BACKGROUND:Prostate cancer (PCa) is the second most common cancer in men. For patients with high-volume metastatic PCa (mPCa) who are fit for docetaxel, a triplet therapy regimen consisting of androgen deprivation therapy (ADT), chemotherapy, and an androgen receptor pathway inhibitor (ARPI) is recommended. Adding local radiotherapy to triplet therapy has been shown to alleviate symptoms and reduce disease progression. However, the benefit of combining triplet therapy with local surgery remains unclear and warrants further investigation in the present study. STUDY DESIGN:This is an open-label, prospective, two-arm, multicentre, randomised controlled trial. ENDPOINTS:Primary endpoints are progression-free survival (PFS) and the 1-year PFS rate. Disease progression is defined as prostate-specific antigen (PSA) progression, radiological progression, or unequivocal clinical progression. Secondary endpoints include overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS:Patients aged 18-75 years with high-volume mPCa will receive ADT (triptorelin 15 mg every 3 months), four-six cycles of chemotherapy (docetaxel 75 mg/m2 every 3 weeks), and an ARPI (rezvilutamide 240 mg once daily). Patients achieving a PSA level ≤0.2 ng/mL and deemed suitable candidates for surgery will be enrolled. A total of 88 eligible patients will be randomised in a 1:1 ratio. The control group will continue treatment with triptorelin and rezvilutamide, while the experimental group will receive robot-assisted cytoreductive prostatectomy in addition to triptorelin and rezvilutamide. Baseline PSA levels will be recorded and re-examined at each chemotherapy cycle and every 3 months thereafter. Radiological evaluations will be performed every 6 months. Clinical progression will be assessed based on pain severity, performance status, and the need to initiate new anticancer therapy. HRQoL will be evaluated every 3 months. PFS and OS will be estimated using Kaplan-Meier curves and compared with the log-rank test. TRIAL REGISTRATION:Chinese Clinical Trial Registry: ChiCTR2600121819.

Lymphangiogenesis is essential for tumor lymphatic metastasis, yet the molecular mechanisms governing the activation of its key cytokine, VEGF-C, remain unclear. Herein, we identified a circRNA, circFOCAD, through VEGF-C maturation-associated multiple transcription sequencing. CircFOCAD is overexpressed in lymph node (LN)-metastatic bladder cancer (BCa) and is associated with poor prognosis. In footpad popliteal LN metastasis and orthotopic BCa models, circFOCAD enhances VEGF-C-dependent lymphangiogenesis and LN metastasis in BCa. Mechanistically, circFOCAD potentiates pro-VEGF-C cleavage by facilitating the expression of CCBE1 and its newly identified partner, the metalloprotease ADAM10. Specifically, circFOCAD promotes ADAM10 promoter H3K9 acetylation by recruiting YBX1. ADAM10 requires CCBE1 as a scaffold, binding at residue R301/R302, to interact with N-terminal propeptide of pro-VEGF-C at residue E58, provoking VEGF-C maturation and sustaining lymphangiogenesis in BCa. Clinically, neutralizing antibodies against CCBE1 and ADAM10 diminished the LN metastatic of BCa in a patient-derived xenograft (PDX) model. Our findings indicate that circFOCAD acts as an initiator of VEGF-C maturation and may represent a promising therapeutic target in LN metastatic BCa.

In vivo CAR-macrophage (CAR-M) therapy exploits macrophages' tumor-tropic homing, phagocytic capacity, and ability to remodel the immunosuppressive tumor microenvironment, with low risk of cytokine release syndrome and potential as an off-the-shelf therapy. However, clinical translation is currently constrained by the lack of efficient non-viral platforms for in situ macrophage engineering. To address this challenge, fluorinated ionizable lipids were rationally designed-capitalizing on fluorine's high electronegativity, low polarizability, and lipophobicity-to enhance lipid nanoparticle (LNP) delivery. Screening a library of 80 fluorinated lipids identified A1F5C5 as the lead candidate, demonstrating superior mRNA delivery to macrophages both in vitro and in vivo. Our investigation into the mechanism revealed that, while fluorination universally enhanced both cellular uptake and subsequent endosomal dissociation, the specific configuration with five fluorine atoms uniquely conferred a superior membrane fusion capability, which proved critical for achieving efficient endosomal escape. F5-LNPs encapsulating mRNA encoding an hPSMA-targeted CAR (F5-CAR) were formulated using this platform. Intravenous F5-CAR administration reprogrammed the tumor microenvironment, reducing M2-like macrophages and boosting granzyme B and perforin expression in CD8+ T cells. Notably, when combined with anti-PD-L1 blockade, this strategy achieved 100% complete and durable regression in MC38-hPSMA tumor-bearing mice. This work establishes fluorinated LNPs as a scalable platform for in vivo CAR-M engineering against solid tumors.

