27–45 years compared with 18–26 years: A prospective cohort study

AbstractData investigating the natural history of high‐risk human papillomavirus (HR‐HPV) infection in mid‐adult women compared with young adult women from regions exhibiting a bimodal distribution pattern are scarce. From November 2012 to September 2019, 3681 healthy women aged 18–45 years from the control group of a bivalent HPV vaccine Phase 3 trial in China were followed over 5.5 years. At scheduled visits (Day 0, months 7, 12, 18, 24, 30, 42, 54, and 66), cervical samples were collected for ThinPrep Pap tests and HPV DNA testing, women with abnormal cytology were referred for colposcopy. Data was analyzed using Cox regression model and a competing risk model. Sensitivity analyses were performed among participants attending all scheduled visits. The incidences of HR‐HPV persistent infections (over 6 months [6mPIs]) were 35.5 and 29.0 per 1000 person‐years (PYs) (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.00, 1.46), and HR‐HPV associated CIN grade 2 or greater (CIN2+) were 4.3 and 1.9 per 1000 PYs (HR = 2.31, 95% CI: 1.25, 4.26) in women aged 18–26 and 27–45 years. Competing risk models showed that the cumulative incidence of HR‐HPV infections that progressed to CIN2+ was significantly higher in women aged 18–26 than in women aged 27–45 (5.3% vs. 2.9%, Gray's test p = .0291). The cumulative clearance rates of HR‐HPV infections in women aged 18–26 and 27–45 were similar (94.7% vs. 95.8%, Gray's test p = .3309) during the study period. In conclusion, although mid‐adult women exhibit lower incidences of HR‐HPV infection and associated cervical lesions compared to young women, this population continues to face a substantial risk of acquiring causal HPV infections, which may progress to cervical lesion.

Intraoperative use of tranexamic acid to reduce blood loss during cytoreductive surgery for advanced ovarian cancer: A randomized controlled clinical trial

AbstractIntroductionTranexamic acid reduces blood loss and allogeneic transfusion requirements in various surgical procedures. The role of tranexamic acid during cytoreductive procedures in advanced ovarian cancer is not clear.Material and methodsThis was a single center randomized, controlled, three‐armed clinical trial. A total of 150 ovarian cancer patients undergoing cytoreductive surgery were recruited and assigned to three groups (n = 50/group): the control group (normal saline), low‐dose group (10 mg/kg bolus + 1 mg/kg continuous infusion of tranexamic acid), and high‐dose group (20 mg/kg bolus + 5 mg/kg continuous infusion of tranexamic acid). The primary endpoint was intraoperative blood loss volume and total blood loss volume, and secondary endpoints included intraoperative blood transfusion volumes, vasoactive agent consumption, admission into the intensive care unit, and incidence of postoperative complications within postoperative 30 days. The study was registered at ClinicalTrials.gov ID: NCT04360629.ResultsThe patients in the high‐dose group had less intraoperative (median [IQR]: 625.3 mL [343.5–1210.5]) and total blood loss volume (748.9 mL [292.2–1650.2]) than those in the control group (1015.5 mL [679.4–1015.5], p = 0.012; and 1700.7 mL [458.7–2419.8], p = 0.004, respectively). In contrast, the intraoperative (992.5 mL [539.0–1404.0], p = 0.874) and total blood loss volume (1025.0 mL [381.8–1819.9], p = 0.113) was not significantly reduced in the low‐dose group when compared with the control group. Correspondingly, the relative risk of blood transfusion (RR [95% CI], 0.405 [0.180–0.909], p = 0.028) was reduced in the high‐dose group and required less intraoperative noradrenaline (881.0 ± 438.3 mg) to maintain stable hemodynamics than the control group (1548.0 ± 349.8 mg, p = 0.001). Furthermore, compared with the control group, the two tranexamic acid groups had decreased intensive care unit admission rates (p = 0.016) without increasing the incidence of postoperative seizure, acute kidney injury, and thromboembolism.ConclusionsHigh‐dose tranexamic acid is more effective in reducing blood loss and blood transfusion without increasing the risk of postoperative complications. The high‐dose regime tended to have a better risk–benefit profile.

