Prostate cancer (PCa) is one of the most common malignancies in men worldwide. Despite advances in treatment, many patients develop resistance to conventional therapies. Solute carrier (SLC) proteins, as transmembrane transporters, have recently emerged as potential therapeutic targets due to their role in tumor metabolism and progression. This review summarizes the key roles of six SLC proteins in PCa, including their involvement in metabolic reprogramming, regulation of signaling pathways, and effects on the tumor microenvironment. Although targeting of SLC family members in prostate cancer remains an underexplored area, the growing body of evidence suggests that it holds potential for future development.

Background: Bladder cancer (BLCA) is a common malignancy with significant impact on patient health. The aim of this study was to explore the potential mechanisms of BLCA through a combination of multi-omics and single-cell analyses. Methods: In this study, samples from BLCA and paracancerous tissues were collected for transcriptome, whole-exome sequencing, metabolome and intratumoural microbiome sequencing. These data were then co-analyzed with publicly available datasets to identify and analyze key genes, metabolites and microbiomes as well as their regulatory mechanisms in the pathogenesis of BLCA. Different BLCA clusters were then identified on the basis of key genes. Differences among the clusters were then investigated in terms of biological pathways, immunological microenvironment, genetic alterations, immunotherapy and drug susceptibility. The prognostic value of the key genes was then analyzed using publicly available data, and their molecular regulatory mechanisms were further investigated. Finally, the expression patterns of the key genes were observed at the single cell level and key cells were identified. Results: In this paper, three key genes (AHNAK, CSPG4, and NCAM1), 90 key metabolites and two key microorganisms (Sphingomonas koreensis and Rhodospirillaceae) were identified in a multi-omics analysis. Of these, key genes and key metabolites were negatively correlated. The BLCA samples from transcriptome sequencing were then divided into cluster 1 and cluster 2 based on key genes. Single-cell analysis identified nine cell types, with fibroblasts exhibiting the highest expression of key genes, thus establishing fibroblasts as the key cell in this study. Notably, AHNAK expression was higher in fibroblast subtypes. Conclusion: The combined multi-omics analysis revealed a significant correlation between three key genes (AHNAK, CSPG4, and NCAM1) and multiple key metabolites and key microorganisms, which offering a new reference and theoretical support for the treatment and research of BLCA.

Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650106, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article Published online ■ ■ *Corresponding author. Address: Kunming Medical University Second Hospital: Kunming Medical University Second Affliated Hospital, CHINA. E-mail address: [email protected] (S. Fu). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/

Objective: Cardiovascular and metabolic diseases, including both obesity and blood pressure, have been previously implicated in observational studies as having some association with the occurrence of adrenal tumors. This study aims to evaluate the causal relationships of these high-risk factors with the disease using a Mendelian randomization approach with two-sample data. Single nucleotide polymorphisms (SNPs) for blood pressure, BMI, blood glucose, and cardiovascular diseases were extracted from publicly available whole-genome databases. These were then compared separately with benign adrenal tumors. It was found that only BMI was associated with the occurrence of benign adrenal tumors, and this process may be mediated by C-reactive protein (CRP). We explore whether C-reactive protein (CRP) can mediate the causal relationship between body mass index (BMI) and benign adrenal tumors, further investigating the mechanism and the proportion of CRP involved in this process. Methods: Utilizing a two-sample Mendelian randomization approach, comparisons were made between BMI, blood pressure, cardiovascular diseases, blood glucose, and the outcome. Subsequently, both two-sample Mendelian randomization and multivariable Mendelian randomization (MVMR) analyses were conducted to investigate whether CRP serves as a mediator in the causal relationship between BMI and benign adrenal tumors, while calculating the proportion of mediation involved. Results: There was no causal relationship observed between blood pressure (OR=0.976, 95%CI=0.931-1.024, p=0.339), blood glucose (OR=0.960, 95%CI=0.648-1.422, p=0.840), cardiovascular diseases (OR=0.724, 95%CI=0.244-2.142, p=0.559), and benign adrenal tumors. However, a positive causal relationship was found between BMI and benign adrenal tumors (OR=1.20, 95%CI=1.06-1.35, p=0.003). There was also a positive causal relationship observed between BMI and CRP (OR=1.07, 95%CI=1.06-1.08, p<0.01), as well as between CRP and benign adrenal tumors (OR=1.401, 95%CI=1.017-1.929, p=0.038). After adjusting for CRP, the causal relationship between BMI and benign adrenal tumors diminished (OR=1.35, 95%CI=1.06-1.73, p=0.014). Even after controlling for BMI, a causal relationship between CRP and benign adrenal tumors persisted (OR=1.32, 95%CI=1.03-1.69, p=0.025). The proportion of mediation by CRP was calculated to be 10.4%. Conclusion: Using Mendelian genetic research methods, this study provides evidence that elevated levels of C-reactive protein may serve as a crucial mediating factor in BMI-induced benign adrenal tumors. Therefore, clinicians should pay particular attention to monitoring and managing levels of C-reactive protein when dealing with obese patients, to more effectively prevent the development of adrenal tumors.

