Objective: To determine the relationships between the incidence rates of testicular and prostatic cancers and food consumptions in order to study the etiologic cause and the mechanism of the development of male genita...Objective: To determine the relationships between the incidence rates of testicular and prostatic cancers and food consumptions in order to study the etiologic cause and the mechanism of the development of male genital organ cancer. Methods: The incidence rates of testicular and prostatic cancers in 42 countries (region) were correlated with the dietary practices in these countries. These data came from the cancer rate database (1988–1992) and the food supply database (1961–1990) provided by the Department of Environmental Health, Medical University of Yamanashi, Japan. Results: The incidence rates of testicular and prostatic cancers varied greatly from country to country but in China the rates of the both malignancies were lower than that of USA and Japan. This may be due to the difference in lifestyle, especially in dietary practices. Among the food items we examined, cheese was most closely correlated with the incidence of testicular cancer at ages 20–39, followed by animal fats and milk. The correlation coefficient (r) was the highest (r=0.804) when calculated for cheese consumed during the period of 1961–1965 (maternal or prepubertal consumption). Stepwise-multiple-regression analysis revealed that cheese (1961–1965) made a significant contribution to the incidence of testicular cancer. Multiple coefficient (r) is 0.920. As far as prostatic cancer was concerned, milk was most closely correlated (r=0.711) with its incidence, followed by meat and coffee. Stepwise-multiple-regression analysis identified milk, meat, butter and coffee as significant factors contributing to the incidence of prostatic cancer (R=0.993). The results of our study suggest a role of milk and dairy practices in the development of testicular and prostatic cancers.展开更多
Objective： MR perfusion-weighted imaging（PWI） has been widely applied in the research of cerebral tumor, benign and malignant musculoskeletal neoplasms and so on. The aim of this study is to explore the application...Objective： MR perfusion-weighted imaging（PWI） has been widely applied in the research of cerebral tumor, benign and malignant musculoskeletal neoplasms and so on. The aim of this study is to explore the application of MR perfusion-weighted imaging in prostatic cancer （Pca）, and evaluate the correlation of PWI features with vascular endothelial growth factor （VEGF） and microvessel density （MVD）. Methods： Twenty-eight consecutive patients who were diagnosed clinically as prostatic cancer and thirty healthy volunteers were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWI, including the steepest slope of signal intensity-time curve （SSmax） and the change in relaxation rate （ΔR2^＊peak） at lesions, were analyzed. Correlation analysis was used to determine the relationship between the results of PWI and that of immunohistochemistry. Results： （1） In the healthy volunteers, the steepest slope of signal intensity-time curve （SSmax） and ΔR2^＊peak of perfusion curve were： 0.430±0.011, 2.01±0.7 respectively; however, in the prostatic cancer, they were 57.8±5.0, 3.0±0.6 respectively; with significant difference （t=-4.11, 3.28, P〈0.01）. （2）The VEGF and MVD expression of twenty-eight Pca patients were significantly higher. Conclusion： On MR perfusion- weighted imaging, SSmax and ΔR2^＊peak can reflect MVD and VEGF expression levels in prostatic cancer, suggesting information on tumor angiogenesis. Thus they are beneficial to the diagnosis and treatment of prostatic cancer.展开更多
Objective： To explore the application of MR perfusion-weighted imaging （PWI） in the benign and malignant prostate diseases, and evaluate the correlations of PWl features with vascular endothelial growth factor （V...Objective： To explore the application of MR perfusion-weighted imaging （PWI） in the benign and malignant prostate diseases, and evaluate the correlations of PWl features with vascular endothelial growth factor （VEGF） and microvessel density （MVD）. Methods： Seventy-four consecutive patients who were diagnosed clinically for the prostate diseases, including forty-four cases with benign prostate hyperplasia and thirty cases with prostatic cancer proved pathologically, were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWl, including the steepest slope of signal intensity-time curve （SSmax） and the change in relaxation rate （ΔR2^＊ peak） at lesions, were analyzed. Correlation analysis was used to determine the relationship between the results of PWl and immunohistochemistry. Results： （1） In the benign prostate hyperplasia （BPH）, SSmax and ΔR2^＊ peak of perfusion curve were 34.2 ± 2.9 and 1.49 ± 0.11, respectively; however, in the prostatic cancer （Pca）, they were 58.6± 4.8 and 3.18 ±0.49 respectively; there were statistical differences （t = 2.16 and 2.31, P 〈 0.05）. （2） The VEGF and MVD expressions of thirty Pca patients were significantly higher than those of forty-four BPH patients （x2 = 28.64, P 〈 0.01; t = 21.2, P 〈 0.01）. MVD expressions of Pca and BPH groups showed positive associations with VEGF expressions （P 〈 0.01）. On MR perfusion-weighted imaging, SSmax and ΔR2^＊ peak showed associations with MVD and VEGF expressions （P 〈 0.01）. Conclusion： On MR perfusion-weighted imaging, SSmax and ΔR2^＊ peak can reflect MVD and VEGF expression levels in the benign and malignant prostate diseases and might be implied the tumor angiogenesis so as to distinguish benign from malignant and provide the important information for the surgeon to diagnose and treat the prostatic diseases.展开更多
Introduction: The burden of prostatic cancer is rising in Sudan. Usually, they present late in their disease with urinary tract obstruction, hematuria, bony pain, or cachexia because there is no screening program. Her...Introduction: The burden of prostatic cancer is rising in Sudan. Usually, they present late in their disease with urinary tract obstruction, hematuria, bony pain, or cachexia because there is no screening program. Here we present a patient with prostatic cancer who presented with left axillary mass as his main concern. Case Description: 82-year-old Sudanese male presented with a left axillary and left supraclavicular lymphadenopathy of a few months’ duration. He underwent a decisional biopsy which showed metastatic adenocarcinoma. Upper and lower GI endoscopy were performed but the latter was complicated by a sigmoid perforation with peritonitis. During laparatomy, multiple enlarged pelvic lymphnodes were encountered and a biopsy result suggested a metastatic prostatic neoplasm. Later, prostatic biopsy confirmed the diagnosis. The patient was treated with bilateral orchidectomy. Clinical discussion: Lymphatic metastasis to axillary lymph nodes is a very rare manifestation of prostate cancer and only a few cases have been reported in the literature. It can cause diagnostic difficulty since prostate cancer typically metastasis to the pelvic lymph node and very rarely involves he supradiaphragmatic lymph node. Conclusion: Metastatic prostatic carcinoma should be considered among the causes of supra-diaphragmatic lymph adenopathy. Careful physical and imaging examinations combined with PSA and pathological analysis are essential in the diagnosis of advanced prostate cancer with unusual presentation.展开更多
