Integrated analysis of histone modification features in clear cell renal cancer for risk stratification and therapeutic prediction.

Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy that is involved in tumor genesis and development. However, few studies have focused on the predictive role of the global histone modification status in ccRCC. A total of 621 patients with complete transcript information and corresponding clinical profiles were obtained from TCGA-KIRC, GSE22541, and EMTAB3267 cohorts. A total of 122 histone modification relevant pathways were derived from MSigDB, and their activation status was quantified using GSVA. Differentially expressed genes (DEGs) were identified and filtrated using univariate Cox regression analysis. The signature was built relied on the least absolute shrinkage and selection operator (LASSO) regression analysis, and evaluated from survival difference, chemotherapy response, and activated pathways. A novel nomogram was established to quantify the probability of death in different patients. Seven risky and fifty-eight protective genes were used in LASSO analysis, and six genes were used to build the histone modification gene (HiMG) signature, which showed significant independent prognostic potential in all three cohorts. The nomogram showed acceptable incremental predictions. CKS2 (p = 0.004) and PD1 (p = 0.002) expression were significantly higher in grade 3 ccRCC than in grades 1-2. CKS2 siRNA in renal cancer cells caused reductions in cellular proliferation, migration, and invasion. Patients with low HiMG may be potential responders to rapamycin, erlotinib and FH535, while AZD6482 and CHIR-99,021 may be more suitable for patients with high HiMG levels. ccRCC histone modification distribution and a clinical signature for prognosis prediction, clinical decision making, and molecular mechanism exploration, were established for risk stratification and personalized treatments.

Characterizing CD8+ TEMRA Cells in CP/CPPS Patients: Insights from Targeted Single-Cell Transcriptomic and Functional Investigations.

Background: The specific involvement of the CD8+ T effector memory RA (TEMRA) subset in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has largely not been explored in the literature. Methods: Targeted single-cell RNA sequencing (scRNA-seq) profiles were generated from peripheral blood mononuclear cells (PBMCs) obtained from two CP/CPPS patients and two healthy controls (HCs) in our recent study. Pseudotime series algorithms were used to reveal the differentiation trajectory, CellChat analysis was used to explore the communication between individual cells, and the SCENIC program was used to identify potential transcription factors (TFs). Based on the cosine similarity, clusters of differentially expressed genes (DEGs) were considered to be further enriched in different pathways. To confirm the functional role of the critical clusters, flow cytometry was employed. Results: The results revealed the molecular landscape of these clusters, with TEMRA cells exhibiting pronounced cytokine-mediated signaling pathway enrichment. Pseudotime trajectory analysis further mapped the evolution from naïve T cells to that of TEMRA cells, elucidating the developmental pathways involved in the immune context. A significant finding from CellChat analysis was the differential expression of ligands and receptors, with CD8+ TEMRA cells showing enhanced signaling, particularly in the CP/CPPS context, compared to HCs. Flow cytometry confirmed these results, revealing a heightened proinflammatory cytokine profile in patients with chronic prostatitis-like symptoms (CP-LS), suggesting that TEMRA cells play a significant role in disease pathogenesis. TF profiling across the T-cell clusters identified key regulators of cellular identity, identifying novel therapeutic targets. Elevated TNF signaling activity in CD8+ TEMRA cells underscored the involvement of these cells in disease mechanisms. Conclusion: This study elucidates the pivotal role of the CD8+ TEMRA cell subset in CP/CPPS, which is characterized by increased TNF signaling and proinflammatory factor expression, highlighting potential biomarkers and opening new avenues for therapeutic intervention.

Molecular classifications of prostate cancer: basis for individualized risk stratification and precision therapy.