Abstract Objectives Development and validation of a computed tomography urography (CTU)‐based machine learning (ML) model for prediction of preoperative pathology grade of upper urinary tract urothelial carcinoma (UTUC). Methods A total of 140 patients with UTUC who underwent CTU examination from January 2017 to August 2023 were retrospectively enrolled. Tumor lesions on the unenhanced, medullary, and excretory periods of CTU were used to extract Features, respectively. Feature selection was screened by the Pearson and Spearman correlation analysis, least absolute shrinkage and selection operator algorithm, random forest (RF), support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost). The logistic regression (LR) was used to screen for independent influencing factors of clinical baseline characteristics. Machine learning models based on different feature datasets were constructed and validated using algorithms such as LR, RF, SVM, and XGBoost. By computing the selected features, a radiomics score was generated, and a diverse feature dataset was constructed. Based on the training set, 16 ML models were created, and their performance was evaluated using the validation set for metrics including sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC), and others. Results The training set consisted of 98 patients (mean age: 64.5 ± 10.5 years; 30 males), whereas the validation set consisted of 42 patients (mean age: 65.3 ± 9.78 years; 17 males). Hydronephrosis was the best independent influence factor (p < 0.05). The RF model had the best performance in predicting high‐grade UTUC, with AUC of 0.914 (95% Confidence Interval [95%CI] 0.852–0.977) and 0.903 (95%CI 0.809–0.997) in the training set and validation set, and accuracy of 0.878 and 0.857, respectively. Conclusions An ML model based on the RF algorithm exhibits excellent predictive performance, offering a non‐invasive approach for predicting preoperative high‐grade UTUC.

To discuss the differences in the effectiveness and security of kidney stones in overweight or obese patients by mini percutaneous nephrolithotomy (MiniPCNL) and retrograde intrarenal surgery (RIRS). We exhaustively searched numerous databases, including PubMed, Embase, Web of Science, Cochrane Library, and CNKI, covering all records from their initiation date until September 2023. This included controlled trials focusing on the use of MiniPCNL and RIRS in the treatment of kidney stones in overweight or obese patients. The gathered data was then analyzed using the Review Manager 5.4 software. 9 studies including 1122 patients were included. Meta-analysis showed that: The MiniPCNL group had higher overall complications, grade I complications, length of hospital stay(LOS), first stone-free rate (SFR), and final SFR in obese patients, with no significant difference between the two groups in terms of operative time(OT), hemoglobin drop, and grade II complication rate. There were more overall complications, grade I complications, final SFR, and LOS with MiniPCNL in patients with stones > 2 cm compared to no significant difference in grade II complications. MiniPCNL performed in the prone position had higher final SFR, less OT, hemoglobin drop, and no statistically significant difference in overall complications or LOS. Sheaths using > 14 F had higher overall complication rates, final SFR, and LOS, and no statistical differences in OT and first SFR between the two modalities. In the MiniPCNL subgroup aged ≤ 50 years, there were higher first SFR, final SFR, and shorter OT, and in the MiniPCNL subgroup aged > 50 years, there were more OT, LOS, and hemoglobin drop, with no statistical difference in overall complications between the two groups. Our study showed that MiniPCNL in obese patients had higher initial SFR and final SFR, fewer procedures, but more postoperative complications, LOS, and grade I complications compared with RIRS. Similar results were seen in patients in the prone position, with stones > 2 cm and age ≤ 50 years. [ https://www.crd.york.ac.uk/PROSPERO/ ], identifier PROSPERO (CRD42023467284).