To assess the role of dynamic contrast-enhanced MRI (DCE-MRI) in thediagnosis and differentiation of prostatic cancer (PC). Methods: Five volunteers, 36 patients withbenign prostatic hyperplasia (BPH) and 13 patients ...To assess the role of dynamic contrast-enhanced MRI (DCE-MRI) in thediagnosis and differentiation of prostatic cancer (PC). Methods: Five volunteers, 36 patients withbenign prostatic hyperplasia (BPH) and 13 patients with biopsy-proven prostate cancer underwentconventional MRI, DCE-MRI and delayed enhancement MRI. The value of the signal intensity in DCE-MRIwas measured and calculated to draw the time-signal intensity curve of the normal peripheral zone(PZ), the prostate cancer and the benign prostatic hyperplasia. Results: In DCE-MRI, the normalperipheral zone was enhanced mildly and slowly and the peak value was located in late phase. Theenhancement of the lesions in 36 patients with the benign prostatic hyperplasia was obvious in earlyphase and strengthened gradually, and then turned to decrease in late phase after peak value. Thelesions in 9 of 13 cases with prostate cancer were enhanced obviously in early phase and washed outrapidly, and the peak value was located in early phase, but the peak value was in mediate and latephase in the other 4 cases with diffuse lesion in the prostate on T_2WI. Conclusion: In DCE-MRI, theenhancement patterns of the normal peripheral zone, the prostate cancer and the benign prostatichyperplasia were significantly different. DCE-MRI was very useful in the diagnosis anddifferentiation of prostate cancer.展开更多
OBJECTIVE To investigate the diagnostic value of modified prostate specific antigen(PSA)parameters in the diagnosis of prostate cancer(PCA) when the serum PSAis in a grey zone of 4~10 ng/ml. METHODS The results of ser...OBJECTIVE To investigate the diagnostic value of modified prostate specific antigen(PSA)parameters in the diagnosis of prostate cancer(PCA) when the serum PSAis in a grey zone of 4~10 ng/ml. METHODS The results of serum PSA determinations of the patients receiving a transrectal ultrasound-guided multiphase prostatic biopsy,were retrospectively analyzed.In the 88 patients with a serum PSA value of 4-10 ng/ml,the final diagnosis of PCA was made in 21,and that of benign prostate hyperplasia(BPH)in 67 patients.The percentage of the free-serum PSA([FPSA]/total-serum PSA[TPSA],F/T),PSA density(PSAD)and the sensitivity and specificity of the new PSA modified parameter(F/T)/PSAD in diagnosing PCA,within a set threshold value,was compared. RESULTS In the 88 patients with serum PSA in the grey zone of 4.0-10.0 ng/ml,there was no significant difference in comparing the TPSA between the 21 PCA patients and 67 BPH patients(P>0.05).However, there was a significant difference in the value of modified PSA parameters, such as F/T,PSAD and(F/T)/PSAD,between the PCA and the BPH groups (P<0.001).As the cut off point-value of the F/T,PSAD and(F/T)/PSAD was set at 0.16,0.15 and 0.8,the diagnostic sensitivity for PCA was 66.7%, 76.2%and 85.7%,and the specificity was 41.8%,43.3%and 68.7%,respectively.There was no significant difference in the sensitivity comparing the modified parameters for diagnosing PCA(P>0.05),whereas an overt predominance was present in the specificity of(F/T)/PSAD for PCAdiagnosis (P<0.05). CONCLUSION In the serum PSA grey zone of 4-10 ng/ml,a modified PSA parameter can improve the PCA diagnostic accuracy rate.With a considerably high sensitivity,application of the(F/T)/PSAD may effectively enhance the diagnostic specificity,which is superior to the F/T and PSAD, and can be expected to be one of the new indices derived from the PSA.展开更多
Background:The burden of common urologic diseases,including benign prostatic hyperplasia(BPH),urinary tract infections(UTI),urolithiasis,bladder cancer,kidney cancer,and prostate cancer,varies both geographically and ...Background:The burden of common urologic diseases,including benign prostatic hyperplasia(BPH),urinary tract infections(UTI),urolithiasis,bladder cancer,kidney cancer,and prostate cancer,varies both geographically and within specific regions.It is essential to conduct a comprehensive and precise assessment of the global burden of urologic diseases.Methods:We obtained data on incidence,prevalence,mortality,and disability-adjusted life-years(DALYs)for the aforementioned urologic diseases by age,sex,location,and year from the Global Burden of Disease(GBD)2021.We analyzed the burden associated with urologic diseases based on socio-demographic index(SDI)and attributable risk factors.The trends in burden over time were assessed using estimated annual percentage changes(EAPC)along with a 95%confidence interval(CI).Results:In 2021,BPH and UTI were the leading causes of age-standardized incidence rate(ASIR)and age-standardized prevalence rate(ASPR),with rates of 5531.88 and 2782.59 per 100,000 persons,respectively.Prostate cancer was the leading cause of both age-standardized mortality rate(ASMR)and age-standardized DALYs rate(ASDR),with rates of 12.63 and 217.83 per 100,000 persons,respectively.From 1990 to 2021,there was an upward trend in ASIR,ASPR,ASMR,and ASDR for UTI,while urolithiasis showed a downward trend.The middle and low-middle SDI quintile levels exhibited higher incidence,prevalence,mortality,and DALYs related to UTI,urolithiasis,and BPH,while the high and high-middle SDI quintile levels showed higher rates for the three cancers.The burden of these 6 urologic diseases displayed diverse age and sex distribution patterns.In 2021,a high body mass index(BMI)contributed to 20.07%of kidney cancer deaths worldwide,while smoking accounted for 26.48%of bladder cancer deaths and 3.00%of prostate cancer deaths.Conclusions:The global burden of 6 urologic diseases presents a significant public health challenge.Urgent international collaboration is essential to advance the improvement of urologic disease management,encompassing the development of effective diagnostic screening tools and the implementation of high-quality prevention and treatment strategies.展开更多
Background Neuroendocrine prostate cancer(NEPC)is an aggressive subtype of castration-resistant prostate cancer(CRPC)that is typically resistant to nearly all current therapies.Methods In this study,single-cell RNA se...Background Neuroendocrine prostate cancer(NEPC)is an aggressive subtype of castration-resistant prostate cancer(CRPC)that is typically resistant to nearly all current therapies.Methods In this study,single-cell RNA sequencing(scRNA-seq)and bioinformatic analysis identified centrosomal protein 55(CEP55)as a critical factor in the transformation from hormone-sensitive prostate cancer(HSPC)to CRPC and,ultimately to,NEPC.Results Subsequent bioinformatics analyses and clinical sample validation showed that CEP55 is significantly upregulated in NEPC tissues relative to HSPC and CRPC.Furthermore,while CEP55 show no significant association with the immune microenvironment or cancer-associated fibroblasts(CAFs),our findings indicated 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 cyclin-dependent kinase 1(CDK1)at the tyrosine 15(Tyr15)site.Conclusions 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.展开更多
Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype ...Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype or develop resistance to therapeutic interventions,leading to tumor metastasis and a poorer prognosis.When PC metastasizes to distant sites,the bone remains the predominant location,and brain metastases are regarded as exceedingly rare.Case Description:The current study focused on a rare clinical PC case that presented multiple brain metastases after prostate surgery.The patient was initially diagnosed with PC through prostate biopsy and subsequently underwent prostate debulking surgery while continuing androgen deprivation therapy,which maintained low prostatespecific antigen(PSA)levels for 4 years.However,a sudden PSA surge to 7.858 ng/mL led to the emergence of two brain metastatic tumors,which were confirmed to have originated from the prostate.Conclusions:Patients with advanced PC require comprehensive evaluations to detect rare metastatic sites,such as the brain,to avoid missed diagnoses.For patients with brain metastases,a multimodal approach combining surgical resection,postoperative radiotherapy,and endocrine therapy can effectively alleviate symptoms and enhance survival.展开更多