The mechanisms by which prostate cancer (PCa) evades anti-tumor immunity and the immune checkpoint blockade (ICB) response are poorly understood. Yes-associated protein 1 (YAP1) activation is a common feature in PCa. However, to date, there is no direct evidence regarding the effect of YAP1 activity on anti-tumor immunity in PCa patients. In this study, we discovered that YAP1 expression is usually abundant in PCa tissues. Transcriptome analysis revealed that PD-L1 and the immune costimulatory molecule CD70 were consistently upregulated in YAP1-activated PCa cells. Meanwhile, CD70 is also abundantly exhibited in ICB non-responder patients, but absent in ICB responders, who usually show high cytotoxic T cell infiltration. More importantly, CD70 inhibition restores the sensitivity to anti-PD-1 immunotherapy in YAP1-activated PCa cells. Mechanistically, YAP1 directly regulates the transcription of CD70 through cooperation with DNA-binding factor RUNX1. The upregulation of CD70 thus suppresses immune cell infiltration into malignant lesions and promotes the exhaustion of CD8 + T cells to facilitate evasion from immunosurveillance. Taken together, our findings define the YAP1-CD70 signaling axis as a novel immunosuppressive mechanism in PCa, which provides new insights into the potential of targeting the CD70 pathway to help further subdivide the population of PCa patients who can benefit from immunotherapy.

mRNA vaccines have emerged as highly promising therapeutic agents in cancer immunotherapy. Nevertheless, the current limited immunogenicity of target antigens and the lack of a robust systemic immune response remain significant challenges for their effective application. This study aimed to evaluate the immunogenicity of the CD73 protein and elucidate the mechanisms by which a CD73 mRNA vaccine mediates antitumor immune effects in murine models. CD73 mRNA was synthesized by in vitro transcription and formulated into lipid nanoparticles (CD73-LNPs) using a microfluidic device. The immunogenicity of CD73 was assessed using ELISPOT assays. The ability of CD73-LNPs to activate antitumor immune responses was evaluated by flow cytometry. Therapeutic efficacy was tested in murine models of melanoma, cervical cancer, ovarian cancer, and prostate cancer. Mechanistic insights were obtained through single-cell transcriptomics sequencing and bulk RNA transcriptomic analysis. The CD73 protein exhibited potent immunogenicity. In vitro, CD73-LNPs promoted the maturation and activation of primary dendritic cells. In vivo, CD73-LNPs induced humoral and cellular immune responses, increased the secretion of interferon-gamma and granzyme B, and effectively suppressed tumor growth across multiple tumor models. Mechanistically, CD73-LNPs activated dendritic cells through toll-like receptor 3 (TLR3) signaling, enhanced dendritic cell activation, and upregulated chemokine receptor expression on CD8+ T cells, thereby promoting CD8+ T cell infiltration into the tumor microenvironment. Safety evaluations revealed no toxic effects on vital organs. CD73 mRNA vaccine safely and effectively induces antitumor immunity through TLR3-dependent mechanisms, highlighting their considerable potential for clinical translation.

