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Background Menopause is associated with an increased risk of kidney stone disease (KSD). However, for postmenopausal women, how to avoid KSD has rarely been studied. The aim of this study was to explore whether drinking tea is associated with a reduction in the prevalence of KSD in postmenopausal women. Methods We collected 11,484 postmenopausal women from the Taiwan Biobank, and used questionnaires to obtain information on tea drinking, KSD, and comorbidities. The participants were divided into two groups according to habitual tea consumption: tea-drinking and non-tea-drinking groups. The association between habitual tea consumption and KSD was examined by logistic regression analysis. Results There were 2,035 postmenopausal women in the tea-drinking group and 9,449 postmenopausal women in the non-tea-drinking group. The mean age of all participants was 61 years. Compared to the non-tea-drinking group, the tea-drinking group had a significantly lower prevalence of KSD (7% vs. 5%). The odds ratio (OR) of KSD was lower in those who habitually drank tea than in those who did not (OR = 0.78; 95% confidence interval [CI] [0.63 to 0.96]) after adjusting for confounders. Moreover, postmenopausal women with a daily intake of two cups of tea or more had a 30% reduced risk of KSD compared to those who did not habitually drink tea (OR = 0.71, 95% CI [0.56 to 0.90]). Conclusions Our results suggest that habitual tea drinking may be associated with a reduction in the prevalence of KSD in postmenopausal women. Further studies are warranted to investigate the protective effect of tea on the development of KSD.

Background: Phthalates, ubiquitous in plastics and softening agents, are pervasive in our daily environment. Growing concerns have emerged regarding their potential impact on renal health, particularly due to their propensity to induce oxidative stress. However, the relationship between phthalate exposure and urolithiasis remains poorly understood. This research seeks to explore the connection between phthalate exposure, oxidative stress, and the risk of urolithiasis. Methods: A case-control study involving 285 patients diagnosed with calcium urolithiasis and 594 healthy controls was conducted. Participants completed structured questionnaires and provided urine samples for measuring 10 phthalate metabolites, biomarkers of oxidative stress (malondialdehyde [MDA]) and early renal injury (N-acetyl-beta-D-glucosaminidase [NAG] and albumin/creatinine ratio [ACR]). For subsequent analyses, we utilized distinct categories: the sum of high-molecular-weight phthalate metabolites (∑HMWm), the sum of low-molecular-weight phthalate metabolites (∑LMWm), and the daily intake of di-2-ethylhexyl phthalate (DEHP)(DI_DEHP_5). Results: Stone patients exhibited significantly elevated urinary biomarkers of oxidative stress (MDA) and early renal injury (NAG and ACR), along with higher levels of 9 out of 10 assessed phthalate metabolites compared to normal controls. Within the study population, significant positive associations were found between almost all individual phthalate metabolites and urinary biomarkers of oxidative stress (MDA) as well as early renal injury (NAG and ACR). Logistic regression further confirmed that elevated phthalate levels, including ∑HMWm, ∑LMWm, and DI_DEHP_5, were uniformly associated with an increased risk of oxidative stress, early renal injury, and urolithiasis after adjusting for confounding factors. Conclusions: Our study uncovers a novel association between phthalate exposure and the risk of urolithiasis, underscoring the heightened risk of kidney injury posed by such exposure. Considering the widespread presence of phthalates, regulatory measures and public health interventions are crucial to mitigate phthalate-related nephrotoxicity, while further large-scale longitudinal research is imperative to validate our initial findings and elucidate the underlying mechanisms.

Accumulating evidence suggests a link between vascular endothelial growth factor (VEGF), erectile dysfunction (ED), and metabolic syndrome (Mets), possibly because VEGF can alter the physiological pathways involved in the regulation of endothelial cell proliferation. This study aimed to investigate the genetic susceptibility of VEGF 2578C>A polymorphism to the development of ED and Mets. Collected data included five-item International Index of Erectile Function (IIEF-5), components of Mets, and VEGF 2578C>A polymorphism. A total of 596 subjects from Kaohsiung with a mean age of 55.5 years were enrolled, data collection was done at our hospital. Individuals carrying the VEGF 2578 A allele (CA+AA genotypes) demonstrated a higher prevalence of ED compared to those with the CC genotype, with an adjusted odds ratio (OR) of 1.582 (95% confidence interval [95% CI] = 1.123–2.227, p value = 0.009) in multivariate binary regression analysis. Similarly, individuals carrying the VEGF 2578 A allele showed a higher prevalence of Mets compared to those with the CC genotype, with an adjusted OR of 2.461 (95% CI = 1.491–4.064, p value < 0.001). Furthermore, A allele carriers had significantly lower IIEF-5 scores and a higher number of Mets components compared to those with the C allele ( P value < 0.001, respectively). In conclusion, VEGF 2578 A allele carriers are at a greater risk of both Mets and ED, suggesting that the VEGF 2578C>A polymorphism may serve as a common genetic susceptibility factor in the development of both disorders. Further research is warranted to evaluate the mechanisms underlying this association.

