Secondhand smoke increases the risk of developing chronic obstructive pulmonary disease.

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.

Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation.

One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS (P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression.

Integrated analysis identifies GABRB3 as a biomarker in prostate cancer.

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 < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. CONCLUSION: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted.

EGFR-mediated hyperacetylation of tubulin induced docetaxel resistance by downregulation of HDAC6 and upregulation of MCAK and PLK1 in prostate cancer cells.

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, ß-tubulin, γ-tubulin, and ßIII-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.

CYBA as a Potential Biomarker for Renal Cell Carcinoma: Evidence from an Integrated Genetic Analysis.

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.

The impact of secondhand smoke on the development of kidney stone disease is not inferior to that of smoking: a longitudinal cohort study.

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).

Nordalbergin Exerts Anti-Neuroinflammatory Effects by Attenuating MAPK Signaling Pathway, NLRP3 Inflammasome Activation and ROS Production in LPS-Stimulated BV2 Microglia.

Microglia-associated neuroinflammation is recognized as a critical factor in the pathogenesis of neurodegenerative diseases; however, there is no effective treatment for the blockage of neurodegenerative disease progression. In this study, the effect of nordalbergin, a coumarin isolated from the wood bark of Dalbergia sissoo, on lipopolysaccharide (LPS)-induced inflammatory responses was investigated using murine microglial BV2 cells. Cell viability was assessed using the MTT assay, whereas nitric oxide (NO) production was analyzed using the Griess reagent. Secretion of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) was detected by the ELISA. The expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, mitogen-activated protein kinases (MAPKs) and NLRP3 inflammasome-related proteins was assessed by Western blot. The production of mitochondrial reactive oxygen species (ROS) and intracellular ROS was detected using flow cytometry. Our experimental results indicated that nordalbergin ≤20 µM suppressed NO, IL-6, TNF-α and IL-1ß production; decreased iNOS and COX-2 expression; inhibited MAPKs activation; attenuated NLRP3 inflammasome activation; and reduced both intracellular and mitochondrial ROS production by LPS-stimulated BV2 cells in a dose-dependent manner. These results demonstrate that nordalbergin exhibits anti-inflammatory and anti-oxidative activities through inhibiting MAPK signaling pathway, NLRP3 inflammasome activation and ROS production, suggesting that nordalbergin might have the potential to inhibit neurodegenerative disease progression.

Anticancer Effects of Morusin in Prostate Cancer via Inhibition of Akt/mTOR Signaling Pathway.

Prostate cancer (PCa) is the second most prevalent cancer in men worldwide. The majority of PCa incidences eventually progress to castration-resistant PCa (CRPC), thereby establishing an urgent need for new effective therapeutic strategies. This study aims to examine the effects of morusin, a prenylated flavonoid isolated from Morus alba L., on PCa progression and identify the regulatory mechanism of morusin. Cell growth, cell migration and invasion, and the expression of EMT markers were examined. Cycle progression and cell apoptosis were examined using flow cytometry and a TUNEL assay, while transcriptome analysis was performed using RNA-seq with results being further validated using real-time PCR and western blot. A xenograft PCa model was used to examine tumor growth. Our experimental results indicated that morusin significantly attenuated the growth of PC-3 and 22Rv1 human PCa cells; moreover, morusin significantly suppressed TGF-[Formula: see text]-induced cell migration and invasion and inhibited EMT in PC-3 and 22Rv1 cells. Significantly, morusin treatment caused cell cycle arrest at the G2/M phase and induced cell apoptosis in PC-3 and 22Rv1 cells. Morusin also attenuated tumor growth in a xenograft murine model. The results of RNA-seq indicated that morusin regulated PCa cells through the Akt/mTOR signaling pathway, while our western blot results confirmed that morusin suppressed phosphorylation of AKT, mTOR, p70S6K, and downregulation of the expression of Raptor and Rictor in vitro and in vivo. These results suggest that morusin has antitumor activities on regulating PCa progression, including migration, invasion, and formation of metastasis, and might be a potential drug for CRPC treatment.

