Abnormal expression of long non-coding RNAs (lncRNA) play a significant role in the incidence and progression of high-grade serous ovarian cancer (HGSOC), which is a leading cause of mortality among gynecologic malignant tumor patients. In this study, our aim is to identify lncRNA-associated competing endogenous RNA (ceRNA ) axes that could define more reliable prognostic parameters of HGSOC, and to investigate the lncRNAs' potential mechanism of in lymphocyte infiltration.The RNA-seq and miRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database; while for obtaining the differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs), we used edgeR, limma and DESeq2. After validating the RNA, miRNA and gene expressions, using integrated three RNA expression profiles (GSE18520, GSE27651, GSE54388) and miRNA profile (GSE47841) from the Gene Expression Omnibus (GEO) database, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses through ClusterProfiler. The prognostic value of these genes was determined with Kaplan-Meier survival analysis and Cox regression analysis. The ceRNA network was constructed using Cytoscape. The correlation between lncRNAs in ceRNA network and immune infiltrating cells was analyzed by using Tumor IMmune Estimation Resource (TIMER), and gene markers of tumor-infiltrating immune cells were identified using Spearman's correlation after removing the influence of tumor purity.A total of 33 DELs (25 upregulated and eight downregulated), 134 DEMs (76 upregulated and 58 downregulated), and 1,612 DEGs (949 upregulated and 663 downregulated) were detected that could be positively correlated with overall survival (OS) of HGSOC. With the 1,612 analyzed genes, we constructed a ceRNA network, which indicated a pre-dominant involvement of the immune-related pathways. Furthermore, our data revealed that LINC00665 influenced the infiltration level of macrophages and dendritic cells (DCs). On the other hand, FTX and LINC00665, which may play their possible roles through the ceRNA axis, demonstrated a potential to inhibit Tregs and prevent T-cell exhaustion.We defined several prognostic biomarkers for the incidence and progression of HGSOC and constructed a network for ceRNA axes; among which three were indicated to have a positive correlation with lymphocyte infiltration, namely: FTX-hsa-miR-150-5p-STK11, LINC00665-hsa-miR449b-5p-VAV3 and LINC00665-hsa-miR449b-5p-RRAGD.
Objective: To compare the clinicopathological features and chemotherapy response of ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC) associated with endometriosis or not.Methods: This was a retrospective study of 128 patients diagnosed with CCC and EC from 2002 to 2017. Clinicopathological features and chemotherapy response were analyzed.Results:There were 34 women with endometriosis-associated ovarian cancer (EAOC) and 94 with non-endometriosis associated ovarian cancer (non-EAOC) according to Sampson's and Scott's criteria. The mean diagnosis age in the EAOC group was 48.65 vs. 54.39 years in non-EAOC (p = 0.002). Compared with non-EAOC, the EAOC patients were more likely to have an earlier menarche age (13 vs. 14 years, p = 0.001), a higher incidence of infertility (26.47% vs. 10.64%, p = 0.026), and an earlier stage tumor (91.18% vs. 73.40% in stages I–II, p = 0.032). At a median follow-up time of 32.9 months, overall survival among patients with EAOC was significantly longer (109.8 vs. 47.4 months, p = 0.007). Association with endometriosis (p = 0.033) was the significant favorable prognostic factors associated with survival. However, stratifying by stage, the overall survival advantage of EAOC was not significant. Although EAOC had a better prognosis, no difference was observed in chemotherapy response between the two groups (p = 0.535).Conclusions: The EAOC patients were often diagnosed at a younger age, an earlier stage, and related to nulliparity and infertility. Patients with EAOC had a better prognosis than non-EAOC, early stage rather than association with endometriosis may be the driver of survival.
