An androgen receptor-based signature to predict prognosis and identification of ORC1 as a therapeutical target for prostate adenocarcinoma.

Background: Aberrant activation of androgen receptor (AR) signaling plays a crucial role in the progression of prostate adenocarcinoma (PRAD) and contributes significantly to the development of enzalutamide resistance. In this study, we aimed to identify a novel AR-driven signature that can predict prognosis and endows potentially reveal novel therapeutic targets for PRAD. Methods: The Seurat package was used to preprocess the single-cell RNA sequencing (scRNA-seq). Differentially expressed genes were visualized using limma and pheamap packages. LASSO and multi-variate Cox regression models were established using glmnet package. The package "Consensus Cluster Plus" was utilized to perform the consensus clustering analysis. The biological roles of origin recognition complex subunit 1 (ORC1) in PRAD were determined by gain- and loss-of-function studies in vitro and in vivo. Result: We characterized the scRNA-seq data from GSE99795 and identified 10 AR-associated genes (ARGs). The ARGs model was trained and validated in internal and external cohorts. The ARGs were identified as an independent hazard factor in PRAD and correlated with clinical risk characteristics. In addition, the ARGs were found to be correlated with somatic tumor mutation burden (TMB) levels. Two groups that have distinct prognostic and molecular features were identified through consensus clustering analysis. ORC1 was identified as a critical target among these ARGs, and it ORC1 promoted proliferation and stem-like properties of PRAD cells. Chromatin immunoprecipitation (ChIP)-qPCR assay confirmed that AR could directly bind the promoter of ORC1. Activated AR/ORC1 axis contributed to enzalutamide resistance, and targeting ORC1 rendered PRAD cells more susceptible to enzalutamide. Conclusions: This study defines an AR-driven signature that AR activates ORC1 expressions to promote PRAD progression and enzalutamide resistance, which may provide novel targets for PRAD treatment.

The role of polyethylenimine-functionalized gold nanoclusters carrying plasmid CMTM5 in impeding the malignant progression of prostate cancer cells by promoting EGFR endocytosis.

In this research, polyethylenimine-functionalized gold nanoclusters (PEI-AuNCs) were synthesized for the delivery of plasmid CMTM5 (pCMTM5) to prostate cancer (PCa) cells, with the objective of elucidating the mechanism underlying its anticancer efficacy. The PEI-AuNCs loaded with pCMTM5 (PEI-AuNCs@pCMTM5) tumor-targeting drug delivery system was established. Subsequently, both the obtained PEI-AuNCs and PEI-AuNCs@pCMTM5 underwent characterization through a transmission electron microscope (TEM) and dynamic light scattering (DLS). Employing RT-qPCR, western blot, flow cytometry, immunofluorescence, and co-immunoprecipitation (co-IP) assays, the consequences of CMTM5 overexpression on the expression of EGFR were investigated. Moreover, the influence of PEI-AuNCs@pCMTM5 on PC-3 cells was assessed through CCK-8, wound healing assay, and Transwell experiments. As a result, the PEI-AuNCs and PEI-AuNCs@pCMTM5 were presented as uniformly dispersed spherical with stable particle sizes and positive charges, showcasing favorable dispersion within the solution. In comparison to Lip2000, the PEI-AuNCs demonstrated superior transfection efficiency and lower cellular toxicity. Following the overexpression of CMTM5, the proliferative capacity of PC-3 cells was markedly suppressed, while both migratory and invasive abilities exhibited noteworthy reduction, with the efficacy of PEI-AuNCs@pCMTM5 consistently outperforming that of free pCMTM5. Subsequent mechanistic investigations unveiled that CMTM5 does not directly inhibit the synthesis of EGFR or facilitate its degradation, but rather influences the endocytic process of EGFR. In conclusion, the PEI-AuNCs nano-delivery system exhibits good biocompatibility and efficaciously conveys pCMTM5 to PCa cells. Crucially, pCMTM5 does not directly interact with EGFR, and CMTM5 governs the malignant progression of PC3 cells by promoting EGFR endocytosis.

The effect of exercise intensity types on the self-rated health status of young-old comorbidities patients: a cross-sectional study in Guangdong, China.