Darolutamide for non-metastatic castration-resistant prostate cancer: Efficacy, safety, and clinical perspectives of use.

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.

ATP8B1: A prognostic prostate cancer biomarker identified via genetic analysis.

BACKGROUND: Controlling the asymmetric distribution of phospholipids across biological membranes plays a pivotal role in the life cycle of cells; one of the most important contributors that maintain this lipid asymmetry are phospholipid-transporting adenosine triphosphatases (ATPases). Although sufficient information regarding their association with cancer exists, there is limited evidence linking the genetic variants of phospholipid-transporting ATPase family genes to prostate cancer in humans. METHODS: In this study, we investigated the association of 222 haplotype-tagging single-nucleotide polymorphisms (SNPs) in eight phospholipid-transporting ATPase genes with cancer-specific survival (CSS) and overall survival (OS) of 630 patients treated with androgen-deprivation therapy (ADT) for prostate cancer. RESULTS: After multivariate Cox regression analysis and multiple testing correction, we found that ATP8B1 rs7239484 was remarkably associated with CSS and OS after ADT. A pooled analysis of multiple independent gene-expression datasets demonstrated that ATP8B1 was under-expressed in tumor tissues and that a higher ATP8B1 expression was associated with a better patient prognosis. Moreover, we established highly invasive sublines using two human prostate cancer cell lines to mimic cancer progression traits in vitro. The expression of ATP8B1 was consistently downregulated in both highly invasive sublines. CONCLUSION: Our study indicates that rs7239484 is a prognostic factor for patients treated with ADT and that ATP8B1 can potentially attenuate prostate cancer progression.

Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer.

Enzalutamide and Quality of Life in Prostate CancerFreedland et al. present the health-related quality of life outcomes for patients with biochemically recurrent prostate cancer who were randomly assigned to enzalutamide plus leuprolide, enzalutamide monotherapy, or leuprolide alone (EMBARK trial). The key objectives were to determine differences in time to first and confirmed clinically meaningful deterioration in pain and time to first and confirmed clinically meaningful deterioration in functional status. There were no differences among the key outcomes among all three groups.

Protodioscin inhibits bladder cancer cell migration and growth, and promotes apoptosis through activating JNK and p38 signaling pathways.

Bladder cancer is one of the most common malignancies of the male genitourinary urinary system. Protodioscin is a steroidal saponin with anti-cancer effects on several types of cancers; however, the anti-cancer activities of protodioscin on bladder cancer have not yet been investigated. Therefore, we aimed to examine the anti-cancer effects of protodioscin on bladder cancer. Two types of bladder cancer cell lines, non-muscle-invasive 5637 cells and muscle-invasive T24 cells, were used to evaluate the effects of protodioscin on cell growth, migration, invasion and epithelial-mesenchymal transition(EMT) marker expressions. Transcriptome analysis was performed by RNA-seq and validated using real-time PCR and western blot; additionally, an in vivo xenograft animal model was established and the anti-tumor effects of protodioscin were tested. Our results demonstrated that protodioscin inhibited cell proliferation, migration, motility and invasion on 5637 and T24 cells. Additionally, protodioscin also induced cell apoptosis and arrested the progression of cell cycle at G2 phase in bladder cancer cells. Moreover, protodioscin inhibited EMT through increased protein expression of E-cadherin and decreased protein expression of N-cadherin and vimentin. RNA-seq analysis indicated that protodioscin regulated mitogen-activated protein kinase(MAPK) and phosphoinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR) signaling pathways as further verified by Western blot. Furthermore, protodioscin significantly inhibited tumor growth in vivo. Our results indicated that protodioscin inhibits cell growth, migration and invasion and induces apoptosis and G2 phase cell cycle arrest by activated p38 and JNK signaling pathways in bladder cancer cells, suggesting that protodioscin could be an effective agent for bladder cancer treatment.

