Epithelial ovarian cancer (EOC) represents the most lethal gynaecological malignancy, yet understanding the connections between its molecular subtypes and their therapeutic implications remains incomplete. We conducted mass spectrometry-based proteomics analyses of 154 EOC tumour samples and 29 normal fallopian tubes, and single-cell RNA sequencing (scRNA-seq) analyses of an additional eight EOC tumours to classify proteomic subtypes and assess their cellular ecosystems and clinical significance. The efficacy of identified therapeutic targets was evaluated in patient-derived xenograft (PDX) and orthotopic mouse models. We identified four proteomic subtypes with distinct clinical relevance: malignant proliferative (C1), immune infiltrating (C2), Fallopian-like (C3) and differentiated (C4) subtypes. C2 subtype was characterized by lymphocyte infiltration, notably an increased presence of GZMK CD8+ T cells and phagocytosis-like MRC+ macrophages. Additionally, we identified CD40 as a specific prognostic factor for C2 subtype. The interaction between CD40+ phagocytosis-like macrophages and CD40RL+ IL17R CD4+ T cells was correlated with a favourable prognosis. Finally, we established a druggable landscape for non-immune EOC patients and verified a TYMP inhibitor as a promising therapeutic strategy. Our study refines the current immune subtype for EOC, highlighting CD40 agonists as promising therapies for C2 subtype patients and targeting TYMP for non-immune patients.

Polyadenylate-binding protein-interacting protein 1 (PAIP1) is a protein that modulates translation initiation in eukaryotic cells. Studies have shown that PAIP1 was overexpressed in various type of cancers, and drives cancer progression by promoting cancer cell proliferation, invasion, and migration. In our previous study, we identified that PAIP1 was overexpressed in breast cancer, and the expression was correlated with poor prognosis. However, the biological function of PAIP1 in breast cancer has not been clearly understood. In this study, we constructed PAIP1 specifically silenced breast cancer cells. Then, cell proliferation, cell cycle distribution, and apoptosis were detected in PAIP1 knockdown cells. RNA-seq analysis was performed to predict the downstream target of PAIP1, and the molecular mechanism was explored. As a results, we found that knockdown of PAIP1 repressed cell proliferation, induced cell cycle arrest, and triggers apoptosis. Xenograft mouse model showed that knockdown of PAIP1 inhibits cell growth in vivo. RNA-seq predicted that CCNE2 mRNA was one of the downstream targets of PAIP1. In addition, we identified that knockdown of PAIP1-inhibited cell proliferation through modulating cyclin E2 expression. Mechanically, knockdown of PAIP1 reduces the expression of cyclin E2 by regulating the mRNA stability of cyclin E2. Moreover, in breast cancer tissues, we found that the expression of PAIP1 was positively correlated with cyclin E2. Taken together, our findings establish the role and mechanism of PAIP1 in breast cancer progression, indicating that PAIP1 would be a new therapeutic target for breast cancer treatment.

Background:To explore the role of vaginal microbiota and metabolomics in the progression of cervical dysplasia. Methods:The patient group consists of female patients with low-grade, high-grade cervical dysplasia, and cervical cancer. Normal cervix samples from health volunteers were used as controls. The metabolic fingerprints of cervicovaginal lavage were analyzed using liquid chromatography-mass spectrometry, while the vaginal microbiota was examined through 16S rRNA sequencing. Bioinformatic analysis was adopted to investigate the interplay between hosts and microbes. The vaginal metabolic and microbiota profiles of 90 female patients with cervical dysplasia and 10 controls were analyzed to discover the biological characteristics underlying the progression of cervical cancer. Results:We found that Valyl-Glutamate, N, N'-Diacetylbenzidine, and Oxidized glutathione, which were involved in oxidative stress response, were discriminators to distinguish the normal cervix, invasive cervical carcinomas, and CIN3 from others. Cervical carcinoma was characterized by a large variety of vaginal microbes (dominated by non-Lactobacillus communities) compared to the control. These microbes affected amino acid and nucleotide metabolism, producing metabolites with cervical carcinoma and genital inflammation compared to the control group. Conclusions:This study revealed that cervicovaginal metabolic profiles were determined by cervical cancer, vaginal microbiota, and their interplays. ROS metabolism can be used to discriminate normal cervix, CIN3, and invasive cervical carcinoma.

