Identification of a novel ferroptosis-inducing micropeptide in bladder cancer.

Bladder cancer (BC) is a common malignancy in males, and currently lacks ideal therapeutic approaches. Exploring emerging therapeutic targets from the perspective of endogenous peptides to improve the prognosis of bladder cancer patients holds promise. In this study, we have identified CTSGDP-13, a novel endogenous peptide, which demonstrates potential anti-cancer effects in BC. Our findings reveal that CTSGDP-13 can promote ferroptosis in BC cells, both in vitro and in vivo, leading to the inhibition of BC progression. Furthermore, we have identified TRIM25 as a downstream regulatory target of CTSGDP-13. The expression of TRIM25 is significantly upregulated in BC, and its inhibition of ferroptosis promotes BC progression. Mechanistic studies have shown that CTSGDP-13 promotes the ubiquitination and subsequent degradation of TRIM25 by disrupting its interaction with the deubiquitinase USP7. Further investigations indicate that CTSGDP-13 promotes ferroptosis in BC by regulating the USP7/TRIM25/KEAP1 axis. The elucidation of the functional mechanisms of natural CTSGDP-13 and TRIM25 holds promise in providing valuable therapeutic targets for BC diagnosis and treatment.

Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment.

Metabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.

Blood lipids, lipid-regulatory medications, and risk of bladder cancer: a Mendelian randomization study.

Background: The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study. Methods: Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests. Results: There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05). Conclusion: This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.

Repair of the Urethral Mucosa Defect Model Using Adipose-Derived Stem Cell Sheets and Monitoring the Fate of Indocyanine Green-Labeled Sheets by Near Infrared-II.

Treatment of urethral mucosa defects is a major challenge in urology. Synthetic materials or autologous mucosa does not provide satisfactory treatment options for long-term or large urethral mucosa defects. In response to this problem, we used autologous adipose-derived stem cells (ADSCs) to synthesize cell sheets in vitro for repairing urethral mucosa defect models. In order to monitor the localization and distribution of cell sheets in vivo, cells and sheets were labeled with indocyanine green (ICG) and the second near-infrared (NIR-II) fluorescence imaging was performed. ICG-based NIR-II imaging can successfully track ADSCs and sheets in vivo up to 8 W. Then, rabbit urethral mucosa defect models were repaired with ICG-ADSCs sheets. At 3 months after operation, retrograde urethrography showed that ADSC sheets could effectively repair urethral mucosa defect and restore urethral patency. Histological analysis showed that in ADSC sheet groups, continuous epithelial cells covered the urethra at the transplantation site, and a large number of vascular endothelial cells could also be seen. In the cell-free sheet group, there was no continuous epithelial cell coverage at the repair site of the urethra, and the expression of pro-inflammatory factor TNF-α was increased. It shows that the extracellular matrix alone without cells is not suitable for repairing urethral defects. Surviving ADSCs in the sheets may play a key role in the repair process. This study provides a new tracing method for tissue engineering to dynamically track grafts using an NIR-II imaging system. The ADSC sheets can effectively restore the structure and function of the urethra. It provides a new option for the repair of urethral mucosa defects.

The potential mechanism of Longsheyangquan Decoction on the treatment of bladder cancer: Systemic network pharmacology and molecular docking.

Our goal was to explore the bioactive constituents of Longsheyangquan (LSYQ) Decoction and elucidate its mechanisms on the treatment of bladder cancer (BCa). A total of 38 compounds were selected based on their pharmacokinetic properties in three large traditional Chinese medicine (TCM) databases. 654 putative targets of LSYQ Decoction were predicted using a structure-based, reverse-docking algorithm online, of which 343 overlapped with BCa-related protein-coding genes. The protein-protein interaction (PPI) network was constructed to perform module analysis for further Gene Ontology (GO) annotations and Kyoto Encyclopedia Genes and Genomes (KEGG) pathway enrichment analysis, which identified CDK2, EGFR, MMP9 and PTGS2 as hub targets. The TCM-compound-target network and compound-target-pathway network together revealed that quercetin, diosmetin, enhydrin and luteolin were the main components of LSYQ Decoction. Finally, molecular docking showed the affinity between the key compounds and the hub target proteins to verify the accuracy of drug target prediction in the first place. The present study deciphered the core components and targets of LSYQ Decoction on the treatment of BCa in a comprehensive systemic pharmacological manner.

m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer.

Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m6A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m6A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m6A regulators. Each subtype's signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m6A subtypes were predicted by Gene Ontology. The m6A score was developed to predict m6A activation. The association of the m6A score with patients' survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m6A score to evaluate the m6A regulator activation for PCa. The m6A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m6A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m6A regulators in PCa progression and the m6A score is a promising predictive biomarker for PCa metastasis.

Transcriptional Repression of Aerobic Glycolysis by OVOL2 in Breast Cancer.

Aerobic glycolysis (Warburg effect), a hallmark of cancer, plays a critical role in cancer cell growth and metastasis; however, direct inhibition of the Warburg effect remains largely unknown. Herein, the transcription factor OVO-like zinc finger 2 (OVOL2) is demonstrated to directly repress the expression of several glycolytic genes, blocking the Warburg effect and breast tumor growth and metastasis in vitro and in vivo. OVOL2 inhibits glycolysis by recruiting the nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3). The tumor suppressor p53, a key regulator of cancer metabolism, activates OVOL2 by binding to the oncoprotein mouse double minute 2 homolog (MDM2) and inhibiting MDM2-mediated ubiquitination and degradation of OVOL2. OVOL2 expression is negatively correlated with glycolytic gene expression and can be a good predictor of prognosis in patients with breast cancer. Therefore, targeting the p53/MDM2/OVOL2 axis provides a potential avenue for cancer treatment, especially breast cancer.

Immunological Characteristics of Alternative Splicing Profiles Related to Prognosis in Bladder Cancer.

Several studies have found that pathological imbalance of alterative splicing (AS) events is associated with cancer susceptibility. carcinogenicity. Nevertheless, the relationship between heritable variation in AS events and carcinogenicity has not been extensively explored. Here, we downloaded AS event signatures, transcriptome profiles, and matched clinical information from The Cancer Genome Atlas (TCGA) database, identified the prognostic AS-related events via conducting the univariate Cox regression algorism. Subsequently, the prognostic AS-related events were further reduced by the least absolute shrinkage and selection operator (LASSO) logistic regression model, and employed for constructing the risk model. Single-sample (ssGSEA), ESTIMATE, and the CIBERSORT algorithms were conducted to evaluate tumor microenvironment status. CCK8, cell culture scratch, transwell invasion assays and flow cytometry were conducted to confirm the reliability of the model. We found 2751 prognostic-related AS events, and constructed a risk model with seven prognostic-related AS events. Compared with high-risk score patients, the overall survival rate of the patients with low-risk score was remarkably longer. Besides, we further found that risk score was also closely related to alterations in immune cell infiltration and immunotherapeutic molecules, indicating its potential as an observation of immune infiltration and clinical response to immunotherapy. In addition, the downstream target gene (DYM) could be a promising prognostic factor for bladder cancer. Our investigation provided an indispensable reference for ulteriorly exploring the role of AS events in the tumor microenvironment and immunotherapy efficiency, and rendered personalized prognosis monitoring for bladder cancer.

USP18 reduces paclitaxol sensitivity of triple-negative breast cancer via autophagy.

Paclitaxol is a first-line treatment for triple-negative breast cancer (TNBC). The molecular mechanisms underlying paclitaxol resistance in TNBC remain largely unclear. In this study, differential expressed genes (DEGs) between TNBC cells and paclitaxol-resistant (taxol-R) TNBC cells were screened by bioinformatics analysis. Among these DEGs, USP18 mRNA expression was significantly increased in taxol-R TNBC cells. USP18 overexpression reduced paclitaxol sensitivity by decreasing paclitaxol-induced apoptosis and cell cycle arrest in TNBC cells. In contrast, USP18 knockdown increased paclitaxol mediated anticancer activity in taxol-R TNBC cells in vitro and in vivo. Mechanistically, USP18 induced autophagy, an important pathway in chemotherapy resistance. The autophagy inhibitor leupeptin could effectively reverse the effect of USP18 on paclitaxol resistance phenotype. These findings suggested that USP18 may be a promising target for overcoming paclitaxol resistance in TNBC.

