The treatment of prostate cancer (PCa) continues to pose substantial clinical challenges. The use of large language models (LLMs) to identify the key molecular determinants of PCa progression, followed by experimental biological validation, helps uncover novel therapeutic targets. We developed hierarchical knowledge-guided LLM for risk gene identification (HKLLM-RG), a PCa risk gene identification method. Among the candidate genes identified, ALKBH5 emerged as particularly noteworthy in the analysis. Reduced expression of ALKBH5 correlated with aggressive clinical features and significantly reduced survival in PCa. ALKBH5 inhibits PCa progression and promotes ferroptosis. CHRM3, which is the downstream molecule of ALKBH5, could promote PCa cell proliferation and migration. ALKBH5 regulates CHRM3 in an m6A-dependent manner. Mechanistically, the ALKBH5/CHRM3 axis suppresses AKT signaling, thereby inducing the upregulation of the transcriptional repressor ZNF281. This regulatory cascade subsequently downregulates the expression of SLC3A2 and GPX4, ultimately sensitizing cells to ferroptosis. Thus, AZD5363 and RSL3 targeting the ALKBH5/CHRM3/ZNF281 axis can effectively synergize to treat PCa by promoting ferroptosis. Taken together, this study leverages LLM-guided discovery to delineate a novel ALKBH5/CHRM3/ZNF281 regulatory axis controlling ferroptotic susceptibility in PCa. Importantly, a synergistic therapeutic strategy was identified by combining RSL3 with AZD5363, providing novel therapeutic targets and directions for PCa treatment.

Although immunotherapy has transformed the treatment of several genitourinary malignancies, its role in prostate cancer remains limited. Combining immunotherapy with targeted therapies has emerged as a promising approach to enhance immune responses in prostate cancer. We aimed to systematically evaluate the efficacy and safety of immunotherapy combined with targeted therapy in the treatment of prostate cancer. We conducted a detailed literature search across Embase, Scopus, PubMed, Web of Science, and the Cochrane Library to include clinical trials enrolling adults with histologically confirmed prostate cancer treated with a combination of targeted therapy and immunotherapy. A systematic review and meta-analysis were performed according to a registered protocol. A total of 21 studies from 19 clinical trials, encompassing 5702 participants, were included. The studies evaluated 12 unique therapeutic combinations involving six targeted agents and four immunotherapies. Seven trials compared combination therapy with monotherapy. Pooled analyses showed that combination therapy significantly improved disease control rate (RR = 1.42), complete response (RR = 2.56), and partial response (RR = 2.13), albeit with a higher incidence of adverse events. In single-arm studies, the pooled median progression-free survival was 5.14 months, and median overall survival was 16.79 months. The androgen receptor signaling inhibitor subgroup exhibited longer survival than the PARP inhibitor subgroup. Combination immunotherapy and targeted therapy demonstrate superior efficacy over monotherapy in prostate cancer but increase the risk of toxicity. These promising results warrant further validation in large-scale, well-designed randomized trials.

The optimal surgical management for T3aN0M0 renal cell carcinoma (RCC) remains debated. Radical nephrectomy (RN) is generally considered the standard treatment, whereas partial nephrectomy (PN) may preserve renal function, but the comparative long-term survival outcomes between these approaches remain unclear. Using the Surveillance, Epidemiology, and End Results (SEER) database, we compared cancer-specific mortality (CSM) and other-cause mortality (OCM) between PN and RN in patients with T3aN0M0 RCC. One-to-one propensity score matching (PSM) was performed. Cumulative incidence curves were generated, and univariable and multivariable Fine–Gray competing-risk regression (CRR) were applied to evaluate CSM and OCM. Subgroup analyses were performed by tumor size and age. A total of 17,032 patients were included, of whom 2805 underwent PN and 14,227 underwent RN. After PSM, multivariable CRR analysis showed that PN was not associated with increased CSM compared with RN in the overall matched cohort (subdistribution hazard ratio (sHR) 0.77; 95