Abstract Background Prostate cancer (PCa) patients with elevated level of androgen receptor (AR) correlate with higher metastatic incidence. Protein expression of AR and its target gene prostate‐specific antigen (PSA) are elevated in metastatic prostate tumors as compared to organ‐confined tumors. Androgen treatment or elevation of AR promotes metastasis of PCa in cell culture and murine model. However, under androgen depleted condition, AR suppressed cell mobility and invasiveness of PCa cells. Androgen deprivation therapy in PCa patients is associated with higher risk of cancer metastasis. We therefore investigated the dual roles of AR and miRNAs on PCa metastasis. Methods The PC‐3AR (PC‐3 cells re‐expressing AR) and LNCaP cells were used as PCa cell model. Transwell migration and invasion assay, wound‐healing assay, zebrafish xenotransplantation assay, and zebrafish vascular exit assay were used to investigate the role of AR and androgen on PCa metastasis. Micro‐Western Array, co‐immunoprecipitation and Immunofluorescence were applied to dissect the molecular mechanism lying underneath. The miRNA array, miRNA inhibitors or plasmid, and chromatin immunoprecipitation assay were used to study the role of miRNAs on PCa metastasis. Results In the absence of androgen, AR repressed the migration and invasion of PCa cells. When androgen was present, AR stimulated the migration and invasion of PCa cells both in vitro and in zebrafish xenotransplantation model. Androgen increased phospho‐AR Ser81 and yes‐associated protein 1 (YAP), decreased phospho‐YAP Ser217, and altered epithelial‐mesenchymal transition (EMT) proteins in PCa cells. Co‐IP assay demonstrated that androgen augmented the interaction between YAP and AR in nucleus. Knockdown of YAP or treatment with YAP inhibitor abolished the androgen‐induced migration and invasion of PCa cells, while overexpression of YAP showed opposite effects. The miRNA array revealed that androgen decreased hsa‐miR‐5001‐5p but increased hsa‐miR‐203a and hsa‐miR‐210‐3p in PC‐3AR cells but not PC‐3 cells. Treatment with inhibitors targeting hsa‐miR‐203a/hsa‐miR‐210‐3p, or overexpression of hsa‐miR‐5001‐5p decreased YAP expression as well as suppressed the androgen‐induced migration and invasion of PCa cells. Chromatin immunoprecipitation (ChIP) assay demonstrated that AR binds with promoter region of has‐miR‐210‐3p in the presence of androgen. Conclusions Our observations indicated that miRNAs 203a/210‐3p/5001‐5p regulate the androgen/AR/YAP‐induced PCa metastasis.

Abstract This study investigates the correlation between body mass index (BMI) and osteoporosis utilizing data from the Taiwan Biobank. Initially, a comprehensive analysis of 119,009 participants enrolled from 2008 to 2019 was conducted to assess the association between BMI and osteoporosis prevalence. Subsequently, a longitudinal cohort of 24,507 participants, initially free from osteoporosis, underwent regular follow-ups every 2–4 years to analyze the risk of osteoporosis development, which was a subset of the main cohort. Participants were categorized into four BMI groups: underweight (BMI

Abstract Smoking is the most important risk factor for chronic obstructive pulmonary disease (COPD), however evidence from large-scale studies on whether secondhand smoke (SHS) increases the risk of COPD is still lacking. We conducted this large longitudinal study to investigate the association between SHS and the development of COPD. This is a longitudinal study. Data on 6519 subjects who were never-smokers, had no history of COPD, and had complete lung function records were extracted from the Taiwan Biobank. They were divided into two groups according to SHS exposure: no exposure and exposure groups. Data were collected when participants enrolled in the study and during regular follow-up. Cox proportional hazards regression models were used to estimate the relative risk (RR) and 95% confidence interval (CI) for the association between SHS and the risk of developing COPD. At 48 months of follow-up, 260 (4%) participants in the no exposure group and 34 (7%) participants in the exposure group developed COPD. The RR of incident COPD development was significantly higher in the exposure group than that in the no exposure group after adjusting for confounders (RR = 1.49; 95% CI 1.04 to 2.14; P value = 0.031). There is a dose–response relationship between the duration of exposure to SHS and the risk of incident COPD, which demonstrates that an additional hour of exposure to SHS per week was associated with a 1.03-fold increased likelihood of developing COPD after adjusting for confounders (RR = 1.03; 95% CI 1.00 to 1.05; P value = 0.027). SHS exposure contributes to the development of COPD. This finding can help raise awareness of the harms of SHS and provide a reference for formulating anti-smoking policies.

Abstract Background Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. Methods We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. Results After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P

Abstract Docetaxel‐based chemotherapy has generally been considered as one of the effective treatments for castration‐resistant prostate cancer (PCa). However, clinical treatment with docetaxel often encounters a number of undesirable effects, including drug resistance. Tubulin isoforms have been previously examined for their resistance to docetaxel in many cancers, but their real mechanisms remained unclear. In this study, a series of docetaxel‐resistant PC/DX cell sublines were established by chronically exposing PC3 to progressively increased concentrations of docetaxel. Western blotting results showed significantly higher expression of acetyl‐tubulin, α‐tubulin, β‐tubulin, γ‐tubulin, and βIII‐tubulin in PC/DX25 than in parental PC3 cells. PC/DX25 with greater resistance to docetaxel had higher levels of acetyl‐tubulin and mitotic centromere‐associated kinesin (MCAK) than PC3 cells. This study found that docetaxel induced the expression of acetyl‐tubulin and MCAK in PC3 cells at a dose‐ and time‐dependent manner. Both mRNA and protein levels of histone deacetylase 6 (HDAC6) were significantly decreased in PC/DX25 compared with PC3 cells. PC3 increased the resistance to docetaxel by HDAC6 knockdown and Tubastatin A (HDAC6 inhibitor). Conversely, PC/DX25 reversed the sensitivity to docetaxel by MCAK knockdown. Notably, flow cytometry analysis revealed that MCAK knockdown induced significantly sub G1 fraction in PC/DX cells. Overexpression of polo‐like kinase‐1 increased the cell survival rate and resistance to docetaxel in PC3 cells. Moreover, epidermal growth factor receptor (EGFR) activation induced the upregulation of acetyl‐tubulin in docetaxel‐resistant PCa cells. These findings demonstrated that the EGFR‐mediated upregulated expression of acetyl‐tubulin played an important role in docetaxel‐resistant PCa.

