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ABSTRACT Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical–protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.

IntroductionIn early-stage epithelial ovarian cancer (EOC), how to perform lymphadenectomy to avoid stage migration and achieve reliable targeted excision has not been explored in depth. This study comprehensively considered the stage migration and survival to determine appropriate numbers of examined lymph node (ELN) for early-stage EOC and high-grade serous ovarian cancer (HGSOC).MethodsFrom the Surveillance, Epidemiology, and End Results database, we obtained 10372 EOC cases with stage T1M0 and ELN ≥ 2, including 2849 HGSOC cases. Generalized linear models with multivariable adjustment were used to analyze associations between ELN numbers and lymph node stage migration, survival and positive lymph node (PLN). LOESS regression characterized dynamic trends of above associations followed by Chow test to determine structural breakpoints of ELN numbers. Survival curves were plotted using Kaplan-Meier method.ResultsMore ELNs were associated with more node-positive diseases, more PLNs and better prognosis. ELN structural breakpoints were different in subgroups of early-stage EOC, which for node stage migration or PLN were more than those for improving outcomes. The meaning of ELN structural breakpoint varied with its location and the morphology of LOESS curve. To avoid stage migration, the optimal ELN for early-stage EOC was 29 and the minimal ELN for HGSOC was 24. For better survival, appropriate ELN number were 13 and 8 respectively. More ELNs explained better prognosis only at a certain range.DiscussionNeither too many nor too few numbers of ELN were ideal for early-stage EOC and HGSOC. Excision with appropriate numbers of lymph node draining the affected ovary may be more reasonable than traditional sentinel lymph node resection and systematic lymphadenectomy.

Abstract Objectives We aimed to compare the prognosis of modified no‐touch laparoscopic radical hysterectomy (MLRH) and laparoscopic radical hysterectomy (LRH) on survival in patients with early stage cervical cancer. Materials and Methods The clinicopathological data of patients with stage IB1 and IIA1 cervical cancer, who underwent radical surgery between 2014 and 2019, were retrospectively reviewed. The 5‐year disease‐free survival (DFS) and overall survival (OS) were compared between the MLRH and LRH groups using the Kaplan–Meier method. Independent prognostic factors for 5‐year DFS and OS were identified using multivariate, forward, stepwise Cox proportional hazards regression models. Results A total of 223 patients with stage IB1 and IIA1 cervical cancer were included. Kaplan–Meier analysis revealed that the 5‐year DFS and OS rates in the MLRH (n = 81) group were significantly higher than those in the LRH group (n = 142) (DFS, 94.5% vs. 78.8%, p = 0.007; OS, 96.7% vs. 87.6%, p = 0.033). No significant differences were identified between the two groups in terms of operative time, blood loss, transfusion requirement, and intraoperative or postoperative complications. MLRH was an independent prognostic factor associated with increased 5‐year DFS (adjusted hazard ratio [HR], 0.202; 95% confidence interval [CI], 0.069–0.594; p = 0.004) and 5‐year OS (adjusted HR, 0.163; 95% CI, 0.035–0.748; p = 0.020). Conclusion The oncologic outcomes were superior with MLRH than with LRH in patients with stage IB1 and IIA1 cervical cancer. Contact of cervical tumor cells with the pelvic cavity likely explains the worse prognosis associated with LRH.

Abstract Background Mixed cell ovarian adenocarcinoma (MCOA) is a malignant gynecologic tumor consisting of serous, mucous, and papillary tumor cells. However, the clinical features and prognosis of MCOA patients are unclear. Methods In this study, univariate and multivariate Cox proportional risk models were performed to identify independent prognostic factors. The Kaplan–Meier method was used to assess the relationship between clinical characteristics and patient survival. Finally, a nomogram was constructed and validated to predict patient survival time, and the C-index was used to evaluate the efficacy of the nomogram. Results A total of 2,818 patients diagnosed with MCOA were identified, and the 5-year survival rate was 62%. Univariate and multivariate Cox models suggested that age (HR=1.28, 95% CI[1.15,1.44]), grade (HR=1.26, 95% CI[1.12,1.41]), SEER stage (HR=1.63, 95% CI[1.25,2.13]) and AJCC (American Joint Committee on Cancer) stage (HR=1.59, 95% CI[1.36,1.86]) were independent prognostic factors for MCOA patients. After propensity score matching for age, grade, SEER stage, and AJCC stage, the 5-year survival rate was 69.7% for ovarian serous cystadenocarcinoma and 62.9% for ovarian papillary serous cystadenocarcinoma. These results mean that serous adenocarcinoma had the best prognosis of the three pathologic types of ovarian carcinoma (p

