METTL3-mediated m6A modification of pri-miR-148a-3p affects prostate cancer progression by regulating TXNIP.

OBJECTIVE: Prostate cancer (PCa) severely affects men's health worldwide. The mechanism of methyltransferase-like 3 (METTL3) in affecting PCa development by regulating miR-148a-3p expression via N6-methyladenosine (m6A) modification was investigated. METHODS: METTL3, miR-148a-3p, and thioredoxin interacting protein (TXNIP) levels were determined using RT-qPCR and Western blotting. The m6A modification level of miR-148a-3p was observed by Me-RIP assay. Bioinformatics website predicted miR-148a-3p and TXNIP levels in PCa and their correlation, and the binding site between them was verified by dual-luciferase assay. The proliferation, migration, invasion, and apoptosis of PCa cells were examined by CCK-8 assay, Transwell assay, and flow cytometry. A transplanted tumor model was established in nude mice to observe the tumor growth ability, followed by determination of TXNIP levels in tumor tissues by immunohistochemistry. RESULTS: METTL3 interference restrained the proliferation, migration, and invasion and promoted apoptosis of PCa cells. METTL3 up-regulated miR-148a-3p by promoting the m6A modification of pri-miR-148a-3p in PCa cells. miR-148a-3p overexpression nullified the inhibitory actions of silencing METTL3 on PCa cell growth. miR-148a-3p facilitated PCa cell growth by silencing TXNIP. METTL3 interference inhibited tumor growth by down-regulating miR-148a-3p and up-regulating TXNIP. CONCLUSION: METTL3 promoted miR-148a-3p by mediating the m6A modification of pri-miR-148a-3p, thereby targeting TXNIP, interfering with METTL3 to inhibit the proliferation, migration and invasion of PCa cells, promote apoptosis, and inhibit tumor growth in nude mice.

Identification of a Novel Pyroptosis-Related Gene Signature for Predicting Prognosis in Bladder Cancer.

Bladder cancer (BC) has an unpredictable prognosis. Pyroptosis is a novel form of programmed cell death. However, whether the pyroptosis-related genes have a prognostic value remains unknown. In this study, we downloaded the mRNA expression and clinical data of BC patients and used the LASSO Cox analysis was employed to build a signature. High-risk patients had a significantly lower overall survival (OS) (p < .0001). Single-sample gene set enrichment analysis (ssGSEA) indicated that the tumor immune microenvironment was different between the two risk groups. In conclusion, a pyroptosis-related signature can be used for OS prediction of patients with BCs.

Integrated Bulk and Single-Cell RNA-Sequencing Reveals the Effects of Circadian Rhythm Disruption on the Metabolic Reprogramming of CD4+ T Cells in Alzheimer's Disease.

Although growing evidence suggests close correlations between Alzheimer's disease (AD) and circadian rhythm disruption (CRD), few studies have focused on the influence of circadian rhythm on levels of immune cells in AD. We aimed to delineate the mechanism underlying the effects of circadian related genes on T cell immune function in AD. A total of 112 brain samples were used to construct the CRD-related model by performing weighted gene co-expression network analysis and machine learning algorithms (LASSO, SVM-RFE, and RF). The ssGSEA method was used to calculate the CRDscore in order to quantify CRD status. Using single-cell transcriptome data of CSF cells, we investigated the CD4+ T cell metabolism and cell-cell communication in high- and low-risk CRD groups. Connectivity map (CMap) was applied to explore small molecule drugs targeting CRD, and the expression of the signature gene GPR4 was further validated in AD. The CRDscore algorithm, which is based on 23 circadian-related genes, can effectively classify the CRD status in AD datasets. The single-cell analysis revealed that the CD4+ T cells with high CRDscore were characterized by hypometabolism. Cell communication analysis revealed that CD4+ T cells might be involved in promoting CD8+ T cell adhesion under CRD, which may facilitate T cell infiltration into the brain parenchyma. Overall, this study indicates the potential connotation of circadian rhythm in AD, providing insights into understanding T cell metabolic reprogramming under CRD.

Predicting Survival in Patients with Neuroendocrine Prostate Cancer: A SEER-Based Comprehensive Study.