Genetic Analysis Implicates Dysregulation of SHANK2 in Renal Cell Carcinoma Progression.

SH3 and multiple ankyrin repeat domains (SHANK) is a family of scaffold proteins that were first identified to be involved in balancing synaptic transmission via regulation of intracellular signalling crosstalk and have been linked to various cancers. However, the role of the SHANK genes in renal cell carcinoma (RCC) remains to be elucidated. In this study, we aimed to evaluate whether genetic variants in SHANK family genes affect the risk of RCC and survival of patients. A genetic association study was conducted using logistic regression and Cox regression analyses, followed by the correction for a false discovery rate (FDR), in 630 patients with RCC and controls. A pooled analysis was further performed to summarise the clinical relevance of SHANK gene expression in RCC. After adjustment for known risk factors and the FDR, the SHANK2 rs10792565 T allele was found to be associated with an increased risk of RCC (adjusted odds ratio = 1.79, 95% confidence interval = 1.32-2.44, p = 1.96 × 10-4, q = 0.030), whereas no significant association was found with RCC survival. A pooled analysis of 19 independent studies, comprising 1509 RCC and 414 adjacent normal tissues, showed that the expression of SHANK2 was significantly lower in RCC than in normal tissues (p < 0.001). Furthermore, low expression of SHANK2 was correlated with an advanced stage and poor prognosis for patients with clear cell and papillary RCC. This study suggests that SHANK2 rs10792565 is associated with an increased risk of RCC and that SHANK2 may play a role in RCC progression.

Aspalathus linearis suppresses cell survival and proliferation of enzalutamide-resistant prostate cancer cells via inhibition of c-Myc and stability of androgen receptor.

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.

TNFRSF13B is a potential contributor to prostate cancer.

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.

Novel insights into the anti-cancer effects of 3-bromopyruvic acid against castration-resistant prostate cancer.

3-bromopyruvic acid (3-BP), a small molecule alkylating agent, has been emerged as a glycolytic inhibitor with anticancer activities. However, the effects of 3-BP on the growth and metastasis in prostate cancer have not been well investigated. Here we investigated the anti-cancer effects of 3-BP on prostate cancer in vitro and in vivo. Cell growth, apoptosis, migration, motility, and invasion were examined. The tumor growth ability was determined using a xenograft murine model. Transcriptome analysis using RNA-seq was performed to explore the mechanism of action of 3-BP. Our experimental results showed that 3-BP effectively inhibits prostate cancer cell growth, especially in castration-resistant prostate cancer (CRPC) cells. Moreover, 3-BP induces apoptosis and suppresses cell migration, motility, epithelial-mesenchymal transition (EMT), and invasion in CRPC cells. In addition, 3-BP also attenuates tumor growth in a xenograft murine model. Through transcriptome analysis using RNA-seq, 3-BP significantly regulates the cell cycle pathway and decreases the expression of downstream cycle cycle-associated genes in CRPC cells. The results of cell cycle analysis indicated that 3-BP arrests cell cycle progression at G2/M in CRPC cells. These results suggest that 3-BP has the potential in inhibiting CRPC progression and might be a promising drug for CRPC treatment.

Enzalutamide in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Asian Multiregional, Randomized Study.