Background:Despite the widespread use of immune checkpoint inhibitors (ICIs) in advanced clear cell renal cell carcinoma (ccRCC), therapeutic resistance persists. The prognostic and immunomodulatory role of ammonia metabolism remains unclear. Methods:We leveraged public RNA-seq data and machine learning to identify ammonia metabolism pathways through enrichment analysis of programmed cell death-related genes. Employing multi-omics data from ccRCC patients, we developed an ammonia metabolism risk score (AMRS) via machine learning, which was validated externally and in immunotherapy cohorts. Additionally, scRNA-seq, WGCNA, TMB analysis, and in vitro assays were performed to characterize the model's functional basis. Results:From 147 prognostic ammonia metabolism-related genes in TCGA, a 4-gene random forest model was constructed using LASSO and multivariate Cox regression. This model demonstrated robust predictive accuracy in external validation (3/5/7-year AUCs: 0.710/0.721/0.771). High-risk patients showed significantly elevated mortality in external cohorts (HR = 4.23, 95% CI 1.57-11.42, p = 0.002) and multiple ICI cohorts (HR = 1.30-1.69, p < 0.05). Functional validation via CSAD-targeted siRNA knockdown suppressed migration and invasion by >44% (p < 0.05) across four ccRCC cell lines. Conclusions:Our integrated approach overcomes modeling constraints from limited samples and high-dimensional data and establishes a novel ammonia metabolism-related prognostic signature for ccRCC. CSAD emerges as a promising biomarker warranting further investigation.

Background:Allium stents are widely used in patients with ureteral stricture, with ongoing research continuously evaluating their clinical safety and efficacy. Objective:This study aimed to describe our technique and report the outcomes of Allium stent in the treatment of refractory ureteral strictures. Design setting and participants:We retrospectively collected perioperative data on all patients treated with Allium stents in our department between January 2017 and April 2024 and assessed their clinical outcomes. Surgical procedure:Following ureteroscopy, a guidewire was advanced under fluoroscopic guidance into the renal pelvis. The retrograde ureterography was performed to determine the location and length of the ureteral stricture. Dilation was performed using a ureteral balloon dilator, a flexible ureteroscope sheath, or a rigid ureteroscope. Subsequently, the Allium stent was deployed into the stricture segment and confirmed via fluoroscopic imaging. Results:A total of 23 patients (25 ureters) were included, with a mean age of 57.7 years (32-76 years). The mean length of ureteral strictures was 4.5 cm (range: 1-18 cm). All stents were successfully positioned. As of December 2024, the stent patency rate was 68%, with a median follow-up of 39.5 months (13-67 months). In eight patency failure cases, the mean indwelling time was 14 months, with the shortest recorded duration being 2 months. Causes of failure included four (50%) stent migration, one (12.5%) encrustation, two (25%) persistent stenosis and severe infection (12.5%). Management strategies for these cases included two (25%) stent removal, two (25%) robot-assisted pyeloureteroplasty, one (12.5%) ureterolithotripsy, one (12.5%) exchange with a new Allium stent, one (12.5%) add new Allium stent, and one (12.5%) replacement with a different type of metal stent. Notably, one case of a ruptured ureter was successfully bridged with an Allium stent, and another case of a uretero-vaginal fistula was effectively treated with Allium stent, both without complications. Conclusions:Allium stents appear to be a feasible and effective treatment for various ureteral strictures, including cases of ureteral perforation and rupture. However, long-term complications such as stent migration and occlusion remain challenges that should not be overlooked.

PURPOSE:Nop2/Sun domain family member 5 (NSUN5), a member of the m5C methylation family, plays a critical role in various biological processes by influencing RNA stability and regulating gene expression. The main purpose of this study was to determine the specific role of NSUN5 in prostate cancer (PCa) progression. METHODS:TCGA-PRAD database was used to analyze the differential expression of NSUN5 between PCa and normal tissues, as well as its association with survival outcomes, signaling pathways, and immune infiltration. Subsequently, immunohistochemistry was performed to evaluate NSUN5 expression in PCa tissues. Functional assays, including gain- and loss-of-function experiments, were conducted to explore the effects of NSUN5 on PCa cell proliferation, migration, and the expression of key proteins in relevant signaling pathways. Cell co-culture, in vivo experiments, and flow cytometry analysis were used to explore the effects of NSUN5 on macrophage polarization and the immune microenvironment of PCa. RESULTS:NSUN5 is significantly overexpressed in PCa tissues and is positively correlated with advanced disease stages and poor patient prognosis. Functionally, NSUN5 enhances in vitro proliferation and migration, as well as in vivo tumor growth, primarily through activation of the PI3K-AKT signaling pathway. Moreover, NSUN5 facilitates the polarization of macrophages into tumor-associated macrophages within PCa tissues, thereby contributing to immune evasion. CONCLUSION:NSUN5 promotes PCa progression through the PI3K-AKT pathway and induces macrophage polarization toward a pro-tumor phenotype, promoting the formation of a suppressive tumor microenvironment.

