Outcomes of prostate cancer screening among men using antidiabetic medication

Diabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference=0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08-1.60 and HR 1.55, 95% CI 1.44-1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8-10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14-1.07 and HR 0.19, 95% CI 0.11-0.33 among users and non-users after three screens, respectively. P for difference=0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors.Peer reviewe

Prostate cancer prognosis after initiation of androgen deprivation therapy among statin users. A population-based cohort study

Purpose Statins' cholesterol-lowering efficacy is well-known. Recent epidemiological studies have found that inhibition of cholesterol synthesis may have beneficial effects on prostate cancer (PCa) patients, especially patients treated with androgen deprivation therapy (ADT). We evaluated statins' effect on prostate cancer prognosis among patients treated with ADT. Materials and methods Our study population consisted of 8253 PCa patients detected among the study population of the Finnish randomized study of screening for prostate cancer. These were limited to 4428 men who initiated ADT during the follow-up. Cox proportional regression model adjusted for tumor clinical characteristics and comorbidities was used to estimate hazard ratios for risk of PSA relapse after ADT initiation and prostate cancer death. Results During the median follow-up of 6.3 years after the ADT initiation, there were 834 PCa deaths and 1565 PSA relapses in a study cohort. Statin use after ADT was associated with a decreased risk of PSA relapse (HR 0.73, 95% CI 0.65-0.82) and prostate cancer death (HR 0.82; 95% CI 0.69-0.96). In contrast, statin use defined with a one-year lag (HR 0.89, 95% CI 0.76-1.04), statin use before ADT initiation (HR 1.12, 95% CI 0.96-1.31), and use in the first year on ADT (HR 1.02, 95% CI 0.85-1.24) were not associated with prostate cancer death, without dose dependency. Conclusion Statin use after initiation of ADT, but not before, was associated with improved prostate cancer prognosis.Peer reviewe

Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction

Introduction: Erectile dysfunction (ED) is strongly associated with physiological and metabolic disturbances, and hyperuricemia has been proposed to predict the onset of ED.Aim: To investigate if hyperuricemia is an independent predictor for ED when all relevant confounding factors are taken into account.Methods: This is a cross-sectional study of men aged between 45 and 70 years. The population was well characterized for established cardiovascular risk factors, metabolic syndrome, as well as kidney function, depression, and socioeconomic factors. Analysis was limited to 254 men with complete data and also serum uric acid (SUA) measurements were available. This included 150 men with and 104 without ED. The presence and severity of ED was evaluated using International Index of Erectile Function-5 questionnaire. Risk of ED by SUA level was calculated using univariate and multivariable-adjusted logistic regression. Effect modification by participant characteristics were evaluated in subgroup analyses.Main outcome measures: The main outcome measures of this study are prevalence and severity of erectile dysfunction.Results: Patients with ED (59% of the study population) were older than men without ED (59 vs 54 years) and had lower serum testosterone (14.3, 95% CI 11.3-17.3 vs 15.1 nmol/l, 95% CI 12.1-18.8, respectively). Regarding all other variables, the groups were comparable. No significant difference was found for SUA by ED. SUA was not associated with ED risk in univariate or multivariable analysis (multivariable-adjusted OR 1.14, 95% CI 0.59-2.19, P = .7) for SUA level higher than median compared with median or lesser (OR 1.00, 95% CI 0.997-1.006, P = .7 for continuous variable). No subgroup analysis modified the association. After multivariable adjustment age, education level and depression were statistically significant predictors of ED.Conclusions: Elevated SUA was not found to be an independent risk factor for ED. Metabolic syndrome, glomerular filtration rate, or cardiovascular risk factors did not modify this result. ED cannot be predicted based on the level of SUA. A Tuokko, T Murtola, P Korhonen, et al. Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction.</p

Prostate cancer risk among users of digoxin and other antiarrhythmic drugs in the Finnish Prostate Cancer Screening Trial

Peer reviewe

Cleavage of pyrene-stabilized RNA bulge loops by trans-(±)-cyclohexane-1,2-diamine

Chemical agents that cleave HIV genome can be potentially used for anti-HIV therapy. In this report, the cleavage of the upper stem-loop region of HIV-1 TAR RNA was studied in a variety of buffers containing organic catalysts. trans-(±)-Cyclohexane-1,2-diamine was found to cleave the RNA with the highest activity (31%, 37°C, 18 h). Cleavage of the RNA in trans-(±)-cyclohexane-1,2-diamine buffer was also studied when the RNA was hybridized with complementary DNAs. A pyrene-modified C3 spacer was incorporated to the DNA strand to facilitate the formation of a RNA bulge loop in the RNA/DNA duplex. In contrast, unmodified DNAs cannot efficiently generate RNA bulge loops, regardless of the DNA sequences. The results showed that the pyrene-stablized RNA bulge loops were efficiently and site-specifically cleaved by trans-(±)-cyclohexane-1,2-diamine

Cancer origin tracing and timing in two high-risk prostate cancers using multisample whole genome analysis: prospects for personalized medicine

BACKGROUND: Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. METHODS: We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and distinguish metastatic and non-metastatic subclones. RESULTS: In patient GP5, CDK12 inactivation was among the first mutations, leading to a PrCa tandem duplicator phenotype and initiating the cancer around age 50, followed by rapid cancer evolution after age 57, and metastasis around age 59, 5 years prior to prostatectomy. In patient GP12, accelerated cancer progression was detected after age 54, and metastasis occurred around age 56, 3 years prior to prostatectomy. Multiple metastasis-originating events were identified in each patient and tracked anatomically. Metastasis from prostate to lymph nodes occurred strictly ipsilaterally in all 12 detected events. In this pilot, metastatic subclone content analysis appears to substantially enhance the identification of key drivers. Evolutionary analysis' potential impact on therapy selection appears positive in these pilot cases. CONCLUSIONS: PrCa evolutionary analysis allows tracking of anatomic site of origin, timing of cancer origin and spread, and distinction of metastatic-capable from non-metastatic subclones. This enables better identification of actionable targets for therapy. If extended to larger cohorts, it appears likely that similar analyses could add substantial biological insight and clinically relevant value

Parameterization of a coarse-grained model of cholesterol with point-dipole electrostatics

© 2018, Springer Nature Switzerland AG. We present a new coarse-grained (CG) model of cholesterol (CHOL) for the electrostatic-based ELBA force field. A distinguishing feature of our CHOL model is that the electrostatics is modeled by an explicit point dipole which interacts through an ideal vacuum permittivity. The CHOL model parameters were optimized in a systematic fashion, reproducing the electrostatic and nonpolar partitioning free energies of CHOL in lipid/water mixtures predicted by full-detailed atomistic molecular dynamics simulations. The CHOL model has been validated by comparison to structural, dynamic and thermodynamic properties with experimental and atomistic simulation reference data. The simulation of binary DPPC/cholesterol mixtures covering the relevant biological content of CHOL in mammalian membranes is shown to correctly predict the main lipid behavior as observed experimentally