Abstract Background Tobacco use and secondhand smoke (SHS) are risk factors of kidney stone disease (KSD). The hypothesis is that tobacco produces chemicals that increase oxidative stress and vasopressin, which leads to decreased urine output, and contributes to stone formation. The aim of this study was to examine the effects of smoking and SHS on the development of KSD. Materials and methods We analyzed a total of 25,256 volunteers with no history of KSD participated in the Taiwan Biobank. The presence of underlying and follow-up KSD was surveyed by a self-administrated questionnaire. They were classified into three groups on the basis of smoking and SHS exposure, accessed with survey questionnaires; never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups. Results KSD was noted in 352 (2.0%), 50 (3.3%) and 240 (4.1%) subjects in the never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups, respectively, with a mean follow-up of 4 years. The odds ratio (OR) of KSD was higher in the never-smokers with SHS exposure (OR, 1.622; 95% confidence interval [95% CI], 1.225 to 2.255) and ever-smokers groups (OR, 1.282; 95% CI, 1.044 to 1.574) than in the never-smokers with no SHS exposure group after adjustment of confounders. In addition, never-smokers with SHS exposure had similar effects on the development of KSD than ever-smokers (OR, 1.223; 95% CI, 0.852 to 1.756). Conclusion Our study suggests that both smoking and SHS are a risk factor for developing KSD and that the impact of SHS is not inferior to that of smoking. Trial registration The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20,210,058).

Renal cell carcinoma (RCC) is characterized by high mortality and morbidity rates. Vav guanine nucleotide exchange factors (VAVs), crucial for signal transduction between cell membrane receptors and intracellular mediators, have been implicated in carcinogenesis. However, their potential prognostic value in RCC remains unclear. The impact of 150 common VAV polymorphisms on RCC risk and survival was investigated in a cohort of 630 individuals. Publicly available gene expression datasets were utilized to analyze VAV gene expression in relation to patient outcomes. The VAV3 rs17019888 polymorphism was significantly associated with RCC risk and overall survival after adjusting for false discovery rates. Expression quantitative trait loci analysis revealed that the risk allele of rs17019888 is linked to reduced VAV3 expression. Analysis of 19 kidney cancer gene expression datasets revealed lower VAV3 expression in RCC tissues compared to normal tissues, with higher expression correlating with better prognosis. Gene set enrichment analysis demonstrated that VAV3 negatively regulates the ubiquitin–proteasome system, extracellular matrix and membrane receptors, inflammatory responses, matrix metalloproteinases, and cell cycle pathways. Furthermore, elevated VAV3 expression was associated with increased infiltration of B cells, macrophages, and neutrophils into the RCC tumor microenvironment. Our findings suggest that VAV3 gene variants influence RCC risk and survival, contributing to a favorable prognosis in RCC.

Darolutamide, a second-generation androgen receptor inhibitor (SGARI), has been shown to increase metastasis-free survival and overall survival among men with non-metastatic castration-resistant prostate cancer (nmCRPC). Its unique chemical structure potentially provides efficacy and safety advantages over the SGARIs apalutamide and enzalutamide, which are also indicated for nmCRPC. Despite a lack of direct comparisons, the SGARIs appear to have similar efficacy, safety, and quality of life (QoL) results. Indirect evidence suggests that darolutamide is preferred for its good adverse event profile, an attribute valued by physicians, patients, and their caregivers for maintaining QoL. Darolutamide and others in its class are costly; access may be a challenge for many patients and may lead to modifications to guideline-recommended regimens.

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a valuable marker for identifying individuals at increased risk of metabolic dysfunction, liver-related complications, and cardiovascular disease. However, the association between MAFLD and testosterone deficiency (TD) in aging men remains poorly understood. This study aimed to investigate the association between MAFLD and the risk of TD in aging Taiwanese men, with a specific focus on those without metabolic syndrome (MetS).MethodsA free health screening program was conducted for Taiwanese men aged over 40 years in Kaohsiung, Taiwan. Participants underwent physical examinations, completed questionnaires regarding demographics, medical history, and clinical symptoms of TD, and provided 20-mL whole blood samples for biochemical, adipocytokine, and hormonal evaluations. Fatty liver index was used to evaluate the risk of fatty liver. Diagnostic criteria for MAFLD included fatty liver along with overweight/obesity, type 2 diabetes, or evidence of metabolic dysregulation.ResultsA total of 631 men (mean age: 54.4 ± 8.4 years) were enrolled. The prevalence rates of TD and MetS were significantly higher in men with MAFLD compared to those without (both p < 0.001). Additionally, the presence of MAFLD showed a significant correlation with adipocytokines associated with insulin resistance, such as adiponectin, leptin, and retinol-binding protein-4 (RBP-4) levels (all p < 0.001). Among men without MetS, those with MAFLD had a 3.89- and 4.74-fold higher risk of total testosterone < 300 ng/dL and TD, respectively, after adjusting for potential covariates.ConclusionMAFLD is associated with an elevated risk of TD in aging Taiwanese men, particularly in the absence of MetS. This finding suggests that MAFLD could serve as an early predictor of TD, facilitating the identification of high-risk individuals and enabling timely interventions. Further research is needed to validate these findings and explore the underlying mechanisms linking MAFLD, TD, and MetS in diverse populations.