PURPOSE: Neuroendocrine prostate cancer (NEPC) represents a particularly aggressive subtype of prostate cancer with a challenging prognosis. The purpose of this investigation is to craft and confirm the reliability of nomograms that can accurately forecast the 1-, 3-, and 5-year overall survival (OS) and cancer-specific survival (CSS) rates for individuals afflicted with NEPC. MATERIALS AND METHODS: Data pertaining to patients diagnosed with NEPC within the timeframe of 2010 to 2020 was meticulously gathered and examined from the Surveillance, Epidemiology, and End Results Program (SEER). To predict OS and CSS, we devised and authenticated two distinct nomograms, utilizing predictive variables pinpointed through both univariate and multivariate Cox regression analyses. RESULTS: The study encompassed 393 of NEPC patients, who were systematically divided into training and validation cohorts at a 2:1 ratio. Key prognostic factors were isolated, verified, and integrated into the respective nomograms for OS and CSS. The performance metrics, denoted by C-indices, stood at 0.730, 0.735 for the training set, and 0.784, 0.756 for the validation set. The precision and clinical relevance of the nomograms were further corroborated by the analysis of receiver operating characteristic curves, calibration plots, and decision curve analyses. CONCLUSIONS: The constructed nomograms have demonstrated impressive efficacy in forecasting the 1-, 3-, and 5-year OS and rates for patients with NEPC. Implementing these predictive tools in clinical settings is anticipated to considerably enhance the care and treatment planning for individuals diagnosed with this aggressive form of prostate cancer, thus providing tailored and more precise prognostic assessments.

Evaluating the effectiveness of cytoreductive surgery in oligometastatic prostate cancer: insights from quantitative analysis and retrospective cohort studies.

BACKGROUND: Oligometastatic prostate cancer (OmPCa) is characterized by a restricted number of metastatic lesions confined to a limited organ range, presenting a distinct clinical challenge. The role of cytoreductive prostatectomy (CRP) in managing this specific metastatic stage has gained attention but remains controversial. This study aims to assess the effectiveness of CRP in OmPCa by synthesizing outcomes from previous studies and analyzing data from a multicenter, retrospective cohort. METHODS: We focused on evaluating overall survival (OS), progression-free survival (PFS), cancer-specific survival (CSS), and castration-resistant prostate cancer-free survival (CRPCFS) as primary outcomes. A multicenter comparative retrospective analysis was also conducted on OmPCa patients treated with CRP versus those receiving androgen deprivation therapy (ADT) alone from January 2008 to June 2018. We gathered and analyzed data on patient demographics, tumor characteristics, surgical outcomes, and survival metrics. RESULTS: The quantitative analysis included 18 studies(2 randomized controlled trial (RCT) and 16 non-RCT studies),comprising a total of 1733 patients with oligometastatic prostate cancer,this is the largest number of samples included in the same subject research at present.The pooled analysis demonstrated that cytoreductive surgery was associated with significantly improved OS (hazard ratio [HR]: 0.50, 95% confidence interval[CI]: 0.40-0.60) ,PFS (HR: 0.39, 95%[CI]: 0.27-0.51) ,CSS (HR: 0.44, 95%[CI]: 0.23-0.65) and CRPCFS (HR: 0.48, 95%[CI]: 0.36-0.59) compared to non-surgical management.In addition,OS ,PFS and CRPCFS showed better results in the CRP group in all analyses(RCT and non-RCT).Additionally,in our multicenter retrospective research analysis, 64 patients with oligometastatic prostate cancer were included ,32 underwent CRP (50%), and 32 underwent ADT alone (50%).The median follow-up time was 40.1 (18.9-51.3) months.The OS (P=0.0182), PFS (P=0.0297), and CRPCFS (P=0.0125) had statistical difference between the two matched cohorts.Moreover,we observed 8(25%) cases of perioperative complications, with the most common being urinary incontinence(9.4%). CONCLUSIONS: Incorporating CRP alongside ADT in the treatment protocol for OmPCa significantly enhances patient outcomes in terms of OS, PFS, and CRPC-free survival, underscoring the potential benefit of this surgical approach in the specified patient population.

FOXA1-dependent PUS1 regulates EIF3b stability in a non-enzymatic pathway mediating prostate cancer bone metastasis.

Bone metastasis is a significant contributor to the poor prognosis in prostate cancer. Recent evidence highlights the pivotal role of pseudouridine synthases in solid tumor progression, yet the specific enzyme driving prostate cancer metastasis remains unidentified. This study uncovers a novel regulatory mechanism of the FOXA1/PUS1/EIF3b signaling axis in prostate cancer bone metastasis. We identified elevated PUS1 expression in prostate cancer tissues, correlating with higher clinical grade and worse prognosis. Knockdown of PUS1 inhibited metastasis independently of its enzymatic activity, with EIF3b acting as a downstream effector, protected from ubiquitin-mediated degradation by PUS1. Overexpression of EIF3b countered the metastasis suppression due to PUS1 knockdown. Additionally, FOXA1 was shown to enhance PUS1 expression by binding to its promoter. Mogroside IV-E, a specific PUS1 inhibitor, demonstrated potent anti-metastatic effects by reducing PUS1 expression. Our findings highlight the FOXA1/PUS1/EIF3b axis as a critical mediator of prostate cancer bone metastasis and suggest that targeting this pathway could be a promising therapeutic strategy.

Women's reproductive traits and major depressive disorder: A two-sample Mendelian randomization study.

