Acetyl Tributyl Citrate (ATBC) is a widely used plasticizer that has been increasingly linked to cancer risks. However, its toxicological impact on bladder cancer (BCa) remains unclear. This study aimed to systematically investigate the molecular targets and mechanisms of ATBC in BCa using integrated computational and experimental approaches. The oncogenic effects of ATBC were assessed via plate colony formation and transwell migration assays. Potential protein targets of ATBC were predicted by integrating the Pharmmapper, SwissTargetPrediction, and TargetNet databases. Functional enrichment analyses were conducted to identify relevant signaling pathways. Molecular docking and dynamics simulations were utilized to validate the interaction between ATBC and the key target AKR1B1. The R package “scTenifoldKnk” was employed for in silico knockout analysis. In vivo experiments and Western blot analysis confirmed that ATBC regulates epithelial-mesenchymal transition (EMT) through AKR1B1. Functional experiments showed that ATBC promoted BCa cell proliferation and migration. A total of 461 potential ATBC binding targets were identified, of which 142 were associated with BCa based on differential expression analysis. Prognostic modeling prioritized twelve key genes and AKR1B1 exhibited the strongest binding affinity to ATBC. Molecular dynamics simulations confirmed the stability of the ATBC-AKR1B1 complex. Multi-omics analyses revealed that AKR1B1 was significantly upregulated in BCa and correlated with advanced disease stage and poor prognosis. In silico knockout analysis revealed the relationship between AKR1B1 and EMT. Western blot and transwell migration assays revealed that ATBC promoted EMT and migration of BCa cells, whereas knockdown of AKR1B1 inhibited this effect. Our study elucidates the role of ATBC in promoting BCa progression and identifies AKR1B1 as a key functional target. These findings provid crucial insights into the environmental toxicology of plasticizers and establish a theoretical foundation for future preventive and therapeutic strategies against ATBC-related malignancies.

Accurate preoperative discrimination of renal cell carcinoma (RCC) subtypes is critical for treatment stratification. We aimed to develop and validate an automated deep learning system for simultaneous tumor segmentation and histopathological subtyping using multicenter contrast-enhanced CT (CECT) imaging. To this end, we constructed a two-stage system comprising separate segmentation and classification models. The segmentation model was trained on 245 scans from Nanfang Hospital and 210 from the KiTS19 public dataset. The classification model was developed and validated on a total of 750 patients, comprising an internal cohort from Nanfang Hospital (553 patients; 328 training, 112 validation, 113 testing) and two external validation cohorts: one from Beijing Tongren Hospital (n = 111) and another combined from two other centers (n = 86). The model demonstrated strong generalizability for discriminating clear cell RCC, with AUCs of 0.878 (internal validation), 0.892 (internal testing), 0.911 (external set Ⅰ), and 0.892 (external set Ⅱ). The model's computational efficiency reached 0.24 s per file and reduced FLOPs by four times compared to conventional 3D CNNs. This study validates the efficiency and clinical applicability of the YOLOv11 framework for RCC subtyping. Future efforts should integrate prospective data and multimodal imaging to enhance sensitivity for small lesions.