Abstract Background Immunodeficiencies are genetic diseases known to predispose an individual to cancer owing to defective immunity towards malignant cells. However, the link between immunodeficiency and prostate cancer progression remains unclear. Therefore, the aim of this study was to evaluate the effects of common genetic variants among eight immunodeficiency pathway-related genes on disease recurrence in prostate cancer patients treated with radical prostatectomy. Methods Genetic and bioinformatic analyses on 19 haplotype-tagging single-nucleotide polymorphisms in eight immunodeficiency pathway-related genes were conducted in 458 patients with prostate cancer after receiving radical prostatectomy. Furthermore, the TNFRSF13B was knocked down in 22Rv1 and PC-3 human prostate cancer cell lines via transfecting short hairpin RNAs and cell proliferation and colony formation assays were performed. The molecular mechanisms underlying the effects of TNFRSF13B were further explored by microarray gene expression profiling. Results TNFRSF13B rs4792800 was found to be significantly associated with biochemical recurrence even after adjustment for clinical predictors and false discovery rate correction (adjusted hazard ratio 1.78, 95% confidence interval 1.16–2.71, p = 0.008), and the G allele was associated with higher TNFRSF13B expression (p = 0.038). Increased TNFRSF13B expression suggested poor prognosis in four independent prostate cancer datasets. Furthermore, silencing TNFRSF13B expression resulted in decreased colony formation of 22Rv1 and PC-3 cells through modulating the cell cycle and p53 signalling pathways. Conclusions The present study suggests the potential role of immunodeficiency pathway-related genes, primarily TNFRSF13B, in prostate cancer progression.

Abstract It is being debated whether prostate-specific antigen (PSA)-based screening effectively reduces prostate cancer mortality. Some of the uncertainty could be related to deficiencies in the age-based PSA cut-off thresholds used in screening. Current study considered 2779 men with prostate cancer and 1606 men without a cancer diagnosis, recruited for various studies in New Zealand, US, and Taiwan. Association of PSA with demographic, lifestyle, clinical characteristics (for cases), and the aldo–keto reductase 1C3 (AKR1C3) rs12529 genetic polymorphisms were analysed using multiple linear regression and univariate modelling. Pooled multivariable analysis of cases showed that PSA was significantly associated with demographic, lifestyle, and clinical data with an interaction between ethnicity and age further modifying the association. Pooled multivariable analysis of controls data also showed that demographic and lifestyle are significantly associated with PSA level. Independent case and control analyses indicated that factors associated with PSA were specific for each cohort. Univariate analyses showed a significant age and PSA correlation among all cases and controls except for the US-European cases while genetic stratification in cases showed variability of correlation. Data suggests that unique PSA cut-off thresholds factorized with demographics, lifestyle and genetics may be more appropriate for prostate cancer screening.

IntroductionWe aim to explore the association between chronic kidney disease (CKD) and cataracts.MethodsA total of 121,380 participants with adequate information collected from 29 community-based recruitment centers since 2008 were analyzed. The association between CKD and self-reported diagnosed cataracts was examined in a cross-sectional cohort and was validated in a longitudinal cohort of 25,263 participants without cataracts at baseline.Results and discussionOf all participants, cataracts occurred in 503/1,947 (26%) and 10,464/119,433 (9%) subjects in the CKD and non-CKD groups, respectively. Multivariate logistic regression showed that CKD was significantly associated with a higher prevalence of self-reported diagnosed cataracts. In the validation cohort, a higher incidence of cataracts was also noted in the CKD group (65/317, 21%) compared to the non-CKD group (1,964/24,252, 8%) during a mean 47-month follow-up. After adjusting for confounders, subjects with CKD had a 1.498-fold higher risk of incident cataracts than those without CKD (95% confidence interval = 1.114 to 2.013, p value = 0.007). We found that CKD was associated with a higher prevalence of cataracts as well as incident cataracts, which suggests CKD patients and their primary physicians should be aware of this disease and can provide a clue for further exploration of the possible mechanisms and treatments.

Regular exercise can regulate bone maintenance and improve bone health. However, large-scale epidemiological studies on the association between regular exercise and incident osteoporosis in menopausal women are still lacking. We aimed to examine the relationship between exercise and the risk of osteoporosis in menopausal women. In cross-sectional analysis, we enrolled 30,046 postmenopausal women with available information from the database of the Taiwan Biobank (TWB). We divided them into two groups according to their status of regular exercise, i.e., no exercise and regular exercise groups. A t-score of −2.5 or more standard deviations (SDs) below that of a young adult was defined as osteoporosis. Logistic regression after adjusting for confounding factors was used to analyze the association between regular exercise and the prevalence of osteoporosis. Furthermore, the risk of incident osteoporosis development was analyzed in a longitudinal cohort of 6,785 postmenopausal women without osteoporosis at baseline using a Kaplan-Meier analysis and a log-rank test. The mean age of subjects in the cross-sectional cohort was 59 years old. Fifty-six percent of them were exercising regularly. Osteoporosis was observed in 1,886 (14.2%) and 2,254 (13.4%) participants in the no exercise and regular exercise groups. Lower risk of osteoporosis was noted in postmenopausal women with regular exercise when compared with those without regular exercise [odds ratio (OR), 0.76; 95% confidence interval (95% CI), 0.71–0.81]. In the longitudinal cohort, incident osteoporosis was found in 430 (10.5%) women with regular exercise and 299 (11.2%) women without exercise during a mean follow-up of 45 months. Cox regression analysis revealed that the risk for incident osteoporosis was lower in postmenopausal women with regular exercise than those without exercise [hazard ratio (HR), 0.83; 95% CI, 0.71–0.97]. Our study suggests that regular exercise is associated with a reduced risk of osteoporosis in postmenopausal women and strengthens the importance of exercise for the prevention of osteoporosis.