Mitochondrial stress-induced mitophagy plays a critical role to maintain cellular homeostasis; however, in cancer cells, this process may also contribute to drug resistance. Our previous work identified CDK12 as a critical regulator of prostate cancer (PCa) cell survival under sustained enzalutamide exposure, though the precise mechanism remains to be elucidated. In this study, we hypothesize that CDK12 plays a key role in mitophagy regulation under mitochondrial stress, potentially modulating PCa cell resistance to enzalutamide, the first-line clinical medication in PCa therapy. Utilising multiple in vitro PCa cell models, we demonstrate that both CDK12 knockdown and pharmacological inhibition with THZ531 impaired mitophagy following treatment with enzalutamide and mitophagy inducer CCCP. Mechanistically, our finding reveal that CDK12 inhibition disrupts FOXO3-induced BNIP3 transcription, thereby preventing receptor-mediated mitophagy and sensitising PCa cells to enzalutamide. This study identifies the CDK12-FOXO3-BNIP3 pathway as a novel regulatory mechanism governing mitophagy under mitochondrial stress. Importantly, these results underscore CDK12's role in preserving mitochondrial function and promoting PCa cell survival during enzalutamide treatment. These findings highlight the therapeutic potential of targeting the CDK12-BNIP3-mitophagy axis in combination with antiandrogen therapies, offering a promising strategy to overcome drug resistance in PCa and improve clinical outcomes.

With the rapid progression of chemotherapies, the occurrence of chemoresistance is becoming a major obstacle in contemporary cancer treatment. As essential organelles, mitochondria perform diverse functions to provide ATP and various intermediates to modulate biosynthetic and bioenergetic processes, which are indispensable to cell survival. Recently, mitochondria have increasingly intrigued researchers for their unique influence on chemoresistance. This review explores the intricate relationship between mitochondria and chemoresistance. We delve into the complex roles that mitochondria play in chemoresistance, focusing on the aberrant alterations in mitochondrial behaviors and interactions with other organelles. We also review the subsequent impact of mitochondrial changes on cellular functions, such as metabolic reprogramming and the dysregulation of cell death. By presenting a retrospective analysis of previous research and elucidating the underlying mechanisms, we aim to reveal the potential of enhancing the efficacy of chemotherapies and overcoming cancer chemoresistance by targeting mitochondria. Hopefully, this review will provide directions for future research and the development of more viable drugs, ultimately improving the prognosis of cancer patients.

Background:Metabolic alterations and inflammatory processes contribute substantially to the pathogenesis of prostate cancer (PCa). This study used Mendelian randomization (MR) to investigate the causal relationships between plasma metabolites and PCa and to identify potential mediators, including immune cell traits and circulating inflammatory proteins. Materials and methods:A 2-sample MR analysis was conducted using data from the Canadian Longitudinal Study on Aging and a diverse genome-wide association study of PCa. A total of 1400 plasma metabolites were analyzed. Single-nucleotide polymorphisms were carefully selected and refined using linkage disequilibrium clumping. The inverse variance weighting method was used for primary analysis, supplemented by sensitivity analyses, including MR-Egger, weighted median, and MR-Pleiotropy RESidual Sum and Outlier, to ensure the robustness of the results. Results:Eight metabolites were significantly associated with PCa. Specifically, a higher phosphate-to-uridine ratio was associated with a decreased risk of PCa, whereas higher levels of N-acetyl-arginine were linked to an increased risk. Other significant metabolites included the phosphate-to-2'-deoxyuridine ratio; N6-methyl-lysine, N-acetyl-leucine, N-succinyl-phenylalanine, and cysteinylglycine disulfide levels; and the α-ketoglutarate-to-ornithine ratio. Sensitivity analyses and the MR-Steiger test confirmed the robustness and causal direction of these associations. In addition, further analysis indicated that certain metabolites may influence PCa risk by modulating the expression of inflammatory markers, such as leukemia inhibitory factor receptor, interleukin-8, and CD33-related markers. Conclusions:This study identified plasma metabolites that exert causal effects on the risk of PCa and highlighted the mediating role of immune traits and inflammatory proteins. These findings underscore the complexity of the biological pathways involved and suggest potential targets for therapeutic interventions.