Macroautophagy/autophagy is an evolutionarily conserved degradation pathway wherein cytoplasmic components are sequestered within double-membrane autophagosomes for lysosomal delivery. The initiation of autophagy is governed by autophagy-related (ATG) proteins, with the ULK1 kinase complex serving as the most upstream regulator. However, how ULK1 senses and integrates metabolic signals via post-translational modifications remains poorly understood. Here, we discover that ULK1 undergoes lactylation at lysine 46, catalyzed by the mitochondrial aminoacyl-tRNA synthetase AARS2, in response to autophagic stimuli. This modification promotes ULK1 kinase activity, leading to enhanced and selective phosphorylation of its downstream substrate ATG14 at Ser29, thereby activating the class III PtdIns3K complex and facilitating autophagosome biogenesis. Furthermore, we demonstrate that AARS2-mediated ULK1 lactylation drives autophagic flux and promotes tumor metastasis in clear cell renal cell carcinoma (ccRCC), and that a cell-penetrating peptide targeting K46 lactylation suppresses ccRCC progression in vitro and in vivo. Our study identifies lactylation as a novel regulatory mechanism controlling autophagy initiation and suggests that targeting AARS2-mediated ULK1 lactylation could be a potential strategy for treating ccRCC.Abbreviations: AARS2: alanyl-tRNA synthetase 2, mitochondrial; ATG14: autophagy related 14; Baf.A1: bafilomycin A1; ccRCC: clear cell renal cell carcinoma; co-IP: co-immunoprecipitation; CPP: cell-penetrating peptide; EBSS: Earle's balanced salt solution; HIF: hypoxia-inducible factor; K46la: lactylation at lysine 46; Kla: lysine lactylation; KO: knockout; LDHA: lactate dehydrogenase A; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PtdIns3K: class III phosphatidylinositol 3-kinase; PTM: post-translational modification; SQSTM1/p62: sequestosome 1; TCGA-KIRC: The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma; TEM: transmission electron microscopy; ULK1: unc-51 like autophagy activating kinase 1; VHL: von Hippel-Lindau tumor suppressor; WT: wild-type.

Cisplatin resistance in bladder cancer (BCa) is driven by metabolic reprogramming that enhances glycolysis and lactate production. Here, we report that lactate-induced histone H3K18 lactylation (H3K18la) drives chemoresistance by activating a novel signaling axis that couples epigenetic regulation with mitochondrial quality control. Through integrative multi-omics analysis, ChIP-qPCR, and promoter reporter assays, we identified HNRNPF as a key functional effector downstream of H3K18la. Unexpectedly, HNRNPF, primarily known as an RNA-binding protein, promotes chemoresistance through a non-canonical mechanism: it directly interacts with the core mitophagy protein Parkin. Mechanistically, the RRM2 domain of HNRNPF binds the R0 domain of Parkin, facilitating Parkin's recruitment to damaged mitochondria. This interaction potentiates Parkin's E3 ubiquitin ligase activity, leading to enhanced ubiquitination of VDAC1 and robust activation of mitophagy. Collectively, our findings establish the H3K18la-HNRNPF-Parkin axis as a previously unrecognized signaling cascade that bridges epigenetic reprogramming and mitochondrial quality control in chemoresistance. Targeting this axis, particularly the HNRNPF-Parkin interaction or mitophagy activation, presents a novel therapeutic strategy to overcome cisplatin resistance in BCa.

BACKGROUND:Bladder cancer (BCa) is a prevalent urinary malignancy with unmet clinical therapeutic needs. Shikonin, a natural anti-tumor compound, exerts anti-BCa activity, yet its direct molecular target and underlying mechanism remain undefined. PURPOSE:This study aimed to identify the direct target of shikonin in BCa and to elucidate the mechanism by which shikonin suppresses tumor progression. METHODS:The anti-BCa effects of shikonin were assessed in vitro and in vivo. Drug affinity responsive target stability (DARTS) combined with 4D quantitative proteomics identified shikonin's direct target, which was validated by molecular docking and cellular thermal shift assay (CETSA). Gain- and loss-of-function experiments and ER-phagy-related assays elucidated the underlying molecular mechanism. RESULTS:Shikonin inhibited BCa cell proliferation, migration, invasion and induced senescence in vitro, and suppressed tumor growth in vivo with no obvious toxicity. Deoxyribonuclease 2 (DNASE2) was identified as shikonin's direct target; shikonin promoted DNASE2 ubiquitination and degradation without altering its mRNA level. DNASE2 was highly expressed in BCa and correlated with poor prognosis, and its knockdown mimicked and enhanced shikonin's anti-BCa effects. Mechanistically, shikonin targeted DNASE2 to downregulate Reticulon 3 (RTN3), thereby inhibiting RTN3-dependent endoplasmic reticulum autophagy (ER-phagy) in BCa. CONCLUSION:This study first identifies DNASE2 as the direct target of shikonin in BCa, and reveals that shikonin exerts anti-BCa activity by promoting DNASE2 ubiquitination/degradation to inhibit the DNASE2/RTN3 axis-mediated ER-phagy. The DNASE2/RTN3 axis is a novel ER-phagy regulatory node in BCa, providing a potential therapeutic target for BCa treatment.

Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder cancer (BCa), yet only 35 % of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA sequencing, together with assay for transposase-accessible chromatin using sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated mitophagy and apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired mitophagy flux, leading to enhanced survival of cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.

BackgroundRenal cell carcinoma (RCC) is a significant urological malignancy with a rising incidence, increasingly linked to metabolic dysregulation and chronic systemic inflammation. While traditional metrics such as body mass index (BMI) are commonly used, they may not fully capture the biological heterogeneity underlying carcinogenesis. This study investigated the associations of the Metabolic Score for Insulin Resistance (METS-IR) and the Systemic Inflammation Response Index (SIRI) with subsequent RCC risk, together with their joint effects and longitudinal trajectory patterns.MethodsWe conducted a retrospective analysis within the UK Biobank prospective cohort, comprising 410,766 participants aged 37-73 years. METS-IR and SIRI were calculated from baseline blood samples. Incident RCC was ascertained through national cancer registries. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), because the outcome was time to incident RCC with variable follow-up and right censoring. Nonlinear relationships were evaluated using restricted cubic splines, and joint effects were assessed on an additive scale. Dynamic trajectory analysis based on repeat assessment data was treated as exploratory.ResultsDuring a median follow-up of 13.65 years, 1,752 (0.43%) participants developed RCC, with a median time to diagnosis of 8.01 years among cases. Both biomarkers were independently associated with RCC risk. In fully adjusted models, each 1-SD increase in METS-IR was associated with a 26% higher RCC risk (HR: 1.26; 95% CI: 1.12-1.42), showing a linear dose-response pattern. SIRI showed a non-linear association, with risk increasing more sharply beyond an index value of approximately 1.2; participants in the highest quartile had a 57% higher risk (HR: 1.57; 95% CI: 1.35-1.83)than those in the lowest quartile. Participants with concomitantly high METS-IR and high SIRI had the highest risk (HR: 2.40; 95% CI: 2.06-2.79), although additive interaction metrics did not show statistical evidence of interaction. In exploratory trajectory analyses, persistently high METS-IR or SIRI was associated with higher RCC risk, whereas estimates for improved and worsened groups were more imprecise.ConclusionMETS-IR and SIRI were independently associated with RCC risk in this cohort. Their combined assessment may improve risk stratification. The findings further suggest that metabolic and inflammatory trajectory patterns may carry different prognostic information, although these longitudinal results should be interpreted cautiously and not as evidence of causality or risk reversibility.

​BackgroundBladder cancer (BCa) is a prevalent urinary malignancy with unmet clinical therapeutic needs. Shikonin, a natural anti-tumor compound, exerts anti-BCa activity, yet its direct molecular target and underlying mechanism remain undefined.Methods: The anti-BCa effects of shikonin were assessed in vitro and in vivo . Drug affinity responsive target stability (DARTS) combined with 4D quantitative proteomics identified shikonin’s direct target, which was validated by molecular docking and cellular thermal shift assay (CETSA). Gain- and loss-of-function experiments and ER-phagy-related assays elucidated the underlying molecular mechanism.ResultsShikonin inhibited BCa cell proliferation, migration, invasion and induced senescence in vitro, and suppressed tumor growth in vivo with no obvious toxicity. DNASE2 was identified as shikonin’s direct target; shikonin promoted DNASE2 ubiquitination and degradation without altering its mRNA level. DNASE2 was highly expressed in BCa and correlated with poor prognosis, and its knockdown mimicked and enhanced shikonin’s anti-BCa effects. Mechanistically, shikonin targeted DNASE2 to downregulate RTN3, thereby inhibiting RTN3-dependent endoplasmic reticulum autophagy (ER-phagy) in BCa.ConclusionThis study first identifies DNASE2 as the direct target of shikonin in BCa, and reveals that shikonin exerts anti-BCa activity by promoting DNASE2 ubiquitination/degradation to inhibit the DNASE2/RTN3 axis-mediated ER-phagy. The DNASE2/RTN3 axis is a novel ER-phagy regulatory node in BCa, providing a potential therapeutic target for BCa treatment.