Objective: Explore the effect of different types of exercise intensity on the self-rated health status of young-old comorbid patients with cardiovascular disease and metabolic disease, as well as the differences in effect among different genders. Provide more references and suggestions for chronic disease management in older comorbidities patients based on the results of the study. Methods: A multi-stage stratified cluster random sampling method was used to select older (≥60 years old) comorbidities patients from communities in Guangdong Province as the survey subjects. Using the "Survey Questionnaire on the Current Status and Influencing Factors of older Comorbidities Patients," face-to-face interviews were conducted with 1,300 old patients. Data from 965 young-old patients (aged 60-74) who simultaneously suffered from cardiovascular and metabolic diseases were selected. Unordered multifactor Logistic regression analysis was used to explore the association between the type of exercise intensity and self-rated health. Stratified analysis was performed based on gender. Results: The results of unordered multivariate logistic regression analysis showed that compared with young-old comorbidities patients with poor self-rated of health status, young-old comorbidities patients who underwent vigorous-intensity exercise were more likely to have better self-rated of health status (OR = 4.368, 95% CI: 2.491-7.661, p < 0.05). Stratified analysis based on gender showed that for young-old comorbidities male patients, those who engaged in vigorous-intensity exercise were more likely to have better self-rated of health status (OR = 2.924, 95% CI = 1.266-6.751, p < 0.05); for young-old comorbidities female patients, those who were encouraged by their family to exercise (OR = 2.460, 95% CI: 1.143-5.291, p < 0.05), participate in social activities (OR = 6.173, 95% CI: 2.285-16.678, p < 0.05), and engage in vigorous-intensity (OR = 4.232, 95% CI: 1.869-9.583, p < 0.05) or moderate-intensity exercise (OR = 4.555, 95% CI: 1.825-11.368, p < 0.05) were more likely to have better self-rated of health status. Conclusion: If the physical condition allows, vigorous-intensity exercise has a significant positive effect on the self-rated of health status of young-old comorbidities patients with cardiovascular disease and metabolic disease. Specifically, for young-old comorbidities male patients, those who engage in vigorous-intensity exercise are more likely to self-evaluate their health as good; for young-old comorbidities female patients, both vigorous-intensity and moderate-intensity exercise can improve their self-rated of health status.

CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway.

Prostate cancer (PCa) endangers the life and health of older men. Most PCa cases develop into castration­resistant PCa (CRPC) within 2 years. At present, the molecular mechanisms of the occurrence and development of PCa and its transformation to CRPC remain unknown. The present study aimed to investigate the role of CKLF­like Marvel transmembrane domain containing family member 5 (CMTM5) in PCa and its molecular mechanism in vitro. PCa tissues and paired adjacent normal prostate tissues from 70 patients were collected to examine the expression levels of CMTM5 and EGFR via immunohistochemistry, reverse transcription­quantitative PCR and western blotting. Then, CMTM5­overexpressing DU145 cells were constructed, and CMTM5 expression in these transfected cells and vector control cells was examined via western blotting. Cell Counting Kit­8 and plate clone formation assays were used to evaluate the proliferation and colony number of CMTM5­overexpressing cells and vector control cells. Then, cell migration and invasion were assessed using wound healing assay, Transwell assay and immunofluorescence analysis with DAPI staining. The effect of CMTM5 on apoptosis and its underlying molecular mechanism were examined using western blotting and flow cytometry. The results demonstrated that CMTM5 expression in PCa tissues and cell lines was significantly downregulated, while EFGR expression was significantly upregulated. The proportion of high CMTM5 expression in PCa tissues was significantly lower compared with that in normal prostate tissues. By contrast, the proportion of high EGFR expression in PCa tissues was significantly increased compared with that in normal prostate tissues. Moreover, CMTM5 overexpression significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis compared with vector control cells in vitro. Furthermore, the regulation of PCa by CMTM5 was associated with the downregulation of PI3K/AKT and its downstream Bcl­2 expression, as well as the upregulation of Bax expression. In conclusion, CMTM5 may be an effective tumor suppressor gene for PCa, especially for castration­resistant PCa, by downregulating EGFR and PI3K/AKT signaling pathway components.

Long-term outcomes of radiofrequency ablation vs. partial nephrectomy for cT1 renal cancer: A meta-analysis and systematic review.

Background: Partial nephrectomy (PN) is one of the most preferred nephron-sparing treatments for clinical T1 (cT1) renal cancer, while radiofrequency ablation (RFA) is usually used for patients who are poor surgical candidates. The long-term oncologic outcome of RFA vs. PN for cT1 renal cancer remains undetermined. This meta-analysis aims to compare the treatment efficacy and safety of RFA and PN for patients with cT1 renal cancer with long-term follow-up of at least 5 years. Method: This meta-analysis was performed following the PRISMA reporting guidelines. Literature studies that had data on the comparison of the efficacy or safety of RFA vs. PN in treating cT1 renal cancer were searched in databases including PubMed, Embase, Web of Science, and the Cochrane Library from 1 January2000 to 1 May 2022. Only long-term studies with a median or mean follow-up of at least 5 years were included. The following measures of effect were pooled: odds ratio (OR) for recurrence and major complications; hazard ratio (HR) for progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Additional analyses, including sensitivity analysis, subgroup analysis, and publication bias analysis, were also performed. Results: A total of seven studies with 1,635 patients were finally included. The treatment efficacy of RFA was not different with PN in terms of cancer recurrence (OR = 1.22, 95% CI, 0.45-3.28), PFS (HR = 1.26, 95% CI, 0.75-2.11), and CSS (HR = 1.27, 95% CI, 0.41-3.95) as well as major complications (OR = 1.31, 95% CI, 0.55-3.14) (P > 0.05 for all). RFA was a potential significant risk factor for OS (HR = 1.76, 95% CI, 1.32-2.34, P < 0.001). No significant heterogeneity and publication bias were observed. Conclusion: This is the first meta-analysis that focuses on the long-term oncological outcomes of cT1 renal cancer, and the results suggest that RFA has comparable therapeutic efficacy with PN. RFA is a nephron-sparing technique with favorable oncologic efficacy and safety and a good treatment alternative for cT1 renal cancer.