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-08 IDENTIFICATION OF A BLADDER CANCER SUBPOPULATION THAT MAY BENEFIT FROM DASATINIB Shi Fu, Haifeng Wang, Jiansong Wang, and Junhao Chen Shi FuShi Fu , Haifeng WangHaifeng Wang , Jiansong WangJiansong Wang , and Junhao ChenJunhao Chen View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cancer progression involves the acquisition of stem-like characteristics that are associated with immune escape and drug resistance. Thus, molecular subtyping based on stemness characteristics of bladder cancer (BC) can help reveal intra-tumor heterogeneity and provide more precise therapeutic methods. METHODS: The stemness indices of each sample in BLCA cohort were computed using the one-class logistic regression algorithm and patients were classified using the unsupervised consensus clustering. Then, we gathered a total of 661 treatment-naïve samples from three datasets (BLCA, GSE31684, and GSE13507) to construct and validate a stemness-related prognostic index (SRPI) using Cox regression, LASSO regression and Random Forest methods. The IMvigor210 and GSE176307 cohorts, including 401 urothelial carcinoma patients treated with PD-1 or PD-L1 inhibitor, were employed to predict immunotherapy response. Afterwards, Gene expression data and their corresponding drug IC50 values for BC cell lines were collected from three datasets (GDSC, PRISM and CTRP). Sensitive drugs were screened for high-risk patients by multi-step strategies. Several in-vitro experiments and PDX model were used to confirm the drug efficacy and toxicity. RESULTS: BC patients were classified into two stemness subtypes with distinct prognosis, functional annotations, genomic variations, and immune profiles. Using the SRPI, we identified a high-risk subgroup of patients who had poorer prognosis, lower tumor mutational burden, a higher proportion of LumP/LumU subtype, activation of EMT pathway, inhibition of DDR pathway, and characteristics of immune exclusion. This high-risk subgroup responded poorly to immunotherapy and were insensitive to commonly used chemotherapeutic agents, FGFR inhibitors, and EGFR inhibitors. We further identified dasatinib as a sensitive agent for this high-risk subgroup. Finally, we confirmed that dasatinib significantly inhibited the growth of BC cells and tumors with higher SRPI. CONCLUSIONS: This study provides a novel subtyping of bladder cancer based on stemness signatures and demonstrates that SRPI is a promising tool for predicting prognosis and therapeutic opportunities for BC patients. With SRPI, we can identify a BC subpopulation that may benefit from dasatinib. Download PPT Source of Funding: The National Natural Science Foundation of China (Grant No. 82060464, Grant No. 82260609) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e356 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Shi Fu More articles by this author Haifeng Wang More articles by this author Jiansong Wang More articles by this author Junhao Chen More articles by this author Expand All Advertisement PDF downloadLoading ...

Background: Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being used in recent years. Whether iRARC offers advantages over open radical cystectomy (ORC) remains controversial. This study aimed to compare the difference of perioperative outcomes, oncological outcomes and complications between iRARC and ORC. Methods: The PubMed, Embase, Cochrane Library, Web of Science and CNKI databases were searched in July 2023 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were identified to be eligible if they compared perioperative outcomes, oncological outcomes and complications in patients who underwent iRARC with ORC. Results: Twenty-two studies involving 7020 patients were included. Compared to ORC, iRARC was superior for estimated blood loss [estimated blood loss (EBL) weighted mean difference (WMD): −555.52; 95% CI, −681.64 to −429.39; P<0.001], blood transfusion rate [odds ratio (OR): 0.16; 95% CI, 0.09–0.28; P<0.001], length of hospital stay [length of hospital stay (LOS) WMD: −2.05; 95% CI, −2.93 to −1.17; P<0.001], Clavien–Dindo grades ≥III complication rate [30 days: OR: 0.57; 95% CI 0.44–0.75; P<0.001; 90 days: OR: 0.71; 95% CI 0.60–0.84; P<0.001], and positive surgical margin [positive surgical margin (PSM) OR: 0.65; 95% CI 0.49–0.85; P=0.002]. However, iRARC had a longer operative time [operative time (OT) WMD: 68.54; 95% CI 47.41–89.67; P<0.001] and a higher rate of ureteroenteric stricture [ureteroenteric stricture (UES) OR: 1.56; 95% CI 1.16–2.11; P=0.003]. Time to flatus, time to bowel, time to regular diet, readmission rate, Clavien–Dindo grades less than III complication rate for iRARC were similar to that for ORC. Interestingly, the results of subgroup analysis revealed no difference in EBL between iRARC and ORC when the diversion type was neobladder. When the ileal conduit was selected as the diversion type, the LOS was similar in both procedures. Conclusion: Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion appears to be superior to open radical cystectomy in terms of effectiveness and safety. However, attention should be paid to the occurrence of ureteroenteric stricture during follow-up.