(Yes-associated protein 1) YAP1 is frequently activated in human prostate cancers (PCa), but the underlying regulatory mechanism remains elusive. Here, we identified a novel scaffold protein HOMER3 in PCa, that can promote YAP1 activity by disrupting LATS-YAP1 phosphorylation. Mechanistically, HOMER3 overexpression in PCa facilitates the SRC kinase to phosphorylate YAP1 accompanied by counteracting LATS1-mediated YAP1 inhibition, thereby maintaining high YAP1 nuclear localization and transcriptional activity. Accordingly, HOMER3 gain-of-function in PCa cells phenocopies the effect of YAP1 activation, including cell hyperproliferation in vitro and rapid tumor growth in vivo. Additionally, transcriptome analysis revealed that CD274 is consistently upregulated in HOMER3 overexpressing PCa cells and patients, which eventually contributed to an immunosuppressive phenotype. More importantly, blocking SRC kinase-mediated YAP1 activation improved the immunotherapy-insensitive phenotypes in PCa caused by HOMER3 overexpression. Taken together, our findings define a novel kinase-substrate interactive platform for HOMER3 to orchestrate YAP1 activity in PCa. Targeting SRC-YAP1 oncogenic axis provides new insights into the therapeutic potential for PCa patients carried HOMER3 overexpression.

Objective:Concealed penis is a common congenital genital abnormality. This study aimed to introduce a penile reconstruction method for concealed penis, namely the modified Devine procedure, and evaluate its safety and efficacy. Methods:We retrospectively reviewed 80 consecutive patients with concealed penis, who underwent surgical correction between May 2019 and May 2023 in our department. All patients underwent a modified Devine procedure. Data on the patients' age, body mass index, operative time, blood loss, preoperative and postoperative penile lengths, and postoperative complications were collected and analyzed. Results:All operations were successful. Patients had a mean age of 10.30 (standard deviation [SD] 1.07) years and a mean body mass index of 20.26 (SD 2.26) kg/m2. The mean operative time was 56.35 (SD 8.62) min, and the mean volume of blood loss was 6.58 (SD 1.34) mL. The mean follow-up time was 15.97 (SD 2.92, range 12-24) months. Penile length increased significantly at 1 month and 12 months postoperatively, with continued growth over time. No major complications occurred. Mild lymphedema was the most common minor complication but resolved spontaneously within 6 weeks. No other adverse events were observed. Conclusion:The modified Devine procedure for concealed penis achieved clinically safe and effective penile reconstruction outcomes, as well as satisfactory cosmetic appearance. Given its favorable results and minimal complications, this surgical approach appears to be a promising surgical option for selected patients with concealed penis.

CDK12 primarily functions as a transcription regulatory cyclin-dependent kinase (CDK) that controls mRNA elongation, splicing, and polyadenylation. The CDK12 gene is implicated in human cancers since it is frequently mutated and/or deleted in prostate and ovarian cancer but paradoxically amplified in breast cancer. Here, we demonstrate that CDK12 promotes serine-933 phosphorylation of DNA2, a nuclease/helicase critical for replication fork stress regulation, and the phosphorylation subsequently facilitates DNA2 polyubiquitination and degradation mediated by the APC/CCDC20 E3 ubiquitin ligase. CDK12 inactivation induces but amplification suppresses genome-wide expression of interferon response and antigen processing and presentation machinery genes in ovarian and breast cancer cells, respectively. Besides causing aberrant DNA2 stabilization, replication stress, genomic instability, and cytosolic double-stranded DNA (dsDNA) accumulation, CDK12 loss also triggers cGAS-STING activation and innate immune response, which can be reversed by forced expression of replication protein A (RPA) subunits or DNA2 depletion. Our findings identify DNA2 as a phosphorylation substrate of CDK12, connecting CDK12 to cell cycle regulation. These data also reveal DNA2 protein destruction as a critical mechanism that dictates genomic instability, cGAS-STING signaling activation, and innate immune response in CDK12-deregulated cancers.