Background: Abnormal expression of long non-coding RNAs (lncRNA) play a significant role in the incidence and progression of high-grade serous ovarian cancer (HGSOC), which is a leading cause of mortality among gynecologic malignant tumor patients.In this study, our aim is to identify lncRNA-associated competing endogenous RNA (ceRNA ) axes that could define more reliable prognostic parameters of HGSOC, and to investigate the lncRNAs' potential mechanism of in lymphocyte infiltration.Methods: The RNA-seq and miRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database; while for obtaining the differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs), we used edgeR, limma and DESeq2.After validating the RNA, miRNA and gene expressions, using integrated three RNA expression profiles (GSE18520, GSE27651, GSE54388) and miRNA profile (GSE47841) from the Gene Expression Omnibus (GEO) database, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses through ClusterProfiler.The prognostic value of these genes was determined with Kaplan-Meier survival analysis and Cox regression analysis.The ceRNA network was constructed using Cytoscape.The correlation between lncRNAs in ceRNA network and immune infiltrating cells was analyzed by using Tumor IMmune Estimation Resource (TIMER), and gene markers of tumor-infiltrating immune cells were identified using Spearman's correlation after removing the influence of tumor purity.Results: A total of 33 DELs (25 upregulated and 8 downregulated), 134 DEMs (76 upregulated and 58 downregulated), and 1, 612 DEGs (949 upregulated and 663 downregulated) were detected that could be positively correlated with overall survival (OS) of HGSOC.With the 1, 612 analyzed genes, we constructed a ceRNA network, which indicated a pre-dominant involvement of the immune-related pathways.Furthermore, our data revealed that LINC00665 influenced the infiltration level of macrophages and dendritic cells (DCs).On the other hand, FTX and LINC00665, which may play their possible roles through the ceRNA axis, demonstrated a
Background: Abnormal expression of long non-coding RNAs (lncRNA) play a significant role in the incidence and progression of high-grade serous ovarian cancer (HGSOC), which is a leading cause of mortality among gynecologic malignant tumor patients.In this study, our aim is to identify lncRNA-associated competing endogenous RNA (ceRNA ) axes that could define more reliable prognostic parameters of HGSOC, and to investigate the lncRNAs' potential mechanism of in lymphocyte infiltration.Methods: The RNA-seq and miRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database; while for obtaining the differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs), we used edgeR, limma and DESeq2.After validating the RNA, miRNA and gene expressions, using integrated three RNA expression profiles (GSE18520, GSE27651, GSE54388) and miRNA profile (GSE47841) from the Gene Expression Omnibus (GEO) database, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses through ClusterProfiler.The prognostic value of these genes was determined with Kaplan-Meier survival analysis and Cox regression analysis.The ceRNA network was constructed using Cytoscape.The correlation between lncRNAs in ceRNA network and immune infiltrating cells was analyzed by using Tumor IMmune Estimation Resource (TIMER), and gene markers of tumor-infiltrating immune cells were identified using Spearman's correlation after removing the influence of tumor purity.Results: A total of 33 DELs (25 upregulated and 8 downregulated), 134 DEMs (76 upregulated and 58 downregulated), and 1, 612 DEGs (949 upregulated and 663 downregulated) were detected that could be positively correlated with overall survival (OS) of HGSOC.With the 1, 612 analyzed genes, we constructed a ceRNA network, which indicated a pre-dominant involvement of the immune-related pathways.Furthermore, our data revealed that LINC00665 influenced the infiltration level of macrophages and dendritic cells (DCs).On the other hand, FTX and LINC00665, which may play their possible roles through the ceRNA axis, demonstrated a
Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.
A dopant-free hole-transporting material (HTM), with (2-ethylhexyl)-9H-carbazole as core and N,N-di-p-methylthiophenylamine as end groups, termed CMT, has been designed and synthesized by a simple method. For the first time, four methylthiol groups have been introduced, rather than methoxy groups, at the para position of the diphenylamine. Under AM 1.5 illumination at 100 mW cm–2, perovskite solar cells based on CH3NH3PbI3 with pristine CMT as the HTM achieved a power conversion efficiency of 13.05%, with a short-circuit current density of 21.82 mA cm–2, an open-circuit voltage (VOC) of 1.03 V, and a fill factor of 58.23%. The value of VOC is comparable to that of the device based on 2,2′,7,7′-tetrakis(N,N-di-para-methoxy-phenylamino)-9,9′-spirobifluorene, which was 1.02 V.
