UNASSIGNED: Prevalent urological cancers, including kidney, prostate, bladder, and testicular cancers, contribute significantly to global cancer incidence and mortality. Metabolomics, focusing on small-molecule intermediates, has emerged as a tool to understand cancer etiology. Given the knowledge gap in this field, we employ a two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between genetically determined metabolites (GDMs) and the susceptibility to four common urological cancers.
UNASSIGNED: The study employs genome-wide association studies (GWAS) data from European populations, featuring the most extensive case count available for both blood metabolites and four prevalent urological cancers. Preliminary and secondary MR analyses were separately conducted, employing inverse variance weighted (IVW) as the primary method. Multiple statistical analyses, including the MR-Steiger test, Cochran\'s Q test, leave-one-out analysis, MR-Egger intercept analysis, and MR-PRESSO analysis, were executed to ensure robustness. Additionally, a meta-analysis was carried out to consolidate findings. The weighted median (WM) method was utilized for a relatively lenient correction (PWM < 0.05).
UNASSIGNED: After rigorous genetic variation filtering, 645 out of 1,400 metabolites were included in both preliminary and secondary MR analyses. Preliminary MR analysis identified 96 potential causal associations between 94 distinct metabolites and four urological cancers. Secondary analysis based on Finnish outcome data revealed 93 potential causal associations. Cross-database meta-analysis identified 68 blood metabolites associated with four urological cancers. Notably, 31 metabolites remained significant after using WM for correction, with additional 37 suggestive causal relationships. Reverse MR analysis revealed a significant causal association between genetically predicted prostate cancer and elevated 4-hydroxychlorothalonil levels (IVW, combined OR: 1.039, 95% CI 1.014-1.064, p = 0.002; WM, combined OR: 1.052, 95% CI 1.010-1.095, p = 0.014).
UNASSIGNED: This comprehensive MR study provides insights into the causal relationships between blood metabolites and urological cancers, revealing potential biomarkers and therapeutic targets, thereby addressing gaps in understanding and laying the foundation for targeted interventions in urological cancer research and treatment.

This comprehensive review critically examines the transformative impact of artificial intelligence (AI) and radiomics in the diagnosis, prognosis, and management of bladder, kidney, and prostate cancers. These cutting-edge technologies are revolutionizing the landscape of cancer care, enhancing both precision and personalization in medical treatments. Our review provides an in-depth analysis of the latest advancements in AI and radiomics, with a specific focus on their roles in urological oncology. We discuss how AI and radiomics have notably improved the accuracy of diagnosis and staging in bladder cancer, especially through advanced imaging techniques like multiparametric MRI (mpMRI) and CT scans. These tools are pivotal in assessing muscle invasiveness and pathological grades, critical elements in formulating treatment plans. In the realm of kidney cancer, AI and radiomics aid in distinguishing between renal cell carcinoma (RCC) subtypes and grades. The integration of radiogenomics offers a comprehensive view of disease biology, leading to tailored therapeutic approaches. Prostate cancer diagnosis and management have also seen substantial benefits from these technologies. AI-enhanced MRI has significantly improved tumor detection and localization, thereby aiding in more effective treatment planning. The review also addresses the challenges in integrating AI and radiomics into clinical practice, such as the need for standardization, ensuring data quality, and overcoming the \"black box\" nature of AI. We emphasize the importance of multicentric collaborations and extensive studies to enhance the applicability and generalizability of these technologies in diverse clinical settings. In conclusion, AI and radiomics represent a major paradigm shift in oncology, offering more precise, personalized, and patient-centric approaches to cancer care. While their potential to improve diagnostic accuracy, patient outcomes, and our understanding of cancer biology is profound, challenges in clinical integration and application persist. We advocate for continued research and development in AI and radiomics, underscoring the need to address existing limitations to fully leverage their capabilities in the field of oncology.