Long noncoding RNA DARS‐AS1 regulates TP53 ubiquitination and affects ovarian cancer progression by modulation miR‐194‐5p/RBX1 axis

AbstractBackgroundOvarian cancer is a malignant tumor with a poor prognosis, its underlying mechanism is still unclear.ObjectiveIn this study, long noncoding RNA DARS‐AS1 was studied to identify its function in the development of ovarian cancer.MethodsPerform functional experiments to detect the effects of DARS‐AS1 on the proliferation, apoptosis, and migration of ovarian cancer cells A2780. The luciferase report, immunoprecipitation (IP) experiment, and ubiquitination level determination verify that RBX1 ubiquitination and mediate the degradation of tumor suppressor gene TP53.ResultsKnockdown of DARS‐AS1 can inhibit cell proliferation, migration, and apoptosis, and the application of miR‐194‐5p inhibitors can prevent this process. Luciferase and IP experiments showed that DARS‐AS1 regulates the expression of RBX1 by binding to miR‐194‐5p, and RBX1 mediates its degradation through ubiquitination of TP53.

Efficacy, Safety, and Immunogenicity of an Escherichia coli-Produced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial

Abstract Background The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. Methods A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18–45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission. Results In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. Conclusions The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18–associated high-grade genital lesions and persistent infection in women.

SMYD2 suppresses p53 activity to promote glucose metabolism in cervical cancer

Reprogrammed energy metabolism, especially the Warburg effect, is emerged as a hallmark of cancer. The protein lysine methyltransferase SMYD2 functions as an oncogene and is implicated in various malignant phenotypes of human cancers. However, the role of SMYD2 in tumor metabolism is still largely unknown. Here, we report that SMYD2 is highly expressed in human cervical cancer and its aberrant expression is linked to a poor prognosis. Bioinformatic analysis revealed a novel link between SMYD2 expression and aerobic glycolysis. Through loss-of-function experiments, we demonstrated that SMYD2 knockdown or inhibition induced a metabolic shift from aerobic glycolysis to oxidative phosphorylation, as evidenced by glucose uptake, lactate production, extracellular acidification, and the oxygen consumption rate. In contrast, SMYD2 overexpression promoted glycolytic metabolism in cervical cancer cells. Moreover, SMYD2 was required for tumor growth in cervical cancer and this oncogenic activity was largely glycolysis-dependent. Mechanistically, SMYD2 altered the methylation status of p53 and inhibited its transcriptional activity. Genetic silencing of p53 largely abrogated the effects of SMYD2 in promoting aerobic glycolysis. Taken together, our findings reveal a novel function of SMYD2 in regulating the Warburg effect in cervical cancer.

FNBP1 Facilitates Cervical Cancer Cell Survival by the Constitutive Activation of FAK/PI3K/AKT/mTOR Signaling

Cervical cancer is the most prevalent gynecological tumor among women worldwide. Although the incidence and mortality of cervical cancer have been declining thanks to the wide-scale implementation of cytological screening, it remains a major challenge in clinical treatment. High viability is one of the leading causes of the chemotherapeutic resistance in cervical cancers. Formin-binding protein 1 (FNBP1) could stimulate F-actin polymerization beneath the curved plasma membrane in the cell migration and endocytosis, which had previously been well defined. Here, FNBP1 was also demonstrated to play a crucial role in cervical cancer cell survival, and the knockdown of which could result in the attenuation of FAK/PI3K/AKT signaling followed by significant apoptotic accumulation and proliferative inhibition. In addition, the epidermal growth factor (hrEGF) abrogated all the biological effects mediated by the silencing of FNBP1 except for the cell adhesion decrease. These findings indicated that FNBP1 plays a key role in maintaining the activity of focal adhesion kinase (FAK) by promoting cell adhesion. The activated FAK positively regulated downstream PI3K/AKT/mTOR signaling, which is responsible for cell survival. Promisingly, FNBP1 might be a potential target against cervical cancer in combination therapy.

