Platinum resistance remains a major obstacle to effective treatment and improved prognosis in ovarian cancer. Although 5-methylcytosine (m5C) RNA modification has been implicated in chemoresistance, its precise functional role in ovarian cancer remains unclear. In this study, we integrated RNA-Seq and single-cell transcriptomic data from cisplatin-resistant ovarian cancer cell lines and patient samples, identifying the m5C reader protein ALYREF as a key regulator of platinum resistance. Functional studies using ALYREF and NSUN2 knockdown, overexpression, and mutant constructs—combined with multi-omics analyses (RNA-Seq, m5C-BIS-Seq, and RIP-Seq)—revealed that ALYREF binds to m5C-modified LGR4 mRNA, enhancing its stability and promoting activation of the Wnt/β-catenin signaling pathway. Critically, this regulatory mechanism is dependent on NSUN2-mediated m5C modification of LGR4 mRNA. Together, our findings demonstrate that the NSUN2/ALYREF/LGR4 axis mediates platinum resistance through m5C-dependent stabilization of LGR4 and downstream Wnt signaling activation. Thus, targeting ALYREF may represent a promising strategy to overcome platinum resistance in ovarian cancer.

AIMS:The challenges in identifying functional variants from genome-wide association studies (GWAS) and unraveling regulatory mechanisms in schizophrenia research persist, particularly in intronic regions. A non-coding regulatory variant, rs1399178, associated with schizophrenia risk, is identified and its impact on NRF1 binding is investigated. METHODS:This study focuses on schizophrenia GWAS risk loci, using functional genomics, expression analyses and structural analysis to identify 736 schizophrenia risk single-nucleotide polymorphisms (SNPs) that disrupt transcription factor (TF) binding. RESULTS:Among these SNPs, rs1399178 stands out as a bifunctional intergenic SNP that can switch between acting as a promoter and an enhancer, potentially influencing MLH1 and LRRFIP2 expression via expression quantitative trait loci analysis. Importantly, mutation of the G allele of rs1399178 to A significantly diminishes its binding affinity to nuclear respiratory factor 1 (NRF1). Structural analysis provides further insight into this alteration in the protein-nucleic acid complex formation. CONCLUSION:Based on our data, a model is proposed in which rs1399178 confers schizophrenia risk by modifying NRF1 binding profiles, thereby regulating the abundance of target genes through promoter-enhancer switching. This study provides novel insights into the regulatory mechanisms of schizophrenia risk variants, highlighting the intricate nature of genetic interactions and potential therapeutic targets.

Tumor-infiltrating lymphocyte (TIL) therapy was recently approved for melanoma patients; however, the dynamic changes in T cell subpopulations during TIL production remain poorly understood. Here, we analyzed epithelial ovarian cancer samples at various stages of ex vivo TIL culture using paired single-cell RNA and TCR sequencing. We also assessed the expansion potential and tumor reactivity of the identified TIL subpopulations. Single-cell transcriptomic analysis revealed that CD8+ TILs exhibited reduced cellular diversity following ex vivo expansion, selectively expanding stem-like TCF7+ precursors of exhausted T cells (Tpex) and effector-like tissue-resident memory (Trm) cells. TCR clonotype analysis showed that Tpex cells accumulated through self-renewal, while Trm cells primarily originated from TCF7+GZMK+ early effector memory cells in tumors. Additionally, TCR tracing identified preferential activation and reprogramming of CD4+ T follicular helper (Tfh)-like cells, especially TCF7+ ones. All three TCF7+ subpopulations showed robust expansion potential and tumor reactivity in vitro. Notably, CCR7+CD200+ T cells, enriched for TCF-1+CD8+ Tpex and CD4+ Tfh-like cells in the tumor microenvironment, exhibited self-renewal during in vitro expansion and demonstrated tumor reactivity both in vivo and in vitro. These findings highlight the selective expansion of tumor-reactive TCF7+ T cells during TIL culture and suggest that CCR7 and CD200 serve as important surface markers for generating stem-like, tumor-reactive cells, potentially improving TIL therapy in cancers.