Glutathione S-transferase M1 and T1 null genotypes and bladder cancer risk: A meta-analysis in a single ethnic group.

AIM OF STUDY: To further evaluate the influence of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null genotypes on bladder cancer risk, we conducted a meta-analysis in the Chinese population. MATERIALS AND METHODS: PubMed and Chinese databases were electronically searched through April 2016. RESULTS: Nine studies were included for our meta-analysis, involving 1646 bladder cancer cases and 1938 controls. In general, our findings indicated that a significant association existed between GSTM1-null genotype and the risk of bladder cancer in the studied Chinese population (odds ratio = 1.56, 95% confidence interval: 1.36-1.79). However, no significant association between GSTT1 polymorphism and bladder cancer was found. After stratification of the subgroup analyses by source of controls and geographical areas, a substantially elevated risk was revealed between GSTM1-null genotype and bladder cancer in the population-based studies and those conducted in South China and North China. CONCLUSION: Our meta-analysis suggested that GSTM1-null genotype is associated with an increased bladder cancer risk in the Chinese individuals.

Massage Alleviates Delayed Onset Muscle Soreness after Strenuous Exercise: A Systematic Review and Meta-Analysis.

Purpose: The purpose of this systematic review and meta-analysis was to evaluate the effects of massage on alleviating delayed onset of muscle soreness (DOMS) and muscle performance after strenuous exercise. Method: Seven databases consisting of PubMed, Embase, EBSCO, Cochrane Library, Web of Science, CNKI and Wanfang were searched up to December 2016. Randomized controlled trials (RCTs) were eligible and the outcomes of muscle soreness, performance (including muscle maximal isometric force (MIF) and peak torque) and creatine kinase (CK) were used to assess the effectiveness of massage intervention on DOMS. Results: Eleven articles with a total of 23 data points (involving 504 participants) satisfied the inclusion criteria and were pooled in the meta-analysis. The findings demonstrated that muscle soreness rating decreased significantly when the participants received massage intervention compared with no intervention at 24 h (SMD: -0.61, 95% CI: -1.17 to -0.05, P = 0.03), 48 h (SMD: -1.51, 95% CI: -2.24 to -0.77, P < 0.001), 72 h (SMD: -1.46, 95% CI: -2.59 to -0.33, P = 0.01) and in total (SMD: -1.16, 95% CI: -1.60 to -0.72, P < 0.001) after intense exercise. Additionally, massage therapy improved MIF (SMD: 0.56, 95% CI: 0.21-0.90, P = 0.002) and peak torque (SMD: 0.38, 95% CI: 0.04-0.71, P = 0.03) as total effects. Furthermore, the serum CK level was reduced when participants received massage intervention (SMD: -0.64, 95% CI: -1.04 to -0.25, P = 0.001). Conclusion: The current evidence suggests that massage therapy after strenuous exercise could be effective for alleviating DOMS and improving muscle performance.

Papaverine selectively inhibits human prostate cancer cell (PC-3) growth by inducing mitochondrial mediated apoptosis, cell cycle arrest and downregulation of NF-κB/PI3K/Akt signalling pathway.

PURPOSE: The main objective of the current research work was to investigate the antitumor effects of papaverine in PC-3 human prostate cancer cells along with testing its toxicity in the normal human fibroblast (NHF) cells. METHODS: The cytotoxic effects of papaverine were examined by the MTT cell viability assay. Flow cytometry using annexin V-FITC/PI was used to study the effects on apoptosis, including its quantification. Effects on cell cycle progression were analyzed by flow cytometry while as effects on apoptosis-related proteins, NF-kB and PI3K/Akt pathways were estimated by Western blot assay. RESULTS: The results indicated that papaverine could induce significant, highly selective and dose-dependent cytotoxic effects in PC-3 cells without causing too much toxicity in normal cells. Papaverine also led to induction of early and late apoptosis along with inducing sub-G1 cell cycle arrest in a dose-dependent manner. Papaverine induced a dose-dependent reduction in the expression levels of Blc-2 proteins and a dose-dependent increase in the expression levels of Bax protein. The expression levels of NF-kB were decreased markedly in comparison to the untreated control. Papaverine treatment also led to a dose-dependent downregulation of PI3K and phospho-Akt expression. CONCLUSION: Papaverine showed selective antitumor properties against PC-3 human prostate cancer cells by inducing early and late apoptosis, sub-G1 cell cycle arrest, modulation of apoptosis-related proteins like Bcl-2, Bax, Bid, XIAP and cytochrome C along with downregulation of NFkB, PI3K/Akt signalling pathway.