Although multiple therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have improved the management of bladder cancer, the clinical outcome of muscle-invasive bladder cancer (MIBC) remains unsatisfactory. To address this challenge, we identified MIBC-related genes (MIBC.RGs) through transcriptomic and proteomic analyses and developed a prognostic model to predict patient outcomes. Among the candidate genes, PSMG1 was prioritized through an integrated framework combining machine learning-based screening and single-cell transcriptomic analysis. Experimental analyses revealed that PSMG1 was markedly upregulated in bladder cancer (BCa), progressively upregulated from normal tissue to MIBC, and PSMG1 silencing reduced cell proliferation, invasion, and clonogenic capacity in vitro, while attenuating tumor growth in vivo. Mechanistically, our data suggest that PSMG1 may promote BCa aggressiveness, at least in part, by affecting E-cadherin stability and EMT-related signaling. Epigenetic profiling revealed significant H3K18la enrichment at the PSMG1 promoter, supporting a potential H3K18la-PSMG1 regulatory axis. Finally, molecular docking, proteomic profiling, and Drug Affinity Responsive Target Stability (DARTS) assays prioritized Curcumin as a candidate compound potentially associated with PSMG1 targeting. Overall, our findings indicate that the H3K18la-PSMG1 axis may participate in BCa progression and support further evaluation of Curcumin in PSMG1-associated therapeutic strategies.

Retroperitoneal fibroids are a rare condition that is often misdiagnosed preoperatively. It typically occurs in women with a history of hysterectomy or myomectomy for benign uterine smooth muscle tumors. In this case report, we present the case of a 50-year-old woman who presented with discomfort in the right perineal area. Imaging showed a large retroperitoneal tumor. The patient underwent robotic-assisted laparoscopic surgery to remove the mass, which was confirmed by histopathological analysis to be a uterine smooth muscle tumor of undetermined malignant potential (STUMP). The patient had no recurrence during the 2-year follow-up. The overall prognosis of STUMP is favorable, but more rigorous and long-term follow-up is required to monitor potential recurrence. Our case highlights that retroperitoneal masses in women with prior uterine fibroid surgery should raise suspicion for retroperitoneal fibroids. Robot-assisted laparoscopic surgery may be a safe and feasible minimally invasive option.

154 Background: LIBERTAS is a global phase 3 study evaluating apalutamide (APA) plus intermittent versus continuous androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer (mCSPC). The study aims to determine reduces hot flash burden compared with APA + continuous ADT and whether APA + intermittent ADT provides noninferior radiographic progression-free survival (rPFS). Initial findings demonstrated that treatment with 6 months of APA + ADT resulted in rapid and deep PSA responses in most patients with mCSPC. This abstract presents PSA response results from patients enrolled in China. Methods: Overall, eligible mCSPC participants had ≤3 months of prior ADT, ECOG PS 0–1, and confirmed metastases by conventional or next-generation imaging. All received APA 240 mg/day + ADT during the initial 6-month treatment phase. In the main phase, 22 participants from China with PSA <0.2 ng/mL were randomized 1:1 to continuous or intermittent ADT. Primary endpoints: reduction of hot flash burden, measured by severity-adjusted hot flash score, and rPFS, measured by 18-mo event-free survival rate. Results: In total, 36 participants from China were enrolled from 8 sites, with 22 randomized to the main treatment phase. Median age was 71.0 years (range: 51–79) and median baseline PSA was 64.7 ng/mL (range: 2.6–2399.0). After 3 months of treatment with apalutamide plus ADT, 100.0% of participants achieved a ≥50% PSA decline (PSA50), 94.4% achieved a ≥90% decline (PSA90), and 30.6% achieved PSA <0.2 ng/mL (PSA0.2). Among those who completed the initial 6-month treatment phase, 100% achieved PSA50, 97.2% achieved PSA90, and 61.1% achieved PSA0.2. No new safety signals were observed in the Chinese subgroup. Conclusions: Participants enrolled in the LIBERTAS study had rapid and deep PSA responses to APA plus ADT, with patients in China having a similar rapid and deep PSA decline. The LIBERTAS results confirm the efficacy of APA + ADT in Chinese patients with mCSPC and aligned with the pivotal TITAN Phase 3. The safety profile of APA remained consistent with prior experience, supporting APA’s tolerability in this population. The LIBERTAS study remains on track for results readout in 2027. We would like to acknowledge Todd Simon for his statistical support. Clinical trial information: NCT05884398 .