Abstract Background Gut microbiota has been reported to be disrupted by cisplatin, as well as to modulate chemotherapy toxicity. However, the precise role of intestinal microbiota in the pathogenesis of cisplatin hepatotoxicity remains unknown. Methods We compared the composition and function of gut microbiota between mice treated with and without cisplatin using 16S rRNA gene sequencing and via metabolomic analysis. For understanding the causative relationship between gut dysbiosis and cisplatin hepatotoxicity, antibiotics were administered to deplete gut microbiota and faecal microbiota transplantation (FMT) was performed before cisplatin treatment. Results 16S rRNA gene sequencing and metabolomic analysis showed that cisplatin administration caused gut microbiota dysbiosis in mice. Gut microbiota ablation by antibiotic exposure protected against the hepatotoxicity induced by cisplatin. Interestingly, mice treated with antibiotics dampened the mitogen-activated protein kinase pathway activation and promoted nuclear factor erythroid 2-related factor 2 nuclear translocation, resulting in decreased levels of both inflammation and oxidative stress in the liver. FMT also confirmed the role of microbiota in individual susceptibility to cisplatin-induced hepatotoxicity. Conclusions This study elucidated the mechanism by which gut microbiota mediates cisplatin hepatotoxicity through enhanced inflammatory response and oxidative stress. This knowledge may help develop novel therapeutic approaches that involve targeting the composition and metabolites of microbiota.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background Ovarian cancer (OV) is one of the most common malignant tumors of gynecology oncology. The lack of effective early diagnosis methods and treatment strategies result in a low five-year survival rate. Also, immunotherapy plays an important auxiliary role in the treatment of advanced OV patient, so it is of great significance to find out effective immune-related tumor markers for the diagnosis and treatment of OV. Methods Based on the consensus clustering analysis of single-sample gene set enrichment analysis (ssGSEA) score transformed via The Cancer Genome Atlas (TCGA) mRNA profile, we obtained two groups with high and low levels of immune infiltration. Multiple machine learning methods were conducted to explore prognostic genes associated with immune infiltration. Simultaneously, the correlation between the expression of mark genes and immune cells components was explored. Results A prognostic classifier including 5 genes (CXCL11, S1PR4, TNFRSF17, FPR1 and DHRS95) was established and its robust efficacy for predicting overall survival was validated via 1129 OV samples. Some significant variations of copy number on gene loci were found between two risk groups and it showed that patients with fine chemosensitivity has lower risk score than patient with poor chemosensitivity (P = 0.013). The high and low-risk groups showed significantly different distribution (P

Ovarian cancer (OC) is the most lethal gynecologic cancer, and the incidence of OC has risen steadily worldwide. Numerous microRNAs (miRNAs) have been found to be involved in the progression of OC. miR-204-5p is down-regulated and functions as a tumor suppressor in various types of human malignant tumors. However, the biological roles and molecular mechanisms of miR-204-5p in OC still remain unclear. In this study, the aberrant down-regulation of miR-204-5p was detected in OC tissues. We also observed that miR-204-5p overexpression represses OC cell proliferation. Ubiquitin-specific peptidase 47 (USP47) is verified as the functional target of miR-204-5p, through which it plays an important biological role in OC. Our results uncover new functions and mechanisms for miR-204-5p in the progression of OC, and provide a potential therapeutic target for the treatment of OC.

[Objective] The development of resource-based cities is trapped in a dilemma due to a singular industrial structure and a closed development model. Exploring the mechanism of impact of network externalities on the economic performance of these cities is of great significance for promoting their economic growth and sustainable development. [Methods] This study first elaborated on the mechanism of impact of urban network externalities on the economic performance of resource-based cities, then analyzed the characteristics of change of the Chinese urban network from 2001 to 2019, and finally established an econometric model to test the impact of agglomeration economic externalities and urban network externalities on the economic performance of both resource-based and non-resource-based cities. [Results] The findings are as follows: (1) The network embeddedness of resource-based cities in the national organizational network had increased significantly, but there was still a considerable gap compared to non-resource-based cities. Resource-based cities had relatively fewer connections with core cities in the network and were generally located on the periphery of the urban network. (2) Investment, innovation, and urban network externalities significantly promoted economic growth. Particularly in the early stages of network embeddedness, resource-based cities showed greater heterogeneity and benefit potential in leveraging urban network externalities compared to non-resource-based cities. However, agglomeration economic externalities did not have a significant impact on the economic growth of resource-based cities. (3) Innovation and investment had a significant positive moderating effect on the relationship between urban network externalities and economic growth, and urban network externalities also significantly enhanced the positive impact of innovation and investment on economic growth, aligning with the principle of interaction symmetry. [Conclusion] Actively integrating into broader regional urban networks and enhancing the investment attractiveness and innovation capacity of resource-based cities are key strategies for promoting the transformation and economic growth of these cities.