Construction and validation of log odds of positive lymph nodes (LODDS)-based nomograms for predicting overall survival and cancer-specific survival in ovarian clear cell carcinoma patients.

Background: Ovarian clear cell carcinoma (OCCC) is one of the special histologic subtypes of ovarian cancer. This study aimed to construct and validate log odds of positive lymph nodes (LODDS)-based nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in patients with OCCC. Methods: Patients who underwent surgical treatment between 2010 and 2016 were extracted from the Surveillance Epidemiology and End Results (SEER) database and the data of OCCC patients from the First Affiliated Hospital of Dalian Medical University were used as the external validation group to test the validity of the prognostic model. The best-fitting models were selected by stepwise Cox regression analysis. Survival probability was calculated by the Kaplan-Meier method, and the differences in survival time between subgroups were compared using the log-rank test. Each nomogram's performance was assessed by the calibration plots, decision curve analysis (DCA), and receiver operating characteristics (ROC) curves. Results: T stage, distant metastasis, marital status, and LODDS were identified as significant risk factors for OS. A model with four risk factors (age, T stage, stage, and LODDS value) was obtained for CSS. Nomograms were constructed by incorporating the prognostic factors to predict 1-, 3- and 5-year OS and CSS for OCCC patients, respectively. The area under the curve (AUC) range of our nomogram model for OS and CSS prediction ranged from 0.738-0.771 and 0.769-0.794, respectively, in the training cohort. The performance of this model was verified in the internal and external validation cohorts. Calibration plots illustrated nomograms have good prognostic reliability. Conclusion: Predictive nomograms were constructed and validated to evaluate the OS and CSS of OCCC patients. These nomograms may provide valuable prognostic information and guide postoperative personalized care in OCCC.

Comparative analysis of the vaginal bacteriome and virome in healthy women living in high-altitude and sea-level areas.

The vaginal microbiota plays an important role in the health of the female reproductive tract and is closely associated with various pregnancy outcomes and sexually transmitted diseases. Plenty of internal and external factors have strong influence on the changes in a woman's vaginal microbiome. However, the effect of a high-altitude on female vaginal microbiota has not been described. In this study, we characterized the vaginal bacteriome and virome of 13 and 34 healthy women living in high-altitude and sea-level areas, using whole-metagenome shotgun sequencing of their vaginal mucus samples. The results revealed that the vaginal bacteriomes of high-altitude individuals are featured by a significant increase of species diversity, depletion of Lactobacillus crispatus, and more abundant of some anaerobic bacteria, such as Chlamydia trachomatis, Mageeibacillus indolicus, Dialister micraerophilus, and Sneathia amnii). In addition, the vagina samples of sea-level subjects harbor more Lactobacillus strains, whereas the anaerobic bacteroidetes strains mostly appeared in high-altitude subjects. Identified and assembled 191 virus operational taxonomic units (vOTUs), there were significant differences in the abundance of 107 vOTUs between the two groups. Together, the results of this study raised the understanding of bacteriome and virome in the vagina of women at different elevations, and demonstrated that the vaginal microbiome is related to the high-altitude geographic adaptation.

From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer.

Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1ß, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.

Association of coffee and caffeine consumption with risk and prognosis of endometrial cancer and its subgroups: a Mendelian randomization.

Background: Previous studies have not established potential causal associations between coffee and caffeine consumption in endometrial cancer (EC) and its subgroups. Therefore, we used a two-sample MR method to assess the causal association between coffee and caffeine consumption and EC risk. We also evaluated the association between these genetically predicted exposures and EC prognosis. Materials and methods: This study used 12 and two independent single-nucleotide polymorphisms (SNPs) associated with coffee and caffeine consumption as instrumental variables at a genome-wide significance level of p < 5 × 10-8. The EC Association Consortium (ECAC) performed a genome-wide association study (GWAS) analysis of 12,906 cases and 108,979 controls. FinnGen Consortium performed a GWAS analysis of 1,967 EC cases and 167,189 controls. The primary technique we employed was inverse-variance weighted, followed by the weighted median, MR-Egger regression, and MR robust adjusted profile score methods. We used the MR pleiotropy residual sum, Outlier test, and MR-Egger regression to assess Outlier and pleiotropic variants. We also conducted a sensitivity analysis through the leave-one-out method. Results: Genetically predicted coffee consumption was not associated with EC and its subgroups in the ECAC, and the association was consistent in the FinnGen consortium. After excluding eight SNPs with confounding factors, the study performed sensitivity analyses, delivering consistent results. We also observed that caffeine consumption was not correlated with EC risk. As confirmed by MR analysis, selected SNPs determined that most do not significantly impact the likelihood of developing EC. Conclusion: Our study indicated no convincing evidence supports coffee and caffeine consumption causing EC or impacting its prognosis. More studies are needed to validate the results.