BACKGROUND:Bladder cancer (BCa), particularly muscle-invasive bladder cancer (MIBC), is associated with poor prognosis, partly because of immune evasion driven by M2 tumor-associated macrophages (TAMs). Understanding the regulatory mechanisms of M2 macrophage polarization via PRKN-mediated mitophagy and histone lactylation (H3K18la) is crucial for improving treatment strategies. METHODS:A single-cell atlas from 46 human BCa samples was constructed to identify macrophage subpopulations. Bioinformatics analysis and experimental validation, including ChIP-seq and lactylation modulation assays, were used to investigate the role of PRKN in M2 macrophage polarization and its regulation by H3K18la. RESULTS:Single-cell analysis revealed distinct macrophage subpopulations, including M1 and M2 types. PRKN was identified as a critical regulator of mitophagy in M2 macrophages, supporting their immunosuppressive function. Bulk RNA-seq and gene intersection analysis revealed a set of mitophagy-related macrophage polarization genes (Mito_Macro_RGs) enriched in mitophagy and immune pathways. Pseudotime analysis revealed that PRKN was upregulated during the M1-to-M2 transition. siRNA-mediated PRKN knockdown impaired M2 polarization, reducing the expression of CD206 and ARG1. ChIP-seq and histone lactylation modulation confirmed that H3K18la enhanced PRKN expression, promoting mitophagy and M2 polarization and thereby facilitating immune suppression and tumor progression. CONCLUSIONS:Histone lactylation regulated PRKN-mediated mitophagy, promoting M2 macrophage polarization and contributing to immune evasion in BCa.

BACKGROUND:Genitourinary diseases significantly affect the quality of life of elderly individuals in Europe, yet comprehensive studies on their burden remain limited. This study used Global Burden of Disease (GBD) 2021 data to analyze the burden of genitourinary diseases in adults aged 55 and older in Europe from 1990 to 2021, with projections to 2030 to inform policy development. MATERIALS AND METHODS:Using GBD 2021 data, we assessed the burden of genitourinary diseases in European adults aged 55 and older, analyzing incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) rates. Associations with socioeconomic indicators, including the Socio-Demographic Index and Human Development Index (HDI), were analyzed using Spearman's correlation. Temporal trends were examined through Estimated Annual Percentage Change and Autoregressive Integrated Moving Average models. RESULTS:In 2021, Europe emerged as the region with the highest proportion of elderly populations globally. Among European nations, the Russian Federation reported the highest incidence rates of certain genitourinary diseases, including urinary tract infections (UTI) and interstitial nephritis (IN) at 10188.73 (95% UI 8549.59-11914.66), urolithiasis at 8538.61 (95% UI 6976.70-10,315.88), and benign prostatic hyperplasia at 1377.63 (95% UI 1040.48-1702.85) per 100 000 population. Greece exhibited the highest DALYs, mortality, and YLL rates related to chronic kidney disease. Notable gender and age disparities were evident, with males generally bearing a heavier burden across the majority of genitourinary disorders, except for UTI and IN, where females, particularly those aged 55-64, demonstrated a higher incidence. Socioeconomic factors also impacted these burdens, with higher HDI scores associated with increased mortality ( R = 0.50, P < 0.001) and YLDs ( R = 0.37, P = 0.014). Projections indicated that the burden of genitourinary diseases would continue to rise across most European countries over the next decade, while countries like Poland and Iceland were expected to experience declines. CONCLUSION:Genitourinary diseases are increasingly burdening Europe's aging population. Addressing regional, gender, and socioeconomic disparities is critical for developing effective, age-sensitive healthcare policies and strengthening healthcare systems.