Background Recent studies have demonstrated that APOC1 is associated with cancer progression, exerting cancer-promoting and immune infiltration-promoting effects. Nevertheless, there is currently no report on the presence of APOC1 in ovarian cancer (OV). Method In this study, we conducted data analysis using the GEO and TCGA databases. We conducted a thorough bioinformatics analysis to investigate the function of APOC1 in OV, utilizing various platforms including cBioPortal, STRING, GeneMANIA, LinkedOmics, GSCALite, TIMER, and CellMarker. Additionally, we performed immunohistochemical staining on tissue microarrays and conducted in vitro cellular assays to validate our findings. Result Our findings reveal that APOC1 expression is significantly upregulated in OV compared to normal tissues. Importantly, patients with high APOC1 levels show a significantly poorer prognosis. Furthermore, our study demonstrated that APOC1 exerted a crucial function in promoting the capacity of ovarian cancer cells to proliferate, migrate, and invade. Additionally, we have identified that genes co-expressed with APOC1 are primarily associated with adaptive immune responses. Notably, the levels of APOC1 in OV exhibit a correlation with the presence of M2 Tumor-associated Macrophages (TAMs). Conclusion APOC1 emerges as a promising prognostic biomarker for OV and exhibits a significant association with M2 TAMs in OV.

Figur 1. xlsx, Results of ANOVA as presented in Figure 1. Figur 2. xlsx, Results of ANOVA as presented in Figure 2. Figur 3. xlsx, Results of ANOVA as presented in Figure 3. Figur 4. xlsx, Results of ANOVA as presented in Figure 4. Figur 5. xlsx, Results of ANOVA as presented in Figure 5. Figur 6. xlsx, Results of ANOVA as presented in Figure 6. Figur s1. xlsx, Results of ANOVA as presented in Figure s1. supplementary figure. docx, Figure S1 Cube maps for the levels of expression for DC markers after sLA exposure and LPS challenge. DCs were first infected with Ad-shCtrl and Ad-shMCT1 adenoviruses for 24 h, then co-cultured with 50 mM sLA or PBS for 48 h, and finally stimulated with 1 ug/mL LPS for 24 h. Flow cytometry was used to detect the expression of CD1a (A), CD80 (B), CD83 (C), CD86 (D) and MHCII (E) in DCs. Table S1. docx, Statistics for Figure S1.

Ovarian cancer (OC) is one of the most common malignancies and a leading cause of death among women worldwide. The ubiquitin pathway plays an important role in OC development. Using the single nucleotide polymorphism data obtained using the prevalence and dominance strategies, four ubiquitin marker genes were identified according to their expression levels: BARD1, BRCA2, FANCA, and BRCA1. Based on these four genes, a consensus clustering of OC expression data was performed. The significant differences in the survival analysis, ESTIMATE, and CIBERSORT results among the clusters indicated the pivotal role of these four genes in OC development. Of the ubiquitin-representative genes in each cluster, two ubiquitin genes, TOP2A and MYLIP, were identified in the survival risk model after univariate survival, Least Absolute Shrinkage and Selection Operator regression, and multivariate survival analyses. The reliability and robustness of both the training and validation data were confirmed by comparing the significant survival difference between high- and low-risk patients. We further explored the association between our risk model and clinical outcomes as well as predicted potentially interacting drugs. The co-expression network showed clear interactions among the four marker genes and two model genes and between high- and low-risk differentially expressed genes. Significantly enriched genes were found in pathways associated with ion channels, channel activity, and neuroactive ligand-receptor interactions. Therefore, suggesting the involvement of ubiquitin genes in the survival and development of OC through neurohumoral regulation. Our results will provide valuable reference or supplementary information for studies investigating OC diagnosis and therapies.

BackgroundWe have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels. MethodsWe conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts. ResultsThere were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information. ConclusionsThis guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off.

Background: RNA methylation is a significant form of post-transcriptional modification that has been implicated in various diseases, including cancers. One prominent type of RNA methylation is 5-Methylcytosine (m(5)C), which primarily regulates RNA stability, transcription, and translation. However, the role of m(5)C-related gene regulation in cell adhesion within uterine corpus endometrial carcinoma (UCEC) remains unexplored. Therefore, the objective of this study was to investigate the association between RNA m(5)C methylation and UCEC and develop a prognostic predictive model to forecast survival outcomes in UCEC patients. Methods: The RNA datasets were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The dataset was used to explore the interaction relationships of m(5)C regulators in UCEC. Unsupervised clustering analysis identified clusters with distinct m(5)C modification patterns. Different clusters underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment level analysis to investigate the effects of pathways related to m(5)C methylation, which were further validated through in vitro cellular experiments. A prognostic predictive model was developed using the least absolute shrinkage and selection operator (LASSO) and multivariate regression analysis. Results: Two clusters with distinct m(5)C modification patterns were identified using unsupervised cluster analysis. Furthermore, the prognosis of cluster 2 was found to be worse. Enrichment analysis showed alterations in cell adhesion-related pathways in both clusters, as well as differences between the clusters. Through this analysis, we identified 25 genes with significant prognostic value. Finally, a prognostic predictive model comprising NSUN2 and YBX1 was constructed. Conclusions: In conclusion, diverse m(5)C modification patterns display distinct cell adhesion properties in UCEC, which are correlated with prognosis and offer significant potential as prognostic markers for UCEC assessment. We developed a prognostic predictive model to accurately predict the prognosis of UCEC.