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Background: The relationship between inflammatory bowel disease (IBD) and urological cancers has been identified in epidemiological and observational studies, while the causality remains uncertain. We examined whether IBD is causally associated with urological cancers in a Mendelian randomization (MR) study. Methods: The causal relationship between IBD, its main subtypes, and urological cancers was investigated using genome-wide association study data. To obtain more reliable conclusions, all outcomes were divided into training and validation sets. Eligible single-nucleotide polymorphisms were selected as instrumental variables based on MR analysis assumptions. The inverse variance-weighted (IVW) method was employed as the main method along with four other complementary methods. Results: In this two-sample MR study, no genetic evidence for the causal effect of IBD on urological cancers was found in either the training or validation sets using the IVW method. Similarly, we did not observe any significant association between Crohn\'s disease or ulcerative colitis and urological cancers. The results of the other methods are in accordance with those obtained using the IVW method. Conclusion: In this study, we confirmed that IBD is not a causal genetic risk factor for urological cancer in a European population.

Typically associated with solid tumors, hypoxia contributes to tumor angiogenesis and lymphangiogenesis through various molecular mechanisms. Accumulating studies indicate that hypoxia-inducible factor is the key transcription factor coordinating endothelial cells to respond to hypoxia in urological cancers, mainly renal cell carcinoma, prostate cancer, and bladder cancer. Moreover, it has been suggested that tumor hypoxia in tumor microenvironment simultaneously recruits stromal cells to suppress immune activities. This review summarizes the mechanisms by which HIF regulates tumorigenesis and elaborates on the associations between HIF and angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers.

In addition to environmental conditions, lifestyle factors, and chemical exposure, aberrant gene expression and mutations involve in the beginning and development of urological tumors. Even in Western nations, urological malignancies are among the top causes of patient death, and their prevalence appears to be gender dependent. The prognosis for individuals with urological malignancies remains dismal and unfavorable due to the ineffectiveness of conventional treatment methods. PI3K/Akt is a popular biochemical mechanism that is activated in tumor cells as a result of PTEN loss. PI3K/Akt escalates growth and metastasis. Moreover, due to the increase in tumor cell viability caused by PI3K/Akt activation, cancer cells may acquire resistance to treatment. This review article examines the function of PI3K/Akt in major urological tumors including bladder, prostate, and renal tumors. In prostate, bladder, and kidney tumors, the level of PI3K and Akt are notably elevated. In addition, the activation of PI3K/Akt enhances the levels of Bcl-2 and XIAP, hence increasing the tumor cell survival rate. PI3K/Akt ] upregulates EMT pathways and matrix metalloproteinase expression to increase urological cancer metastasis. Furthermore, stimulation of PI3K/Akt results in drug- and radio-resistant cancers, but its suppression by anti-tumor drugs impedes the tumorigenesis.

MicroRNAs (miRNAs) are emerging as biomarkers for the detection and prognosis of cancers due to their inherent stability and resilience. To summarize the evidence regarding the role of urinary miRNAs (umiRNAs) in the detection, prognosis, and therapy of genitourinary cancers, we performed a systematic review of the most important scientific databases using the following keywords: (urinary miRNA) AND (prostate cancer); (urinary miRNA) AND (bladder cancer); (urinary miRNA) AND (renal cancer); (urinary miRNA) AND (testicular cancer); (urinary miRNA) AND (urothelial cancer). Of all, 1364 articles were screened. Only original studies in the English language on human specimens were considered for inclusion in our systematic review. Thus, a convenient sample of 60 original articles was identified. UmiRNAs are up- or downregulated in prostate cancer and may serve as potential non-invasive molecular biomarkers. Several umiRNAs have been identified as diagnostic biomarkers of urothelial carcinoma and bladder cancer (BC), allowing us to discriminate malignant from nonmalignant forms of hematuria. UmiRNAs could serve as therapeutic targets or recurrence markers of non-muscle-invasive BC and could predict the aggressivity and prognosis of muscle-invasive BC. In renal cell carcinoma, miRNAs have been identified as predictors of tumor detection, aggressiveness, and progression to metastasis. UmiRNAs could play an important role in the diagnosis, prognosis, and therapy of urological cancers.