Highlights•It is the first study to identify neoandrographolide as a novel inhibitor of Rab5.•Neoandrographolide can occupy the surface groove of Rab5 for inhibiting its activity.•Neoandrographolide exhibits anticancer effect on lung cancer by targeting Rab5.Graphical abstractAbstractRab5 is a small GTPase that plays a crucial role in oncogenic signal transduction, which was considered as an attractive target for cancer therapy. Rapid GDP/GTP exchange in the packet of Rab5 sustains its high activity for promoting cancer progression. However, Rab5 currently remains undruggable due to the lack of specific inhibitor. Herein, we reported the discovery of a novel Rab5 inhibitor, neoandrographolide (NAP), by using high-throughput virtual screening with a natural product library containing 7459 compounds, which can occupy the surface groove of Rab5, competing with GDP/GTP for the binding. Ser34 is the most important residue in the groove of Rab5, as it forms most hydrogen-bond interactions with GDP/GTP or NAP, and in silico mutation of Ser34 decreased the stabilization of Rab5. Moreover, fluorescence titration experiment and isothermal titration calorimetry (ITC) assay revealed a direct binding between NAP and Rab5. Biochemical and cell-based assays showed that NAP treatment not only diminished the activity of Rab5, but also suppressed cell growth of cancer cell. This finding firstly identifies NAP as a novel inhibitor of Rab5, which directly binds with Rab5 by occupying the GDP/GTP binding groove to suppress its functions, highlighting a great potential of NAP to be developed as a chemotherapeutic agent in cancer therapy.
Background: Recent findings suggest that both dietary protein intake and hand grip strength (HGS) were associated with cognitive function, however, few studies have been devoted specifically to the mediation effect of HGS on the association of the dietary protein with cognitive function. Objectives: To confirm the hypothesis that HGS mediated the association of dietary protein intake with cognitive function in the elderly, which was modified by triglyceride level and methylenetetrahydrofolate reductase (MTHFR) gene status. Methods: This cross-sectional study included 3,268 participants. Dietary protein intake, HGS, and cognitive function were collected by food frequency questionnaires (FFQ), grip measurements and mini mental state examination (MMSE), respectively. In this mediation analysis, dietary protein intake was entered as an independent variable, HGS was entered as a mediator, and cognitive function was entered as a dependent variable. Results: HGS significantly mediated the associations of dietary protein (β = 0.0013, 95% CI: 0.0007, 0.0022), animal protein (β = 0.0024, 95% CI: 0.0012, 0.0037), and plant protein intake (β = 0.0011, 95% CI: 0.0001, 0.0023) with cognitive function in total participants, with the mediated proportion of 16.19%, 12.45% and 20.57%, respectively. Furthermore, significant mediation effects of HGS on the associations of dietary protein, animal protein, and plant protein intake with MMSE score were found in the elderly without hypertriglyceridemia or in MTHFR C677T CC/CT carriers. Conclusion: This study suggested that HGS mediated the association of dietary protein intake with cognitive function, and this mediation effect was modified by triglyceride level and MTHFR C677T gene status.
Background: Abnormal expression of long non-coding RNAs (lncRNA) play a significant role in the incidence and progression of high-grade serous ovarian cancer (HGSOC), which is a leading cause of mortality among gynecologic malignant tumor patients.In this study, our aim is to identify lncRNA-associated competing endogenous RNA (ceRNA ) axes that could define more reliable prognostic parameters of HGSOC, and to investigate the lncRNAs' potential mechanism of in lymphocyte infiltration.Methods: The RNA-seq and miRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database; while for obtaining the differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs), we used edgeR, limma and DESeq2.After validating the RNA, miRNA and gene expressions, using integrated three RNA expression profiles (GSE18520, GSE27651, GSE54388) and miRNA profile (GSE47841) from the Gene Expression Omnibus (GEO) database, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses through ClusterProfiler.The prognostic value of these genes was determined with Kaplan-Meier survival analysis and Cox regression analysis.The ceRNA network was constructed using Cytoscape.The correlation between lncRNAs in ceRNA network and immune infiltrating cells was analyzed by using Tumor IMmune Estimation Resource (TIMER), and gene markers of tumor-infiltrating immune cells were identified using Spearman's correlation after removing the influence of tumor purity.Results: A total of 33 DELs (25 upregulated and 8 downregulated), 134 DEMs (76 upregulated and 58 downregulated), and 1, 612 DEGs (949 upregulated and 663 downregulated) were detected that could be positively correlated with overall survival (OS) of HGSOC.With the 1, 612 analyzed genes, we constructed a ceRNA network, which indicated a pre-dominant involvement of the immune-related pathways.Furthermore, our data revealed that LINC00665 influenced the infiltration level of macrophages and dendritic cells (DCs).On the other hand, FTX and LINC00665, which may play their possible roles through the ceRNA axis, demonstrated a
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