Ovarian cancer (OC) is one of the common malignant tumors that seriously threaten women's health, and there is a lack of clinical prognostic predictors, while m5c and lncRNA have been shown to be predictive of multiple cancers, including OC. Therefore, our goal was to construct a risk model for OC based on m5c-related lncRNA.340 m5c-related lncRNA were identified and a novel risk model of OC ground on nine m5C-related lncRNA was constructed using LASSO-COX regression analysis. Kaplan-Meier analysis showed there was a significant difference in prognosis between risk groups. We established a nomogram which was a good predictor of overall survival. In addition, GSEA was enriched in multiple pathways and immune function analysis suggested that immune infiltration varies depending on the risk group. In vitro experiments show that AC005562.1, a key lncRNA of the risk model, is highly expressed in OC cells and promotes OC cell proliferation. Finally, we further explored the potential biological markers of m5c-related lncRNA in OC with WGCNA analysis and established a ceRNA network. In conclusion,we have developed a reliable m5c-related prediction model and performed systematic validation and exploration of various aspects. These results can be used for the assessment of OC prognosis and the discovery of novel biomarkers.

Introduction: Owing to their low incidence, no reliable statistics about prognostication derived from large sample sizes have been reported of malignant ovarian germ cell tumors (MOGCTs) and sex cord-stromal tumors (SCSTs). The present study aimed to investigate the clinicopathological prognostic factors and the survival trends of MOGCTs and SCSTs. Materials and Methods: Patients with MOGCTs and SCSTs were recorded in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed between 2000 and 2019. Clinical, demographic, and treatment characteristics were compared between groups of MOGCTs and SCSTs. Cox risk regression analysis and Kaplan-Meier survival curves were used to compare overall survival (OS) and cancer-specific survival (CSS) and to assess the prognostic factors. Results: Information about 2,506 patients with MOGCTs and 1,556 patients with SCSTs was extracted from the SEER database, respectively. Aged <40 years and single were more common in patients with MOGCTs than in those with SCSTs. The vast majority of patients with MOGCTs and SCSTs underwent surgery (98.1% vs. 94.5%; p < 0.001), and women with MOGCTs were more likely to receive chemotherapy than women with SCSTs (56.1% vs. 32.2%; p < 0.001). For both patients before and after propensity-score matching, the 5-year OS rates of patients with SCSTs were lower than those of patients with MOGCTs (p < 0.05). In multivariate Cox regression analysis, both age and surgery were independent predictors of OS in patients with MOGCTs and SCSTs. FIGO staging was an independent predictor of CSS in MOGCT patients. Tumor size and chemotherapy were also independent predictors of CSS in patients with SCSTs. Conclusion: Compared to patients with SCSTs, those with MOGCTs tended to be younger and had a higher OS and CSS. Adjuvant chemotherapy after surgery did not prolong OS and CSS in patients with SCSTs.

RNA methyltransferase nucleolar protein p120 (NOP2), commonly referred to as NOP2/Sun RNA methyltransferase family member 1 (NSUN1), is involved in cell proliferation and is highly expressed in various cancers. However, its role in high-grade serous ovarian cancer (HGSOC) remains unclear. Our study investigated the expression of NOP2 in HGSOC tissues and normal fimbria tissues, and found that NOP2 was significantly upregulated in HGSOC tissues. Our experiments showed that NOP2 overexpression promoted cell proliferation in vivo and in vitro and increased the migration and invasion ability of HGSOC cells in vitro. Furthermore, we identified Rap guanine nucleotide exchange factor 4 (RAPGEF4) as a potential downstream target of NOP2 in HGSOC. Finally, our findings suggest that the regulation of NOP2 and RAPGEF4 may depend on m5C methylation levels.

甲基化是一种RNA转录后修饰的主要方式,目前对于RNA甲基化的研究在编码和非编码RNA中都有着突破性的进展,发现其跟包括癌症在内的多种疾病中都有着独特的作用,并且无论是正常的生理过程还是疾病的发生发展,RNA甲基化修饰都是不可或缺的存在.RNA甲基化可以分成许多不同的类型,而本综述主要介绍5-甲基胞嘧啶(5-methylcytosine,m5C),它是RNA甲基化中最主要的方式之一,其作用机制的研究主要集中在参与调节RNA的稳定性、核输出、转录和翻译方面.尤其本研究集中在肿瘤的发生发展中,m5 C甲基化修饰能起到促进转移、侵袭和耐药性等方面的作用.我们将介绍甲基化,包括与其相关的甲基转移酶、去甲基化酶、相关结合蛋白及与RNA的作用方式,重点在介绍其与肿瘤的关系,包括调控机制和功能等,为肿瘤的治疗提供新的思路.