Tumour classifications play a pivotal role in prostate cancer (PCa) management. It can predict the clinical outcomes of PCa as early as the disease is diagnosed and then guide therapeutic schemes, such as active monitoring, standalone surgical intervention, or surgery supplemented with postoperative adjunctive therapy, thereby circumventing disease exacerbation and excessive treatment. Classifications based on clinicopathological features, such as prostate cancer-specific antigen, Gleason score, and TNM stage, are still the main risk stratification strategies and have played an essential role in standardized clinical decision-making. However, mounting evidence indicates that clinicopathological parameters in isolation fail to adequately capture the heterogeneity exhibited among distinct PCa patients, such as those sharing identical Gleason scores yet experiencing divergent prognoses. As a remedy, molecular classifications have been introduced. Currently, molecular studies have revealed the characteristic genomic alterations, epigenetic modulations, and tumour microenvironment associated with different types of PCa, which provide a chance for urologists to refine the PCa classification. In this context, numerous invaluable molecular classifications have been devised, employing disparate statistical methodologies and algorithmic approaches, encompassing self-organizing map clustering, unsupervised cluster analysis, and multifarious algorithms. Interestingly, the classifier PAM50 was used in a phase-2 multicentre open-label trial, NRG-GU-006, for further validation, which hints at the promise of molecular classification for clinical use. Consequently, this review examines the extant molecular classifications, delineates the prevailing panorama of clinically pertinent molecular signatures, and delves into eight emblematic molecular classifications, dissecting their methodological underpinnings and clinical utility.

Feasibility and safety of bipolar-plasmakinetic transurethral enucleation and resection of the prostate in day surgery mode. / åŒæžç­‰ç¦»å­ç»å°¿é“å‰åˆ—è ºå‰œåˆ‡æ—¥é—´æ‰‹æœ¯ä¸´åºŠå®žè·µ.

OBJECTIVES: To evaluate the feasibility and safety of bipolar-plasmakinetic transurethral enucleation and resection of the prostate (B-TUERP) in day surgery. METHODS: From January 2021 to August 2022, 34 patients with benign prostatic hyperplasia (BPH) underwent B-TUERP in day surgery in the First Affiliated Hospital of Anhui Medical University. Patients completed the screening and anesthesia evaluation before admission and received the standard surgery which implements "anatomical enucleation of the prostate" and "absolute bleeding control" on the same day of admission, and by the same doctor. Bladder irrigation was stopped, catheter was removed and the discharge evaluation was performed on the first day after operation. The baseline data, perioperative conditions, time of recovery, treatment outcomes, hospitalization costs, and postoperative complications were analyzed. RESULTS: All operations were successfully conducted. The average age of the patients was (62.2±7.8) years, average prostate volume was (50.2±29.3) mL. The average operation time was (36.5±19.1) min, the average hemoglobin and blood sodium were decreased by (16.2±7.1) g/L and (2.2±2.0) mmol/L, respectively. The average postoperative length of hospital stay, and total length of hospital stay were (17.7±2.2) and (20.8±2.1) h, respectively, and the average hospitalization cost was (13 558±2320) CNY. All patients were discharged on the day after surgery except for one patient who was transferred to a general ward. Three patients received indwelling catheterization after catheter removal. The 3-month follow-up results showed a substantial improvement in the International Prostate Symptom Score, quality of life score and maximum urinary flow rate (all P<0.01). Three patients experienced temporary urinary incontinence, 1 patient experienced urinary tract infection, 4 patients were diagnosed with urethral stricture and 2 patients experienced bladder neck contracture. No complications above Clavien grade Ⅱ occurred. CONCLUSIONS: The preliminary results showed that B-TUERP ambulatory surgery is a safe, feasible, economical and effective treatment for appropriately selected patients with BPH.

Non-coding RNAs: Emerging roles in the characterization of immune microenvironment and immunotherapy of prostate cancer.

Prostate cancer is the most common tumor among men. Although the prognosis for early-stage prostate cancer is good, patients with advanced disease often progress to metastatic castration-resistant prostate cancer (mCRPC), which usually leads to death owing to resistance to existing treatments and lack of long-term effective therapy. In recent years, immunotherapy, especially immune checkpoint inhibitors (ICIs), has made great progress in the treatment of various solid tumors, including prostate cancer. However, the ICIs have only shown modest outcomes in mCRPC compared with other tumors. Previous studies have suggested that the suppressive tumor immune microenvironment (TIME) of prostate cancer leads to poor anti-tumor immune response and tumor resistance to immunotherapy. It has been reported that non-coding RNAs (ncRNAs) are capable of regulating upstream signaling at the transcriptional level, leading to a "cascade of changes" in downstream molecules. As a result, ncRNAs have been identified as an ideal class of molecules for cancer treatment. The discovery of ncRNAs provides a new perspective on TIME regulation in prostate cancer. ncRNAs have been associated with establishing an immunosuppressive microenvironment in prostate cancer through multiple pathways to modulate the immune escape of tumor cells which can promote resistance of prostate cancer to immunotherapy. Targeting these related ncRNAs presents an opportunity to improve the effectiveness of immunotherapy in this patient population.