Long non-coding RNA linc00261 suppresses gastric cancer progression via promoting Slug degradation.

Gastric cancer (GC) remains a threat to public health with high incidence and mortality worldwide. Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) play critical regulatory roles in cancer biology, including GC. Previous profiling study showed that lncRNA linc00261 was aberrantly expressed in GC. However, the role of linc00261 in GC progression and the precise molecular mechanism remain unknown. In this study, we report that linc00261 was significantly down-regulated in GC tissues and the expression level of linc00261 negatively correlated with advanced tumour status and clinical stage as well as poor prognostic outcome. In vitro functional assays indicate that ectopic expression of linc00261 suppressed cell invasion by inhibiting the epithelial-mesenchymal transition (EMT). By RNA pull-down and mass spectrum experiments, we identified Slug as an RNA-binding protein that binds to linc00261. We confirmed that linc00261 down-regulated Slug by decreasing the stability of Slug proteins and that the tumour-suppressive function of linc00261 can be neutralized by Slug. linc00261 may promote the degradation of Slug via enhancing the interaction between GSK3ß and Slug. Moreover, linc00216 overexpression repressed lung metastasis in vivo. Together, our findings suggest that linc00261 acts a tumour suppressor in GC by decreasing the stability of Slug proteins and suppressing EMT. By clarifying the mechanisms underlying GC progression, these findings may facilitate the development of novel therapeutic strategies for GC.

A Prospective Randomized Trial Comparing Pneumatic Lithotripsy and Holmium Laser for Management of Middle and Distal Ureteral Calculi.

PURPOSE: The aim of this study was to compare the efficacy and safety between pneumatic and holmium:yttrium-aluminum-garnet (Ho:YAG) laser in the treatment of patients with ureteral stones located in the middle and distal ureter. PATIENTS AND METHODS: We conducted a prospective study in recruiting 982 eligible patients from 2009 to 2012. Patients were randomly divided into two groups-the pneumatic lithotripsy (PL) group or the Ho:YAG laser lithotripsy (LL) group. Patient demographics, stone characteristics, intraoperative parameters, and postoperative complications were evaluated and analyzed. RESULTS: The baseline demographics of patients and stone characteristics were similar in the two groups. The LL group showed significant benefits compared with the PL group in terms of mean operative time (28±9.2 vs 41±12.4 min, P=0.001) and early stone-free rate (80.8% vs 91.3%, P=0.04), but there was no statistically significant difference at the third month (92.6% vs 95.5%, P=0.15). In the LL group, 24 postoperative cases of stricture were seen, whereas only 5 cases occurred in the PL group (P=0.02). The other complications, such as perforation, bleeding, and mucosal injury, were comparable in the two groups. The average postoperative stay was also similar (1.7±2.4 days for PL and 1.5±3.1 days for LL (P=0.62). CONCLUSION: Both PL and LL are effective in the management of middle and distal impacted stones. Ho:YAG laser has advantages in better efficacy of stone fragmentation and a higher early stone-free rate but seems to have to face the increased risks of postoperative stricture.

Long noncoding RNA GHET1 promotes the development of bladder cancer.

In spite of the advances in the diagnosis and treatment of bladder cancer, the prognosis of bladder cancer remains relatively poor. As a result, it is vital to identify novel diagnostic and prognostic marker of bladder cancer. A growing volume of literature has implicated the vital role of long noncoding RNA in the development of cancer. GHET1, a recently identified lncRNA, was initially characterized in gastric cancer. However, its role in bladder cancer remains largely unknown. In this study, we demonstrated that GHET1 was upregulated in bladder cancer tissues compared to adjacent normal tissues and its over-expression correlates with tumor size, advanced tumor and lymph node status, and poor survival. GHET1 knockdown suppressed the proliferation and invasion of bladder cancer cells in vitro. In the meantime, inhibition of GHET1 reversed the epithelial-mesenchymal-transition in bladder cancer cell line. Taken together, our study suggests that the potential use of GHET1 as a prognostic marker and therapeutic target of bladder cancer.