Abstract Anoctamins were originally identified as a family of calcium‐activated chloride channels, but recently their roles in the development of different types of malignancies were suggested. Here, we evaluated the associations between 211 common single‐nucleotide polymorphisms in 10 anoctamin genes with biochemical recurrence (BCR) after radical prostatectomy (RP) for localized prostate cancer. Four SNPs (ANO4 rs585335, ANO5 rs4622263, ANO7 rs62187431, and ANO10 rs118005571) remained significantly associated with BCR after multiple test correction (P

Enzalutamide, a nonsteroidal antiandrogen, significantly prolonged the survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patients receiving enzalutamide frequently develop drug resistance. Rooibos (Aspalathus linearis) is a shrub-like leguminous fynbos plant endemic to the Cedarberg Mountains area in South Africa. We evaluated the possibility of using a pharmaceutical-grade green rooibos extract (GRT, containing 12.78% aspalathin) to suppress the proliferation and survival of enzalutamide-resistant prostate cancer (PCa) cells. Treatment with GRT dose-dependently suppressed the proliferation, survival, and colony formation of enzalutamide-resistant C4-2 MDV3100r cells and PC-3 cells. Non-cancerous human cells were more resistant to GRT treatment. GRT suppressed the expression of proteins involved in phosphoinositide 3-kinase (PI3K)-Akt signaling, androgen receptor (AR), phospho-AR (Ser81), cyclin-dependent kinase 1 (Cdk1), c-Myc and Bcl-2 but increased the expression of apoptotic proteins. Overexpression of c-Myc antagonized the suppressive effects of GRT, while knockdown of c-Myc increased the sensitivity of PCa cells to GRT treatment. Expression level of c-Myc correlated to resistance of PCa cells to GRT treatment. Additionally, immunofluorescence microscopy demonstrated that GRT reduced the abundance of AR proteins both in nucleus and cytoplasm. Treatment with cycloheximide revealed that GRT reduced the stability of AR. GRT suppressed protein expression of AR and AR's downstream target prostate specific antigen (PSA) in C4-2 MDV3100r cells. Interestingly, we observed that AR proteins accumulate in nucleus and PSA expression is activated in the AR-positive enzalutamide-resistant PCa cells even in the absence of androgen. Our results suggested that GRT treatment suppressed the cell proliferation and survival of enzalutamide-resistant PCa cells via inhibition of c-Myc, induction of apoptosis, as well as the suppression of expression, signaling and stability of AR. GRT is a potential adjuvant therapeutic agent for enzalutamide-resistant PCa.

Purpose: Deficiencies in methionine sulfoxide reductase (MSR) enzymes, which function as a defense system against oxidative stress, have been linked to age-related diseases, including cancer and neurodegenerative diseases. This study aimed to assess the association between genetic variants in MSR genes and susceptibility to renal cell carcinoma (RCC). Materials and methods: We systematically evaluated the effects of 89 common MSR gene polymorphisms on the risk of developing RCC in a cohort of 630 patients and controls. Furthermore, publicly available gene expression datasets were used to analyze gene expression and patient prognosis. Results: After adjusting for covariates and multiple testing corrections, MSRA rs56198596 and rs11782000 showed significant associations with the risk of RCC. Analysis of expression quantitative trait loci indicated that the risk alleles of these 2 variants tended to correlate with reduced MSRA expression. Pooled analyses of 19 kidney cancer gene expression datasets revealed that RCC exhibited lower MSRA expression than did normal tissues (P < 0.001) and that higher MSRA expression was associated with improved patient prognosis (P < 0.001). Conclusion: These findings suggest that MSRA gene variants may affect the risk of RCC, highlighting the potential protective role of MSRA and its contribution to a favorable RCC prognosis. [ABSTRACT FROM AUTHOR]

Abstract The aberrant expression of cell adhesion molecules is a hallmark of epithelial‐to‐mesenchymal transition, resulting in the transformation of cancer cells to a more aggressive phenotype. This study investigated the association between genetic variants in cell adhesion pathways and the prognosis of patients with prostate cancer following radical prostatectomy (RP). A total of 18 haplotype‐tagging single‐nucleotide polymorphisms (SNPs) in eight cancer‐related adhesion molecules were genotyped in 458 prostate cancer patients, followed by the replication of the top SNPs in an additional set of 185 patients. Log‐rank test and multivariate Cox regression analysis adjusted for covariates were used to evaluate associations with the risk of biochemical recurrence (BCR) after RP. In the discovery set, four SNPs in CDH2 were marginally associated with BCR. Among these, CDH2 rs643555C > T was found to be associated with BCR in the replication set. Patients with rs643555TT genotype had a significantly shorter BCR‐free survival compared with those with CC/CT genotypes in the combined analysis (adjusted hazard ratio 1.78, 95% confidence interval 1.19‐2.67, P = 0.005). Additional analyses revealed that rs643555T was associated with higher expression of CDH2, and upregulated CDH2 was correlated with tumor aggressiveness and shortened BCR‐free survival. In conclusion, rs643555C > T affects CDH2 expression, and thus influences BCR in localized prostate cancer patients treated with RP. CDH2 rs643555 may be a promising biomarker to identify patients at high risk of poor prostate cancer prognosis.

Abstract Background To determine the association between circadian pathway genetic variants and the risk of prostate cancer progression. Methods We systematically evaluated 79 germline variants in nine circadian pathway genes in a cohort of 458 patients with localized prostate cancer as the discovery phase. We then replicated the significant findings in another cohort of 324 men with more advanced disease. The association of each variant with prostate cancer progression was evaluated by a log-rank test and Cox regression. Results A single nucleotide polymorphism of the neuronal PAS domain protein 2 (NPAS2) gene (rs6542993 A>T) was found to be associated with a significantly higher risk of disease progression in both localized (P = 0.001) and advanced (P = 0.039) prostate cancer cases. In silico analysis revealed decreased expression levels of NPAS2 in carriers of the T allele of rs6542993 compared with those carrying the A allele. Consistently, downregulation of NPAS2 expression was associated with more aggressive prostate cancer and poor progression-free survival (log-rank P = 0.002). Conclusions The NPAS2 rs6542993 polymorphism may be a promising biomarker, and may shed light on the pathways that govern prostate cancer progression.