Background:Low-dose rate(LDR)prostate brachytherapy is a recommended treatment of localized prostate cancer in current guidelines.The study aimed to determine biochemical relapse-free survival(BRFS)in patients treated...Background:Low-dose rate(LDR)prostate brachytherapy is a recommended treatment of localized prostate cancer in current guidelines.The study aimed to determine biochemical relapse-free survival(BRFS)in patients treated with dynamic real-time low-dose rate(LDR)brachytherapy using Iodine 125(I^(125)).Methods:We retrospectively reviewed 499 patients with localized prostate cancer treated with I^(125) LDR realtime brachytherapy between 2003 and 2021.The mean patient age was 65 years(range:45–84 years).Based on the National Comprehensive Cancer Network(NCCN)risk classification,230 patients(46.1%)were categorized as low risk,235(47.1%)as intermediate risk,and 34(6.8%)as high risk.Gleason scores were distributed as follows:3+3 in 283 cases(56.7%),3+4 in 157 cases(31.5%),4+3 in 46 cases(9.2%),and 4+4 in 13 cases(2.6%).The mean follow-up was 70.5 months.Results:Tumor relapse was observed in 47 patients(9.4%)over a mean follow-up period of 6.26 years(SD 4.16).Local recurrence within the prostate occurred in 20 cases(4%).Patients with nadir PSA<0.2 ng/mL at 5 years of follow-up had a significantly lower incidence of tumor recurrence(3%)compared to those with a nadir PSA>0.2 ng/mL(21.9%)(p=0.0001).Biochemical relapse-free(BRFS)rates at 5,10 and 15 years were 96%,91.5% and 88.9%,respectively.When stratified by NCCCN risk groups,5-year BRFS was 96% in low risk,98% in intermediate risk and 85% in high risk patients(p=0.003).Inmultivariate analysis,only age at the time of brachytherapy(p=0.009),initial PSA(p=0.007)and Gleason grade(p=0.007)were significantly associated with tumor recurrence.Cancer-specific survival and overall survival were 99.8% and 98.0%,respectively.Conclusions:LDR with I^(125) has excellent longterm oncological outcomes for patients with low and intermediate-risk prostate cancer,in particular,patients achieving a nadir PSA<0.2 ng/mL at 5 years post-treatment.展开更多
Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(P...Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(PC)remain not fully explored.The study aimed to explore how gut metabolites regulate death-ligand 1(PD-L1)blockade via exosomes and boost immune checkpoint inhibitors(ICIs)in PC.Methods:We recruited 70 PC patients to set up into five subgroups.The integrated multi-omics analysis was performed.In parallel,we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate(TRAMP)models.Results:We identified two metabolites,16(R)-Hydroxyeicosatetraenoic acid(16(R)-HETE)and 6-Keto-Prostaglandin E1(6-Keto-PGE1),that positively correlated with the plasma exosomal PD-L1 levels.The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA,protein,and exosome levels in both human and mouse PC cell lines,which were also validated in vivo based on subcutaneous mouse models.Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model.Conclusions:Targeting the“gut-tumor metabolic axis”is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.展开更多
Objectives:PSMA PET/CT(Prostate-Specific MembraneAntigen Positron Emission Tomography/Computed Tomography)offers improved accuracy in detecting lymph node invasion(LNI)in prostate cancer(PC)patients,potentially reduci...Objectives:PSMA PET/CT(Prostate-Specific MembraneAntigen Positron Emission Tomography/Computed Tomography)offers improved accuracy in detecting lymph node invasion(LNI)in prostate cancer(PC)patients,potentially reducing the need for extended pelvic lymph node dissection(ePLND).This study aims to evaluate a patient-tailored care pathway in which ePLND is performed only in patients with unfavorable intermediate-or high-risk PC who are deemed at risk for LNI based on PSMA PET/CT findings.Methods:In this interventional cohort study,81 patients were managed according to the new care pathway.ePLND was omitted in cases of negative PSMA PET/CT findings(N0M0),while those with positive PSMA PET/CT findings(N1M0)underwent ePLND.A comparator group of 81 patients was selected from a prospectively generated database for comparison.Results:The intervention group experienced a 75% reduction in the number of ePLNDs performed compared to the comparator group(p<0.001).ePLND-related complications were significantly lower in the intervention group(p=0.008).No significant difference was observed in 3-year biochemical-recurrence free survival(BRFS)between the two groups(p=0.958).Conclusion:Omitting ePLND in patients with negative PSMA PET/CT findings(N0M0)leads to a substantial reduction in the number of ePLNDs performed,resulting in a decrease in morbidity,without compromising early oncological outcomes.展开更多
Poly-and perfluoroalkyl substances(PFAS),including perfluorooctanoic acid(PFOA)and perfluorooctane sul-fonate(PFOS),are persistent environmental pollutants with potential toxicological effects on human health.The aim ...Poly-and perfluoroalkyl substances(PFAS),including perfluorooctanoic acid(PFOA)and perfluorooctane sul-fonate(PFOS),are persistent environmental pollutants with potential toxicological effects on human health.The aim of this study was to investigate the impact of PFOS and PFOA on the effectiveness of selected drugs used in the treatment of prostate cancer based on in vitro tests on cell lines.Three cell lines were used in the study:two human prostate cancer cells(DU-145 and PC3)and one human normal prostate cell line(PNT1A).Using dose-response experiments,it was observed that PFAS had differential effects on cancer and normal cells.At low concentrations,PFOA and PFOS stimulated the proliferation of cancer cells,particularly PC3,while higher concentrations led to reduced viability.In normal cells,PFOS exhibited greater cytotoxicity compared to PFOA.Furthermore,PFOS enhanced docetaxel cytotoxicity in PC3 cells but reduced its efficacy in DU-145 cells.Similarly,PFOA diminished cabazitaxel effectiveness in DU-145 cells,suggesting PFAS-drug interactions may depend on the cell type,drug,and PFAS concentration.Results suggest that PFAS may influence cellular processes through receptor-mediated pathways,oxidative stress modulation,and protein binding,altering drug bioavailability and cellular uptake.The study also highlights the non-monotonic dose-response relationships observed in PFAS-treated cells.These findings raise concerns about the potential risks associated with PFAS exposure,particularly in the context of cancer treatment.Future studies should focus on long-term,low-dose PFAS exposure,the use of primary cells,and the molecular mechanisms driving these interactions to better inform therapeutic strategies.展开更多