Overexpression of DDX49 in prostate cancer is associated with poor prognosis.

BACKGROUND: There is increasing evidence that DEAD-box helicases (DDX) can act either as promoters or suppressors in various cancer types. Nevertheless, the function of DDX49 in prostate cancer (PCa) is unknown. This study reveals the prognostic and predictive value of DDX49 in PCa. METHODS: First, we evaluated the expression of DDX49 between PCa and normal tissues based on TCGA and GEO databases. Univariate and multivariate regression analyses were conducted to reveal the risk factors for PCa recurrence. A K-M curve was employed to assess the relationship between DDX49 and recurrence-free survival. In vitro, DDX49 expression was evaluated in PCa and normal prostate cell lines. Furthermore, we constructed a shDDX49 lentivirus to knock down the expression of DDX49. Celigo® Image Cytometer and MTT assay were performed to analyse cell proliferation in PC-3 cells. Cell cycle distribution was detected with flow cytometry analysis. Apoptosis affected by the lack of DDX49 was metred with the PathScan® Stress and Apoptosis Signalling Antibody Array Kit. RESULTS: This study shows a high increase in DDX49 in PCa tissues in comparison with normal tissues and that increased DDX49 indicates a poor prognosis among PCa patients. Meanwhile, DDX49 knockdown suppressed the proliferation and migration of PC-3 cells, causing cell cycle arrest in the G1 phase. Stress and apoptosis pathway analysis revealed that the phosphorylation of HSP27, p53, and SAPK/JNK was reduced in the DDX49 knockdown group compared with the control group. CONCLUSIONS: In summary, these results suggest that high expression of DDX49 predicts a poor prognosis among PCa patients. Downregulation of DDX49 can suppress cell proliferation, block the cell cycle, and facilitate cell apoptosis. Therefore, knockdown of DDX49 is a promising novel therapy for treating patients with PCa.

Landscape of the intratumroal microenvironment in bladder cancer: Implications for prognosis and immunotherapy.

Introduction: This study aims to present the landscape of the intratumoral microenvironment and by which establish a classification system that can be used to predict the prognosis of bladder cancer patients and their response to anti-PD-L1 immunotherapy. Methods: The expression profiles of 1554 bladder cancer cases were downloaded from seven public datasets. Single-sample gene set enrichment analysis (ssGSEA), univariate Cox regression analysis, and meta-analysis were employed to establish the bladder cancer immune prognostic index (BCIPI). Extensive analyses were executed to investigate the association between BCIPI and overall survival, tumor-infiltrated immunocytes, immunotherapeutic response, mutation load, etc. Results: The results obtained from seven independent cohorts and meta-analyses suggested that the BCIPI is an effective classification system for estimating bladder cancer patients' overall survival. Patients in the BCIPI-High subgroup revealed different immunophenotypic outcomes from those in the BCIPI-Low subgroup regarding tumor-infiltrated immunocytes and mutated genes. Subsequent analysis suggested that patients in the BCIPI-High subgroup were more sensitive to anti-PD-L1 immunotherapy than those in the BCIPI-Low subgroup. Conclusions: The newly established BCIPI is a valuable tool for predicting overall survival outcomes and immunotherapeutic responses in patients with bladder cancer.

Multiomics characterization and verification of clear cell renal cell carcinoma molecular subtypes to guide precise chemotherapy and immunotherapy.