BackgroundThe incidence of thyroid cancer has increased annually, but the risk factors for thyroid cancer are still unclear. In this umbrella review, we aimed to identify associations between nongenetic risk factors and thyroid cancer incidence, and assess the quality and validity of the evidence.MethodsPubMed, Embase and the Cochrane Database of Systematic Reviews were searched to identify related meta-analyses or systematic reviews of epidemiological studies. We extracted the estimated summary effect and 95% confidence interval (CI) through fixed or random effects models of each meta-analysis. AMSTAR2 and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) were used to evaluate the methodological quality of the included meta-analyses and the quality of evidence respectively. Further subgroup analyses by sex and sensitivity analyses were conducted.ResultsWe identified 53 articles with 112 associations, of which 69 had significant relationships with thyroid cancer risk, including factors related to iodine, nitrates, fish, vitamin D, tea, alcohol, smoke, body mass index (BMI), pesticides, X-ray, I131, oral contraceptives, flavonoids, reproductive factors and some medical conditions. However, most studies (65%) were categorized as "critically low" on the basis of AMSTAR2, and most evidence (86%) was of weak quality since the classification by GRADE was very low. Moreover, subgroup and sensitivity analyses revealed more risk factors in women than in men.ConclusionWe found that several modifiable factors have essential effects in the primary prevention of thyroid cancer, but few high-quality studies exist. In the future, more well-conducted, especially prospective, studies are needed to confirm the results.Trial registrationThe protocol for this review was registered in PROSPERO (CRD42022352841).

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal cell carcinoma. However, our understanding of ccRCC risk genes remains limited. This gap in knowledge poses challenges to the effective diagnosis and treatment of ccRCC. To address this problem, we propose a deep reinforcement learning-based computational approach named RL-GenRisk to identify ccRCC risk genes. Distinct from traditional supervised models, RL-GenRisk frames the identification of ccRCC risk genes as a Markov Decision Process, combining the graph convolutional network and Deep Q-Network for risk gene identification. Moreover, a well-designed data-driven reward is proposed for mitigating the limitation of scant known risk genes. The evaluation demonstrates that RL-GenRisk outperforms existing methods in ccRCC risk gene identification. Additionally, RL-GenRisk identifies eight potential ccRCC risk genes. We successfully validated epidermal growth factor receptor (EGFR) and piccolo presynaptic cytomatrix protein (PCLO), corroborated through independent datasets and biological experimentation. This approach may also be used for other diseases in the future.

The treatment of prostate cancer (PCa) remains challenging, and while melatonin (MEL) has demonstrated therapeutic potential, its precise mechanisms require further elucidation. Through integrated in vitro, in vivo, and bioinformatics analyses, this study demonstrated that MEL functioned as a novel ferroptosis inducer in PCa by disrupting androgen receptor (AR) liquid-liquid phase separation (LLPS). We found that MEL effectively inhibited PCa proliferation, migration, and invasion in vitro while suppressing tumor growth safely in mice models. Mechanistically, MEL impaired AR LLPS dynamics, reducing AR-driven transcription of minichromosome maintenance protein 5 (MCM5). MCM5 was a clinically relevant biomarker associated with aggressive PCa and poor survival. Crucially, downregulated MCM5 attenuated its physical interaction with NRF2, leading to uncontrolled activation of the NRF2/HMOX1 pathway, GPX4 suppression, and accumulation of ferroptosis hallmarks. These findings defined an AR/MCM5/NRF2 axis regulating ferroptosis susceptibility, establishing MEL as the first-reported ferroptosis inducer that expands the mechanistic foundation and therapeutic potential of MEL-based PCa treatment strategies.

Advances in cancer management have improved oncologic outcomes, but the extent of these improvements and disparities across demographic and socioeconomic groups over the past two decades remains unclear. We identified patients diagnosed with primary cancer at eight sites (lung and bronchus, liver and intrahepatic bile ducts [IHBD], esophagus, colon, kidney, pancreas, rectum, and stomach) between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER)-17 database. Kaplan-Meier curves were used to evaluate cancer-specific survival (CSS) across different diagnostic periods, and Cox proportional hazards models were employed to adjust for confounding factors. We found that CSS for eight cancers improved significantly between 2000 and 2019, but the extent of improvement varied by population characteristics. Elderly patients, unmarried individuals, those with low income, and rural residents showed poorer relative CSS improvement across all eight cancers. Relative CSS improvement differences by sex were present across the eight cancers but remained small. Black patients exhibited less relative CSS improvement than White patients only in pancreatic cancer. Absolute 5-year CSS differences by race (White vs. Black) decreased in six cancers except pancreatic and gastric cancers. In summary, the extent of improvement in CSS for the eight cancers varied by demographic characteristics between 2000 and 2019. Absolute survival differences by age, marital status, income, and place of residence widened for most cancers, while racial differences (White vs. Black) narrowed for most cancers. This provides potential recommendations for further adjustments in medical resources.