Glucocorticoids play a pivotal role in tumorigenesis and cancer progression. However, the prognostic significance of glucocorticoid signaling-related genes remains poorly understood, particularly in kidney renal clear cell carcinoma (KIRC). Collected samples indicated KIRC patients exhibited elevated serum glucocorticoid levels compared to healthy donors (P < 0.05). Glucocorticoid signaling-related genes were curated from the MSigDB database. The TCGA-KIRC cohort was utilized for training, while 7 independent public KIRC cohorts and local samples were employed for validation. Through LASSO and random forest analyses, ACADM, ANGPTL4, and NFKB2 were identified and subsequently incorporated into a multivariate Cox regression model. This gene signature emerged as a robust prognostic indicator across multiple cohorts (pooled hazard ratio [HR] = 2.73, 95% confidence interval [CI] = 2.05-3.65). In local samples, KIRC tissues exhibited increased infiltration of NFKB2+ cells and decreased levels of ACADM+ and ANGPTL4+ cells (all P < 0.05). Meta-analyses and spatial transcriptomics revealed a positive association between the signature and CD8+ T cell infiltration. Furthermore, the signature was associated with T cell exhaustion levels and could predict immunotherapeutic responses in both computational simulations and real-world clinical settings (all P < 0.05). In vivo experiments showed that NFKB2 knockdown inhibited tumor growth and the expansion of CD8+PDCD1+ T cells, effects that were reversible with corticosterone treatment (all P < 0.05). Collectively, a glucocorticoid signaling-related gene signature was developed and rigorously validated as a predictive tool for prognosis and immunotherapeutic response in KIRC, offering valuable insights for guiding personalized treatment strategies.

OBJECTIVE:Parabens, esters of p-hydroxybenzoic acid, are widely utilized as antimicrobial preservatives in consumer products. While increasing evidence implicates parabens in tumor progression across cancers, their role and mechanisms in bladder cancer (BLCA) remain uncharacterized. METHODS:Methylparaben (MP) and propylparaben (PP) effects on invasion, migration, and proliferation were assessed in BLCA T24 and SW780 cells. The above effects have also been verified through in vivo experiments. Genes linked to MP, PP, and BLCA were curated from public databases. Hub genes were identified through protein-protein interaction (PPI) networks and an optimized prognostic model using 101 machine learning algorithms. Molecular docking (MD) and molecular dynamics simulations (MDS) evaluated hub gene-paraben interactions, followed by functional validation via transfection assays. RESULTS:MP and PP significantly enhanced BLCA cell invasion (all P < 0.05) without affecting proliferation or migration. It can also promote tumor growth in nude mice (all P < 0.05). Network toxicology and prognostic modeling identified MMP2 and PPARG as key targets for MP and PP, respectively. MD/MDS confirmed stable binding between parabens and their targets. MP upregulated MMP2 expression, while PP downregulated PPARG (all P < 0.05). MMP2 knockdown and PPARG overexpression partly reversed paraben-induced invasion (all P < 0.05). CONCLUSION:This study reveals that MP and PP promote BLCA invasion via MMP2 and PPARG modulation, providing mechanistic insights into paraben-associated tumorigenesis and underscoring potential public health implications of paraben exposure. These findings have raised concerns about the risk of BLCA caused by low level environmental exposure to parabens, especially among people with impaired detoxification pathways.