The Drosophila zeste enhancer homolog 2 gene (enhancer of zeste homolog 2; EZH2) is an important member of the polycomb group (PcG) gene family, which maintains the homologous gene via chromosome modification during embryonic development. EZH2 is overexpressed in various tumors, is closely related to tumor formation and growth, and has a malignant phenotype that promotes tumor cell proliferation, proliferation and metastasis. In the present study, a meta- and bioinformatic analysis was performed using data from multiple online databases until August 30, 2022. EZH2 upregulation was found in kidney, bladder and prostate cancers. EZH2 expression was negatively related to TNM staging and pathological grade in kidney and prostate cancers (P<0.05), as well as invasion depth and pathological grade in bladder cancer. According to the KM-plotter database, EZH2 expression was inversely associated with poor overall survival in patients with kidney clear cell renal cell carcinoma (RCC) and papillary RCC and with favorable survival in bladder cancer. EZH2 expression was negatively related to relapse-free survival in kidney papillary RCC and bladder cancer but positively associated with kidney clear cell RCC. According to GEPIA and UALCAN databases, EZH2 expression was higher in tumor tissue than normal tissue. The TIMER database showed that EZH2 was closely associated with the proportion of seven immune cell infiltrates in kidney, bladder, and prostate cancers. High EZH2 expression may be a potential marker of tumorigenesis and metastasis in patients with urological cancers.

Prostate carcinoma is a malignant situation that arises from genomic alterations in the prostate, leading to changes in tumorigenesis. The NF-κB pathway modulates various biological mechanisms, including inflammation and immune responses. Dysregulation of NF-κB promotes carcinogenesis, including increased proliferation, invasion, and therapy resistance. As an incurable disease globally, prostate cancer is a significant health concern, and research into genetic mutations and NF-κB function has the efficacy to facilitate the introduction of novel therapies. NF-κB upregulation is observed during prostate cancer progression, resulting in increased cell cycle progression and proliferation rates. Additionally, NF-κB endorses resistance to cell death and enhances the capacity for metastasis, particularly bone metastasis. Overexpression of NF-κB triggers chemoresistance and radio-resistance, and inhibition of NF-κB by anti-tumor compounds can reduce cancer progression. Interestingly, non-coding RNA transcripts can regulate NF-κB level and its nuclear transfer, offering a potential avenue for modulating prostate cancer progression.

A high number of cancer-related deaths (up to 90) are due to metastasis and simple definition of metastasis is new colony formation of tumor cells in a secondary site. In tumor cells, epithelial-mesenchymal transition (EMT) stimulates metastasis and invasion, and it is a common characteristic of malignant tumors. Prostate cancer, bladder cancer and renal cancer are three main types of urological tumors that their malignant and aggressive behaviors are due to abnormal proliferation and metastasis. EMT has been well-documented as a mechanism for promoting invasion of tumor cells and in the current review, a special attention is directed towards understanding role of EMT in malignancy, metastasis and therapy response of urological cancers. The invasion and metastatic characteristics of urological tumors enhance due to EMT induction and this is essential for ensuring survival and ability in developing new colonies in neighboring and distant tissues and organs. When EMT induction occurs, malignant behavior of tumor cells enhances and their tend in developing therapy resistance especially chemoresistance promotes that is one of the underlying reasons for therapy failure and patient death. The lncRNAs, microRNAs, eIF5A2, Notch-4 and hypoxia are among common modulators of EMT mechanism in urological tumors. Moreover, anti-tumor compounds such as metformin can be utilized in suppressing malignancy of urological tumors. Besides, genes and epigenetic factors modulating EMT mechanism can be therapeutically targeted for interfering malignancy of urological tumors. Nanomaterials are new emerging agents in urological cancer therapy that they can improve potential of current therapeutics by their targeted delivery to tumor site. The important hallmarks of urological cancers including growth, invasion and angiogenesis can be suppressed by cargo-loaded nanomaterials. Moreover, nanomaterials can improve chemotherapy potential in urological cancer elimination and by providing phototherapy, they mediate synergistic tumor suppression. The clinical application depends on development of biocompatible nanomaterials.