Metabolic syndrome and risk of ovarian cancer: a systematic review and meta-analysis.

Background: MetS is associated with greater morbidity and mortality in relation to a number of malignancies, but its association with ovarian cancer remains contested. The present study was a systematic review and meta-analysis of case-control and cohort studies examining the association between MetS and ovarian cancer risk. Methods: The study was registered on the PROSPERO platform in January 2023 (CRD42023391830). Up until February 13, 2023, a complete search was undertaken in PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials. On the basis of inclusion and exclusion criteria, eligible studies for meta-analysis were screened to determine the association between MetS and ovarian cancer risk. Results: Five studies were included in total, including three cohort studies and two case-control studies. Meta-analysis showed no significant correlation between metabolic syndrome and ovarian cancer (OR=1.29, 95% CI: 0.90-1.84). Significant heterogeneity (I2 = 92.6, P<0.05) existed between the included studies. We performed a subgroup analysis of the risk of bias and showed that only unadjusted stratification of risk of bias for smoking (OR= 3.19, 95% CI: 2.14-4.76) and hysterectomy (OR= 3.19, 95% CI: 2.14-4.76) demonstrated a relationship between metabolic syndrome and ovarian cancer risk. The meta-regression analysis revealed that smoking and hysterectomy excision were substantially linked with heterogeneity (p < 0.05). Conclusion: Our research revealed no statistically significant association between MetS and ovarian cancer risk. The prevalence of metabolic syndrome has highlighted the need of enhancing and controlling women's metabolic health. However, the evaluation of metabolic syndrome as a cancer risk factor may be deceptive and etiologically uninformative.

Are "additional cuts" effective for positive margins in cervical conization? It varies according to the doctor.

BACKGROUND: High-grade squamous intraepithelial lesion (HSIL) is a disease that is closely related to the development of cervical cancer. In clinical work, cold knife conization and a loop electrosurgical excision procedure (LEEP) are often selected for diagnosis and treatment. OBJECTIVE: In this paper, we aimed to discuss additional cuts, a common practice in cervical conization, and determine whether the doctor's choice to use additional cuts in conization can reduce the occurrence of a positive cone margin. METHODS: From January 2018 to October 2019, 965 patients underwent cervical conization at the First Affiliated Hospital of Dalian Medical University (Dalian, China). Of these, 174 were in the positive cone margin group, and 791 were in the negative cone margin group. Age, preoperative pathology, pathological results of conization, additional cuts, cone depth, and cone volume were studied. Additionally, the additional cut rate and the efficiency of doctors with a habit of additional cuts were analyzed. RESULTS: Of the 965 patients included in the study, the median age was 41 years (range 35-50). Multivariable logistic regression analysis suggested that additional cuts (OR, 2.480; 95% CI 1.608 to 3.826; p = 0.01) and smaller cone depth (OR, 0.591; 95% CI, 0.362 to 0.965, p = 0.036) were independent risk factors for positive margins. Six of the 64 doctors who performed conizations had a habit of making additional cuts, and there was no positive correlation between their additional cut rate and their effective additional cut rate. CONCLUSION: This study showed that a certain proportion of additional cuts can be effectively excised from the positive margin that cannot be removed in the initial conization. The practice of additional cuts in conization tends to be the personal habit of a small number of doctors.

CDC20 inhibitor Apcin inhibits embryo implantation in vivo and in vitro.

For successful implantation, endometrial receptivity must be established. The high expression of CDC20 in many kinds of malignant tumours has been reported, and it is related to the occurrence and development of tumours. According to these functions, we think that CDC20 may also play important roles in the process of embryo implantation. To prove our hypothesis, we observed the distribution and expression of CDC20 in mouse and human early pregnancy. The effect of E2 and/or P4 on the expression of CDC20 in human endometrial cells was detected by Western blot. To further explore whether CDC20 is an important factor in adhesion and proliferation. The results showed that the expression of CDC20 in the uterus and menstrual cycle of early pregnant mice was spatiotemporal. E2 can promote the expression of CDC20. On the contrary, P4 and E2 + P4 inhibited the expression of CDC20. We also detected the proliferation and adhesion of human endometrial cells. We found that the inhibition of CDC20 with its inhibitor Apcin could reduce the adhesion rate and proliferation ability to RL95-2 and HEC-1A cells, respectively. Inhibiting CDC20 by Apcin could interfere the embryo implantation of mouse. It is suggested that CDC20 may play an important role in the process of embryo implantation. SIGNIFICANCE OF THE STUDY: Embryo implantation is an extremely complex and delicate process, including identification, localisation, adhesion and invasion between embryo and endometrium. Studies have shown the process of embryo implantation is very similar to that of tumour invasion. CDC20 is a cancer-promoting factor. We found CDC20 is spatially and spatially expressed in mouse and human menstrual cycles and is regulated by oestrogen and progesterone. Apcin can inhibit the adhesion of JAR cells and embryo implantation of mouse. CDC20 may provide a new way to improve the success rate of assisted reproduction.

The tumor suppressor OVCA1 is a short half-life protein degraded by the ubiquitin-proteasome pathway.

Ovarian cancer gene 1 (OVCA1) is a tumor suppressor associated with ovarian cancer, which is involved in cell proliferation regulation, embryonic development and tumorigenesis. Loss of heterozygosity in the OVCA1 gene occurs in 50-86% of cases of ovarian cancer; however, the physiological and biochemical functions of OVCA1 are not yet clear. In the present study, the stability and degradation of OVCA1 were investigated in A2780, Hela and 293 cells. The results revealed that the OVCA1 protein was unstable by MG132 inhibiting proteasome mediated degradation, co-immunoprecipitation and half-life measurement experiments. The cellular protein levels of endogenous OVCA1 were too low to be detected by western blotting. In addition, carbobenzoxy-L-leucyl-L-leucyl-L-leucinal inhibited the degradation of OVCA1 in cells. The co-immunoprecipitation assay revealed that the OVCA1 protein interacted with ubiquitin to form a poly-ubiquitinated complex in cells. The half-life of OVCA1, measured by inhibiting protein synthesis with cycloheximide, was <2 h. The present study demonstrated that OVCA1 may be degraded by the ubiquitin-mediated proteasome pathway and may be considered a short half-life protein. In conclusion, the regulation of OVCA1 protein degradation via the ubiquitin-proteasome pathway may represent a novel direction in the development of ovarian cancer therapy.

Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARγ and downregulating MMP­9 expression.

The mortality rate of ovarian cancer is the highest of all gynecological malignancies. Telmisartan is a commonly used clinical angiotensin receptor blocker, which has antihypertensive, anti­inflammatory and antithrombotic effects. In the present study, it was investigated whether telmisartan could exert anticancer effects on ovarian cancer cells through upregulating peroxisome proliferator­activated receptor γ (PPARγ) and downregulating matrix metalloproteinase­9 (MMP­9) expression. A 3.3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was conducted to analyze the proliferation of HEY cells. A Caspase­3 Activity Assay kit and an Annexin V­fluorescein isothiocyanate/propidium iodide kit were used to analyze the apoptosis of HEY cells. In addition, a gelatin zymography assay and reverse trancription­quantitative polymerase chain reaction were included to analyze the expression of PPARγ and MMP­9 in HEY cells. The data showed that telmisartan could significantly decrease cell viability and induce the apoptosis of HEY cells in a time­ and dose­dependent manner. Furthermore, telmisartan could also dose­dependently increase the expression of PPARγ and decrease the expression of MMP­9 in HEY cells. In addition, downregulation of the expression of PPARγ by small interfering (si)RNA could reduce the effect of telmisartan on ovarian cancer cells and increase the expression of MMP­9. In conclusion, the results indicated that telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells by upregulating PPARγ and downregulating MMP­9 expression.

Mirk/Dyrk1B mediates G0/G1 to S phase cell cycle progression and cell survival involving MAPK/ERK signaling in human cancer cells.

BACKGROUND: Mirk/Dyrk1B contributes to G0 arrest by destabilization of cyclin D1 and stabilization of p27kip1 to maintain the viability of quiescent human cancer cells, and it could be negatively regulated by mitogenic-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling. This study was performed to investigate the effect of Mirk/Dyrk1B on cell cycle and survival of human cancer cells involving MAPK/ERK signaling. METHODS: The correlations between Mirk/Dyrk1B expression and active ERK1/2 detected by western blot in both ovarian cancer and non-small cell lung cancer (NSCLC) cells were analyzed by simple regression. Mirk/Dyrk1B unique phosphopeptides with sites associated with Mirk/Dyrk1B protein were isolated and quantitated by liquid chromatography coupled to tandem mass/mass spectrometry (LC-MS/MS) proteomics analysis. The human cancer cells were treated with small interfering RNAs (siRNAs) and/or U0126, an inhibitor of MEK for indicated duration, followed by investigating the alterations of cell cycle and apoptosis as well as related proteins examined by flow cytometry and Western blot, respectively. RESULTS: Our study demonstrated the widely expressed Mirk/Dyrk1B proteins in the human cancer cells were positively correlated with the levels of activated ERK1/2. Moreover, Mirk/Dyrk1B protein expressions consistent with the tyrosine autophosphorylated levels in the human cancer cells were increased by U0126 or growth factor-depleted culture. Conversely, knockdown of Mirk/Dyrk1B by siRNA led to up-regulated activation of c-Raf-MEK-ERK1/2 pathway and subsequent changes in cell cycle proteins (cyclin D1, p27kip1), accompanied by increased growth rate and cells from G0/G1 into S of cell cycle which could be blocked by U0126 in a dose-dependent manner, indicating Mirk/Dyrk1B may sequester MAPK/ERK pathway, and vice versa. Whereas, combined Mirk siRNA and U0126 induced cell apoptosis in the human cancer cells. CONCLUSIONS: These data together show that Mirk/Dyrk1B mediates cell cycle and survival via interacting with MAPK/ERK signals and simultaneous inhibition of both pathways may be a novel therapeutic target for human cancer.

OVCA1 inhibits the proliferation of epithelial ovarian cancer cells by decreasing cyclin D1 and increasing p16.

OVCA1, a tumor suppressor gene, is deleted or lower expressed in about 80% of ovarian cancer. Over expression of OVCA1 in human ovarian cancer A2780 cells inhibits cell proliferation and arrests cells in G1 stage. However, the fact that the molecular mechanism of OVCA1 inhibits cell growth is presently elusive. Here we investigated the potential signaling pathway induced by over-expression of OVCA1. Our results show that over-expression of human OVCA1 in ovarian cancer cells A2780 leads to down-regulation of cyclin D1, and up-regulation of p16, but no effect on the expression of NF-κB. It indicates that OVCA1 could inhibit the proliferation of ovarian cancer cell A2780 by p16/cyclin D1 pathway, but not by NF-κB.

Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells.

Hyperleptinemia is a common feature of obese women who have a higher risk of endometrial cancer than women with normal weights, and epidemiologic studies have suggested a correlation between obesity and endometrial carcinoma. Therefore, understanding of the molecular mechanism involved in leptin signaling transduction is important in endometrial cancer prevention and treatment. In this study, both isoforms of the leptin receptor (Ob-R), the long form (Ob-Rb) and short form (Ob-Ra), were detected as being expressed in six endometrial cancer cell lines with various differentiation status by western blotting, and Ob-Ra was found to be more abundant than Ob-Rb in these cells. Moreover, the expressions of both isoforms were inversely correlated with histoprognostic grading. We also showed that leptin stimulated cell proliferation and induced activations of signal transducers and activators of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK1/2), AKT, and cyclooxygenase (COX)-2 in endometrial cancer cells dose-dependently by [(3)H] thymidine incorporation assay and western blotting. Leptin-stimulation resulted in increased expression of COX-2 mRNA and prostaglandin E2 (PGE2) production of endometrial cancer cells by reverse transcription-polymerase chain reaction and enzyme immunoassay, respectively, which was effectively blocked by pharmacological inhibitors of Janus tyrosine kinase 2 (JAK2), AG490; of mitogen-activated protein kinase (MAPK) kinase, U0126; of phosphatidylinositol 3-kinase (PI3K), LY294002; and of COX-2, NS398. These results suggest that leptin promotes cell proliferation of endometrial cancer cells via the aforementioned multiple signal-transduction pathways. Leptin-induced functional activation of COX-2 is JAK2/STAT3-, MAPK/ERK-, and PI3K/AKT-dependent, indicating that COX-2 may be a critical factor of endometrial carcinogenesis in obesity.