Prostate cancer (PCa) progression is driven by intricate molecular mechanisms involving dysregulated signaling networks and posttranslational modifications of key regulatory proteins. In this study, we identify a novel oncogenic pathway wherein cyclin-dependent kinase 12 (CDK12) physically interacts with and phosphorylates forkhead box A1 (FOXA1) at serine 234 (S234). Phosphorylation at this residue markedly enhances FOXA1 transcriptional activity, leading to up-regulation of downstream targets including murine double minute 2 (MDM2), a critical negative regulator of the p53 tumor suppressor. Mechanistically, this CDK12-FOXA1-MDM2 axis destabilizes p53, attenuates apoptotic signaling, and promotes PCa cell survival and proliferation. Therapeutic targeting of CDK12 using the small-molecule inhibitor THZ531 or RNA interference effectively abrogates FOXA1 phosphorylation, restores p53 stability, reactivates apoptotic pathways, and suppresses tumor growth. Notably, the identification of S234 as a functional phosphorylation site in FOXA1 reveals a previously uncharacterized posttranslational regulatory mechanism in PCa biology. These findings establish the CDK12-FOXA1-MDM2 axis as a pivotal driver of PCa progression and underscore the therapeutic potential of targeting FOXA1 phosphorylation to restore tumor suppressor function and induce apoptosis in PCa. Our work provides a mechanistic framework for developing precision therapies aimed at disrupting this oncogenic cascade in PCa.

Prostate cancer (PCa) has previously been established as a cold tumor with highly complex tumor environment. Transforming growth factor (TGF)-β1 plays pro-oncogenic roles in PCa. TGF-β3, another isoform of the TGF-β family, is reported to have different and even opposite regulatory roles to TGF-β1. However, the effect of TGF-β3 in PCa has not been elucidated. TGF-β3 expression and its association with multiple clinicopathological characteristics were analyzed immunohistochemically in human PCa specimens. The antitumor effect of TGF-β3 and its combination with immunochemotherapy was observed by subcutaneous xenograft tumor model. RNA-seq of mouse tumor tissues identified differentially expressed genes (DEGs) that were enriched in vascular biological processes. The angiogenesis effect of TGF-β3 was evaluated using tube formation assay. Hypoxic area, NG2+ pericytes, Col IV+ basement membrane, adhesion molecules and immune cells were analyzed by immunofluorescence. Vascular permeability was measured by Evans blue staining. The flow cytometry was conducted to examine the composition of tumor-infiltrating CD8+ T cells. Low TGF-β3 expression in prostate cancer (PCa) was correlated with higher Gleason scores and pathological T stage. While intratumoral TGF-β3 injection demonstrated antitumor effects in vivo, it did not directly affect PCa cell proliferation, migration or invasion in vitro. GO analysis revealed significant enrichment of DEGs in vascular-related biological process. TGF-β3 treatment normalized tumor vascular architecture and reduced vascular leakage. This vascular normalization upregulated endothelial adhesion molecules and enhanced CD8+ T cell infiltration, suppressing tumor growth. Critically, TGF-β3-induced vascular normalization synergized with anti-PD-L1 immunotherapy or paclitaxel chemotherapy, enhancing CD8+ T cell or drug infiltration and significantly boosting therapeutic efficacy. TGF-β3 potentially acts as a protective factor in PCa by promoting vascular normalization and remodeling of the tumor environment, which facilitates infiltration of CD8+ T cells or drugs, significantly enhancing their antitumor effects.