BackgroundPaclitaxel hypersensitivity reactions (HSRs) are prevalent, especially in females. The common paclitaxel pretreatment, dexamethasone, may inhibit chemotherapy efficacy and accelerate tumor progression. We aimed to balance paclitaxel HSRs and the lowest dexamethasone dose for gynecologic malignancies. MethodsWe retrospectively examined 1,074 cycles of 3-weekly paclitaxel-containing treatment for 231 gynecologic malignancies at Xiangya Hospital. HSR incidence with different dexamethasone regimens was the primary outcome. Risk factors were examined in all cycles using univariate and multivariate models with generalized estimating equations. A subgroup analysis of initial exposure to paclitaxel was also conducted. ResultsHSR occurred in 33 patients (14.29%) and 49 cycles (4.56%), including 69.39% in cycles 1-2. There were no severe HSRs (grade >= 3). Different premedication regimens, including dexamethasone dosage and route, ranitidine presence or absence, didn't affect HSR incidence in univariate and multivariate analyzes (p > 0.05). Premenopausal women exerted fewer HSRs (ORadj 0.22, 95%CI 0.08-0.58; p = 0.002). At the first exposure to paclitaxel, more than 10 mg of dexamethasone didn't diminish HSRs (OR 0.83, 95%CI 0.27-2.59; p = 0.753). ConclusionsIn gynecologic malignancies, 10 mg dexamethasone along with 20 mg diphenhydramine may be adequate to prevent paclitaxel HSRs without ranitidine. It is necessary to reevaluate paclitaxel premedication regimens.

The study utilized 5-ALA-PDT to treat patients with CIN or VaIN and assessed their clinical response, HPV clearance, and influencing factors after photodynamic therapy (PDT). This study involved 56 patients who received 5-ALA-PDT in a single center from May 2020 to March 2022, including 12 patients with CIN, 30 patients with VaIN, and 14 patients with both CIN and VaIN. Follow-up were conducted within 6 and 12 months after treatment to evaluate the clinical effectiveness of PDT. The assessment criteria included histological response (ER, elimination rate, RR, regression rate) and HPV clearance. Additionally, factors that could potentially influence the outcomes were analyzed. After PDT, the histological response showed an ER of 48.2

Ferroptosis is a new programmed cell death characterized by iron-dependent lipid peroxidation. Targeting ferroptosis is considered a promising strategy for anti-cancer therapy. Recently, natural compound has gained increased attention for their advantage in cancer treatment, and the exploration of natural compounds as ferroptosis inducers offers a hopeful avenue for advancing cancer treatment modalities. Emodin is a natural anthraquinone derivative in many widely used Chinese medicinal herbs. In our previous study, we predicted that the anti-cancer effect of Emodin might related to ferroptosis by using RNA-seq in colorectal cancer (CRC). Thus, in this study, we aim to investigate the molecular mechanism underlying Emodin-mediated ferroptosis in CRC. Cell-based assays including CCK-8, colony formation, EdU, and Annexin V/PI staining were employed to assess Emodin’s impact on cell proliferation and apoptosis. Furthermore, various techniques such as FerroOrange staining, C11-BODIPY 581/591 staining, iron, MDA, GSH detection assay and transmission electron microscopy were performed to examine the role of Emodin in ferroptosis. Additionally, specific NCOA4 knockdown cell lines were generated to elucidate the involvement of NCOA4 in Emodin-induced ferroptosis. Moreover, the effects of Emodin on ferroptosis were further confirmed through the application of inhibitors, including Ferrostatin-1, 3-MA, DFO, and PMA. As a results, Emodin inhibited proliferation and induced apoptosis in CRC cells. Emodin could decrease GSH content, xCT and GPX4 expression, meanwhile increasing ROS generation, MDA, and lipid peroxidation, and these effects could reverse by ferroptosis inhibitor, Ferostatin-1, iron chelator DFO, autophagy inhibitor 3-MA and NCOA4 silencing. Moreover, Emodin could inactivate NF-κb pathway, and PMA, an activator of NF-κb pathway could alleviate Emodin-induced ferroptosis in CRC cells. Xenograft mouse model also showed that Emodin suppressed tumor growth and induced ferroptosis in vivo. In conclusion, these results suggested that Emodin induced ferroptosis through NCOA4-mediated ferritinophagy by inactivating NF-κb pathway in CRC cells. These findings not only identified a novel role for Emodin in ferroptosis but also indicated that Emodin may be a valuable candidate for the development of an anti-cancer agent.