aDepartment of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650106, China bDepartment of Urology, Kunming Children's Hospital, Yunnan, 650106, China Study design:Commentary Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author. Address: Kunming Medical University Second Affliated Hospital CHINA. E-mail address: [email protected] (H. Wang). This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0/

Background The benefits of first-line, cisplatin-based chemotherapy for muscle-invasive bladder cancer are limited due to intrinsic or acquired resistance to cisplatin. Increasing evidence has revealed the implication of cancer stem cells in the development of chemoresistance. However, the underlying molecular mechanisms remain to be elucidated. This study investigates the role of LASS2, a ceramide synthase, in regulating Wnt/β-catenin signaling in a subset of stem-like bladder cancer cells and explores strategies to sensitize bladder cancer to cisplatin treatment. Methods Data from cohorts of our center and published datasets were used to evaluate the clinical characteristics of LASS2. Flow cytometry was used to sort and analyze bladder cancer stem cells (BCSCs). Tumor sphere formation, soft agar colony formation assay, EdU assay, apoptosis analysis, cell viability, and cisplatin sensitivity assay were used to investigate the functional roles of LASS2. Immunofluorescence, immunoblotting, coimmunoprecipitation, LC–MS, PCR array, luciferase reporter assays, pathway reporter array, chromatin immunoprecipitation, gain-of-function, and loss-of-function approaches were used to investigate the underlying mechanisms. Cell- and patient-derived xenograft models were used to investigate the effect of LASS2 overexpression and a combination of XAV939 on cisplatin sensitization and tumor growth. Results Patients with low expression of LASS2 have a poorer response to cisplatin-based chemotherapy. Loss of LASS2 confers a stem-like phenotype and contributes to cisplatin resistance. Overexpression of LASS2 results in inhibition of self-renewal ability of BCSCs and increased their sensitivity to cisplatin. Mechanistically, LASS2 inhibits PP2A activity and dissociates PP2A from β-catenin, preventing the dephosphorylation of β-catenin and leading to the accumulation of cytosolic phospho-β-catenin, which decreases the transcription of the downstream genes ABCC2 and CD44 in BCSCs. Overexpression of LASS2 combined with a tankyrase inhibitor (XAV939) synergistically inhibits tumor growth and restores cisplatin sensitivity. Conclusions Targeting the LASS2 and β-catenin pathways may be an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer patients.

Purpose: To investigate whether C-reactive protein (CRP) can mediate the causal relationship between body mass index (BMI) and the development of bladder cancer (BC), further elucidate the underlying mechanisms and the mediating role of CRP, and quantify the proportion of CRP in this mechanism. Methods: Using two-sample Mendelian randomization and multivariable Mendelian randomization studies, we explored whether CRP serves as a mediator in the causal relationship between BMI and BC, and calculated the proportion of mediation in this context. Results: There is a positive causal relationship between BMI and BC (OR=1.655, 95% CI=1.122-2.441, p=0.011). BMI is positively causally related to CRP (OR=1.237, 95% CI=1.175-1.304, p=9.417×10 -16 ). CRP is also positively causally related to BC (OR=1.401, 95% CI=1.017-1.929, p=0.038). After adjusting for CRP, there is no causal relationship between BMI and BC (OR=1.413, 95% CI=0.959-2.081, p=0.079). Even after controlling for BMI, there is still a causal relationship between CRP and BC (OR=1.434, 95% CI=1.042-1.973, p=0.026). The mediating effect of CRP is 15.9%. Conclusion: Using genetic data, this study provides evidence that higher levels of C-reactive protein (CRP) may serve as a mediator in the pathway through which BMI leads to BC. Clinical practitioners should pay closer attention to the inflammatory marker CRP levels in obese individuals for better BC prevention strategies.