Transcriptome subtyping of metastatic Castration Resistance Prostate Cancer (mCRPC) for the precision therapeutics: an in silico analysis.

BACKGROUND: Men with metastatic prostate cancer who are treated with androgen deprivation therapy (ADT) typically develop therapeutic resistance eventually and have a dismal outcome. Moreover, the limited survival benefit observed in only a proportion of patients receiving novel therapeutics including immune checkpoint blockade and PARP inhibitors suggests the biological heterogeneity of mCRPCs. METHODS: To understand the heterogeneity of mCRPC, we analyzed the transcriptome of 231 mCRPCs and identified four disparate biological subtypes (Basal, Homologous Recombination Repair (HRR), Neuroendocrine and Luminal). The package "randomForest" was used to construct a Random Forest model. Circular plots were used for visualization of TMPRSS2-ERG fusion in each subtype. RESULTS: The Luminal subtype of mCRPCs has higher Androgen Receptor (AR) expression and copy number alterations as compared with the other subtypes. Genes in HRR pathway are relatively downregulated in most subtypes regardless of the genetic alterations, except for the HRR and NE subtypes, suggesting potential resistance of the HRR and NE mCRPCs to PARP inhibitor treatment. The HRR subtype has relatively more immune cell infiltration and higher expression of immune checkpoints, highlighting that the efficacy of immunotherapy should be evaluated in this particular subtype. TMPRSS2-ERG fusion is the most frequent gene fusion in all mCRPCs, and the Basal subtype has a higher frequency of this fusion than the other subtypes. CONCLUSIONS: Our results reveal that the stratification of mCRPC according to transcriptome is informative of personalized therapeutics in the treatment of mCRPCs. The predictive capacity of the transcriptome subtyping of mCRPC warrants further exploration in the future.

DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer.

Background: Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy. Methods: We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis. Findings: Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses. Conclusion: Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.

Radiogenomics Map Reveals the Landscape of m6A Methylation Modification Pattern in Bladder Cancer.

We aimed to develop a noninvasive radiomics approach to reveal the m6A methylation status and predict survival outcomes and therapeutic responses in patients. A total of 25 m6A regulators were selected for further analysis, we confirmed that expression level and genomic mutations rate of m6A regulators were significantly different between cancer and normal tissues. Besides, we constructed methylation modification models and explored the immune infiltration and biological pathway alteration among different models. The m6A subtypes identified in this study can effectively predict the clinical outcome of bladder cancer (including m6AClusters, geneClusters, and m6Ascore models). In addition, we observed that immune response markers such as PD1 and CTLA4 were significantly corelated with the m6Ascore. Subsequently, a total of 98 obtained digital images were processed to capture the image signature and construct image prediction models based on the m6Ascore classification using a radiomics algorithm. We constructed seven signature radiogenomics models to reveal the m6A methylation status, and the model achieved an area under curve (AUC) degree of 0.887 and 0.762 for the training and test datasets, respectively. The presented radiogenomics models, a noninvasive prediction approach that combined the radiomics signatures and genomics characteristics, displayed satisfactory effective performance for predicting survival outcomes and therapeutic responses of patients. In the future, more interdisciplinary fields concerning the combination of medicine and electronics remains to be explored.