Zerumbone is a natural product isolated from the pinecone or shampoo ginger, Zingiber zerumbet (L.) Smith, which has a wide range of pharmacological activities, including anti-inflammatory effects. However, the effects of zerumbone on activation of the NLRP3 inflammasome in macrophages have not been examined. This study aimed to examine the effects of zerumbone on LPS-induced inflammatory responses and NLRP3 inflammasome activation using murine J774A.1 cells, murine peritoneal macrophages, and murine bone marrow-derived macrophages. Cells were treated with zerumbone following LPS or LPS/ATP treatment. Production of nitric oxide (NO) was measured by Griess reagent assay. The levels of IL-6, TNF-α, and IL-1β secretion were analyzed by ELISA. Western blotting analysis was performed to determine the expression of inducible NO synthase (iNOS), COX-2, MAPKs, and NLRP3 inflammasome-associated proteins. The activity of NF-κB was determined by a promoter reporter assay. The assembly of NLRP3 was examined by immunofluorescence staining and observed by confocal laser microscopy. Our experimental results indicated that zerumbone inhibited the production of NO, PGE2 and IL-6, suppressed the expression of iNOS and COX-2, repressed the phosphorylation of ERK, and decreased the activity of NF-κB in LPS-activated J774A.1 cells. In addition, zerumbone suppressed the production of IL-1β and inhibited the activity of NLRP3 inflammasome in LPS/ATP- and LPS/nigericin-activated J774A.1 cells. On the other hand, we also found that zerumbone repressed the production of NO and proinflammatory cytokines in LPS-activated murine peritoneal macrophages and bone marrow-derived macrophages. In conclusion, our experimental results demonstrate that zerumbone effectively attenuates the LPS-induced inflammatory response in macrophages both in vitro and ex vivo by suppressing the activation of the ERK-MAPK and NF-κB signaling pathways as well as blocking the activation of the NLRP3 inflammasome. These results imply that zerumbone may be beneficial for treating sepsis and inflammasome-related diseases.

In response to a variety of stresses, mammalian cells activate the inflammasome for targeted caspase-dependent pyroptosis. The research community has recently begun to deduce that the activation of inflammasome is instigated by several known oncogenic stresses and metabolic perturbations; nevertheless, the role of inflammasomes in the context of cancer biology is less understood. In manipulating the expression of inflammasome, researchers have found that NLRP3 serves as a deterministic player in conducting tumor fate decisions. Understanding the mechanistic underpinning of pro-tumorigenic and anti-tumorigenic pathways might elucidate novel therapeutic onco-targets, thereby providing new opportunities to manipulate inflammasome in augmenting the anti-tumorigenic activity to prevent tumor expansion and achieve metastatic control. Accordingly, this review aims to decode the complexity of NLRP3, whereby summarizing and clustering findings into cancer hallmarks and tissue contexts may expedite consensus and underscore the potential of the inflammasome in drug translation.

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

Objective: The use of 10–12-core systemic transrectal ultrasound (TRUS)-guided prostate biopsy protocols with extended-sampling has been an optimizing strategy for diagnosis of prostate cancer. In this study, we aim to examine the cancer detection rate (CDR) and the complications following prostate biopsy at our institution. Materials and Methods: We retrospectively reviewed medical data of patients who underwent TRUS-guided prostate biopsy between 2007 and 2013 at our institution. The pathological outcomes, major complications, and morbidities were recorded and assessed clinically. Results: During the study period, 425 patients who underwent TRUS-guided prostate biopsy were enrolled. The mean age of the participants was 67.9 years. Overall, 75 (17.6%) patients were diagnosed with prostate cancer. Cancer was detected in 0% (0/10), 7.0% (15/215), 16.5% (20/121), and 50.6% (40/79) of patients in the subgroups with patient prostate-specific antigen (PSA) 20 ng/ml, respectively. The optimal cutoff values of PSA density were 0.19, 0.29, and 0.78 in the subgroups with patient PSA 4–10 ng/ml, 10–20 ng/ml, and >20 ng/ml. In total, 11 patients had afebrile urinary tract infections (UTI), 9 patients had febrile UTI, and another 2 patients had septic shock after biopsy. The overall incidence of infectious complications was 5.17% (22/425). Other complications were infrequent, consisting only of urinary retention in three patients, hematospermia in two patients, and acute hemorrhagic cerebellar infarction in 1 patient. Conclusion: Our study demonstrated the CDR, the incidence, and type of complications following TRUS-guided prostate biopsy. Further prospective studies are required to determine methods for reducing complications from prostate biopsy.

Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E2 (PGE2)), decreased the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), inhibited the activation of c-Jun amino-terminal kinase (JNK), p38 and nuclear factor-κB (NF-κB) signaling pathways, and repressed the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. These results indicated that mycotoxin ZEA attenuates macrophage-mediated innate immunity upon LPS stimulation, suggesting that the intake of mycotoxin ZEA-contaminated food might result in decreasing innate immunity, which has a higher risk of adverse effects during infection.