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-06 TARGETING LASS2: A NEW WAY OUT FOR CHEMORESISTANT BLADDER CANCER Shi Fu, Haifeng Wang, Jiansong Wang, and Hongjin Shi Shi FuShi Fu , Haifeng WangHaifeng Wang , Jiansong WangJiansong Wang , and Hongjin ShiHongjin Shi View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The benefits of first-line, cisplatin-based chemotherapy for muscle-invasive bladder cancer are limited due to intrinsic or acquired resistance to cisplatin. Increasing evidence has revealed the implication of cancer stem cells in the development of chemoresistance. However, the underlying molecular mechanisms remain to be elucidated. We previously found that LASS2 is closely related to chemotherapy efficacy in bladder cancer, and we hope to elucidate the mechanism and find chemo-sensitization methods in this study. METHODS: Data from our cohorts and published datasets were used to evaluate the clinical characteristics of LASS2. We isolated primary cells from a chemotherapy-resistant patient and sorted CD44+ALDH1A1+ bladder cancer stem cells (BCSCs) by flow cytometry. The roles of LASS2 in BCSCs were evaluated by spheroid formation assay, soft agar colony formation assay, EdU assay, and cisplatin sensitivity assay. Then, pathway reporter array, luciferase reporter assay, and ChIP assay were used to determine the transcriptional process. Immunofluorescence, immunoblotting, co-immunoprecipitation, mass spectrometry, protein half-life assay, and enzyme activity assay were used to determine the LASS2 signaling. Cell- and patient-derived xenograft models were used to investigate the effect of LASS2 overexpression and a combination of XAV939 on cisplatin sensitization and tumor growth. RESULTS: Patients with low LASS2 expression respond poorly to cisplatin-based chemotherapy and had a worse prognosis. Loss of LASS2 confers a stem-like phenotype and contributes to cisplatin resistance. Overexpression of LASS2 results in inhibition of self-renewal ability of BCSCs and increased their sensitivity to cisplatin. Mechanistically, LASS2 inhibits PP2A activity and dissociates PP2A from β-catenin, preventing the dephosphorylation of β-catenin and leading to the accumulation of cytosolic phospho-β-catenin, which decreases the transcription of the downstream genes ABCC2 and CD44. LASS2-overexpressing adenovirus combined with a tankyrase inhibitor synergistically inhibits tumor growth and restores cisplatin sensitivity. It has been proven to be a safe treatment through animal evaluation. CONCLUSIONS: Targeting LASS2 is an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer. Download PPT Source of Funding: This research is supported by the National Natural Science Foundation of China (Grant No. 81860452, Grant No. 82260609) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e355 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Shi Fu More articles by this author Haifeng Wang More articles by this author Jiansong Wang More articles by this author Hongjin Shi More articles by this author Expand All Advertisement PDF downloadLoading ...

BackgroundThe metabolism of arginine, a conditionally essential amino acid, plays a crucial role in cancer progression and prognosis. However, a more detailed understanding of the influence of arginine biosynthesis genes in cancer is currently unavailable.MethodsWe performed an integrative multi-omics analysis using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to determine the characteristics of these genes across multiple cancer types. To measure the overall activity of arginine biosynthesis genes in cancer, we calculated arginine biosynthesis scores based on gene expression.ResultsOur results indicated that the arginine biosynthesis score was negatively correlated with immune-related pathways, immune infiltration, immune checkpoint expression, and patient prognosis, and single-cell data further clarified that patients with high arginine biosynthesis scores showed a reduced proportion of T and B cells in an immune desert tumor microenvironment and were insensitive to immunotherapy. We also identified several potential drugs through the Cancer Therapeutic Response Portal (CTRP) and Genomics of Drug Sensitivity in Cancer (GDSC) databases that could target arginine biosynthesis genes and potentially improve the response rate to immunotherapy in patients with a high arginine biosynthesis fraction.ConclusionOverall, our analyses emphasize that arginine biosynthesis genes are associated with immune evasion in several cancers. Targeting these genes may facilitate more effective immunotherapy.

Prostate cancer (PCa), with high heterogeneity and poor prognosis, is one of the most common malignant tumors in men. Circular RNAs (circRNAs) have been identified in tumor progression and resistance to medication in numerous studies. However, the role of circ_0001047 in PCa is unclear. In this research, we found that circ_0001047 had low expression in PCa cells and tissues and was negatively correlated with testosterone secretion in vivo. Overexpression of circ_0001047 inhibited the proliferation, migration, invasion, and anti-apoptotic abilities of human PCa cells in vitro. Mechanistically, circ_0001047 promoted the expression of FKBP5 through sponge adsorption of miR-122-5p and then inhibited the proliferation, anti-apoptotic migration, and invasion abilities of PCa cells. In addition, overexpression of circ_0001047 enhanced the sensitivity of PCa cells to abiraterone by inhibiting AKT phosphorylation activation through upregulation of FKBP5/PHLPP1. This study revealed a novel mechanism by which circ_0001047 regulates PCa progression and treatment sensitivity via the miR-122-5p/FKBP5/PHLPP1/AKT axis. These findings deepen our comprehension of the molecular mechanisms in latent PCa progression and treatment resistance.