Objective:To identify chromatin regulators(CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence(BCR)after radical prostatectomy(RAP)in prostate cancer(PCa)patients.Methods:Dif...Objective:To identify chromatin regulators(CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence(BCR)after radical prostatectomy(RAP)in prostate cancer(PCa)patients.Methods:Differentially expressed genes(DEGs)between tumor and normal samples from The Cancer Genome Atlas(TCGA)and gene expression omnibus(GEO)databases were intersected with CR-related and prognostic genes.Consensus clustering,risk score analysis,functional analysis,immune microenvironment,m6A,and heterogeneity assessments were performed using R software.In vitro validation used DU145 and C42B PCa cell lines.Topoisomerase II alpha(TOP2A)was knocked down via si RNA.Assays included CCK-8 proliferation,colony formation,transwell migration/invasion,wound healing,and western blotting(WB)for pathway validation.Results:TOP2A and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)defined molecular subtypes and a risk score in TCGA,validated in a GEO dataset.Cluster 2 exhibited significantly shorter BCR-free survival vs.cluster 1 in TCGA[hazard ratio(HR):2.21;95%confidence interval(95%CI):1.32-3.73;P=0.003],GEO(HR:2.05;95%CI:1.05-4.02;P=0.010),and MSKCC2010(HR:5.93;95%CI:1.96-17.87;P<0.001).Similar survival differences were observed between high-and low-risk groups(defined by the median risk score).Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression.Gene set variation analysis(GSVA)revealed downregulated cell-cycle pathways in cluster 2,alongside suppressed tumor-infiltrating immune cells.TOP2A knockdown significantly impaired PCa cell proliferation,colony formation,migration,and invasion.Mechanistically,it suppressed phosphoinositide 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)pathway activation,reducing phosphorylated PI3K and AKT levels without altering total protein.Conclusions:TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients.TOP2A drives malignant progression via the PI3K/AKT pathway.展开更多
Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly can...Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly cancer-associated fibroblasts(CAFs),as a critical determinant of disease behavior.CAFs constitute a heterogeneous population originating from fibroblasts,mesenchymal stem cells,endothelial cells,epithelial cells undergoing epithelial-mesenchymal transition(EMT),and adipose tissue.Through dynamic crosstalk with tumor,immune,endothelial,and adipocyte compartments,CAFs orchestrate oncogenic processes including tumor proliferation,invasion,immune evasion,extracellular matrix remodeling,angiogenesis,and metabolic reprogramming.This review comprehensively summarizes the cellular origins,phenotypic and functional heterogeneity,and spatial distribution of CAFs within the prostate TME.We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance,and critically evaluate emerging strategies to therapeutically target CAFmediated signaling,metabolic,and immune pathways.By integrating recent advances from single-cell and spatial transcriptomics(ST),our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.展开更多
Objectives:Prostate cancer(PCa)is a highly prevalent male malignancy with limited efficacy in advanced stages.Dysregulated modulation of necroptosis was reported to be tightly correlated with PCa initiation and progre...Objectives:Prostate cancer(PCa)is a highly prevalent male malignancy with limited efficacy in advanced stages.Dysregulated modulation of necroptosis was reported to be tightly correlated with PCa initiation and progression.Herein,we aimed to identify necroptosis-associated long non-coding RNAs(lncRNAs)and delineate their functional roles in PCa through an integrated approach combining bioinformatic analyses and in vitro experimental validation.Methods:RNA sequencing data and corresponding clinical information of PCa were downloaded from The Cancer Genome Atlas(TCGA).Differentially expressed necroptosis-related genes(NRGs)and lncRNAs were screened,and necroptosis activity was assessed by single-sample gene set enrichment analysis(ssGSEA).Weighted Gene Co-expression Network Analysis(WGCNA)identified necroptosis-related lncRNA modules,with key lncRNAs prioritized via Cox regression.Clinical correlation analyses and in vitro experiments validated the function of the key lncRNA LINC00595.Results:A total of 50 differentially expressed NRGs were identified,among which pro-necroptotic genes exhibited pronounced downregulation,while anti-necroptotic genes were significantly upregulated.Consistently,ssGSEA confirmed reduced necroptosis activity in PCa.WGCNA further identified 13 core necroptosis-related lncRNAs(NRlncRNAs),with Cox regression analysis pinpointing LINC00595 and LINC00908 as the top prognostic candidates.Both lncRNAs were downregulated in PCa,with low expression correlating with advanced T stage,lymph node metastasis,and poor prognosis.Functional experiments demonstrated that LINC00595 overexpression inhibited PCa cell proliferation,migration,and invasion,and enhanced necroptosis.Conclusions:Collectively,our findings identified LINC00595 and LINC00908 as novel regulators of necroptosis in PCa.Specifically,LINC00595 exerted tumor-suppressive effects by enhancing necroptosis,holding potential as prognostic biomarkers and therapeutic targets.展开更多
Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study invest...Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.展开更多
Objective:Prostate cancer is the second most common fatal cancer in men.Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients.Ovarian tumor family d...Objective:Prostate cancer is the second most common fatal cancer in men.Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients.Ovarian tumor family deubiquitinase 4(OTUD4)is a member of the ovarian tumor-associated protease domain(OTUDs)family.Although previous studies have shown that the expression and function of OTUD4 vary across different tumors,its role in prostate cancer remains unknown.The aim of this study is to explore new therapeutic targets and diagnostic markers for prostate cancer and investigate their mechanisms of action.Methods:Cell culture,Cell Counting Kit-8(CCK-8)assay,colony formation assay,Transwell assay,5-Ethynyl-2′-deoxyuridine(EdU)assay,immunofluorescence,Western blot,Quantitative real-time PCR(qRT-PCR),protein mass spectrometry,nude mouse xenograft models,immunohistochemistry(IHC),and hematoxylin and eosin(H&E)staining were utilized.Results:We found that OTUD4 expression was reduced in prostate cancer and negatively correlated with poor prognosis in both in vivo and in vitro experiments.Subsequent mechanistic studies revealed that OTUD4 directly inhibits the degradation of myosin-9(MYH9)protein via deubiquitination.Although MYH9 has been previously reported to act as a tumor suppressor in prostate cancer,no experimental evidence had demonstrated that MYH9 inhibits prostate cancer growth.Our results indicate that MYH9 overexpression effectively suppresses prostate cancer through interactions with cell adhesion molecules.Conclusion:Collectively,these results suggest that OTUD4 functions as a tumor suppressor in prostate cancer.Specifically,OTUD4 inhibits MYH9 degradation via deubiquitination,thereby enabling MYH9-mediated suppression of prostate cancer.展开更多