Endometrial cancer (EC) is one of the most common gynecologic cancers and its incidence is rising globally. Although advanced EC has a poor prognosis; diagnosing EC at an earlier stage could improve long-term patient outcomes. However, there is no consensus on the early detection strategies for EC and the current diagnostic practices such as transvaginal ultrasound, hysteroscopy and endometrial biopsy are invasive, costly and low in specificity. Thus, accurate and less invasive screening tests that detect EC in women with early stages of the disease are needed. Current research has revolutionized novel EC early detection methodologies in many aspects. This review aims to comprehensively characterizes minimally invasive screening techniques that can be applied to EC in the future, and fully demonstrate their potential in the early detection of EC.

OBJECTIVE:To identify the optimal triage procedure for endometrial biopsies in postmenopausal women. METHODS:The clinical information of 470 postmenopausal women with endometrial biopsy results and postmenopausal bleeding (PMB) and/or transvaginal ultrasonography (TVU) abnormalities were collected at the gynecology departments of four general hospitals from March 2021 to March 2022. In the validation cohort, 112 women with TVU abnormalities who underwent endometrial biopsy at Xiangya hospital between May 2022 and May 2023 were enrolled. The endpoint was the final diagnosis based on hysteroscopy reports and biopsy pathology results. The sensitivity, specificity, positive predictive value, and negative predictive value were compared among the three triage methods. A nomogram prediction model was developed and validated. RESULTS:Referring women with TVU abnormalities for endometrial biopsy identified 100% malignant/premalignant lesions despite low specificity (19.7%). Among women with measurable endometrial thickness (ET), we suggest that the ET cutoff value for biopsy referral should be ≥4 mm. The PMB (odds ratio [OR], 3.241; 95% confidence interval [CI], 1.073-9.789), diabetes (OR, 10.915; 95% CI, 3.389-35.156), and endometrial thickness (OR, 1.277; 95% CI, 1.156-1.409) were independent predictive factors for endometrial (pre)malignancy. A nomogram prediction model was constructed (area under curve [AUC] = 0.802, 95% CI: 0.715 to 0.889). The ideal cutoff point was 22.5, with a sensitivity of 100.0% and a specificity of 15.7%. The external validation achieved an AUC of 0.798 (95% CI, 0.685-0.911). CONCLUSIONS:It was possible to refer all postmenopausal women with TVU abnormity (ET ≥ 4 mm or other abnormal findings) for endometrial biopsy. Among women with TVU abnormalities, a nomogram was constructed, and a score greater than 22.5 suggested the need for referral for endometrial biopsy, while a score less than 22.5 suggested that regular follow-up was required, further improving the triage procedure.