INTRODUCTION:Associations of cigarette use, e-cigarette use, and dual use, with nocturia and urge urinary incontinence (UUI) remain unclear. We performed this study to investigate the associations of cigarette use, e-cigarette use, and dual use, with nocturia and UUI. METHODS:This is a secondary analysis using data from the 2005 to 2020 National Health and Nutrition Examination Survey (NHANES). Participants aged ≥20 years were included. The use of cigarettes and e-cigarettes and symptoms of nocturia and UUI were self-reported. Logistic regression was used to calculate the adjusted odd ratios (AORs) of nocturia and UUI for cigarette use, e-cigarette use, and dual use. Subgroup analyses were conducted among participants with prostate cancer. RESULTS:Compared to never cigarette users, current and former cigarette users had higher odds of nocturia (AOR=1.12; 95% CI: 1.02-1.23; AOR=1.12; 95% CI: 1.01-1.24; all p<0.05) and UUI (AOR=1.23; 95% CI: 1.09-1.39; AOR=1.13; 95% CI: 1.03-1.24; all p<0.01). Compared to never e-cigarette users, current e-cigarette users had higher odds of nocturia (AOR=1.43; 95% CI: 1.01-2.02; p<0.05) and UUI (AOR=1.56; 95% CI: 1.13-2.16; p<0.01) and former e-cigarette users had higher odds of UUI (AOR=1.29; 95% CI: 1.02-1.62; p<0.05). Dual users of cigarettes and e-cigarettes had higher odds of nocturia (AOR=1.61; 95% CI: 1.03-2.51; p<0.05) and UUI (AOR=1.79; 95% CI: 1.19-2.68; p<0.01) compared to never users. In participants with prostate cancer, current cigarette use was associated with higher odds of UUI (AOR=2.40; 95% CI: 1.04-5.57; p<0.05. CONCLUSIONS:This study found that cigarette use, e-cigarette use, and dual use were associated with higher odds of nocturia and UUI. Cohort studies are needed to determine the causality of this cross-sectional assessment.

Background Association of cigarette use with risk of prostate cancer remains unclear. We performed this study to examine whether cigarette use is associated with increased risk of prostate cancer. Methods This cross-sectional study used data from the 1999 to 2020 National Health and Nutrition Examination Survey (NHANES), a population-based nationally representative survey designed to assess the health and nutritional status of US adults and children. Males were eligible if they were aged ≥ 20 years at the time of participation. Cigarette use (ever use, categorized into former use and current use) was defined as having smoked at least 100 cigarettes in life. Smoking duration was calculated in former smokers and current smokers. Primary outcome was self-reported diagnosis of prostate cancer by participants. Logistic regression was used to calculate the adjusted odd ratios (aOR) and 95% CI for the associations of cigarette use with risk of prostate cancer, adjusting for demographic characteristics. Subgroup analyses by age group were conducted. Data were analyzed from June 4 to November 30, 2023. Results Of the 107 622 participants in 1999–2020 NHANES, 28 170 were included in the analysis. The mean (SD) age of the 28 170 participants was 46.4 (16.4) years, 68.0% were non-Hispanic White. Compared with never smokers, ever (aOR, 2.23 [95% CI, 1.06–4.68]) and former smokers (aOR, 3.54 [95% CI, 1.60–7.79]), but not current smokers (aOR, 1.04 [95% CI, 0.38–2.85]) had a higher risk of prostate cancer. This higher risk in former (aOR, 3.81 [95% CI, 1.69–8.59) and ever smokers (aOR, 2.77 [95% CI, 1.25–6.13) was also found in participants aged 20–59 years. But a lower risk was observed in current smokers aged ≥ 60 years (aOR, 0.52 [95% CI, 0.32–0.84). Dose-response analysis showed a positive association between smoking duration and risk of prostate cancer in current smokers (aOR, 1.07 [95% CI, 1.03–1.11]) but not in former smokers (aOR, 1.00 [95% CI, 0.99–1.02]). Conclusions This study suggests that cigarette use was associated with an increased risk of prostate cancer in US males, especially among those aged 20–59 years. This modifiable risk factor represents a target for further research into preventing prostate cancer in males.

Prostate cancer (PCa), a significant health concern among middle-aged and elderly men globally, has increasingly been associated with metabolic and inflammatory processes. The advanced lung cancer inflammation index (ALI), a novel marker reflecting nutritional and inflammatory status, has not yet been thoroughly investigated in the context of PCa. This study investigated the potential link between ALI and PCa. We first conducted a cross-sectional study utilizing data from the National Health and Nutrition Examination Survey (NHANES). The relationship between ALI and PCa was examined by NHANES-provided survey weights. Smoothed curve fitting and threshold effect analyses were conducted to evaluate possible nonlinear associations. Then we analyzed the correlation between the prognosis of PCa patients and ALI. Out of 15,042 adult participants, 683 (4.54

High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation.. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.