Prostate-specific membrane antigen(PSMA)is a surface membrane antigen that is highly overexpressed in prostate cancer,with heterogenous expression throughout the natural history of the disease.This has generated signi...Prostate-specific membrane antigen(PSMA)is a surface membrane antigen that is highly overexpressed in prostate cancer,with heterogenous expression throughout the natural history of the disease.This has generated significant interest as a potential biomarker for use in early diagnosis and treatment of prostate cancer.We reviewed the literature surrounding PSMA and its current clinical applications in diagnosing and managing early prostate cancer that is confined to the prostate and local lymph nodes.A search on PubMed,Medline,and Web of Science was performed using the following keywords:“PSMA”,“Prostate Specific Membrane Antigen”,“Prostate cancer”,“Biomarker”,“Diagnosis”.We considered all available articles relevant to the topic of PSMA as a biomarker in early prostate cancer when developing this narrative review.Key articles assessing the biology of PSMA,as well as its use as a potential diagnostic and therapeutic target in early prostate cancer,were assessed.The role of PSMA PET as a potential diagnostic and risk stratification tool was assessed.The current use of antibody-drug conjugates and radioligand therapy targeting PSMA was assessed,along with any current evidence to support their use in early prostate cancer.PSMA is heavily expressed throughout the early stages of prostate cancer,and this has significant therapeutic implications.There is a growing body of evidence that shows PSMA PET can play a role in the diagnosis,risk stratification,and prognostication of localised prostate cancer.PSMA-targeted therapies such as Lu-177 currently do not have any proven benefit in treating early prostate cancer;however,this remains an area of ongoing research.展开更多
文摘Objective: To determine the relationships between the incidence rates of testicular and prostatic cancers and food consumptions in order to study the etiologic cause and the mechanism of the development of male genital organ cancer. Methods: The incidence rates of testicular and prostatic cancers in 42 countries (region) were correlated with the dietary practices in these countries. These data came from the cancer rate database (1988–1992) and the food supply database (1961–1990) provided by the Department of Environmental Health, Medical University of Yamanashi, Japan. Results: The incidence rates of testicular and prostatic cancers varied greatly from country to country but in China the rates of the both malignancies were lower than that of USA and Japan. This may be due to the difference in lifestyle, especially in dietary practices. Among the food items we examined, cheese was most closely correlated with the incidence of testicular cancer at ages 20–39, followed by animal fats and milk. The correlation coefficient (r) was the highest (r=0.804) when calculated for cheese consumed during the period of 1961–1965 (maternal or prepubertal consumption). Stepwise-multiple-regression analysis revealed that cheese (1961–1965) made a significant contribution to the incidence of testicular cancer. Multiple coefficient (r) is 0.920. As far as prostatic cancer was concerned, milk was most closely correlated (r=0.711) with its incidence, followed by meat and coffee. Stepwise-multiple-regression analysis identified milk, meat, butter and coffee as significant factors contributing to the incidence of prostatic cancer (R=0.993). The results of our study suggest a role of milk and dairy practices in the development of testicular and prostatic cancers.
文摘Objective： MR perfusion-weighted imaging（PWI） has been widely applied in the research of cerebral tumor, benign and malignant musculoskeletal neoplasms and so on. The aim of this study is to explore the application of MR perfusion-weighted imaging in prostatic cancer （Pca）, and evaluate the correlation of PWI features with vascular endothelial growth factor （VEGF） and microvessel density （MVD）. Methods： Twenty-eight consecutive patients who were diagnosed clinically as prostatic cancer and thirty healthy volunteers were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWI, including the steepest slope of signal intensity-time curve （SSmax） and the change in relaxation rate （ΔR2^＊peak） at lesions, were analyzed. Correlation analysis was used to determine the relationship between the results of PWI and that of immunohistochemistry. Results： （1） In the healthy volunteers, the steepest slope of signal intensity-time curve （SSmax） and ΔR2^＊peak of perfusion curve were： 0.430±0.011, 2.01±0.7 respectively; however, in the prostatic cancer, they were 57.8±5.0, 3.0±0.6 respectively; with significant difference （t=-4.11, 3.28, P〈0.01）. （2）The VEGF and MVD expression of twenty-eight Pca patients were significantly higher. Conclusion： On MR perfusion- weighted imaging, SSmax and ΔR2^＊peak can reflect MVD and VEGF expression levels in prostatic cancer, suggesting information on tumor angiogenesis. Thus they are beneficial to the diagnosis and treatment of prostatic cancer.
文摘Objective： To explore the application of MR perfusion-weighted imaging （PWI） in the benign and malignant prostate diseases, and evaluate the correlations of PWl features with vascular endothelial growth factor （VEGF） and microvessel density （MVD）. Methods： Seventy-four consecutive patients who were diagnosed clinically for the prostate diseases, including forty-four cases with benign prostate hyperplasia and thirty cases with prostatic cancer proved pathologically, were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWl, including the steepest slope of signal intensity-time curve （SSmax） and the change in relaxation rate （ΔR2^＊ peak） at lesions, were analyzed. Correlation analysis was used to determine the relationship between the results of PWl and immunohistochemistry. Results： （1） In the benign prostate hyperplasia （BPH）, SSmax and ΔR2^＊ peak of perfusion curve were 34.2 ± 2.9 and 1.49 ± 0.11, respectively; however, in the prostatic cancer （Pca）, they were 58.6± 4.8 and 3.18 ±0.49 respectively; there were statistical differences （t = 2.16 and 2.31, P 〈 0.05）. （2） The VEGF and MVD expressions of thirty Pca patients were significantly higher than those of forty-four BPH patients （x2 = 28.64, P 〈 0.01; t = 21.2, P 〈 0.01）. MVD expressions of Pca and BPH groups showed positive associations with VEGF expressions （P 〈 0.01）. On MR perfusion-weighted imaging, SSmax and ΔR2^＊ peak showed associations with MVD and VEGF expressions （P 〈 0.01）. Conclusion： On MR perfusion-weighted imaging, SSmax and ΔR2^＊ peak can reflect MVD and VEGF expression levels in the benign and malignant prostate diseases and might be implied the tumor angiogenesis so as to distinguish benign from malignant and provide the important information for the surgeon to diagnose and treat the prostatic diseases.
文摘Introduction: The burden of prostatic cancer is rising in Sudan. Usually, they present late in their disease with urinary tract obstruction, hematuria, bony pain, or cachexia because there is no screening program. Here we present a patient with prostatic cancer who presented with left axillary mass as his main concern. Case Description: 82-year-old Sudanese male presented with a left axillary and left supraclavicular lymphadenopathy of a few months’ duration. He underwent a decisional biopsy which showed metastatic adenocarcinoma. Upper and lower GI endoscopy were performed but the latter was complicated by a sigmoid perforation with peritonitis. During laparatomy, multiple enlarged pelvic lymphnodes were encountered and a biopsy result suggested a metastatic prostatic neoplasm. Later, prostatic biopsy confirmed the diagnosis. The patient was treated with bilateral orchidectomy. Clinical discussion: Lymphatic metastasis to axillary lymph nodes is a very rare manifestation of prostate cancer and only a few cases have been reported in the literature. It can cause diagnostic difficulty since prostate cancer typically metastasis to the pelvic lymph node and very rarely involves he supradiaphragmatic lymph node. Conclusion: Metastatic prostatic carcinoma should be considered among the causes of supra-diaphragmatic lymph adenopathy. Careful physical and imaging examinations combined with PSA and pathological analysis are essential in the diagnosis of advanced prostate cancer with unusual presentation.