Background: Previous studies have reported that STAT1 (Signal Transducer and Activator of Transcription 1) is associated with multiple tumor progression. This study aimed to investigate the role and related mechanisms of STAT1 in bladder cancer. Methods: STAT1 expression in bladder cancer tissues and human bladder cancer cell lines was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The bladder cancer cell line T24 was transfected with overexpressing lentivirus targeting STAT1. Cell proliferation, invasion, and apoptosis were measured by Cell Counting Kit-8, Transwell assays, and flow cytometric analysis. Furthermore, RNA-Seq was performed to identify the downstream signaling pathways. Finally, the signaling pathway-related molecules were determined by RT-qPCR and western blot assays. Results: The overexpression of STAT1 inhibited bladder cancer cell proliferation and invasion while enhancing apoptosis. Moreover, the overexpression of STAT1 in bladder cancer cells delayed tumor tumorigenesis in vitro. Mechanistically, RNA-Seq analysis revealed that the JAK-STAT signaling pathway was up-regulated, especially SOCS1 (suppressor of cytokine signaling 1) and SOCS3 (suppressor of cytokine signaling 3) in STAT1-sufficient cells. Conclusions: These results indicate the potential of STAT1 as a therapeutic target in bladder cancer.

Background: Patients with bladder cancer (BLCA) have a poor prognosis and little progress has been made in treatment. Therefore, the purpose of this work was to employ Mendelian randomization (MR) and transcriptome analysis to identify a novel biomarker that could be used to reliably diagnose BLCA. Methods: TCGA-BLCA and GSE121711 datasets were obtained from public databases. Genome-wide association study (GWAS) data of BLCA outcome (373,295 samples containing 9,904,926 single nucleotide polymorphisms) were obtained through the IEU OpenGWAS database. Differentially expressed genes were applied as exposure factors, and MR analysis was performed to identify genes that had a causal relationship with BLCA. Then, the patients were divided into high and low expression groups according to the expression levels of candidate genes, and genes with survival differences were identified. Univariate and multivariate Cox regression were used to investigate the prognostic value of the expression of these genes. A nomogram was constructed based on independent prognostic factors, and we analyzed the functions and pathways associated with the identified genes as well as their relationship with the immune microenvironment. Results: HES4 was identified as a biomarker. HES4 status, age, and stage were identified as independent prognostic factors, and an excellent nomogram was established. Bioinformatic analysis suggested that HES4 might be associated with the activation of the immune response, bone development, and cancer pathways. The BLCA samples were divided into high and low HES4 groups. The stromal score and 33 immune cells were remarkably different between the two groups, with HES4 expression being negatively correlated with macrophages and mast cells, and positively correlated with eosinophils and central memory CD4+ T cells. Finally, HES4 was up-regulated in cancer samples in both TCGA-BLCA and GSE121711 datasets. Conclusion: This study identified HES4 as an independent prognostic factor for BLCA outcome based on MR and transcriptome analysis, which provides useful information for future research on and treatment of BLCA.