OBJECTIVE:Prostate-specific antigen (PSA) has served as a screening tool for prostate cancer (PCa) for over 30 years, but its low specificity remains a significant limitation. Liquid biopsy based on promoter methylation, an epigenetic modification, holds significant potential to complement PSA testing and enhance the diagnostic accuracy of PCa. Our objective was to assess the diagnostic accuracy of liquid biopsy for promoter methylation in PCa. METHODS:We conducted a comprehensive search to screen clinical studies on the application of liquid biopsy for promoter methylation in PCa diagnosis. Subgroup analyses were performed based on sample type, area, control type, method, timing of prostatectomy or prostate massage, and promoter type. The quality of the included articles was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS:We included 31 studies with a total of 3,880 participants. The results indicated that the sensitivity of promoter methylation detected via liquid biopsy for PCa was 0.55 (95% confidence interval [CI], 0.42-0.67) and the specificity was 0.87 (95% CI, 0.83-0.89), with an area under the curve (AUC) of 0.87 (95% CI, 0.83-0.89). In the serum sample group, specificity reached 0.97 (95% CI, 0.92-0.98), and both the positive likelihood ratio and AUC demonstrated excellent diagnostic performance. CONCLUSIONS:Liquid biopsy for promoter methylation shows excellent specificity for PCa diagnosis, particularly in serum samples. However, further large-scale studies are required before its superiority over PSA testing can be fully established.

The treatment of advanced prostate cancer (PCa) primarily based on androgen deprivation therapy (ADT); however, patients inevitably progress to the castration-resistant prostate cancer (CRPC) stage. Despite the recent advancements in CRPC treatment with novel endocrine drugs that further inhibit androgen receptor signaling, resistance ultimately develops, underscoring the urgent need for new effective therapeutic strategies. Therapeutic cancer vaccines, a form of immunotherapy, exert anti-cancer effects by activating the host's immune system. Over the past few decades, various conventional therapeutic PCa vaccines based on cells, microbes, proteins, peptides, or DNA have been developed and tested in patients with advanced PCa. These attempts have largely failed to improve survival, with the sole exception of sipuleucel-T, which extended the median overall survival of asymptomatic or minimally symptomatic metastatic CRPC (mCRPC) patients by four months. The rapid development and high efficacy of mRNA vaccines during the COVID-19 pandemic have garnered worldwide attention. Compared to conventional vaccines, mRNA vaccines offer several unique advantages, including high production efficiency, low cost, high safety, strong immune response induction, and high adaptability and precision. These attributes make mRNA vaccines a promising frontier in the treatment of advanced PCa.

BACKGROUND:The global COVID-19 pandemic in 2020 has exerted multidimensional effects on cancer, yet detailed investigations into these impacts remain largely insufficient. PATIENTS AND METHODS:We evaluated the impact of the COVID-19 pandemic in 2020 on cancers of six major sites, including lung & bronchus, female breast, prostate, colon & rectum, pancreas, and corpus & uterus. Annual changes in the number of new cases were assessed using the Surveillance, Epidemiology, and End Results (SEER)-22 dataset. The impact of the epidemic on diagnosis, treatment, and prognosis was analyzed using the SEER-17 dataset. Specifically, Ordinal logistic regression models were used to investigate the impact of the pandemic on stage. Logistic regression was used to elucidate the impact of the pandemic on diagnosis in different subgroups. Finally, we assessed both the time interval from diagnosis to treatment and cancer-specific survival (CSS). RESULTS:Compared with 2019, new diagnoses of the six major cancers decreased in 2020, with smaller changes in distant-stage cancers. Except for lung cancer (OR = 1.01, 95% CI, 0.97-1.05, P = 0.549), five of the six cancers diagnosed in 2020 tended to be at an advanced stage (all OR > 1, P < 0.005). During the pandemic, patients diagnosed with all six cancers in 2020 were more likely to have high-grade tumors, and for four cancers (excluding lung & bronchus and pancreatic cancers), patients were less likely to reside in areas with populations exceeding 1 million. No significant delay in the time from diagnosis to treatment was observed for any of the six cancers during the pandemic. With the exception of colorectal cancer (HR = 1.08, 95% CI, 1.02-1.14, P = 0.006), no significant deterioration in CSS was observed for the other five cancers (all P > 0.05). CONCLUSION:The number of new cases of the six major cancers decreased during the COVID-19 pandemic, but the impact on patients with different characteristics was different. Most cancer types tended to be diagnosed at a later stage, but the timeliness of treatment was not adversely affected. Some cancer types exhibited significantly worse CSS, or a trend toward worse CSS, but longer follow-up is needed to confirm these findings.