文摘To assess the role of dynamic contrast-enhanced MRI (DCE-MRI) in thediagnosis and differentiation of prostatic cancer (PC). Methods: Five volunteers, 36 patients withbenign prostatic hyperplasia (BPH) and 13 patients with biopsy-proven prostate cancer underwentconventional MRI, DCE-MRI and delayed enhancement MRI. The value of the signal intensity in DCE-MRIwas measured and calculated to draw the time-signal intensity curve of the normal peripheral zone(PZ), the prostate cancer and the benign prostatic hyperplasia. Results: In DCE-MRI, the normalperipheral zone was enhanced mildly and slowly and the peak value was located in late phase. Theenhancement of the lesions in 36 patients with the benign prostatic hyperplasia was obvious in earlyphase and strengthened gradually, and then turned to decrease in late phase after peak value. Thelesions in 9 of 13 cases with prostate cancer were enhanced obviously in early phase and washed outrapidly, and the peak value was located in early phase, but the peak value was in mediate and latephase in the other 4 cases with diffuse lesion in the prostate on T_2WI. Conclusion: In DCE-MRI, theenhancement patterns of the normal peripheral zone, the prostate cancer and the benign prostatichyperplasia were significantly different. DCE-MRI was very useful in the diagnosis anddifferentiation of prostate cancer.
文摘OBJECTIVE To investigate the diagnostic value of modified prostate specific antigen(PSA)parameters in the diagnosis of prostate cancer(PCA) when the serum PSAis in a grey zone of 4~10 ng/ml. METHODS The results of serum PSA determinations of the patients receiving a transrectal ultrasound-guided multiphase prostatic biopsy,were retrospectively analyzed.In the 88 patients with a serum PSA value of 4-10 ng/ml,the final diagnosis of PCA was made in 21,and that of benign prostate hyperplasia(BPH)in 67 patients.The percentage of the free-serum PSA([FPSA]/total-serum PSA[TPSA],F/T),PSA density(PSAD)and the sensitivity and specificity of the new PSA modified parameter(F/T)/PSAD in diagnosing PCA,within a set threshold value,was compared. RESULTS In the 88 patients with serum PSA in the grey zone of 4.0-10.0 ng/ml,there was no significant difference in comparing the TPSA between the 21 PCA patients and 67 BPH patients(P>0.05).However, there was a significant difference in the value of modified PSA parameters, such as F/T,PSAD and(F/T)/PSAD,between the PCA and the BPH groups (P<0.001).As the cut off point-value of the F/T,PSAD and(F/T)/PSAD was set at 0.16,0.15 and 0.8,the diagnostic sensitivity for PCA was 66.7%, 76.2%and 85.7%,and the specificity was 41.8%,43.3%and 68.7%,respectively.There was no significant difference in the sensitivity comparing the modified parameters for diagnosing PCA(P>0.05),whereas an overt predominance was present in the specificity of(F/T)/PSAD for PCAdiagnosis (P<0.05). CONCLUSION In the serum PSA grey zone of 4-10 ng/ml,a modified PSA parameter can improve the PCA diagnostic accuracy rate.With a considerably high sensitivity,application of the(F/T)/PSAD may effectively enhance the diagnostic specificity,which is superior to the F/T and PSAD, and can be expected to be one of the new indices derived from the PSA.
基金supported(in part)by the National Key Research and Development Program(2022YFC3600700)the Fundamental Research Funds for the Central Universities(2042024YXA008)the Young Top-Notch Talent Cultivation Program of Hubei Province(for Prof.Xian-Tao Zeng).
文摘Background:The burden of common urologic diseases,including benign prostatic hyperplasia(BPH),urinary tract infections(UTI),urolithiasis,bladder cancer,kidney cancer,and prostate cancer,varies both geographically and within specific regions.It is essential to conduct a comprehensive and precise assessment of the global burden of urologic diseases.Methods:We obtained data on incidence,prevalence,mortality,and disability-adjusted life-years(DALYs)for the aforementioned urologic diseases by age,sex,location,and year from the Global Burden of Disease(GBD)2021.We analyzed the burden associated with urologic diseases based on socio-demographic index(SDI)and attributable risk factors.The trends in burden over time were assessed using estimated annual percentage changes(EAPC)along with a 95%confidence interval(CI).Results:In 2021,BPH and UTI were the leading causes of age-standardized incidence rate(ASIR)and age-standardized prevalence rate(ASPR),with rates of 5531.88 and 2782.59 per 100,000 persons,respectively.Prostate cancer was the leading cause of both age-standardized mortality rate(ASMR)and age-standardized DALYs rate(ASDR),with rates of 12.63 and 217.83 per 100,000 persons,respectively.From 1990 to 2021,there was an upward trend in ASIR,ASPR,ASMR,and ASDR for UTI,while urolithiasis showed a downward trend.The middle and low-middle SDI quintile levels exhibited higher incidence,prevalence,mortality,and DALYs related to UTI,urolithiasis,and BPH,while the high and high-middle SDI quintile levels showed higher rates for the three cancers.The burden of these 6 urologic diseases displayed diverse age and sex distribution patterns.In 2021,a high body mass index(BMI)contributed to 20.07%of kidney cancer deaths worldwide,while smoking accounted for 26.48%of bladder cancer deaths and 3.00%of prostate cancer deaths.Conclusions:The global burden of 6 urologic diseases presents a significant public health challenge.Urgent international collaboration is essential to advance the improvement of urologic disease management,encompassing the development of effective diagnostic screening tools and the implementation of high-quality prevention and treatment strategies.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(Nos:2024A1515012687)the National Natural Science Foundation of China(No.82303052).
文摘Background Neuroendocrine prostate cancer(NEPC)is an aggressive subtype of castration-resistant prostate cancer(CRPC)that is typically resistant to nearly all current therapies.Methods In this study,single-cell RNA sequencing(scRNA-seq)and bioinformatic analysis identified centrosomal protein 55(CEP55)as a critical factor in the transformation from hormone-sensitive prostate cancer(HSPC)to CRPC and,ultimately to,NEPC.Results Subsequent bioinformatics analyses and clinical sample validation showed that CEP55 is significantly upregulated in NEPC tissues relative to HSPC and CRPC.Furthermore,while CEP55 show no significant association with the immune microenvironment or cancer-associated fibroblasts(CAFs),our findings indicated 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 cyclin-dependent kinase 1(CDK1)at the tyrosine 15(Tyr15)site.Conclusions 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.
基金supported by the National Natural Science Foundation[Grant Number:82102788]Anhui Province Key Project for Clinical Medical Research Translation and Advancement[202204295107020031,202204295107020007]Anhui Provincial University Excellent Scientific Research and Innovation Team Project[2022AH010071].
文摘Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype or develop resistance to therapeutic interventions,leading to tumor metastasis and a poorer prognosis.When PC metastasizes to distant sites,the bone remains the predominant location,and brain metastases are regarded as exceedingly rare.Case Description:The current study focused on a rare clinical PC case that presented multiple brain metastases after prostate surgery.The patient was initially diagnosed with PC through prostate biopsy and subsequently underwent prostate debulking surgery while continuing androgen deprivation therapy,which maintained low prostatespecific antigen(PSA)levels for 4 years.However,a sudden PSA surge to 7.858 ng/mL led to the emergence of two brain metastatic tumors,which were confirmed to have originated from the prostate.Conclusions:Patients with advanced PC require comprehensive evaluations to detect rare metastatic sites,such as the brain,to avoid missed diagnoses.For patients with brain metastases,a multimodal approach combining surgical resection,postoperative radiotherapy,and endocrine therapy can effectively alleviate symptoms and enhance survival.