Globally, bladder cancer is the tenth most common cancer. Mitophagy, a critical process regulating mitochondrial quantity and quality, has attracted increasing attention for its pivotal function in cancer. Nonetheless, its roles and underlying mechanisms in bladder cancer are yet to be elucidated. Therefore, in this study, 16 mitophagy-related genes were screened to construct a robust prognostic model with exceptional predictive accuracy for the outcomes of patients with bladder cancer. Of these genes, DARS2 was identified as a key regulator that significantly affected cancer progression. The findings established that DARS2 promoted the G1-to-S phase transition by upregulating CDK4 expression, thereby suppressing cellular senescence and driving cell proliferation. In addition, DARS2 augmented PINK1 expression, leading to increased PINK1-mediated mitophagy. Both in vitro and in vivo experiments confirmed that DARS2 inhibited cellular senescence and facilitated tumor progression by enhancing PINK1-mediated mitophagy. The observations from this study have provided novel insights into the multifaceted roles of DARS2-mediated mitophagy in bladder cancer. Targeting DARS2 and its regulation of mitophagy is a promising therapeutic strategy to improve the outcomes for patients with bladder cancer.

Bladder cancer (BCa) is a prevalent malignancy with a poor prognosis. SLC7A7 has been linked to BCa progression and angiogenesis, but its specific role remains unclear. We established a SLC7A7-knockdown BCa cell line to investigate its effects on angiogenesis. In vivo experiments assessed tumor vascularization, while in vitro studies explored exosome involvement. MiRNA sequencing identified miR-152-3p as a key regulator. Further investigation using dual-luciferase reporter assays, qRT-PCR, and Western blot revealed that miR-152-3p inhibits the expression of FGFR3 by binding to its 3’ UTR. Meanwhile, functional assays, including angiogenesis assays, Transwell assays, and wound healing assays, were performed to evaluate the effects of miR-152-3p on angiogenesis. We confirmed the significant role of SLC7A7 in BCa progression, specifically in promoting angiogenesis, through the involvement of exosomes and the regulatory axis of miR-152-3p/ FGFR3. Targeting FGFR3 might be a promising strategy to reverse control BCa progression for an improved prognosis.

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration-resistant prostate cancer (CRPC) that is typically resistant to nearly all current therapies. In this study, single-cell RNA sequencing (scRNA-seq) and dataset analyses identified Centrosomal Protein 55 (CEP55) as a critical factor in the transformation from hormone-sensitive prostate cancer (HSPC) to CRPC and, ultimately, NEPC. Subsequent bioinformatics analyses and validation with clinical samples demonstrated that CEP55 is significantly upregulated in NEPC tissues compared to HSPC and CRPC. Furthermore, while CEP55 does not appear to be associated with the immune microenvironment or cancer-associated fibroblasts (CAFs), our findings indicate that it directly mediates the plasticity of prostate cancer cells, thereby promoting NEPC progression. Specifically, in vivo and in vitro experiments confirmed that CEP55 enhances cell proliferation, migration, and invasion and the expression of NEPC biomarkers in prostate cancer. Importantly, although cisplatin is the primary treatment for NEPC clinically, CEP55 has been shown to regulate cisplatin resistance through the phosphorylation of CDK1 at the tyrosine 15 (Tyr15) site. In summary, our study identifies a key gene that influences the neuroendocrine differentiation process in prostate cancer, suggesting its potential as an important therapeutic target.