Radium-223 is a first-in-class α-emitting radiopharmaceutical that targets bone metastases associated with metastatic castration-resistant prostate cancer (mCRPC). In the pivotal phase III trial ALSYMPCA, radium-223 significantly increased overall survival (OS), compared with placebo (median 14.9 vs 11.3 months; hazard ratio 0.70; 95% CI 0.58–0.83; p

Abstract In addition to testosterone (T), the emerging role of sex hormone-binding globulin (SHBG) in pathogenesis of metabolic syndrome (MetS) has been noted recently. However, reports of associations with serum adipocytokine levels are still limited. Therefore, we conducted this study to evaluate whether serum T and SHBG levels are independent predictors for the risk of MetS that are associated with adiponectin and leptin levels in 614 Taiwanese men over 40 years old collected from a free health screening. Subjects in the lowest quartile of TT and SHBG levels are exposed to a 1.58 and 3.22 times risk of developing MetS, as compared to those in the highest quartile of TT and SHBG levels. However, SHBG retains its significance independent of TT as a MetS risk predictor, but not vice versa. In addition, SHBG was significantly correlated with both adiponectin and leptin levels even after adjusting for TT levels. In conclusion, SHBG served as a major predictor for the risk of MetS and was correlated with serum adiponectin and leptin levels that are independent of T. Further studies are needed to elucidate the true role of SHBG in the pathogenesis of MetS and possible mechanisms associated with serum adiponectin and leptin levels.

Objective: Nephroureterectomy with bladder cuff excision is the current gold standard for the treatment of upper-tract urothelial carcinoma (UTUC). Currently, routine follow-up cystogram is performed prior to Foley catheter removal to evaluate the bladder cuff excision wound. The aim of this study was to investigate the role of the postoperative cystogram in the bladder cuff excision procedure. Materials and methods: This was a retrospective study of 193 patients diagnosed with UTUC post nephroureterectomy and bladder cuff excision between January, 2010, and January, 2016. Patient demographics, performance of cystogram, types of bladder cuff excision, and postoperative outcomes were recorded. Patients were classified into two groups depending on whether or not routine postoperative cystogram was performed. Results: A total of 125 patients were included in this study and, of these, 102 patients underwent routine cystogram on Postoperative Day 7 (Group 1), while 23 patients underwent Foley catheter removal on Postoperative Day 7 without any imaging studies (Group 2). Univariate analysis showed no differences in age, sex, comorbidities, surgical approach, or stage of the primary tumor. No patient from either group had urinoma, pelvic abscesses, and tumor growth from bladder cuff wound was not observed in any patient within the 1-year postoperative follow-up period. Both groups of patients had a similar rate of postoperative urinary tract infections with sepsis (p = 0.639), time to Foley catheter removal (p = 0.630), time to drainage tube removal (p = 0.264), and length of hospitalization (p = 0.373). Conclusion: Foley catheter removal on Postoperative Day 7 after nephroureterectomy with bladder cuff excision without routine cystogram appears to be safe in the majority of the UTUC patients. A large, multi-institutional study is required before this method can be recommended for widespread clinical practice.

Piplartine (or Piperlongumine) is a natural alkaloid isolated from Piper longum L., which has been proposed to exhibit various biological properties such as anti-inflammatory effects; however, the effect of piplartine on sepsis has not been examined. This study was performed to examine the anti-inflammatory activities of piplartine in vitro, ex vivo and in vivo using murine J774A.1 macrophage cell line, peritoneal macrophages, bone marrow-derived macrophages and an animal sepsis model. The results demonstrated that piplartine suppresses iNOS and COX-2 expression, reduces PGE2, TNF-α and IL-6 production, decreases the phosphorylation of MAPKs and NF-κB and attenuates NF-κB activity by LPS-activated macrophages. Piplartine also inhibits IL-1β production and suppresses NLRP3 inflammasome activation by LPS/ATP- and LPS/nigericin-activated macrophages. Moreover, piplartine reduces the production of nitric oxide (NO) and TNF-α, IL-6 and IL-1β, decreases LPS-induced tissue damage, attenuates infiltration of inflammatory cells and enhances the survival rate. Collectively, these results demonstrate piplartine exhibits anti-inflammatory activities in LPS-induced inflammation and sepsis and suggest that piplartine might have benefits for sepsis treatment.

Neuregulins (NRGs) activate receptor tyrosine kinases of the ErbB family, and play essential roles in the proliferation, survival, and differentiation of normal and malignant tissue cells. We hypothesized that genetic variants of NRG signalling pathway genes may influence treatment outcomes in prostate cancer. To test this hypothesis, we performed a comprehensive analysis to evaluate the associations of 459 single-nucleotide polymorphisms in 19 NRG pathway genes with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in 630 patients with prostate cancer receiving androgen-deprivation therapy (ADT). After multivariate Cox regression and multiple testing correction, we found that NRG1 rs144160282 C > T is significantly associated with worsening CSS, OS, and PFS during ADT. Further analysis showed that low expression of NRG1 is closely related to prostate cancer, as indicated by a high Gleason score, an advanced stage, and a shorter PFS rate. Meta-analysis of 16 gene expression datasets of 1,081 prostate cancer samples and 294 adjacent normal samples indicate lower NRG1 expression in the former compared with the latter (p < 0.001). These results suggest that NRG1 rs144160282 might be a prognostic predictor of the efficacy of ADT. Further studies are required to confirm the significance of NRG1 as a biomarker and therapeutic target for prostate cancer.