Calculated identification of mutator-derived lncRNA signatures of genomic instability to predict the clinical outcome of muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is one of the most important type of bladder cancer, with a high morbidity and mortality rate. Studies have found that long non-coding RNA (lncRNA) plays a key role in maintaining genomic instability. However, Identification of lncRNAs related to genomic instability (GIlncRNAs) and their clinical significance in cancers have not been extensively studied yet. METHODS: Here, we downloaded the lncRNA expression profiles, somatic mutation profiles and clinical related data in MIBC patients from The Cancer Genome Atlas (TCGA) database. A lncRNA computational framework was used to find differentially expressed GIlncRNAs. Multivariate Cox regression analysis was used to construct a genomic instability-related lncRNA signature (GIlncSig). Univariate and multivariate Cox analyses were used to assess the independent prognostic for the GIlncSig and other key clinical factors. RESULTS: We found 43 differentially expressed GIlncRNAs and constructed the GIlncSig with 6 GIlncRNAs in the training cohort. The patients were divided into two risk groups. The overall survival of patients in the high-risk group was lower than that in the low-risk group (P < 0.001), which were further verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression showed that the GIlncSig was an independent prognostic factor. In addition, the GIlncSig correlated with the genomic mutation rate of MIBC, indicating its potential as a measure of the degree of genomic instability. The GIlncSig was able to divide FGFR3 wild- and mutant-type patients into two risk groups, and effectively enhanced the prediction effect. CONCLUSION: Our study introduced an important reference for further research on the role of GIlncRNAs, and provided prognostic indicators and potential biological therapy targets for MIBC.

A novel survival model based on a Ferroptosis-related gene signature for predicting overall survival in bladder cancer.

BACKGROUND: The effective treatment and prognosis prediction of bladder cancer (BLCA) remains a medical problem. Ferroptosis is an iron-dependent form of programmed cell death. Ferroptosis is closely related to tumour occurrence and progression, but the prognostic value of ferroptosis-related genes (FRGs) in BLCA remains to be further clarified. In this study, we identified an FRG signature with potential prognostic value for patients with BLCA. METHODS: The corresponding clinical data and mRNA expression profiles of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to extract FRGs related to survival time, and a Cox regression model was used to construct a multigene signature. Both principal component analysis (PCA) and single-sample gene set enrichment analysis (ssGSEA) were performed for functional annotation. RESULTS: Clinical traits were combined with FRGs, and 15 prognosis-related FRGs were identified by Cox regression. High expression of CISD1, GCLM, CRYAB, SLC7A11, TFRC, ACACA, ZEB1, SQLE, FADS2, ABCC1, G6PD and PGD was related to poor survival in BLCA patients. Multivariate Cox regression was used to construct a prognostic model with 7 FRGs that divided patients into two risk groups. Compared with that in the low-risk group, the overall survival (OS) of patients in the high-risk group was significantly lower (P < 0.001). In multivariate regression analysis, the risk score was shown to be an independent predictor of OS (HR = 1.772, P < 0.01). Receiver operating characteristic (ROC) curve analysis verified the predictive ability of the model. In addition, the two risk groups displayed different immune statuses in ssGSEA and different distributed patterns in PCA. CONCLUSION: Our research suggests that a new gene model related to ferroptosis can be applied for the prognosis prediction of BLCA. Targeting FRGs may be a treatment option for BLCA.

Corrigendum: MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect.

[This corrects the article DOI: 10.3389/fcell.2020.615154.].

MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect.

The Warburg effect (aerobic glycolysis) is a hallmark of cancer and is becoming a promising target for diagnosis and therapy. Phosphoglycerate kinase 1 (PGK1) is the first adenosine triphosphate (ATP)-generating glycolytic enzyme in the aerobic glycolysis pathway and plays an important role in cancer development and progression. However, how microRNAs (miRNAs) regulate PGK1-mediated aerobic glycolysis remains unknown. Here, we show that miR-16-1-3p inhibits PGK1 expression by directly targeting its 3'-untranslated region. Through inhibition of PGK1, miR-16-1-3p suppressed aerobic glycolysis by decreasing glucose uptake, lactate and ATP production, and extracellular acidification rate, and increasing oxygen consumption rate in breast cancer cells. Aerobic glycolysis regulated by the miR-16-1-3p/PGK1 axis is critical for modulating breast cancer cell proliferation, migration, invasion and metastasis in vitro and in vivo. In breast cancer patients, miR-16-1-3p expression is negatively correlated with PGK1 expression and breast cancer lung metastasis. Our findings provide clues regarding the role of miR-16-1-3p as a tumor suppressor in breast cancer through PGK1 suppression. Targeting PGK1 through miR-16-1-3p could be a promising strategy for breast cancer therapy.

The study on analysis of risk factors for severity of white matter lesions and its correlation with cerebral microbleeds in the elderly with lacunar infarction.