文摘Background:Low-dose rate(LDR)prostate brachytherapy is a recommended treatment of localized prostate cancer in current guidelines.The study aimed to determine biochemical relapse-free survival(BRFS)in patients treated with dynamic real-time low-dose rate(LDR)brachytherapy using Iodine 125(I^(125)).Methods:We retrospectively reviewed 499 patients with localized prostate cancer treated with I^(125) LDR realtime brachytherapy between 2003 and 2021.The mean patient age was 65 years(range:45–84 years).Based on the National Comprehensive Cancer Network(NCCN)risk classification,230 patients(46.1%)were categorized as low risk,235(47.1%)as intermediate risk,and 34(6.8%)as high risk.Gleason scores were distributed as follows:3+3 in 283 cases(56.7%),3+4 in 157 cases(31.5%),4+3 in 46 cases(9.2%),and 4+4 in 13 cases(2.6%).The mean follow-up was 70.5 months.Results:Tumor relapse was observed in 47 patients(9.4%)over a mean follow-up period of 6.26 years(SD 4.16).Local recurrence within the prostate occurred in 20 cases(4%).Patients with nadir PSA<0.2 ng/mL at 5 years of follow-up had a significantly lower incidence of tumor recurrence(3%)compared to those with a nadir PSA>0.2 ng/mL(21.9%)(p=0.0001).Biochemical relapse-free(BRFS)rates at 5,10 and 15 years were 96%,91.5% and 88.9%,respectively.When stratified by NCCCN risk groups,5-year BRFS was 96% in low risk,98% in intermediate risk and 85% in high risk patients(p=0.003).Inmultivariate analysis,only age at the time of brachytherapy(p=0.009),initial PSA(p=0.007)and Gleason grade(p=0.007)were significantly associated with tumor recurrence.Cancer-specific survival and overall survival were 99.8% and 98.0%,respectively.Conclusions:LDR with I^(125) has excellent longterm oncological outcomes for patients with low and intermediate-risk prostate cancer,in particular,patients achieving a nadir PSA<0.2 ng/mL at 5 years post-treatment.
基金supported by Tianjian advanced biomedical laboratory key research and development projectHenan Province Natural Science Foundation(Grant Number 242300421283)Major Science and Technology Project of Henan Province(221100310200)。
文摘Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(PC)remain not fully explored.The study aimed to explore how gut metabolites regulate death-ligand 1(PD-L1)blockade via exosomes and boost immune checkpoint inhibitors(ICIs)in PC.Methods:We recruited 70 PC patients to set up into five subgroups.The integrated multi-omics analysis was performed.In parallel,we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate(TRAMP)models.Results:We identified two metabolites,16(R)-Hydroxyeicosatetraenoic acid(16(R)-HETE)and 6-Keto-Prostaglandin E1(6-Keto-PGE1),that positively correlated with the plasma exosomal PD-L1 levels.The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA,protein,and exosome levels in both human and mouse PC cell lines,which were also validated in vivo based on subcutaneous mouse models.Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model.Conclusions:Targeting the“gut-tumor metabolic axis”is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.
基金supported by a grant from Kom op tegen Kanker(Stand Up to Cancer,Belgium).
文摘Objectives:PSMA PET/CT(Prostate-Specific MembraneAntigen Positron Emission Tomography/Computed Tomography)offers improved accuracy in detecting lymph node invasion(LNI)in prostate cancer(PC)patients,potentially reducing the need for extended pelvic lymph node dissection(ePLND).This study aims to evaluate a patient-tailored care pathway in which ePLND is performed only in patients with unfavorable intermediate-or high-risk PC who are deemed at risk for LNI based on PSMA PET/CT findings.Methods:In this interventional cohort study,81 patients were managed according to the new care pathway.ePLND was omitted in cases of negative PSMA PET/CT findings(N0M0),while those with positive PSMA PET/CT findings(N1M0)underwent ePLND.A comparator group of 81 patients was selected from a prospectively generated database for comparison.Results:The intervention group experienced a 75% reduction in the number of ePLNDs performed compared to the comparator group(p<0.001).ePLND-related complications were significantly lower in the intervention group(p=0.008).No significant difference was observed in 3-year biochemical-recurrence free survival(BRFS)between the two groups(p=0.958).Conclusion:Omitting ePLND in patients with negative PSMA PET/CT findings(N0M0)leads to a substantial reduction in the number of ePLNDs performed,resulting in a decrease in morbidity,without compromising early oncological outcomes.
文摘Poly-and perfluoroalkyl substances(PFAS),including perfluorooctanoic acid(PFOA)and perfluorooctane sul-fonate(PFOS),are persistent environmental pollutants with potential toxicological effects on human health.The aim of this study was to investigate the impact of PFOS and PFOA on the effectiveness of selected drugs used in the treatment of prostate cancer based on in vitro tests on cell lines.Three cell lines were used in the study:two human prostate cancer cells(DU-145 and PC3)and one human normal prostate cell line(PNT1A).Using dose-response experiments,it was observed that PFAS had differential effects on cancer and normal cells.At low concentrations,PFOA and PFOS stimulated the proliferation of cancer cells,particularly PC3,while higher concentrations led to reduced viability.In normal cells,PFOS exhibited greater cytotoxicity compared to PFOA.Furthermore,PFOS enhanced docetaxel cytotoxicity in PC3 cells but reduced its efficacy in DU-145 cells.Similarly,PFOA diminished cabazitaxel effectiveness in DU-145 cells,suggesting PFAS-drug interactions may depend on the cell type,drug,and PFAS concentration.Results suggest that PFAS may influence cellular processes through receptor-mediated pathways,oxidative stress modulation,and protein binding,altering drug bioavailability and cellular uptake.The study also highlights the non-monotonic dose-response relationships observed in PFAS-treated cells.These findings raise concerns about the potential risks associated with PFAS exposure,particularly in the context of cancer treatment.Future studies should focus on long-term,low-dose PFAS exposure,the use of primary cells,and the molecular mechanisms driving these interactions to better inform therapeutic strategies.