Dear Editor, Ovarian cancer is the most lethal gynecologic malignancy, primarily characterized by frequent mutations in the TP53 gene. While platinum-based chemotherapy has been widely utilized in the treatment of ovarian cancer, patients often experience relapse due to the development of drug resistance. Cytoskeleton-associated protein 4 (CKAP4) was found to maintain the tubular network along the endoplasmic reticulum-to-Golgi pathway and promote cancer progression through various mechanisms.1 In this study, we report the novel finding that CKAP4 contributes to mutant p53 (mtp53)-mediated cancer progression and drug resistance in ovarian cancer. First, we identified CKAP4 as a possible mtp53-interacting protein through co-immunoprecipitation (co-IP) and mass spectrometric analysis using an ovarian tumour carrying the mtp53-S241F mutation (Figure S1).2-4 A set of reciprocal co-IP assays were conducted to confirm that CKAP4 could bind to various p53 mutants, but not wild-type p53 (wtp53) (Figure 1A–E). One possible reason for this could be that missense mutations may cause conformational or structural changes to p53, thereby facilitating their interaction. This interaction was further validated by mapping the mtp53-binding domain on CKAP4 (Figure S2A,B). In addition, our results showed that CKAP4 and mtp53 were present in both the nucleus and cytoplasm (Figure S2C,D). Although CKAP4 did not affect mtp53 expression (Figure S3A,B), we found that ectopic expression of CKAP4 up-regulated the expression of mtp53 target genes (Figure 1F-H), while ablation of CKAP4 reduced the expression of these genes (Figure 1I,J). Consistently, our analysis of TCGA database revealed a positive correlation between the levels of CKAP4 expression and the expression of mtp53 target genes in primary ovarian cancer tissues (Figure S4A–I). To further understand the function of CKAP4 in ovarian cancer, we conducted an analysis using the CPTAC and KM plotter databases. Our analysis showed that both RNA and protein levels of CKAP4 were higher in ovarian cancer tissues than normal tissues (Figure S5A,B). This elevated expression was correlated with poor prognosis of patients with ovarian cancer (Figure S5C–H). Through cell-based assays, we found that CKAP4 overexpression increased the growth of ovarian cancer cells, while CKAP4 knockdown suppressed their growth (Figure 2A-F). Consistently, ectopic CKAP4 inhibited ovarian cancer cell apoptosis, whereas CKAP4 depletion promoted apoptosis (Figure 2G-J). Moreover, the biological function of CKAP4 was investigated in xenograft mouse models. Our results demonstrated that CKAP4 overexpression increased tumour growth rate, weight and size (Figure 3K–M). However, CKAP4 depletion suppressed tumour growth in vivo (Figure 3N–P). Furthermore, CKAP4 overexpression promoted ovarian cancer cell migration (Figure S6A,B), whereas CKAP4 depletion inhibited their migration (Figure S6C–E), probably because CKAP4 regulated metastasis-associated genes via mtp53 (Figure 1F–J). Lastly, our findings demonstrated that depletion of mtp53 negated the effects of CKAP4 on ovarian cancer cell growth, resistance to apoptosis and migration (Figure S7A–E). We observed that CKAP4 significantly induced the expression of several G2/M checkpoint genes, including CDK1, CDC25C, CCNA2, CCNB1 and CCNB2, which are regulated by the transcription factor nuclear transcription factor (NF)-Y, as evidenced by the cell-based results (Figure 1F–J) and in vivo xenograft models (Figure 3A,B). NF-Y is composed of three subunits, NF-YA, NF-YB and NF-YC, all of which are essential for the binding to the consensus CCAAT motif of eukaryotic promoters.5 It was reported that mtp53 gained the oncogenic function by interacting with NF-Y and boosting its transcriptional activity.6 Therefore, we postulated that CKAP4 might regulate cell cycle progression through the mtp53-NF-Y pathway. Our findings revealed that CKAP4 overexpression markedly increased mtp53 interactions with NF-YB and NF-YC (Figure 3C, D). CKAP4 might serve as a link between mtp53 and NF-Y by physically interacting with both components. However, further investigation is required to provide more details on the biochemical process. In addition, the chromatin immunoprecipitation (ChIP) assay showed that mtp53 associated with the promoters of various NF-Y target genes, including CDK1, CDC25C, CCNB1 and CCNB2, in response to DNA damage stress, while CKAP4 depletion hindered these interactions in ovarian cancer cells (Figure 3E–H). Furthermore, we found that CKAP4 overexpression reduced G2 phase accumulation, whereas CKAP4 depletion resulted in cell cycle arrest at G2 phase (Figure 3I,J). Cisplatin treatment reduces membrane integrity during G2 cell cycle arrest, consequently leading to apoptosis,7 and an increase in G2 arrest enhances tumour sensitivity to cisplatin.8, 9 Thus, we speculated that CKAP4 overexpression could be associated with cisplatin resistance, while targeting CKAP4 might increase ovarian cancer cell sensitivity to cisplatin. Several lines of evidence supported this hypothesis. First, CKAP4 overexpression restored cell growth back to normal levels in the presence of cisplatin (Figure 4A), whereas CKAP4 knockout promoted cisplatin-induced inhibition of cell growth (Figure 4B). Additionally, CKAP4 overexpression increased the half-maximal inhibitory concentration (IC50) of cisplatin from 6.503 to 12.15 μM in ES-2 cells (Figure 4C); conversely, CKAP4 ablation could reduce the IC50 of cisplatin in multiple ovarian cancer cell lines (Figure 4D–F). Furthermore, the colony formation assay again revealed that CKAP4 overexpression induced cisplatin resistance, whereas its depletion increased ovarian cancer cell sensitivity to cisplatin (Figure 4G–I). In agreement with these cell-based results, our findings demonstrated that CKAP4 depletion augmented the anti-tumour activity of cisplatin in vivo, as evidenced by the marked reduction of tumour growth rate, weight, and size (Figure 4J–L). Chemotherapeutic resistance can arise from various mechanisms, one of which is the activation of oncogenic signals.10 Mtp53 and NF-Y signaling pathways were found to coordinately promote chemoresistance in cancer, as mtp53 interacts with the trimeric NF-Y transcription factor to enhance the expression of multiple genes that regulate cell cycle progression in response to DNA damage stress.6 Our study uncovers an oncogenic role for CKAP4 in promoting ovarian cancer progression and chemoresistance. CKAP4 enhances the recruitment of mtp53 to NF-Y target gene promoters, resulting in the abrogation of the G2/M checkpoint and cisplatin resistance, whereas depleting CKAP4 sensitizes ovarian cancer to cisplatin by triggering cell cycle arrest at G2 phase. C.H. and W.Z. conducted most of the experiments and analyzed the data; Q.H. conducted part of experiments; J.C. and H.L. provided important instructions; L.W. and W.Y. analyzed the data; Q.H., Y.Z. and X.Z. conceived, designed and supervised the study and analyzed the data; H.L., Y.Z. and X.Z. wrote and revised the manuscript. The authors thank the laboratory members for active and helpful discussion, and the innovative research team of the high-level local university in Shanghai. The authors declare no conflict of interest. The National Natural Science Foundation of China, Grant Numbers: 82273098, 82072879, 81874053, 82073323 and 82173022; The Natural Science Foundation of Hunan Province, Grant Number: 2021JJ31106; The Reynolds and Ryan Families Chair Fund of Translational Cancer. The present study was approved by the ethics committee of the participating institutions. The data generated or analyzed during this study are included in the article and/or supplementary materials. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background 2020 World Health Organization Classification of Female Genital Tumors removed ovarian seromucinous carcinoma as a distinct entity and recategorized it as ovarian endometrioid carcinoma with mucinous differentiation according to its pathological features. The aim of this study was to find whether ovarian seromucinous carcinoma truly represented a distinct category of ovarian tumors or an analogue of ovarian endometrioid carcinoma. Methods Twelve patients diagnosed with ovarian seromucinous carcinoma and received surgery at the Xiangya Hospital from January 2010 to December 2019 were included in this study. Clinicopathological features such as clinical symptoms, serological indicators, surgical information, postoperative findings, chemotherapy sensitivity, follow-up information, HE staining and IHC staining images and other clinicopathologic features were collected. Using t-test and Kaplan Meier to perform statistical analysis. Pathological review was conducted using the 2014 World Health Organization criteria. All pathological diagnoses were reviewed by two experienced pathologists. Results The age of 12 patients diagnosed with ovarian seromucinous carcinoma ranged from 23 to 68 years, with a median age of 46.8 years. Serum level of CA125 was elevated in 10 patients, and CA125/CEA ratio was less than 25 in 6 patients. Eleven patients underwent radical ovarian cancer surgery, and one patient underwent fertility preservation surgery. The progression free survival and overall survival of ovarian seromucinous carcinoma is 46.8 months and 50.2 months. Kaplan-Meier survival curve showed that the prognosis of ovarian seromucinous carcinoma and ovarian endometrioid carcinoma was significantly different ( P = 0.03). The prognosis of ovarian seromucinous carcinoma and ovarian mucinous carcinoma was similar. Conclusion Although ovarian seromucinous carcinoma and ovarian endometrioid carcinoma are similar in pathologic morphology, their clinical features and prognosis are significantly different. The signs, serum biomarker and prognosis of the ovarian seromucinous carcinoma are similar with ovarian mucinous carcinoma. Therefore, ovarian seromucinous carcinoma is not suitable to be directly classified as ovarian endometrioid carcinoma.