This study aimed to explore the risk factors for severity of white matter lesions and its correlation with in the elderly with lacunar infarction.Patients (range, 70-85 years) with lacunar infarction treated in a hospital in China from 2016 to 2017were enrolled. Fazekas rating scale (0-6 points) was used to assess severity of white matter lesions. Risk factors for the severity of white matter lesions and correlation between cerebral microbleeds and white matter lesions in the elderly with lacunar infarction were studied.The elderly (81-85 years' old, odds ratio [OR]: 2.423, 95% confidence interval [CI]: 1.795-3.271, P = .018; 76∼80 years' old, OR: 3.113, 95% CI: 1.723-5.625, P = .043), carotid atherosclerosis (OR: 3.062, 95% CI:1.715-5.468, P < .001), history of hypertension (OR: 3.694, 95% CI: 2.031-6.717, P < .001) were risk factors for the severity of white matter lesions. The white matter lesions score increased corresponding to increase in the cerebral microbleeds grade (P < .001). The white matter lesions score was higher in the cerebral microbleeds combined with the white matter lesions group than in the white matter lesions group (P < .01). After correcting the effects of age, there was a correlation between white matter lesions and cerebral microbleeds (P < .001). Logistic analysis revealed that the patients' age (81-85 years' old, OR: 2.722, 95% CI: 1.985-3.734, P = .019; 76∼80 years' old, OR: 1.857, 95% CI: 1.075-3.207, P = .031), history of hypertension (OR: 2.931, 95% CI: 1.136-7.567, P = 0.0.036), systolic blood pressure (OR: 1.049, 95% CI: 1.015-1.084, P = .007), high-sensitivity C-reactive protein (OR: 1.504, 95% CI: 1.254-1.803, P < .001), homocysteine (OR: 1.076, 95% CI: 1.020-1.136, P = .009), and carotid atherosclerosis (OR: 1.389, 95% CI: 1.103-1.748, P = .010) were significant risk factors for combined cerebral microbleeds with white matter lesions in patients with lacunar infarction.The elderly, carotid atherosclerosis, history of hypertension were risk factors for the severity of white matter lesions. Cerebral microbleeds were positively correlated with the severity of white matter lesions.

Prognosis and clinicopathological characteristics of renal cell carcinoma: does bilateral occurrence influence overall and cancer-specific survival?

BACKGROUND: To compare clinicopathological characteristics and prognosis of bilateral and unilateral renal cell carcinoma. METHODS: Data from patients who had been diagnosed with renal cell carcinoma (RCC) and undergone radical nephrectomy (RN) from 2004 to 2014 were extracted from the Surveillance, Epidemiology, and End Results (SEER) registry. The χ2 test was used to compare relevant characteristics between patients with bilateral and unilateral RCC. Survival curves were generated by the Kaplan-Meier method and the log-rank test was used to compare overall survival (OS) and cancer-specific survival (CSS). Cox proportional hazards regression analysis was used to determine the risk factors for OS and CSS. RESULTS: The study cohort comprised 41,573 patients. A nonlinear relationship between age and OS and CSS was identified with and without adjusting for potential factors. Threshold effect analysis revealed that ages 54 and age 74 were the turning points associated with changes in OS and CSS, respectively. Multivariate Cox regression analysis demonstrated that age category, race, grade, and T, N, and M stage were prognostic factors for OS and CSS of patients with RCC. Additionally, sex and pathology were significantly associated with OS. CONCLUSIONS: Bilateral occurrence does not influence OS and CSS in patients with RCC who have undergone RN. The risk of poor OS and CSS was higher with greater age category, tumor grade, and T stage. Patients in different age categories (<54, ≥54 and <74, ≥74 years) may benefit from individualized attention and therapeutic strategies.

Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.