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor with different genetic and molecular alterations. Schemes for ccRCC classification system based on multiomics are urgent, to promote further biological insights. Two hundred and fifty-five ccRCC patients with paired data of clinical information, transcriptome expression profiles, copy number alterations, DNA methylation, and somatic mutations were collected for identification. Bioinformatic analyses were performed based on our team's recently developed R package "MOVICS." With 10 state-of-the-art algorithms, we identified the multiomics subtypes (MoSs) for ccRCC patients. MoS1 is an immune exhausted subtype, presented the poorest prognosis, and might be caused by an exhausted immune microenvironment, activated hypoxia features, but can benefit from PI3K/AKT inhibitors. MoS2 is an immune "cold" subtype, which represented more mutation of VHL and PBRM1, favorable prognosis, and is more suitable for sunitinib therapy. MoS3 is the immune "hot" subtype, and can benefit from the anti-PD-1 immunotherapy. We successfully verified the different molecular features of the three MoSs in external cohorts GSE22541, GSE40435, and GSE53573. Patients that received Nivolumab therapy helped us to confirm that MoS3 is suitable for anti-PD-1 therapy. E-MTAB-3267 cohort also supported the fact that MoS2 patients can respond more to sunitinib treatment. We also confirm that SETD2 is a tumor suppressor in ccRCC, along with the decreased SETD2 protein level in advanced tumor stage, and knock-down of SETD2 leads to the promotion of cell proliferation, migration, and invasion. In summary, we provide novel insights into ccRCC molecular subtypes based on robust clustering algorithms via multiomics data, and encourage future precise treatment of ccRCC patients.

Identification and validation of an E2F-related gene signature for predicting recurrence-free survival in human prostate cancer.

BACKGROUND: It is well-established that biochemical recurrence is detrimental to prostate cancer (PCa). In the present study, we explored the mechanisms underlying PCa progression. METHODS: Five cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to perform gene set variation analysis (GSVA) between nonrecurrent and recurrent PCa patients. We obtained the intersection of pathway enrichment results and extracted the corresponding gene list. LASSO Cox regression analysis was used to identify recurrence-free survival (RFS)-related significant genes and establish an RFS prediction gene signature and nomogram. MTT and colony formation assays were conducted to validate our findings. RESULTS: The E2F signaling pathway was activated in recurrent PCa patients compared to nonrecurrent patients. We established an E2F-related gene signature for RFS prediction based on the four identified E2F-related genes (CDKN2C, CDKN3, RACGAP1, and RRM2) using LASSO Cox regression in the Memorial Sloan Kettering Cancer Center (MSKCC) cohort. The risk score of each patient in MSKCC was calculated based on the expression levels of CDKN2C, CDKN3, RACGAP1, and RRM2. PCa patients with low-risk scores exhibited higher RFS than those with high-risk scores. Receiver operating characteristic (ROC) curve analysis validated the good performance and prognostic accuracy of the E2F-related gene signature, which was validated in the TCGA-prostate adenocarcinoma (TCGA-PRAD) cohort. Compared to patients with low Gleason scores and early T stages, PCa patients with high Gleason scores and advanced T stages had high-risk scores. Moreover, the E2F-related gene signature-based nomogram yielded good performance in RFS prediction. Functional experiments further confirmed these results. CONCLUSIONS: The E2F signaling pathway is associated with biochemical recurrence in PCa. Our established E2F-related gene signature and nomogram yielded good accuracy in predicting the biochemical recurrence in PCa.

EPM2A acts as a protective factor in prostate cancer, evidence from a real-world patient cohort.

EPM2A encodes a dual specificity phosphatase and has been proven to be a potential biomarker in several cancers but has not been mentioned in prostate cancer (PCA). We investigated the prognostic and therapeutic value of EPM2A in PCA. The TCGA-PRAD cohort was collected to evaluate the differential expression, prognostic value, immunocyte infiltration and drug sensitivity of EPM2A in PCA. We constructed a nomogram model to predict the recurrence probability for PCA patients. Immunohistochemistry was used to validate the different transcript levels of EPM2A between tumor and normal tissues. A real-world AHMU-PC cohort was employed for validation. The results showed decreased expression of EPM2A in 95.65% of tumor tissues and was related to their prognosis, especially PCA (p = 0.008, HR = 0.57, 95% CI: 0.371-0.863). Further multiple analysis by adjusting clinical features revealed that EPM2A acted as an independent prognostic factor (p = 0.014, HR = 0.589, 95% CI: 0.386-0.898). Pathway enrichment analysis showed variable signaling activation between high EPM2A expression patients (HEXP) and low EPM2A expression patients (LEXP). The HEXP group contained higher infiltration of immunocytes than the LEXP group, as well as high levels of PD-1, PD-L1 and PD-L2, while LEXP patients were more sensitive to cisplatin, paclitaxel and bicalutamide therapy. The nomogram containing the EPM2A group, T stage and Gleason score showed a preferable prognostic value (AUC = 0.755; Hosmer‒Lemeshow, p = 0.486). In validation, we confirmed the lower transcript level of EPM2A in PCA than in normal tissues (120.5 ± 2.159 vs. 138.3 ± 1.83, p = 0.035) and correlated it with the expression level of PD-1 (R = 0.283). Among the 66 patients from the AHMU-PC cohort, we further validated the function of EPM2A in PCA patients. HEXP patients had longer recurrence-free survival times (1207 ± 110 vs. 794.2 ± 97.02, p = 0.0063) and favorable prognoses (HR: 0.417, 95% CI: 0.195-0.894, p = 0.0245). Collectively, we identified the prognostic value of EPM2A in PCa via a bioinformatics method. Patients with higher EPM2A may be more sensitive to immunotherapy, and patients with lower EPM2A were more suitable for bicalutamide, cisplatin and paclitaxel therapy.