BACKGROUND: Evidence suggested strong associations between women's reproductive factors and major depressive disorder (MDD), but their causalities are unclear. METHODS: Using female-specific SNPs as genetic instruments obtained from large-scale genome-wide association studies for women's reproductive traits, we designed two-sample univariable and multivariable Mendelian randomization (MR) analysis to evaluate the causal effects of women's reproductive traits on MDD. For both univariable MR (UVMR) and multivariable MR (MVMR), the inverse variance weighting estimates were reported as main results. MR-Egger, weighted median, and generalized summary-data-based MR (GSMR) methods for UVMR, and MVMR-Egger and MVMR-robust methods for MVMR were used as sensitivity analyses. Negative control analyses, MVMR of age at first birth (AFB) and age at first sexual intercourse (AFS) on MDD, and sex-combined genetic variants for AFB and AFS were performed to enhance the robustness of our study. RESULTS: There was substantial evidence for associations of genetically predicted later age at menarche (AAM) (odds ratio (OR) = 0.97, 95 % confidence interval (CI) = 0.94-0.99, P = 0.007), AFB (OR = 0.91, 95 % CI = 0.86-0.97, P = 0.002) and AFS (OR = 0.70, 95 % CI = 0.60-0.80, P < 0.001) with lower MDD risk in UVMR. After adjustment of BMI and educational attainment using MVMR, we found consistently significant causal effects of AAM (OR = 0.95, 95 % CI = 0.92-0.99, P = 0.006), AFB (OR = 0.88, 95 % CI = 0.84-0.91, P < 0.001) and AFS (OR = 0.71, 95 % CI = 0.64-0.79, P < 0.001) on MDD. CONCLUSIONS: Our results provide compelling evidence that early AAM, AFB, and AFS are risk factors for MDD. Promoting the cognition of reproductive health care for women may reduce the risk of MDD.

Classification of pyroptosis patterns and construction of a novel prognostic model for prostate cancer based on bulk and single-cell RNA sequencing.

Background: Emerging evidence suggests an important role for pyroptosis in tumorigenesis and recurrence, but it remains to be elucidated in prostate cancer (PCa). Considering the low accuracy of common clinical predictors of PCa recurrence, we aimed to develop a novel pyroptosis-related signature to predict the prognosis of PCa patients based on integrative analyses of bulk and single-cell RNA sequencing (RNA-seq) profiling. Methods: The RNA-seq data of PCa patients was downloaded from several online databases. PCa patients were stratified into two Classes by unsupervised clustering. A novel signature was constructed by Cox and the Least Absolute Shrinkage and Selection Operator (LASSO) regression. The Kaplan-Meier curve was employed to evaluate the prognostic value of this signature and the single sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to analysis tumor-infiltrating immune cells. At single-cell level, we also classified the malignant cells into two Classes and constructed cell developmental trajectories and cell-cell interaction networks. Furthermore, RT-qPCR and immunofluorescence were used to validate the expression of core pyroptosis-related genes. Results: Twelve prognostic pyroptosis-related genes were identified and used to classify PCa patients into two prognostic Classes. We constructed a signature that identified PCa patients with different risks of recurrence and the risk score was proven to be an independent predictor of the recurrence free survival (RFS). Patients in the high-risk group had a significantly lower RFS (P<0.001). The expression of various immune cells differed between the two Classes. At the single-cell level, we classified the malignant cells into two Classes and described the heterogeneity. In addition, we observed that malignant cells may shift from Class1 to Class2 and thus have a worse prognosis. Conclusion: We have constructed a robust pyroptosis-related signature to predict the RFS of PCa patients and described the heterogeneity of prostate cancer cells in terms of pyroptosis.

1470 nm/980 nm dual-wavelength laser is safe and efficient for the en-bloc resection of non-muscle invasive bladder cancer: A propensity score-matched analysis.

OBJECTIVE: To evaluate the efficacy and safety of a 1470 nm/980 nm dual-wavelength laser system used for the en-bloc resection of non-muscle invasive bladder cancer (NMIBC) compared with transurethral resection of bladder tumour (TURBT). METHODS: This retrospective study analysed the demographic and clinical data from patients diagnosed with NMIBC that were treated by either dual laser or TURBT. Intraoperative characteristics, postoperative characteristics and outcomes between the two groups were compared. RESULTS: This study analysed 64 patients, 32 in each group. No severe complications were identified in either group. After propensity score-matching, there were no significant differences between the two groups in terms of the demographics, clinical and tumour characteristics. There was no significant difference between the two groups in terms of specimen quality. In the laser group, intraoperative blood loss was significantly lower and significantly fewer patients required continuous bladder irrigation after surgery, compared with the TURBT group. No significant differences were observed in the catheterization time, gross haematuria time and hospitalization time. Operation time in the laser group was significantly longer compared with the TURBT group. No significant difference was found in the recurrence and progression rates between the two groups. CONCLUSIONS: The 1470 nm/980 nm dual-wavelength laser provides a safe and effective surgical treatment option for patients with NMIBC.