INTRODUCTION: Enzalutamide significantly improved clinical outcomes compared with placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with disease progression despite androgen deprivation therapy (ADT) in the PREVAIL study. However, few patients from Asia were enrolled. Our study (NCT02294461) aimed to evaluate the safety and efficacy of enzalutamide in this disease setting in patients in mainland China, Korea, Taiwan, and Hong Kong. METHODS: In this double-blind, phase III study, patients with asymptomatic/mildly symptomatic metastatic prostate cancer and disease progression despite ADT were randomized to enzalutamide (160 mg/day) or placebo. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included overall survival, radiographic progression-free survival, time to first skeletal-related event (SRE), time to initiation of cytotoxic chemotherapy, PSA response ≥ 50%, best overall soft-tissue response, and safety. Pre-planned interim analysis was scheduled following approximately 175 PSA-progression events (67% of targeted total of 261 events). An additional 5-year landmark analysis of overall survival, time to antineoplastic therapy, and safety was performed. RESULTS: The double-blind study period was stopped after interim analysis owing to the benefit of enzalutamide over placebo. Overall, 388 patients were randomized (enzalutamide, n = 198; placebo, n = 190). Baseline characteristics were balanced between treatment groups. Enzalutamide significantly reduced risk of PSA progression vs placebo (hazard ratio 0.38; 95% CI 0.27-0.52; P < 0.0001). Median time to PSA progression was 8.31 months with enzalutamide and 2.86 months with placebo. Secondary endpoints, including 5-year overall survival, were significantly improved with enzalutamide, except time to first SRE. Adverse-event incidence was similar between enzalutamide and placebo. Fatigue was the most common drug-related adverse event in both treatment groups. CONCLUSION: Enzalutamide significantly reduced risk of PSA progression, improved secondary efficacy endpoints, and was well tolerated in chemotherapy-naïve Asian patients with mCRPC with disease progression despite ADT. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT02294461.

Identification of a Steroid Hormone-Associated Gene Signature Predicting the Prognosis of Prostate Cancer through an Integrative Bioinformatics Analysis.

The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, we sought to identify core genes in regulating steroid hormone pathways and associating them with the disease progression of PC. The selection of steroid hormone-associated genes was identified from functional databases, including gene ontology, KEGG, and Reactome. The gene expression profiles and relevant clinical information of patients with PC were obtained from TCGA and used to examine the genes associated with steroid hormone. The machine-learning algorithm was performed for key feature selection and signature construction. With the integrative bioinformatics analysis, an eight-gene signature, including CA2, CYP2E1, HSD17B, SSTR3, SULT1E1, TUBB3, UCN, and UGT2B7 was established. Patients with higher expression of this gene signature had worse progression-free interval in both univariate and multivariate cox models adjusted for clinical variables. The expression of the gene signatures also showed the aggressiveness consistently in two external cohorts, PCS and PAM50. Our findings demonstrated a validated eight-gene signature could successfully predict PC prognosis and regulate the steroid hormone pathway.

Association of Warmer Weather and Infectious Complications Following Transrectal Ultrasound-Guided Prostate Biopsy.

The seasonal and meteorological factors in predicting infections after urological interventions have not been systematically evaluated. This study aimed to determine the seasonality and the effects of the weather on the risk and severity of infectious complications (IC) after a transrectal ultrasound-guided prostate biopsy (TRUS-Bx). Using retrospectively collected data at the tertiary care hospital in Taiwan, we investigated the seasonal and meteorological differences in IC after TRUS-Bx. The IC included urinary tract infection (UTI), sepsis, and a positive culture finding (PCF). The severity was assessed on the basis of the Common Terminology Criteria for Adverse Events grading system. The prevalences of the infectious complications (UTI, sepsis, PCF and grade ≥ 3 IC) were significantly higher in the summer than in the winter. Monthly temperature and average humidity were significant factors for IC. After adjusting the demographic factors, multivariate regression revealed that UTI, sepsis, PCF, and grade ≥ 3 IC increased by 12.1%, 16.2%, 21.3%, and 18.6% for every 1 °C increase in the monthly average temperature, respectively (UTI: p = 0.010; sepsis: p = 0.046; PCF: p = 0.037; grade ≥ 3 IC: p = 0.021). In conclusion, the development and severity of IC after TRUS-Bx had significant seasonality. These were dose-dependently associated with warmer weather. Infectious signs after TRUS-Bx should be monitored more closely and actively during warm weather.

Genetic Analysis Reveals the Prognostic Significance of the DNA Mismatch Repair Gene MSH2 in Advanced Prostate Cancer.

DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63-0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings.