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

Abstract 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 1β, 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

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

Abstract 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. Graphical Abstrac

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

Abstract 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.</p

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

Abstract 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