Abstract Background The colposcopy-conization inconsistency is common in women with cervical intraepithelial neoplasia grade 3 (CIN3). No adequate method has been reported to identify the final pathology of conization. In this study, we explored the ability of PAX1 and ZNF582 methylation to predict the pathological outcome of conization in advance. Methods This was a multicenter study and included 277 histologically confirmed CIN3 women who underwent cold knife conization (CKC) from January 2019 to December 2020. The methylation levels of PAX1 (PAX1m) and ZNF582 (ZNF582m) were determined by quantitative methylation-specific polymerase chain reaction (qMSP) and expressed in ΔCp. Receiver operating characteristic curves were used to evaluate predictive accuracy. Results The final pathological results in 48 (17.33%) patients were inflammation or low-grade squamous intraepithelial lesion (LSIL), 190 (68.59%) were high-grade squamous intraepithelial lesion (HSIL), and 39 (14.08%) were squamous cervical cancer (SCC). PAX1m and ZNF582m increased as lesions progressed from inflammation/LSIL, HSIL, to SCC. PAX1 and ZNF582 methylation yielded better prediction performance compared with common screening strategies, whether individually or combined. A 4.33-fold increase in the probability of inflammation/LSIL was observed in patients with lower ZNF582 methylation levels (ΔCpZNF582 ≥ 19.18). A 6.53-fold increase in SCC risk was observed in patients with elevated ZNF582 methylation (ΔCpZNF582 < 7.09). Conclusions DNA methylation would be an alternative screening method to triage and predict the final outcome of conization in CIN3 cases.