Objective: The necessity of bone scans in newly diagnosed prostate cancer patients is still a matter of debate. We attempt to evaluate the validity of currently published guidelines by analyzing bone scan results in newly diagnosed prostate cancer (PCa) patients to determine the optimal staging strategies. Materials and methods: Between January 2011 and July 2014, there were 362 consecutive newly diagnosed PCa patients at Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Bone scans were performed for all patients at initial staging. Patients positive for bone metastasis were characterized at diagnosis in terms of age, prostate-specific antigen (PSA) level, Gleason score (GS), and clinical stage. We analyzed the sensitivity and specificity of the American Urological Association (AUA) best practice policy, European Association of Urology guidelines, National Comprehensive Cancer Network guidelines, and the classification and regression tree by Briganti et al for diagnostic performance in predicting bone metastasis. Results: A total 73 of 362 (20.2%) patients were diagnosed with bone metastasis. Patients positive for metastasis on bone scans had significantly higher PSA levels (median: 196.5 ng/mL, interquartile range: 904.3 vs. median: 18.5 ng/mL, interquartile range: 35.7; p

Upper tract urothelial carcinomas are tumors derived from urothelium along the urinary tract. Currently, there are no reliable biomarkers for their diagnosis or for prediction of tumor progression outcomes. It has a high incidence in Taiwanese populations at specific locations with exposure histories, and occurs relatively more frequent in the ureter than in the pyelocaliceal cavities. Radical nephroureterectomy with bladder cuff excision is the gold standard treatment for adequate local tumor control and better long-term survival. Despite optimal surgical treatment, the patient outcomes are still not satisfactory. An improved understanding of the biomolecular predictors is urgently needed to plan neoadjuvant/adjuvant therapy and proper follow-up strategies. In this study, a literature search was carried out through the PubMed database using the key words “upper tract urothelial carcinoma,” “prognostic factors,” and “outcome” from January 1985 to August 2015. The results showed that several preoperative clinical characteristics (such as chronic kidney disease, female sex, synchronous urothelial carcinoma of the bladder, and tumor location) and molecular markers (such as glutathione S-transferase, p53 protein, cyclooxygenase-2, TG-interacting factor, nuclear factor-kB, osteopontin, and hypoxia-inducible factor-1α) could serve as candidate biomarkers for the early detection of progression to upper tract urothelial carcinomas. Additional investigations of these results are required to resolve the gene combinations precisely and personalize the management of upper tract urothelial carcinomas.

Introduction: Docetaxel-based chemotherapy has been demonstrated to improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of this study is to analyze the possible prognostic factors associated with survival and to attract physicians' attention to high-risk patients. Material and methods: Thirty-nine consecutive patients with mCRPC who received docetaxel-based chemotherapy between July 2007 and November 2013 were enrolled in this study. The Kaplan–Meier curve was used to assess the association between prostate-specific antigen (PSA) response (defined as PSA level decreases ≥ 50%), and overall survival and cancer-specific survival. Cox regression analysis was performed to identify the independent significant predictors of overall survival and cancer-specific survival. Results: Twenty-one of the 39 patients (54%) experienced PSA response and the median overall survival was 13.51 months (range, 3–43 months). Patients with PSA response had longer time to PSA nadir level compared with patients without PSA response (p = 0.010). PSA response was an independent factor of overall survival and cancer-specific survival from Cox regression analysis (p = 0.014 and p = 0.05, respectively). In both univariate and multivariate analysis, cycles of chemotherapy, time to PSA nadir, and time to PSA progression were significant predictors for overall survival. Conclusion: The present study showed that PSA response demonstrated significance as a predictor for clinical outcome. However, Charlson comorbidity index (CCI) is not related to survival. A further prospective analysis is warranted.

In Taiwanese patients, carcinoma of the penis is an uncommon disease. We retrospectively reviewed potential prognostic factors in Taiwanese patients with invasive-penile squamous cell carcinoma (SCC). From 1997 to 2009, 52 patients were enrolled. The median patient age at diagnosis was 66.5 years and the peak incident occurred during the 6th and 7th decades of life. Thirteen patients (25%) died of penile cancer, with a mean follow-up time of 45 months (interquartile range: 15–64 months). The 5-year cumulative cancer-specific survival rate was 81%, with 100% for those with Stage I, 90% for those with Stage II, 60% for those with Stage III, and 14% for those with Stage IV. Eleven variables, including grade, tumor, node, metastasis (TNM) stage, involvement of corpus spongiosum or corpora cavernosa, lymphovascular or perineural invasion, lymphadenectomy, and palpable lymph node, with p

It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2) and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites) involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene combinations and personalize the management of prostate cancer.

Background/Aim: Oxidative stress plays an important role in various pathogenic processes, and disruption in the coordinated production of NADPH oxidase (NOX)-derived reactive oxygen species has been associated with carcinogenesis. However, little is known about whether genetic variants in NOX can contribute to the development of renal cell carcinoma (RCC). Patients and Methods: This study aimed to bridge this knowledge gap by analysing the association of 10 single-nucleotide polymorphisms in the phagocyte NOX genes, CYBA and CYBB, with RCC risk and tumour characteristics in 630 RCC patients and controls. Differential gene expression and patient prognosis analyses were performed using gene expression data obtained from public databases. Results: Multivariate analysis and multiple testing corrections revealed the A allele of rs7195830 in CYBA to be a significant risk allele for RCC, compared to the G allele [odds ratio (OR)=1.70, 95% confidence interval (CI)=1.27-2.26, p<0.001]. A pooled analysis of 17 renal cancer gene expression datasets revealed a higher CYBA expression in RCC than in normal tissues. Moreover, high CYBA expression was associated with advanced tumour characteristics and worse patient prognosis. Conclusion: CYBA might play an oncogenic role in RCC and serve as a predictive indicator of patient prognosis. [ABSTRACT FROM AUTHOR]

A 52-year-old male, diagnosed with paraganglioma of the urinary bladder, underwent transurethral resection of the bladder tumor 10 years ago. He was lost to follow-up after the operation but was recently admitted to our hospital for the treatment of nasopharyngeal cancer. However, refractory hypertension with palpitation was noted and a computed tomography scan revealed a round, well-defined mass at the right pelvic region. Retroperitoneal tumor excision surgery was performed and a subsequent pathological analysis revealed paraganglioma. The diagnosis of paraganglioma of the urinary bladder with pelvic metastasis was confirmed and his blood pressure returned to normal level without medication after the operation.