Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

Chamaejasmine induces apoptosis in HeLa cells through the PI3K/Akt signaling pathway.

Chamaejasmine is one of the major bioactive components of Stellera chamaejasme L, which is a Chinese traditional herbal medicine that has been used widely in the treatment of cancer. The aim of this study is to investigate the potential effect of chamaejasmine on cervical cancer cells and elucidate the underlying mechanisms of action. We first examined the antitumor activity of chamaejasmine both in vitro and in vivo. In the following experiments with HeLa cells, cell apoptosis and ultrastructure changes were assessed by flow cytometry and transmission electron microscopy, respectively. The effects of chamaejasmine on reactive oxygen species production and mitochondrial membrane potential (Δψm) were examined using 2',7'-dichlorohydrofluorescein and rhodamine-123 staining. The mRNA and protein levels of apoptosis-related proteins were detected by real-time PCR and western blot. The activity of caspases 3, 8, and 9 was measured using the corresponding assay kit. The effect of chamaejasmine on the phosphoinositide 3-kinase (PI3K)/Akt pathway was evaluated by luciferase assay and western blot, and further confirmed in Akt overexpressing HeLa cells. We found that chamaejasmine has potent antitumor effects on cervical cancer cell lines both in vitro and in vivo. Mechanistic studies showed that chamaejasmine could induce apoptosis in HeLa cells, and this apoptosis-inducing effect may be mediated through the suppression of PI3K/Akt signaling cascades. These findings not only indicate the therapeutic potential of chamaejasmine for cervical cancer, but provide valuable insight into its mechanism of action.

A stemness-based signature with inspiring indications in discriminating the prognosis, immune response, and somatic mutation of endometrial cancer patients revealed by machine learning.

Endometrial cancer (EC) is a fatal gynecologic tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. Our study aimed to identify stemness-related prognostic biomarkers for new therapeutic strategies in EC. In this study, we explored the prognostic value of cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, and its correlation with immune infiltrates in EC. Transcriptome and somatic mutation profiles of EC were downloaded from TCGA database. Based on their stemness signature and DEGs, EC patients were divided into two subtypes via consensus clustering, and patients in Stemness Subtype I presented significantly better OS and DFS than Stemness Subtype II. Subtype I also displayed better clinicopathological features, and genomic variations demonstrated different somatic mutation from subtype II. Additionally, two stemness subtypes had distinct tumor immune microenvironment patterns. In the end, three machine learning algorithms were applied to construct a 7-gene stemness subtype risk model, which were further validated in an external independent EC cohort in our hospital. This novel stemness-based classification could provide a promising prognostic predictor for EC and may guide physicians in selecting potential responders for preferential use of immunotherapy. This novel stemness-dependent classification method has high value in predicting the prognosis, and also provides a reference for clinicians in selecting sensitive immunotherapy methods for EC patients.

A cellular senescence-related genes model allows for prognosis and treatment stratification of cervical cancer: a bioinformatics analysis and external verification.

BACKGROUND: Cervical cancer (CC) is highly lethal and aggressive with an increasing trend of mortality for females. Molecular characterization-based methods hold great promise for improving the diagnostic accuracy and for predicting treatment response. METHODS: The mRNAs expression data of CC patients and cellular senescence-related genes were obtained from the Cancer Genome Atlas (TCGA) and CellAge databases, respectively. Differentially expressed genes (DEGs) of senescence related genes between tumor and normal tissues were used for Least absolute shrinkage and selection operator (LASSO) regression to construct a prognostic model. Univariate and LASSO regression analyses were applied to establish a predictive nomogram. The performance of the nomogram were evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index (C-index), and calibration curve. GSE44001 and GSE52903 were used for external validation. RESULTS: We established a cellular senescence-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of CC patients in the TCGA database. The Kaplan-Meier curve indicated that patients in the low-risk group had considerably better overall survival (OS, P =2.021e-05). The area under the ROC curve (AUC) of this model was 0.743 for OS. Multivariate analysis found that the 6-gene risk signature (HR=3.166, 95%CI: 1.660-6.041, P<0.001) was an independent risk factor for CC patients. We then designed an OS-associated nomogram that included the risk signature and clinicopathological factors. The AUC reached 0.860 for predicting 5-year OS. The nomogram showed excellent consistency between the predictions and actual survival observations. Two external GEO validations were corresponding to the gene expression pattern in TCGA. CONCLUSIONS: Our results suggested a six-senescence related signature and established a prognostic nomogram that reliably predicted the overall survival for CC. These findings may be beneficial to personalized treatment and medical decision-making.