Type‐ and age‐specific natural history of high‐risk human papillomavirus infections in healthy women: A prospective cohort study in China

Abstract As cervical cancer screening shifts from cytology to HPV testing, clarifying the type‐ and age‐specific natural history of HR‐HPV is crucial, especially in regions with bimodal prevalence patterns where longitudinal data remain limited. We analyzed baseline HR‐HPV‐positive participants from the control arm of a bivalent HPV‐16/18 vaccine trial in China, with follow‐up over 5.5 years. Cox regression and competing risk models were applied to evaluate the progression, clearance, and persistence of these HR‐HPV infections. Among 534 HR‐HPV‐positive women at baseline, 98 CIN2+ lesions were identified (52 at baseline, 46 during follow‐up). HPV‐16 and HPV‐31 exhibited the highest immediate CIN2+ risk (21.1%), followed by HPV‐33 (17.1%) and HPV‐58 (12.7%). When stratified by baseline cytology, the LSIL+ group showed the highest immediate risk of CIN2+ (29.5% among the HR‐HPV‐positive participants), followed by the ASC‐US (10.5%). In the longitudinal analysis, competing risk models revealed significant type‐specific differences in progression (Gray's test P  = 0.0158) and clearance (Gray's test P  &lt;0.0001). HPV‐16, ‐31, ‐18, and ‐58 showed relatively high progression (27.1%, 19.2%, 16.1%, and 11.2%) and low clearance (72.9%, 69.2%, 83.9%, and 88.8%). CIN2+ risk was strongly genotype‐dependent; beyond HPV‐16/18, types ‐31, ‐33, and ‐58 also warrant particular attention in screening and clinical management. Additionally, although a slightly higher CIN2+ progression risk was observed in younger women compared to older women, the difference was not statistically significant (Gray's test P =  0.4389), indicating the need for confirmation in larger studies. These findings enhance the understanding of the natural history of type‐specific HR‐HPV and age‐specific progression in initially screen‐positive populations.

Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors

Abstract Purpose: Zilovertamab vedotin, an antibody–drug conjugate targeting receptor tyrosine kinase–like orphan receptor 1 (ROR1), had manageable safety and promising antitumor activity in participants with relapsed or refractory non–Hodgkin lymphomas. We evaluated zilovertamab vedotin in participants with previously treated metastatic solid tumors. Patients and Methods: This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor–positive breast cancer, nonsquamous non–small-cell lung cancer, platinum-resistant ovarian cancer, or pancreatic cancer. Participants received zilovertamab vedotin ≤2.5 mg/kg once every 3 weeks (Q1/3W) or &amp;lt;1.75 mg/kg twice every 3 weeks (Q2/3W). The primary endpoint was objective response rate per RECIST version 1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes. Results: A total of 102 participants were enrolled (Q1/3W, n = 70; Q2/3W, n = 32). The objective response rate was 1% [95% confidence interval (CI), 0%–8%] with Q1/3W dosing (one partial response, hormone receptor–positive/HER2-negative breast cancer cohort) and 0% with Q2/3W dosing. The median progression-free survival (95% CI) was 2.3 (2.0–4.1) and 1.9 (1.7–2.1) months, respectively; the median overall survival (95% CI) was 8.3 (5.2–10.3) and 5.5 (4.4–11.0) months, respectively. Across dosing regimens, treatment-related adverse events were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related adverse events led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 IHC was available on 17 participants, with only 3 (all nonresponders) showing ROR1 expression. Conclusions: Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously treated metastatic solid tumors. Significance: Zilovertamab vedotin had minimal antitumor activity and manageable safety in participants with previously treated metastatic solid tumors of various histologic subtypes. The results suggest that further development of zilovertamab vedotin in these solid tumors is not warranted.

Efficacy and Safety of Tranexamic Acid in Cytoreductive Surgery for Ovarian Cancer

Tranexamic acid has been used in surgery for more than 30 years. It's effect on reducing bleeding and blood transfusing has been demonstrated. In our hospital, the amount of cytorsductive surgery for ovarian cancer is big. During the perioperation , bleeding probability is high, and the supply of blood products is limited. In order to reduce bleeding, we're planning to use tranexamic acid in the operations. In this experiment, we will observe the efficacy of tranexamic acid in cytoreductive surgery for ovarian cancer, find the best dosage which can reach the desired effect, and the possible side-effect.