Upper urinary tract urothelial carcinoma (UTUC) is a rare and highly aggressive malignancy characterized by poor prognosis, making the accurate identification of high-grade (HG) UTUC essential for subsequent treatment strategies. This study aims to develop and validate a nomogram model using computed tomography urography (CTU) images to predict HG UTUC. A retrospective cohort study was conducted to include patients with UTUC who underwent radical nephroureterectomy and received a CTU examination prior to surgery. In the CTU images, tumor lesions located in the renal calyces, renal pelvis and ureter were segmented, and radiomics features from the unenhanced, medullary, and excretory phases were extracted. The maximum relevance minimum redundancy algorithm, least absolute shrinkage and selection operator, and various machine learning (ML) algorithms—including random forest, support vector machine, and eXtreme gradient boosting—were employed to select radiomics features and calculate radiomics scores. Logistic regression (LR) analysis was performed to identify the independent influencing factors of clinical baseline characteristics. Multiple datasets of radiomics features were constructed by integrating single-phase radiomics features with the most significant independent factor. Both LR and ML algorithms were utilized to develop predictive models. The area under the receiver operating characteristic curve (AUC values), accuracy, sensitivity, and specificity were assessed for model performance evaluation. Decision curve analysis was conducted to evaluate the clinical net benefits. A total of 167 patients were enrolled in this study. Among them, 56 were diagnosed with low-grade UTUC (including papillary urothelial neoplasms with low malignant potential and low-grade urothelial carcinoma) as confirmed by postoperative pathological examination results, and 111 were of HG. These patients were randomly allocated to the training set and the validation set at a ratio of 7:3. The training set comprised 116 patients with a mean age of 63.5 ± 9.38 years and 38 males. The validation set comprised 51 patients with a mean age of 65.6 ± 11.1 years and 18 males. Hydronephrosis was identified as the most significant independent factor in the clinical baseline features. Models that include mixed-phase development achieve better performance compared to models that rely simply on single-phase development. The nomogram model had excellent predictive ability for HG UTUC, with AUC values of 0.844 and an accuracy of 0.793 in the validation sets. The nomogram model can enhance accuracy by 14.1

Background:The causal relationship between certain immune cells and erectile dysfunction (ED) is still uncertain. Aim:The study sought to investigate the causal effect of 731 types of immune cells on ED through Mendelian randomization (MR) using genome-wide association studies (GWAS). Methods:Genetic instruments for 731 immune cells were identified through GWAS, and ED data were obtained from the FinnGen database. Univariable and multivariable bidirectional MR studies were conducted to explore potential causal relationships between these immune cells and ED. The inverse-variance weighted method was primarily used, with Cochran's Q test and MR-Egger intercept test assessing pleiotropy and heterogeneity. Bayesian weighted Mendelian randomization (BWMR) was also employed. Outcomes:Six immune cells were identified as related to ED. CD45 on Natural Killer (NK) cells, CD33dim HLA DR+ CD11b + Absolute Count, CD19 on IgD- CD38dim B cells, and CD3 on CD39+ resting CD4 regulatory T cells were identified as risk factors, whereas CD20 on IgD+ CD38dim B cells and Activated & resting CD4 regulatory T cell %CD4+ T cells were protective factors. Further multivariable MR analysis confirmed that 5 of these immune cells independently impacted ED, except for CD45 on NK cells. Reverse MR analysis indicated that ED occurrence decreases certain immune cell counts, but BWMR found no causal relationship for CD20 on IgD+ CD38dim B cells. Results:Our MR analysis confirmed a potential bidirectional causal relationship between immune cells and ED, providing new insights into potential mechanisms and therapeutic strategies. Clinical Translation:This study provides evidence for the impact of certain immune cells on the development of ED and suggests potential therapeutic targets. Strengths and Limitations:We performed both univariable and multivariable MR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry. Conclusion:Our MR analysis confirmed a potential bidirectional causal relationship between immune cells and ED. This provides new insights into potential mechanisms of pathogenesis and subsequent therapeutic strategies.

Bladder cancer (BC) is a heterogeneous disease with varying clinical outcomes. Recent evidence suggests that cancer progression involves the acquisition of stem-like signatures, and assessing stemness indices help uncover patterns of intra-tumor molecular heterogeneity. We used the one-class logistic regression algorithm to compute the mRNAsi for each sample in BLCA cohort. We subsequently classified BC patients into two subtypes based on 189 mRNAsi-related genes, using the unsupervised consensus clustering. Then, we identified nine hub genes to construct a stemness-related prognostic index (SRPI) using Cox regression, LASSO regression and Random Forest methods. We further validated SRPI using two independent datasets. Afterwards, we examined the molecular and immune characterized of SRPI. Finally, we conducted multiply drug screening and experimental approaches to identify and confirm the most proper agents for patients with high SRPI. Based on the mRNAsi-related genes, BC patients were classified into two stemness subtypes with distinct prognosis, functional annotations, genomic variations and immune profiles. Using the SRPI, we identified a specific subgroup of BC patients with high SRPI, who had a poor response to immunotherapy, and were less sensitive to commonly used chemotherapeutic agents, FGFR inhibitors, and EGFR inhibitors. We further identified that dasatinib was the most promising therapeutic agent for this subgroup of patients. This study provides further insights into the stemness classification of BC, and demonstrates that SRPI is a promising tool for predicting prognosis and therapeutic opportunities for BC patients.