Development and verification of a 7-lncRNA prognostic model based on tumor immunity for patients with ovarian cancer.

BACKGROUND: Both immune-reaction and lncRNAs play significant roles in the proliferation, invasion, and metastasis of ovarian cancer (OC). In this study, we aimed to construct an immune-related lncRNA risk model for patients with OC. METHOD: Single sample GSEA (ssGSEA) algorithm was used to analyze the proportion of immune cells in The Cancer Genome Atlas (TCGA) and the hclust algorithm was used to conduct immune typing according to the proportion of immune cells for OC patients. The stromal and immune scores were computed utilizing the ESTIMATE algorithm. Weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) analyses were utilized to detect immune cluster-related lncRNAs. The least absolute shrinkage and selection operator (LASSO) regression was conducted for lncRNA selection. The selected lncRNAs were used to construct a prognosis-related risk model, which was then validated in Gene Expression Omnibus (GEO) database and in vitro validation. RESULTS: We identify two subtypes based on the ssGSEA analysis, high immunity cluster (immunity_H) and low immunity cluster (immunity_L). The proportion of patients in immunity_H cluster was significantly higher than that in immunity_L cluster. The ESTIMATE related scores are relative high in immunity_H group. Through WGCNA and LASSO analyses, we identified 141 immune cluster-related lncRNAs and found that these genes were mainly enriched in autophagy. A signature consisting of 7 lncRNAs, including AL391832.3, LINC00892, LINC02207, LINC02416, PSMB8.AS1, AC078788.1 and AC104971.3, were selected as the basis for classifying patients into high- and low-risk groups. Survival analysis and area under the ROC curve (AUC) of the signature pointed out that this risk model had high accuracy in predicting the prognosis of patients with OC. We also conducted the drug sensitive prediction and found that rapamycin outperformed in patient with high risk score. In vitro experiments also confirmed our prediction. CONCLUSIONS: We identified 7 immune-related prognostic lncRNAs that effectively predicted survival in OC patients. These findings may offer a valuable indicator for clinical stratification management and personalized therapeutic options for these patients.

[WITHDRAWN] miR-144-3p Functions as a Tumor Suppressor in Endometrial Cancer by Targeting PRR11.

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CD44v6-O-MWNTS-Loaded Gemcitabine and CXCR4 siRNA Improves the Anti-tumor Effectiveness of Ovarian Cancer.

Ovarian cancer is one of the most common malignancies of the female reproductive system and the deadliest gynecologic cancer. CXCR4 is expressed in a variety of malignant tumors such as breast, prostate, and ovarian cancers. It is also closely related to the migration, invasion, and metastasis of tumor cells. Carbon nanotubes have great potential for targeted therapy of tumors. CD44v6 is not expressed in normal ovarian tissues but is highly expressed in ovarian epithelial carcinoma. In the present study, we applied small interfering RNA targeting the CXCR4 gene and the clinical treatment gemcitabine and oxaliplatin of ovarian cancer as the therapeutic drug, and organically integrated chemotherapy and gene therapy through carbon nanotubes, and used CD44v6 single chain antibody as the targeting moiety to explore its application in ovarian cancer treatment. Significantly, we successfully synthesized CD44v6-O-MWNTS/Gemcitabine/1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/siRNA system and the results were observed by transmission electron microscope (TEM) and scanning electron microscope (SEM). CD44v6-O-MWNTS/Gemcitabine/DOTAP was able to fully load siRNA at the ratio of 1:2.5. The carbon nanotubes could protect the siRNA. The drug release analysis showed that O-MWNTS/drug/DOTAP/siRNA was able to effectively release the siRNA, and gemcitabine or oxaliplatin in a time-dependent manner. O-MWNTS/drug/DOTAP/siRNA was able to be effectively uptake by ovarian cancer cells. The cellular uptake of CD44v6-O-MWNTS/drug/DOTAP/siRNA mainly depends on lipid raft-mediated endocytosis. CD44v6-O-MWNTS/drug/DOTAP/siRNA improved the effect of siRNA on the inhibition of ovarian cancer cell viability and the induction of cell apoptosis. The expression of CXCR4 was decreased by CD44v6-O-MWNTS/drug/DOTAP/siRNA in ovarian cancer cells. Tumorigenicity analysis in nude mice showed that CD44v6-O-MWNTS/drug/DOTAP/siRNA significantly repressed the tumor growth of ovarian cancer cells in vivo. The levels of Ki-67 and CXCR4 were repressed by CD44v6-O-MWNTS/drug/DOTAP/siRNA in the system. Thus, we concluded that the obtained CD44v6-O-MWNTS could effectively load gemcitabine or oxaliplatin, and CXCR4 siRNA, internalized by cancer cells and realized notable in vitro and in vivo inhibitory function against ovarian cancer growth. Our study provides a promising nanomaterial for the co-delivery of siRNA and anti-tumor drugs for the therapy of ovarian cancer.