Signature for Prostate Cancer Based on Autophagy-Related Genes and a Nomogram for Quantitative Risk Stratification.

Background: Prostate cancer (PCa) ranks as the most common malignancy and the second leading cause of cancer-related death among males worldwide. The essential role of autophagy in the progression of PCa and treatment resistance has been preliminarily revealed. However, comprehensive molecular elucidations of the correlation between PCa and autophagy are rare. Method: We obtained transcription information and corresponding clinicopathological profiles of PCa patients from TCGA, MSKCC, and GEO datasets. LAASO analysis was employed to select gene signatures and estimate the autophagy score for each patient. Correlations between the signature and prognosis of PCa were investigated by K-M and multivariate Cox regression analyses. A nomogram was established on the basis of the above results. Further validations relied on ROC, calibration analysis, decision curve analysis, and external cohorts. Variable activated signaling pathways were revealed using GSVA algorithms, and the genetic alteration landscape was elucidated via the oncodrive module from the "maftools" R package. In addition, we also examined the therapeutic role of the signature based on phenotype data from GDSC 2016. Result: Six autophagy-related genes were eventually selected to establish the signature, including ULK1, CAPN10, FKBP5, UBE2T, NLRC4, and BNIP3L. We used these genes and corresponding coefficients to calculate an autophagy score (AutS) for each patient in this study. A high AutS group and a low AutS group were divided on the mean AutS of the patients. Longer overall survival, higher Gleason score and PSA, and better response to ADT were observed in patients with high AutS. Meanwhile, we found that high AutS PCa was related to more proliferation-associated signaling activation and higher genetic mutation frequencies, manifesting a poor prognosis. A nomogram was constructed based on GS, T stage, PSA, and AutS as covariates. Its discriminative efficacy and clinical value were validated using robust statistical methods. Finally, we tested its prognostic value through two external cohorts and six published signatures. Conclusion: The autophagy-related gene signature is a highly discriminative model for risk stratification and drug therapy in PCa, and a nomogram incorporating AutS might be a promising tool for precision medicine.

Macrophages and monocytes mediated activation of oxidative phosphorylation implicated the prognosis and clinical therapeutic strategy of Wilms tumour.

Wilms tumour is the fourth leading cause of paediatric malignancy, but the detailed relationship between the tumour microenvironment and prognosis remains largely unclear. In this research, gene expression profile and clinical information from TARGET and the First Affiliated Hospital of Anhui Medical University were collected. After comparing the prognostic value of the associated immune cells, we established a nomogram to predict the prognosis of Wilms tumour based on monocyte infiltration, macrophage infiltration, stage, and sex. Further results showed that the most significant relationship between matrix metallopeptidase 9 and prognosis or macrophage infiltration. Meanwhile, by gene set enrichment or variation analyses and immunohistochemistry staining, we demonstrated that the most highly enriched hub genes were closely related to the activated oxidative phosphorylation pathway. Finally, through tumour immune dysfunction and an exclusion algorithm, the satisfactory discriminative performance of our nomogram was revealed for predicting the response to clinical therapy. Anti-PD1 therapy is more suitable for Wilms tumour patients with high nomogram points, and chemotherapies are more effective for patients with low nomogram score.