OBJECTIVES:Ovarian cancer is a fatal gynecological cancer due to the lack of effective screening strategies at early stage. This study explored the utility of DNA methylation profiling of blood samples for the detection of ovarian cancer.METHODS:Targeted bisulfite sequencing was performed on tissue (n = 152) and blood samples (n = 373) obtained from healthy women, women with benign ovarian tumors, or malignant epithelial ovarian tumors. Based on the tissue-derived differentially-methylated regions, a supervised machine learning algorithm was implemented and cross-validated using the blood-derived DNA methylation profiles of the training cohort (n = 178) to predict and classify each blood sample as malignant or non-malignant. The model was further evaluated using an independent test cohort (n = 184).RESULTS:Comparison of the DNA methylation profiles of normal/benign and malignant tumor samples identified 1272 differentially-methylated regions, with 49.4% hypermethylated regions and 50.6% hypomethylated regions. Five-fold cross-validation of the model using the training dataset yielded an area under the curve of 0.94. Using the test dataset, the model accurately predicted non-malignancy in 96.2% of healthy women (n = 53) and 93.5% of women with benign tumors (n = 46). For patients with malignant tumors, the model accurately predicted malignancy in 44.4% of stage I-II (n = 9), 86.4% of stage III (n = 59), 100.0% of stage IV tumors (n = 6), and 81.8% of tumors with unknown stage (n = 11). Overall, the model yielded a predictive accuracy of 89.5%.CONCLUSIONS:Our study demonstrates the potential clinical application of blood-based DNA methylation profiling for the detection of ovarian cancer.

目的:探究PRDX4和GRP78在子宫内膜癌中的表达水平与患者的临床病理特征和预后的关系.方法:利用GEPIA在线生信分析工具对TCGA和GTEx数据库中子宫内膜癌患者PRDX4和GRP78的表达量进行分析,同时收集76例子宫内膜癌患者的癌组织及癌旁组织并用免疫组化方法检测PRDX4和GRP78的表达.卡方检验分析PRDX4和GRP78与患者临床特征的关系,Kaplan-Meier方法分析PRDX4和GRP78与子宫内膜癌患者生存期的关系,COX回归方法分析子宫内膜癌患者预后的独立风险因子.结果:子宫内膜癌组织中PRDX4和GRP78表达水平明显升高,两者呈正相关关系.子宫内膜癌组中PRDX4和GRP78的表达与FIGO分期、远处转移有关;PRDX4和GRP78共表达是影响子宫内膜癌预后的独立风险因素,PRDX4和GRP78高表达者总生存期明显低于低表达者.结论:PRDX4和GRP78的高表达与子宫内膜癌患者的不良预后和临床病理特征相关,两者可能存在协同作用.

To explore treatment strategies for patients with positive margins after cervical cold knife conization (CKC) by estimating the risk of residual or recurrent CIN2 or worse (CIN2+).

The human microbiome, often termed as "the forgotten organ", is an aggregation of microorganisms and their genomes that forms a mutualistic complex with the host. Recent research has shown the symbiotic merits of a microbiome ecosystem and its crucial role in the hosts' physiological functions. Disruption of this symbiotic relationship is prone to cause a broad spectrum of ailments, including cancer. The compositional and environmental factors that tip the scales from beneficial co-existence to the development of malignancy is actively investigated. Herein we review the latest research in knowledge regarding the association between the vaginal microbiomes and oncogenesis, with a particular focus on ovarian carcinoma.