目的:ALKBH5最近被证明是与各种癌症相关的RNAN6-甲基腺苷(m6A)去甲基转移酶之一,但其在上皮性卵巢癌中的作用缺乏研究.本研究旨在探讨ALKBH5在上皮性卵巢癌中的机制.方法:利用蛋白免疫印迹、免疫组化检测ALKBH5在卵巢癌细胞和组织中的表达情况,并分析其与临床病理特征和预后关系;通过慢病毒感染构建ALKBH5稳定过表达或敲减卵巢癌细胞系,采用CCK-8、平板克隆、划痕、Transwell迁移和侵袭等实验研究ALKBH5对细胞增殖、迁移及侵袭能力的影响;通过蛋白免疫印迹和斑点印迹实验,探究ALKBH5-HIF-1α环的相互作用情况.结果:ALKBH5在卵巢癌细胞系和卵巢癌组织中高表达,ALKBH5蛋白在卵巢癌组织中的表达与CA125水平、FIGO分期和组织学类型相关,且高表达的ALKBH5水平与较差的预后相关.通过慢病毒感染构建出可靠的ALKBH5敲减/过表达稳转细胞系,CCK-8、平板克隆实验表明敲减ALKBH5降低卵巢癌细胞体外增殖速率和集落形成,划痕、Transwell迁移和侵袭实验表明敲减ALKBH5可抑制卵巢癌细胞体外迁移和侵袭能力.与对照组相比,过表达ALKBH5增强卵巢癌细胞体外增殖速率、集落形成、迁移和侵袭能力.进一步的实验发现ALKBH5和HIF-1α互相促进表达.结论:m6A去甲基化酶ALKBH5在上皮性卵巢癌中高表达且与预后相关,通过促进卵巢癌细胞增殖、迁移及侵袭发挥致癌基因的作用.因此,抑制ALKBH5的表达可能是靶向治疗上皮性卵巢癌的潜在策略.

Intravenous-cardiac leiomyomatosis is an uncommon tumor arising from invasive uterine leiomyomata, with nodular masses extending into the inferior vena cava, right heart chamber, and even pulmonary arteries or lung. This report describes two cases of intravenous leiomyomatosis invading the right heart. A total hysterectomy with bilateral salpingo-oophorectomy and intravenous leiomyomata was performed. However, the intracardiac tumor was pulled apart, and the residual tumor remained unchanged at the 4-year follow-up in one patient. Its early diagnosis might be difficult because cardiac symptoms only develop once the tumor extends into the right heart or pulmonary arteries, resulting in cardiac insufficiency. The treatment depends on radical resection of pelvic and intravenous leiomyomatosis and bilateral salpingo-oophorectomy.

"CGE22-101: Dynamically Accumulating Homologous Recombination Deficiency (HRD) Status Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer" published on 31 Mar 2022 by National Comprehensive Cancer Network.

Aim The aim of the present study was to summarize the clinical characteristics and analyze the independent prognostic factors in patients with high-grade endometrial neuroendocrine carcinoma (ENC). Methods Patients diagnosed with ENC, endometrioid adenocarcinoma (EAC), endometrial clear-cell carcinoma (ECC), endometrial serous carcinoma (ESC), endometrioid carcinoma with mucinous features (EMC) from 1987 to 2016 were screened from the National Cancer Institute database (surveillance, epidemiology, and end results [SEER]). Kaplan-Meier were used to assess survival. Univariate and multivariate Cox proportional hazards analysis were done to examine factors affecting survival. Results The median survival times of ENC were 11 months, shorter than that of EAC, ECC, ESC, and EMC (p < 0.01). There was no significant difference in ages, survival rate, and median survival time between large-cell ENC (LCENC) and small-cell ENC (SCENC), which were all belong to ENC. In a multivariable model, the hazard ratio (HR) of death for women with Federation International of Gynecology and Obstetrics (FIGO) stage I-II of ENC was 0.37 compared to FIGO stage III-IV (p < 0.01). The HR of patients who under the surgery was 0.39 compared to the patients who without surgery (p < 0.01), and the HR of patients who received chemotherapy was 0.51 compared to the patients who did not received chemotherapy (p < 0.01). Radiotherapy did not significantly reduce the mortality risk of patients. Conclusion ENC was a kind of devastating endometrial cancers with the poorest prognosis. Surgical treatment and chemotherapy were necessary for improving prognosis of ENC. Early diagnosis favored better prognosis. There was no prognostic difference between with and without radiotherapy.