Background:Genitourinary cancers constitute a significant portion of the global cancer burden and have emerged as a prominent cause of cancer-related mortality. However, there remains a paucity of up-to-date statistical analyses that meticulously examine the global and national shifts in the epidemiology of genitourinary cancers. Our study aimed to provide a comprehensive understanding of the global distribution and progression of genitourinary cancers through analyses of the recently updated 2021 Global Burden of Disease (GBD) database. Methods:This study presented the incidence, mortality, disability-adjusted life years (DALYs), and their respective age-standardized rates for four genitourinary cancers (bladder, kidney, prostate, and testicular cancers) by sex, age, and location from 1990 to 2021. Estimates for these data were presented with their 95% uncertainty intervals (UIs). Estimated annual percentage changes (EAPCs) and Bayesian Age-Period-Cohort (BAPC) models were utilized to further quantify the temporal dynamics of age-standardized rates (ASRs) in genitourinary cancers. Countries and territories were categorized according to socio-demographic index (SDI) quintiles. Results:Globally, with the exception of a sustained decline in age-standardized incidence rates (ASIRs) for bladder cancer (EAPC = -0.36%), the ASIRs for kidney, prostate, and testicular cancers demonstrated an upward trend from 1990 to 2021 (EAPC = 0.53%, 0.20%, and 1.43%, respectively). In terms of geographical regions, High-income North America had the highest ASIRs for both bladder (13.98 per 100,000 persons [95% UI, 12.96 to 14.61]) and prostate (47.02 per 100,000 persons [95% UI, 44.47 to 49.04]) cancers. Southern Latin America recorded the highest ASIRs for kidney (13.44 per 100,000 persons [95% UI, 12.27 to 14.73]) and testicular (4.98 per 100,000 persons [95% UI, 4.33 to 5.72]) cancers. Additionally, Central Europe (1.25% [95% CI, 1.12% to 1.38%]), East Asia (2.40% [95% CI, 2.21% to 2.59%]), Eastern Europe (3.74% [95% CI, 3.55% to 3.92%]), and the Caribbean (5.52% [95% CI, 4.32% to 6.74%]) exhibited the highest EAPCs for bladder, kidney, prostate, and testicular cancers, respectively. Unlike the ASIRs, age-standardized mortality rates (ASMRs) and age-standardized DALYs rates (ASDRs) showed a downward trend over time in all types of genitourinary cancers. The disease burdens of bladder, kidney, and prostate cancers were primarily distributed among older men, while testicular cancer mainly occurred in young men. Smoking remained the primary risk factor for bladder cancer. Meanwhile, high fasting plasma glucose and high body-mass index exerted increasingly significant impacts on bladder and kidney cancers, respectively, during the study period. Projections to 2050 suggest that the global burdens of genitourinary cancers are expected to decline to varying degrees. However, regional disparities in genitourinary cancer burdens are projected to persist. Conclusions:Although the results demonstrate a marginal decline in ASRs caused by genitourinary cancers, they still impose a considerable global burden and result in numerous deaths. Our study obtained and analyzed the latest epidemiological data of genitourinary cancers from the GBD 2021, offering valuable information for national healthcare professionals and policymakers to optimize resource allocation, manage costs more efficiently, and develop practical healthcare policies.

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration-resistant prostate cancer (CRPC) that is typically resistant to nearly all current therapies. In this study, single-cell RNA sequencing (scRNA-seq) and dataset analyses identified Centrosomal Protein 55 (CEP55) as a critical factor in the transformation from hormone-sensitive prostate cancer (HSPC) to CRPC and, ultimately to, NEPC. Subsequent bioinformatics analyses and validation with clinical samples demonstrated that CEP55 is significantly upregulated in NEPC tissues compared to HSPC and CRPC. Furthermore, while CEP55 show no significant association with the immune microenvironment or cancer-associated fibroblasts (CAFs), our findings indicate that it directly mediates the plasticity of prostate cancer cells, thereby driving NEPC progression. Specifically, in vivo and in vitro experiments confirmed that CEP55 enhances cell proliferation, migration, invasion and the expression of NEPC biomarkers in prostate cancer. Importantly, although cisplatin is the primary treatment for NEPC clinically, CEP55 has been shown to regulate cisplatin resistance through the phosphorylation of CDK1 at the tyrosine 15 (Tyr15) site. In summary, our study identifies a key gene that influences the neuroendocrine differentiation process in prostate cancer, suggesting its potential as an important therapeutic target.