Over the past two decades, treatment advancements have significantly changed the management of metastatic prostate cancer (PCa), clear cell renal cell carcinoma (ccRCC), and urothelial carcinoma of the bladder (UCB), but it remains unclear how these advancements have translated into survival improvements at the population level. In this study, newly diagnosed cases of metastatic PCa, ccRCC, and UCB were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and multivariable Cox regression were used to estimate cancer-specific survival (CSS) improvement during 2000-2019. For metastatic PCa, there was no significant improvement in CSS for patients diagnosed in 2005-2009 compared to 2000-2004 (HR = 0.95, 95% CI, 0.88-1.02), but significant improvements were observed in 2010-2014 (HR = 0.93, 95% CI, 0.88-0.98) and 2015-2019 (HR = 0.75, 95% CI, 0.70-0.82). For metastatic ccRCC, compared to 2000-2004, patients diagnosed in 2005-2009 (HR = 0.87, 95% CI, 0.81-0.94), 2010-2014 (HR = 0.77, 95% CI, 0.71-0.83), and 2015-2019 (HR = 0.55, 95% CI, 0.51-0.60) showed continuous CSS improvement. For metastatic UCB, no significant improvement was shown in 2005-2009 (HR = 1.01, 95% CI, 0.92-1.10) or 2010-2014 (HR = 0.92, 95% CI, 0.85-1.00), but significant improvement emerged in 2015-2019 (HR = 0.83, 95% CI, 0.76-0.90). Subgroup analysis revealed a "catch-up" effect among Black patients, who generally had poorer outcomes but demonstrated greater improvements in CSS than White patients in metastatic PCa, ccRCC, and UCB. Overall, survival has improved for patients with metastatic PCa, ccRCC, and UCB between 2000 and 2019, but the extent of improvement varies across different socioeconomic groups.

BACKGROUND AND OBJECTIVE:We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets.METHODS:Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis.RESULTS:We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group.CONCLUSIONS:Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Kidney & Bladder I (MP69)1 May 2024MP69-19 NON-ANTIBIOTIC INTERVENTIONS TO PREVENT URINARY TRACT INFECTIONS: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Zeyu Han, Xianyanling Yi, Jin Li, Tianyi Zhang, and Jianzhong Ai Zeyu HanZeyu Han , Xianyanling YiXianyanling Yi , Jin LiJin Li , Tianyi ZhangTianyi Zhang , and Jianzhong AiJianzhong Ai View All Author Informationhttps://doi.org/10.1097/01.JU.0001008892.86171.de.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The guidelines updated in 2022 by the American Urological Association (AUA), Canadian Urological Association (CUA), and the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) indicate that, along with antibiotics, non-antibiotic measures such as cranberries, D-mannose, and probiotics serve as preventive options for urinary tract infections (UTIs). This study aimed to compare the efficacy and safety of various non-antibiotic interventions using network meta-analysis in preventing UTIs among individuals with a history of UTI or those presenting risk factors for such infections. METHODS: The authors systematically searched PubMed, EMBASE, Web of Science, and the Cochrane Library from their inception up to October 2023 without language restrictions. The inclusion criteria encompassed randomized controlled trials (RCTs) focusing on one or more non-antibiotic interventions for UTI prevention, with the incidence of UTIs being a key outcome measure. The methodological quality of studies was assessed using the risk of bias assessment tool from Cochrane Collaboration. RESULTS: This study incorporated a total of 32 articles, encompassing 5,474 subjects. 87.5% of RCTs employed double-blind or triple-blind designs. The vast majority of studies were of high methodological quality and had a low risk of bias. Nearly 80% of the participants were female, and most studies featured a follow-up period ranging from 6 to 12 months. The interventions encompassed nine measures, including cranberry, propolis plus cranberry, probiotics, vaccines, vitamins, etc. In both all-age and adult groups (25 RCTs), D-mannose, vaccine, cranberry, and a combination of cranberry, probiotics, and vitamins exhibited a significant reduction in UTI incidence compared to the placebo. The top three SUCRA rankings were for D-mannose, a combination including cranberries, probiotics and vitamins, and vaccines. No statistically significant differences in adverse event incidence were observed for the various interventions compared to the placebo group. All results were devoid of publication bias. CONCLUSIONS: In summary, D-mannose, vaccine, cranberry, and a combination of cranberry, probiotics, and vitamins present as a potentially effective regimen for UTI prevention. Download PPT Source of Funding: This study was supported by grants from the National Natural Science Foundation of China (82070784, 81702536) to J. A., a grant from Science & Technology Department of Sichuan Province, China (2022JDRC0040) to J. A © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1126 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Zeyu Han More articles by this author Xianyanling Yi More articles by this author Jin Li More articles by this author Tianyi Zhang More articles by this author Jianzhong Ai More articles by this author Expand All Advertisement PDF downloadLoading ...