目的:探讨卵巢癌细胞UWB1.289中miR-155-5p对PARP抑制剂敏感性的影响及可能涉及的分子机制研究.方法:采用qRT-PCR技术检测miR-155-5p在有BRCA1/2突变和无BRCA1/2突变的卵巢癌组织及卵巢癌细胞中的表达情况.利用细胞转染、qRT-PCR以及Western Blot技术检测转染miR-155-5p模拟物和抑制剂的卵巢癌细胞UWB1.289中miR-155-5p的表达以及同源重组修复相关基因SIRT1、BRG1的表达.通过双荧光素酶报告基因实验验证miR-155-5p与SIRT1、BRG1之间的靶向性.运用CCK-8检测卵巢癌细胞UWB1.289中miR-155-5p对PARP抑制剂敏感性的影响.结果:与无BRCA1/2突变的卵巢癌组织及卵巢癌细胞相比,miR-155-5p在有BRCA1/2突变的卵巢癌组织及卵巢癌细胞中低表达.转染miR-155-5p模拟物可增加卵巢癌细胞UWB1.289中miR-155-5p的表达,同时降低同源重组修复相关基因SIRT1、BRG1的表达;转染miR-155-5p抑制剂可下调卵巢癌细胞UWB1.289中miR-155-5p的表达,同时增加SIRT1、BRG1的表达,进一步通过双荧光素酶报告基因实验证实miR-155-5p与SIRT1、BRG1存在特异性靶向结合序列.与对照组相比,干扰同源重组修复相关基因以及miR-155-5p过表达均可增强卵巢癌细胞UWB1.289对PARP抑制剂的敏感性.结论:miR-155-5p可能通过影响同源重组修复基因增强卵巢癌细胞UWB1.289对PARP抑制剂的敏感性.

Tissue-resident memory T (Trm) cells can trigger a secondary immune response when they encounter the same antigen, playing an important role in antitumor immunity. However, whether Trm cells are protective against female genital tract tumors remainunknown. Here, we show that cervicovaginal vaccination with HPV16 E7aa43-62peptide/CPG-1826 can generate CD103+CD8+Trm cells in the genital tract. These Trm cells can result in subsequent CD8+ T cell expansion and cytokine production when they encounter the same antigen. Importantly, this secondary response can control rechallenge with tumor cells. In vitro,BMDCs can promote the production of TGF-β, which induces CD103 expression in CD8+ T cells. In human cervical cancer samples, DCs were correlated with the Trm gene signature, which was positively associated with overall survival. Our results indicate that cervicovaginal Trm cells have the capacity tocontrol tumor growth and that BMDCs may induce Trm cell generation via the TGF-β signaling pathway.

Background Protein-L-isoaspartate O-methyltransferase-1 (PCMT1) is a protein carboxyl methyltransferase enzyme, which has been found to play roles in cancers. However, no clinical information about the correlation between cervical cancer and PCMT1 expression has been reported. Methods We used immunohistochemistry (IHC) to characterize the protein level of PCMT1 in human cervical intraepithelial neoplasia and cervical cancer specimens. The mRNA expression profile of PCMT1 in cervical cancer was also analyzed by using Gene Expression Omnibus (GEO) databases. The prognostic value of PCMT1 in patients with cervical cancer was evaluated by using the Kaplan-Meier plotter. Gene set enrichment analysis (GSEA) was conducted by using The Cancer Genome Atlas (TCGA) cervical cancer dataset. Results The protein level of PCMT1 was increased in cervical high-grade squamous intraepithelial lesion (HSIL) (7.40±0.42) and cervical cancer tissues (10.70±0.54), compared to normal cervix (5.00±0.86) and low-grade squamous intraepithelial lesion (LSIL) (6.22±0.57) (P<0.05). the immunoreactivity score (IRS) of PCMT1 was also higher in cervical cancer tissues than in paired adjacent non-cancerous cervical tissues (9.03±0.52 vs. 6.32±0.46) (P<0.05). High expression of PCMT1 was associated with decreased overall survival (OS) of patients with cervical cancer (P=0.0022). GSEA demonstrated that cervical cancer patients with high expression of PCMT1 were enriched in the various cancer-related signaling pathways. Conclusions These results suggest that PCMT1 might be a diagnostic and prognostic biomarker for cervical cancer, and further validation studies should be performed.