基金supported by NIGMS(SC1GM140907 to G.-Y.L.)the Prostate Cancer Research Racial Disparity Grant from the Prostate Cancer Research(PCR)in the United Kingdom(grant reference[5001],to G.-Y.L.)the AU Medical Center,Inc.with a Grant/Contract Number CAU-AU Partnership-Kavuri-Liou and by NIMHDsupported Research Capacity Core at CAU(U54MD007590)。
基金supported by the funding of Chinese Scholarship Council(No.202206240086)。
文摘Objective:To identify chromatin regulators(CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence(BCR)after radical prostatectomy(RAP)in prostate cancer(PCa)patients.Methods:Differentially expressed genes(DEGs)between tumor and normal samples from The Cancer Genome Atlas(TCGA)and gene expression omnibus(GEO)databases were intersected with CR-related and prognostic genes.Consensus clustering,risk score analysis,functional analysis,immune microenvironment,m6A,and heterogeneity assessments were performed using R software.In vitro validation used DU145 and C42B PCa cell lines.Topoisomerase II alpha(TOP2A)was knocked down via si RNA.Assays included CCK-8 proliferation,colony formation,transwell migration/invasion,wound healing,and western blotting(WB)for pathway validation.Results:TOP2A and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)defined molecular subtypes and a risk score in TCGA,validated in a GEO dataset.Cluster 2 exhibited significantly shorter BCR-free survival vs.cluster 1 in TCGA[hazard ratio(HR):2.21;95%confidence interval(95%CI):1.32-3.73;P=0.003],GEO(HR:2.05;95%CI:1.05-4.02;P=0.010),and MSKCC2010(HR:5.93;95%CI:1.96-17.87;P<0.001).Similar survival differences were observed between high-and low-risk groups(defined by the median risk score).Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression.Gene set variation analysis(GSVA)revealed downregulated cell-cycle pathways in cluster 2,alongside suppressed tumor-infiltrating immune cells.TOP2A knockdown significantly impaired PCa cell proliferation,colony formation,migration,and invasion.Mechanistically,it suppressed phosphoinositide 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)pathway activation,reducing phosphorylated PI3K and AKT levels without altering total protein.Conclusions:TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients.TOP2A drives malignant progression via the PI3K/AKT pathway.
文摘Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly cancer-associated fibroblasts(CAFs),as a critical determinant of disease behavior.CAFs constitute a heterogeneous population originating from fibroblasts,mesenchymal stem cells,endothelial cells,epithelial cells undergoing epithelial-mesenchymal transition(EMT),and adipose tissue.Through dynamic crosstalk with tumor,immune,endothelial,and adipocyte compartments,CAFs orchestrate oncogenic processes including tumor proliferation,invasion,immune evasion,extracellular matrix remodeling,angiogenesis,and metabolic reprogramming.This review comprehensively summarizes the cellular origins,phenotypic and functional heterogeneity,and spatial distribution of CAFs within the prostate TME.We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance,and critically evaluate emerging strategies to therapeutically target CAFmediated signaling,metabolic,and immune pathways.By integrating recent advances from single-cell and spatial transcriptomics(ST),our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.
文摘Objectives:Prostate cancer(PCa)is a highly prevalent male malignancy with limited efficacy in advanced stages.Dysregulated modulation of necroptosis was reported to be tightly correlated with PCa initiation and progression.Herein,we aimed to identify necroptosis-associated long non-coding RNAs(lncRNAs)and delineate their functional roles in PCa through an integrated approach combining bioinformatic analyses and in vitro experimental validation.Methods:RNA sequencing data and corresponding clinical information of PCa were downloaded from The Cancer Genome Atlas(TCGA).Differentially expressed necroptosis-related genes(NRGs)and lncRNAs were screened,and necroptosis activity was assessed by single-sample gene set enrichment analysis(ssGSEA).Weighted Gene Co-expression Network Analysis(WGCNA)identified necroptosis-related lncRNA modules,with key lncRNAs prioritized via Cox regression.Clinical correlation analyses and in vitro experiments validated the function of the key lncRNA LINC00595.Results:A total of 50 differentially expressed NRGs were identified,among which pro-necroptotic genes exhibited pronounced downregulation,while anti-necroptotic genes were significantly upregulated.Consistently,ssGSEA confirmed reduced necroptosis activity in PCa.WGCNA further identified 13 core necroptosis-related lncRNAs(NRlncRNAs),with Cox regression analysis pinpointing LINC00595 and LINC00908 as the top prognostic candidates.Both lncRNAs were downregulated in PCa,with low expression correlating with advanced T stage,lymph node metastasis,and poor prognosis.Functional experiments demonstrated that LINC00595 overexpression inhibited PCa cell proliferation,migration,and invasion,and enhanced necroptosis.Conclusions:Collectively,our findings identified LINC00595 and LINC00908 as novel regulators of necroptosis in PCa.Specifically,LINC00595 exerted tumor-suppressive effects by enhancing necroptosis,holding potential as prognostic biomarkers and therapeutic targets.
文摘Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.
基金supported by the Clinical Research of Tianjin Medical University(No.2018kylc004)the Medical Science Research Project of Hebei(No.20250372).
文摘Objective:Prostate cancer is the second most common fatal cancer in men.Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients.Ovarian tumor family deubiquitinase 4(OTUD4)is a member of the ovarian tumor-associated protease domain(OTUDs)family.Although previous studies have shown that the expression and function of OTUD4 vary across different tumors,its role in prostate cancer remains unknown.The aim of this study is to explore new therapeutic targets and diagnostic markers for prostate cancer and investigate their mechanisms of action.Methods:Cell culture,Cell Counting Kit-8(CCK-8)assay,colony formation assay,Transwell assay,5-Ethynyl-2′-deoxyuridine(EdU)assay,immunofluorescence,Western blot,Quantitative real-time PCR(qRT-PCR),protein mass spectrometry,nude mouse xenograft models,immunohistochemistry(IHC),and hematoxylin and eosin(H&E)staining were utilized.Results:We found that OTUD4 expression was reduced in prostate cancer and negatively correlated with poor prognosis in both in vivo and in vitro experiments.Subsequent mechanistic studies revealed that OTUD4 directly inhibits the degradation of myosin-9(MYH9)protein via deubiquitination.Although MYH9 has been previously reported to act as a tumor suppressor in prostate cancer,no experimental evidence had demonstrated that MYH9 inhibits prostate cancer growth.Our results indicate that MYH9 overexpression effectively suppresses prostate cancer through interactions with cell adhesion molecules.Conclusion:Collectively,these results suggest that OTUD4 functions as a tumor suppressor in prostate cancer.Specifically,OTUD4 inhibits MYH9 degradation via deubiquitination,thereby enabling MYH9-mediated suppression of prostate cancer.
文摘Prostate-specific membrane antigen(PSMA)is a surface membrane antigen that is highly overexpressed in prostate cancer,with heterogenous expression throughout the natural history of the disease.This has generated significant interest as a potential biomarker for use in early diagnosis and treatment of prostate cancer.We reviewed the literature surrounding PSMA and its current clinical applications in diagnosing and managing early prostate cancer that is confined to the prostate and local lymph nodes.A search on PubMed,Medline,and Web of Science was performed using the following keywords:“PSMA”,“Prostate Specific Membrane Antigen”,“Prostate cancer”,“Biomarker”,“Diagnosis”.We considered all available articles relevant to the topic of PSMA as a biomarker in early prostate cancer when developing this narrative review.Key articles assessing the biology of PSMA,as well as its use as a potential diagnostic and therapeutic target in early prostate cancer,were assessed.The role of PSMA PET as a potential diagnostic and risk stratification tool was assessed.The current use of antibody-drug conjugates and radioligand therapy targeting PSMA was assessed,along with any current evidence to support their use in early prostate cancer.PSMA is heavily expressed throughout the early stages of prostate cancer,and this has significant therapeutic implications.There is a growing body of evidence that shows PSMA PET can play a role in the diagnosis,risk stratification,and prognostication of localised prostate cancer.PSMA-targeted therapies such as Lu-177 currently do not have any proven benefit in treating early prostate cancer;however,this remains an area of ongoing research.