Clinical trials of adeno-associated virus (AAV)-based gene therapy have made remarkable progress in recent years. We aimed to perform a systematic review and meta-analysis of the literature to assess the efficacy and safety of AAV-based gene therapy for hemophilia. We systematically searched the Web of Science, Embase, PubMed, and the Cochrane Database of Systematic Reviews databases, for clinical trials involving patients diagnosed with hemophilia and treated with AAV-mediated gene therapy. Data on the annualized bleeding rate (ABR), annualized infusion rate (AIR), the incidence of treatment-related adverse events (TRAEs), severe adverse events (SAEs), and alanine aminotransferase (ALT) elevation were extracted as our outcomes. A total of 12 articles from 11 clinical trials were selected from 868 articles for meta-analysis. Pooled analyses showed that AAV-based gene therapy in hemophilia patients reduced the number of bleeding events and the number of factor infusion events by an approximate average of 7 per year and 103 per year, respectively. Eighty percent, 18%, and 63% of hemophilia patients had elevated TRAE, SAE, and ALT levels, respectively. Moreover, subgroup analysis found a significant reduction in ABR and AIR 2-3 years after the therapy. Additional findings that were not pooled including coagulation factor activity are presented in the accompanying tables. Our analysis supported the efficacy and safety of AAV-mediated gene therapy for hemophilia, providing evidence for its application as a therapeutic option for widespread clinical use in hemophilia patients in the future.

PURPOSE:To compare the oncological outcomes between standard radical cystectomy (SRC) and organ-sparing cystectomy (OSC) in male patients diagnosed with bladder cancer. METHODS:Patients with stage Ta-T3 bladder cancer who underwent OSC or SRC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The association between preoperative factors and the implementation of OSC was analyzed using logistic regression. Propensity score matching (PSM) was employed to balance baseline characteristics between the two groups. Patients' overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Subgroup analyses based on the T stage were also conducted. RESULTS:A total of 7264 patients were included, with 96.8% (7033 patients) receiving SRC and 3.2% (231 patients) receiving OSC. Patients with higher T stages and high-grade tumors were less likely to undergo OSC. After PSM, OSC was associated with significantly worse OS and CSS than SRC. Subgroup analysis revealed that OSC did not lead to worse OS and CSS in non-muscle invasive bladder cancer and T2 stage patients, but it resulted in significantly worse outcomes in T3 stage patients. CONCLUSION:Our study indicates that OSC is associated with poorer oncological outcomes compared to SRC, particularly in patients with advanced-stage tumors. These findings suggest the need for stringent selection criteria for OSC in bladder cancer patients. Given the negative impact on prognosis, stage T3 should potentially be considered a contraindication for OSC. Further evidence is required to confirm these assertions.

ObjectiveThis review aims to conduct a comprehensive study of the diagnostic accuracy of interleukin-6 (IL-6) for multiple diseases by utilizing existing systematic reviews and meta-analyses.MethodsWe performed a thorough search of Embase, Web of Science, PubMed, and Cochrane Database of Systematic Reviews up to April 2023 to gather meta-analyses that investigate the diagnostic accuracy of IL-6. To assess the methodological quality of the studies, we employed the Assessing the Methodological Quality of Systematic Reviews-2 and Grading of Recommendations, Assessment, Development and Evaluation criteria.ResultsWe included 34 meta-analyses out of the 3024 articles retrieved from the search. These meta-analyses covered 9 categories of diseases of the International Classification of Diseases-11. Studies rated as "Critically Low" or "Very Low" in the quality assessment process were excluded, resulting in a total of 6 meta-analyses that encompassed sepsis, colorectal cancer, tuberculous pleural effusion (TPE), endometriosis, among others. Among these diseases, IL-6 demonstrated a relatively high diagnostic potential in accurately identifying TPE and endometriosis.ConclusionsIL-6 exhibited favorable diagnostic accuracy across multiple diseases, suggesting its potential as a reliable diagnostic biomarker in the near future. Substantial evidence supported its high diagnostic accuracy, particularly in the cases of TPE and endometriosis.

Recent guidelines indicated that, in addition to antibiotics, nonantibiotic interventions serve as available preventive options for urinary tract infections (UTIs). This study aimed to compare the efficacy and safety of various nonantibiotic interventions in preventing UTIs. The authors systematically searched databases for eligible studies. The inclusion criteria encompassed randomized controlled trials (RCTs) focusing on one or more nonantibiotic interventions for UTI prevention, with the incidence of UTIs being a key outcome measure. Subgroup analyses were performed according to age, sex, and follow-up. 50 RCTs comprising 10,495 subjects and investigating 14 interventions, were included. Nearly 80