Abstract Purpose: Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer. Experimental Design: Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy. Results: We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell-cycle regulator, WEE1. Mechanistically, PA facilitates c-JUN N-terminal kinase recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacologic inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA–c-JUN–WEE1 signaling positively correlated with platinum resistance in tumors derived from patients with ovarian cancer. Conclusions: Our study demonstrates how the DGKA-derived lipid messenger, PA, contributes to cisplatin resistance by intertwining with kinase and transcription networks, and provides preclinical evidence for targeting DGKA as a new strategy in ovarian cancer treatment to battle cisplatin resistance.

Introduction:Malignant germ cell tumors (MGCT) can occur in both genders. In this study, we present eight cases of mixed ovarian MGCT in patients. Most patients reported in the current study are young women, among whom clinical characteristics of gonadal dysgenesis associated MGCT were rarely reported. Methods:Comprehensive information of eight patients with mixed ovarian MGCTs, including patients' age, clinical features, tumor markers, imaging findings, surgical records, pathology, karyotyping tests, chemotherapy and follow-up were collected. Surgical specimens were evaluated by two specialized gynecologic pathologists. Results:All patients received surgery, while seven received chemotherapy. Among them, two received a second surgery and three patients received hormone replacement therapy (HRT) after gonadectomy. Four of five patients with amenorrhea were found to have 46, XY karyotype. All patients showed no sign of recurrence at the latest follow-up. Discussion:Karyotyping or genetics testing in patients with amenorrhea is necessary, especially for patients with pelvic mass, which can help surgeons to evaluate the necessity of gonadectomy before surgery. The patients with gonadal dysgenesis associated mixed ovarian MGCT seem to have better prognosis and long survival time. Thus, HRT, an option that can improve life quality, is worth considering for these patients after gonadectomy.

Objective To evaluate the course of chemotherapy-induced peripheral neuropathy (CIPN) among patients with ovarian cancer receiving taxanes. Methods In a retrospective case-control study conducted between January 1, 2016, and May 31, 2018, in Xiangya Hospital in Changsha, China, women with ovarian cancer received taxane and platinum-complex combination therapy. The European Organization for Research and Treatment of Cancer Quality of Life, Ovarian cancer module questionnaire, was used to assess the severity of neuropathy by telephone. Results Out of the 88 women included in the study, 61 (69.3%) reported CIPN. Twelve months after chemotherapy, the percentage was 19.3%. The percentage of patients suffering from sensory peripheral neuropathy (SPN) was higher than motor peripheral neuropathy at any time during the study. Sensory peripheral neuropathy was associated with the use of docetaxel and paclitaxel (docetaxel vs liposomal paclitaxel: odds ratio [OR] 4.39, 95% confidence interval [CI] 1.69-11.42, POR 5.91, 95% CI 1.09-31.97, P=0.04). The average weakness score in acute CIPN was lower than chronic CIPN (1.46 vs 2.00, P=0.019). Patients treated with vitamin B-1 and amifostine experienced better relief from CIPN. Conclusion The present study showed a significant proportion of patients with ovarian cancer receiving taxanes suffered from long-term residual neuropathy, and the use of docetaxel and paclitaxel was associated with SPN. Vitamin B-1 or amifostine may improve the symptoms of CIPN.

OBJECTIVE:To investigate the role of HELQ in chemo-resistance of epithelial ovarian carcinoma (EOC), which is a critical factor of patients' prognosis.METHODS:Immunohistochemistry, survival analysis of our 87 EOC patients and bioinformatics analysis of The Cancer Genome Atlas (TCGA) datasets (Nature, 2011) disclosed the clinical importance of HELQ expression. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western Blot analyses of EOC tissue were used to confirm it. Ectopic overexpression and RNA interference knockdown of HELQ were carried out in OVCAR3 and A2780 cell lines, respectively, to determine the effect of altered HELQ expression on cellular response to cisplatin by CCK8 assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Western Blot analyses were carried out to determine the effect of HLEQ on the DNA repair genes by using cells with altered HELQ expression.RESULTS:HELQ expression associates with response of EOC patients to platinum-based chemotherapy and their overall survival (OS), disease free survival (DFS). HELQ overexpression or knockdown, respectively, increased and decreased the cellular resistance to cisplatin, DNA repair activity, and expression of DNA repair proteins of Nucleotide excision repair (NER) pathway.CONCLUSIONS:HELQ plays an important role in regulating the expression of DNA repair proteins NER pathway which, in turn, contributes to cellular response to cisplatin and patients' response to platinum-based chemotherapy. Our results demonstrated that HELQ could serve as a novel indicator for chemo-resistance of EOC, which can predict the prognosis of the disease.