A seven-m6A regulator-related CpG site-based prognostic signature for endometrial carcinoma.

BACKGROUND: Endometrial carcinoma (EC) has become a common gynecologic malignancy with a high mortality. The m6A regulators have been identified to be closely associated with multiple human cancers including EC. However, the CpG methylation signature related to m6A regulators in EC remains unclear. METHOD: The methylation profiles of EC patients including cancer samples and adjacent normal samples were obtained from The Cancer Genome Atlas (TCGA) database. The CpG sites in 20 m6A regulators were identified. Univariate Cox regression and LASSO Cox regression analysis were used to screen key CpG sites which were located at m6A regulators and significantly related to the prognosis of EC. The predictive model for EC prognosis was constructed, and multivariate Cox regression analysis was applied to explore whether the risk score derived from the model could function as an independent signature for EC prognosis. Meanwhile, a nomogram model was constructed by combing the independent prognostic signatures for prediction of the long-term survival in EC patients. RESULTS: A total of 396 CpG sites located at 20 m6A regulators were identified. A specific predictive model for EC prognosis based on 7 optimal CpG sites was constructed, which presented good performance in prognosis prediction of EC patients. Moreover, risk score was determined to be an independent signature both in the training set and validation set. By bringing in three independent prognostic factors (age, risk score, and TNM stage), the nomogram was constructed and could effectively predict the 3- and 5-year survival rates of EC patients. CONCLUSION: Our study suggested that the CpG sites located at m6A regulators might be considered as potential prognostic signatures for EC patients.

Development and validation of m6A regulators' prognostic significance for endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is the sixth most common cancer in women globally. It has been found that the expression levels of m6A regulators can be potentially used for prognostic stratification in some cancers, but the role of m6A regulators in EC prognosis remains unclear. METHODS: The data of 584 EC samples were downloaded from The Cancer Genome Atlas and the mRNA expression profiles of 20 m6A regulators were analyzed, followed by functional enrichment analysis, immune infiltration analysis, and least absolute shrinkage and selection operator method-COX regression analysis. RESULTS: The mRNA expression levels of 20 m6A regulators were significantly different between cancer samples across different grades. The 548 EC samples could be clearly divided into 2 clusters. Kaplan-Meier survival analysis proved that these two groups had highly different overall survival probabilities. Besides, the univariate regression analysis further reserved eight genes related to overall survival from the 20 m6A regulators. We established a prognostic signature including two genes, that is, IGF2BP1 and YTHDF3, that showed a strong ability for stratifying prognostically different EC patients. We identified 3239 differentially expressed genes between the high- and low-risk groups, involving in multiple biological processes and signaling pathways. Meanwhile, 6 differentially infiltrated immune cell types between the high- and low-risk groups could effectively distinguish the high- and low-risk EC groups. The expressions of immune checkpoints were different between high- and low-risk EC patients. CONCLUSION: We first report the prognostic role of m6A regulators in EC, which should contribute to a better understanding of the underlying mechanisms of EC pathogenesis and progression.

Transcriptional factor Yin Yang 1 facilitates the stemness of ovarian cancer via suppressing miR-99a activity through enhancing its deacetylation level.