Short- and Long-Term Response of Vagus Nerve Stimulation Therapy in Drug-Resistant Epilepsy: A Systematic Review and Meta-Analysis.

OBJECTIVES: To compare the short- and long-term efficacies as well as tolerability of vagus nerve stimulation (VNS) for the patients with drug-resistant epilepsy (DRE) in comparison with status at baseline. MATERIALS AND METHODS: We conducted a specific and systematic search in online data bases for relevant literature published prior to December 2020. The literature retrieved, including randomized clinical trials (RCTs) and observational studies, were then reviewed and analyzed. A fixed-effect model was used to evaluate the pooled odds ratio (OR) of responder rates and complications associated with RCTs. A random-effect model was used to generate overall responder rates and overall incidences of complication. RESULTS: A total of 61 studies, featuring 5223 patients, were included in our study. The pooled ORs of responder rates, hoarseness/voice change, throat pain, coughing, dyspnea, paresthesia, muscle pain, and headache during the short-term phase were 2.195 (p = 0.001), 5.527 (p = 0.0001), 0.935 (p = 0.883), 1.119 (p = 0.655), 2.901 (p = 0.005), 1.775 (p = 0.061), 3.606 (p = 0.123), and 0.928 (p = 0.806), respectively. The overall responder rates in 3, 6, 12, 24, 36, 48, and 60 months postoperatively were 0.421, 0.455, 0.401, 0.451, 0.482, 0.502, and 0.508, respectively. The overall incidences of complication were 0.274 for hoarseness/voice change, 0.099 for throat pain, 0.133 for coughing, 0.099 for dyspnea, 0.102 for paresthesia, 0.062 for muscle pain, 0.101 for headache, 0.015 for dysphagia, 0.013 for neck pain, 0.040 for infection, 0.030 for lead fracture, 0.019 for vocal cord palsy, and 0.020 for device malfunction, respectively. CONCLUSIONS: The estimating of efficacy and tolerability, using data from the existing literature, indicated VNS therapy is a safe and effective treatment option for patients with DRE.

[Omics molecular subtyping, prognostic prediction and individualized treatment of prostate cancer: Advances in studies].

Prostate cancer (PCa) is a most common malignancy in males. It has a greater heterogeneity than other cancers, which poses a real challenge to the clinical diagnosis, classification and prognostic monitoring. At present, high-, medium- and low-risk PCa patients are classified mainly by Gleason scores and the PSA level, which, however, fail to reveal the diverse molecular heterogeneity and precisely distinguish the molecular subtypes of PCa. With the development of high-throughput sequencing, more and more studies on the molecular classification of the malignancy have paved the theoretical ground for the early diagnosis, efficacy prediction and individualized treatment of PCa. This study reviews the molecular classification, prognosis prediction and individualized treatment of PCa to date, hoping to contribute to the development of the precise treatment of PCa.

Tumor immune microenvironment-based classifications of bladder cancer for enhancing the response rate of immunotherapy.

Immunotherapy is a potential way to save the lives of patients with bladder cancer, but it only benefits approximately 20% of them. A total of 4,028 bladder cancer patients were collected for this study. Unsupervised non-negative matrix factorization and the nearest template prediction algorithms were employed for the classification. We identified the immune and non-immune classes from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA-BLCA) training cohort. The 150 most differentially expressed genes between these two classes were extracted, and the classification reappeared in 20 validation cohorts. For the activated and exhausted subgroups, a stromal activation signature was assessed by the NTP algorithm. Patients in the immune class showed highly enriched signatures of immunocytes, while the exhausted subgroup also exhibited activated transforming growth factor (TGF)-ß1, and cancer-associated extracellular matrix signatures. Patients in the immune-activated subgroup showed a lower genetic alteration and better overall survival. Anti-PD-1/PD-L1 immunotherapy was more beneficial for the immune-activated subgroup, while immune checkpoint blockade therapy plus a TGF-ß inhibitor or an EP300 inhibitor might achieve greater efficacy for patients in the immune-exhausted subgroup. Novel immune molecular classifier was identified for the innovative immunotherapy of patients with bladder cancer.