BACKGROUND: Previous randomised trials have shown an overwhelming benefit of mechanical thrombectomy for treating patients with stroke caused by large vessel occlusion of the anterior circulation. Whether endovascular treatment is beneficial for vertebrobasilar artery occlusion remains unknown. In this study, we aimed to investigate the safety and efficacy of endovascular treatment of acute strokes due to vertebrobasilar artery occlusion. METHODS: We did a multicentre, randomised, open-label trial, with blinded outcome assessment of thrombectomy in patients presenting within 8 h of vertebrobasilar occlusion at 28 centres in China. Patients were randomly assigned (1:1) to endovascular therapy plus standard medical therapy (intervention group) or standard medical therapy alone (control group). The randomisation sequence was computer-generated and stratified by participating centres. Allocation concealment was implemented by use of sealed envelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 or lower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treat basis. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial haemorrhage, device-related complications, and other severe adverse events. The BEST trial is registered with ClinicalTrials.gov, NCT02441556. FINDINGS: Between April 27, 2015, and Sept 27, 2017, we assessed 288 patients for eligibility. The trial was terminated early after 131 patients had been randomly assigned (66 patients to the intervention group and 65 to the control group) because of high crossover rate and poor recruitment. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0-3 at 90 days according to treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of 65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81-3·74). Secondary prespecified analyses of the primary outcome, done to assess the effect of crossovers, showed higher rates of mRS 0-3 at 90 days in patients who actually received the intervention compared with those who received standard medical therapy alone in both per-protocol (28 [44%] of 63 patients with intervention vs 13 [25%] of 51 with standard therapy; adjusted OR 2·90, 95% CI 1·20-7·03) and as-treated (36 [47%] of 77 patients with intervention vs 13 [24%] of 54 with standard therapy; 3·02, 1·31-7·00) populations. The 90-day mortality was similar between groups (22 [33%] of 66 patients in the intervention vs 25 [38%] of 65 in the control group; p=0·54) despite a numerically higher prevalence of symptomatic intracranial haemorrhage in the intervention group. INTERPRETATION: There was no evidence of a difference in favourable outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone. Results might have been confounded by loss of equipoise over the course of the trial, resulting in poor adherence to the assigned study treatment and a reduced sample size due to the early termination of the study. FUNDING: Jiangsu Provincial Special Program of Medical Science.

Identification of key DNA methylation-driven genes in prostate adenocarcinoma: an integrative analysis of TCGA methylation data.

BACKGROUND: Prostate cancer (PCa) remains the second leading cause of deaths due to cancer in the United States in men. The aim of this study was to perform an integrative epigenetic analysis of prostate adenocarcinoma to explore the epigenetic abnormalities involved in the development and progression of prostate adenocarcinoma. The key DNA methylation-driven genes were also identified. METHODS: Methylation and RNA-seq data were downloaded for The Cancer Genome Atlas (TCGA). Methylation and gene expression data from TCGA were incorporated and analyzed using MethylMix package. Methylation data from the Gene Expression Omnibus (GEO) were assessed by R package limma to obtain differentially methylated genes. Pathway analysis was performed on genes identified by MethylMix criteria using ConsensusPathDB. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also applied for the identification of pathways in which DNA methylation-driven genes significantly enriched. The protein-protein interaction (PPI) network and module analysis in Cytoscape software were used to find the hub genes. Two methylation profile (GSE112047 and GSE76938) datasets were utilized to validate screened hub genes. Immunohistochemistry of these hub genes were evaluated by the Human Protein Atlas. RESULTS: A total of 553 samples in TCGA database, 32 samples in GSE112047 and 136 samples in GSE76938 were included in this study. There were a total of 266 differentially methylated genes were identified by MethylMix. Plus, a total of 369 differentially methylated genes and 594 differentially methylated genes were identified by the R package limma in GSE112047 and GSE76938, respectively. GO term enrichment analysis suggested that DNA methylation-driven genes significantly enriched in oxidation-reduction process, extracellular exosome, electron carrier activity, response to reactive oxygen species, and aldehyde dehydrogenase [NAD(P)+] activity. KEGG pathway analysis found DNA methylation-driven genes significantly enriched in five pathways including drug metabolism-cytochrome P450, phenylalanine metabolism, histidine metabolism, glutathione metabolism, and tyrosine metabolism. The validated hub genes were MAOB and RTP4. CONCLUSIONS: Methylated hub genes, including MAOB and RTP4, can be regarded as novel biomarkers for accurate PCa diagnosis and treatment. Further studies are needed to draw more attention to the roles of these hub genes in the occurrence and development of PCa.