The promoting effects of transcriptional factor Yin Yang 1 (YY1) have been confirmed in various tumors, however, its roles in ovarian cancer (OC) progression are still unclear. Here, Kaplan-Meier Plotter analysis was used to determine the correlation between YY1 expression and the survival of OC patients. It was found that YY1 expression was negatively correlated with the overall survival, progression-free survival and post-progression survival of OC patients. Functional experiments indicated that overexpression of YY1 facilitated the stemness of OC cells, while YY1 knockdown reduced it. MiRNAs-based RNA-sequencing analysis showed that miR-99a was the mostly upregulated miRNA in RNA extracted from OC cells with YY1 knockdown. Mechanistic studies revealed that YY1 recruited (Histone deacetylase) HDAC5 to the promoter of miR-99a, and subsequently enhanced miR-99a deacetylation level and decreased miR-99a level. Additionally, overexpression of miR-99a or knockdown of HDAC5 attenuated the promoting effects of YY1 on the stemness of OC cells. This work firstly indicated a novel YY1/miR-99a axis, which promotes the stemness of OC cells.

Gastrodin Protects Neural Progenitor Cells Against Amyloid ß (1-42)-Induced Neurotoxicity and Improves Hippocampal Neurogenesis in Amyloid ß (1-42)-Injected Mice.

The aim of this study was to investigate the neuroprotective effects of gastrodin (GAS), one of the major bioactive components of Gastrodia elata Blume (Tian Ma), against amyloid ß (Aß) (1-42)-induced neurotoxicity in primary neural progenitor cells (NPCs). We found that pretreatment with GAS not only prevents a loss in cell viability following treatment with Aß (1-42) but also counteracts Aß (1-42)-triggered release of pro-inflammatory cytokines and nitric oxide (NO) in a dose-dependent manner. Additionally, GAS was able to attenuate Aß (1-42)-induced apoptosis in NPCs, evidenced by the decreased percentage of apoptotic cells and altered expression of apoptosis-related proteins in response to GAS pretreatment prior to Aß (1-42) exposure. Furthermore, in Aß (1-42)-injected C57BL/6 mice, we found that systemic administration of GAS could improve hippocampal neurogenesis, manifested by the increased number of SOX-2 and doublecortin (DCX)-positive cells in the DG area. Mechanistic studies revealed that in NPCs, GAS could reverse the Aß (1-42)-induced increase in phosphorylation of MEK-1/2, extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinase (JNK). When combining GAS with the MEK inhibitor U0126 or the JNK inhibitor SP600125, we observed a synergistic effect against Aß (1-42)-induced reduction in cell viability of NPCs. Taken together, these results show the efficacy and underlying mechanism of GAS against amyloid ß (1-42)-induced neurotoxicity and provide substantial insight into the potential merits of GAS for its clinical application in the treatment of Alzheimer's disease.

Study on the mesothelin-specific cytotoxicity against epithelial ovarian cancer with full-length mesothelin cDNA-transduced dendritic cells.

Epithelial ovarian cancer (EOC) has the highest mortality rate among the various types of gynecological cancers. As the current therapeutic approaches are not enough, the development of more effective treatments to improve the survival of patients with EOC is urgently needed. Mesothelin (MSLN) is a cell surface glycoprotein, which is overexpressed in ovarian cancer tissues. As an immunotherapeutic approach, in this study, we investigated whether the genetically modified dendritic cells (DCs) expressing MSLN could induce cytotoxic T lymphocytes (CTLs) to produce MSLN-specific cytotoxic activity against EOCs. Here, we report that DCs transfected with full-length coding sequence of MSLN could induce MSLN-specific CTLs responses against ovarian cancer lines SKOV3 and OVCAR3 in vitro. Additionally, we identified that the death rates of ovarian cancer cells, killed by MSLN-specific CTLs, were significantly higher than the normal CTLs. Furthermore, IFN-γ production by stimulated MSLN-specific CTLs was significantly higher than that of unstimulated CTLs. This study showed that induced CTLs by DCs with full-length MSLN cDNA have effective immune response against the ovarian cancer cells, indicating that MSLN-transfected DCs vaccine has a promising prospect for the treatment of EOC.