Dasatinib targets c-Src kinase in cardiotoxicity.

Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.

Non-Gaussian Tail of the Curvature Perturbation in Stochastic Ultraslow-Roll Inflation: Implications for Primordial Black Hole Production.

We consider quantum diffusion in ultraslow-roll (USR) inflation. Using the ΔN formalism, we present the first stochastic calculation of the probability distribution P(R) of the curvature perturbation during USR. We capture the nonlinearity of the system, solving the coupled evolution of the coarse-grained background with random kicks from the short wavelength modes, simultaneously with the mode evolution around the stochastic background. This leads to a non-Markovian process from which we determine the highly non-Gaussian tail of P(R). Studying the production of primordial black holes in a viable model, we find that stochastic effects during USR increase their abundance by a factor of ∼10^{5} compared with the Gaussian approximation.

Antipsychotic Use and the Risk of Initiating Medication for Benign Prostate Hyperplasia in Persons With Alzheimer Disease: A Matched Cohort Study.

BACKGROUND: Antipsychotics (APs) are known to exacerbate symptoms of benign prostate hyperplasia (BPH) and may even cause urinary retention. The anticholinergic effects of APs and their dopamine D2- and α-receptor blockade may lead to voiding dysfunction of BPH patients. The objective of our study was to investigate whether the use of APs is associated with an increased risk of initiating medication for BPH in men with Alzheimer disease (AD). METHODS: Data from the nationwide MEDALZ (MEDication use and ALZheimer's disease) cohort, including all community-dwelling persons diagnosed with AD in Finland, were utilized. Register-based data included medication dispensing, comorbidities, and hospital discharge diagnoses. Men who initiated APs (n = 4579) were 1:1 matched with men who did not initiate APs (n = 4579), according to time since AD diagnoses and age. The risk of starting BPH medication was investigated with Cox regression. RESULTS: Among AP users, BPH medication was initiated to 345 persons (7.5%). Antipsychotic use was not associated with risk of initiating BPH medication (comorbidity-adjusted hazard ratio, 0.92; 95% confidence interval, 0.74-1.15) compared with no use of APs. In addition, no risk was found when AP drug substances were analyzed separately. CONCLUSIONS: Use of APs did not increase the risk of initiating medication for BPH in men with AD.

Increased Peroxiredoxin 6 Expression Predicts Biochemical Recurrence in Prostate Cancer Patients After Radical Prostatectomy.

BACKGROUND/AIM: Elevated levels of oxidative stress biomarkers have been shown to associate with more aggressive behavior in malignancies. The aim of the present study was to determine the relationship between the expression of peroxiredoxins (Prx) and sulfiredoxin (Srx) in localized prostate cancer (PC) with clinicopathological parameters and outcome after radical prostatectomy (RP). MATERIALS AND METHODS: Samples of 240 RP patients were analyzed for Prx1, 2, 5 and 6 and Srx expression by immunohistochemistry and the results were correlated with clinicopathological data, biochemical recurrence-free survival (BFS), prostate cancer-specific survival (PCS) and overall survival (OS). RESULTS: Augmented Prx2 and Prx6 expression was associated with several conventional prognostic factors. Increased Prx2 and Prx6 expression predicted for shortened BFS (p=0.027 and p=0.020) and worse OS (p=0.045 and p=0.033). In the multivariate analysis, Prx6 expression was an independent predictor of BFS (p=0.030). CONCLUSION: Elevated Prx6 expression associates with a worse prognosis after RP for clinically localized PC.

TWIST overexpression predicts biochemical recurrence-free survival in prostate cancer patients treated with radical prostatectomy.

OBJECTIVE: The aim of this study was to determine whether TWIST and androgen receptor (AR) expression can predict the outcome in radical prostatectomy (RP) patients. MATERIAL AND METHODS: Samples from different tumour areas of 181 prostate cancer patients were analysed for TWIST and AR expression, and the results were correlated with known clinicopathological data and biochemical recurrence-free survival (BFS). RESULTS: TWIST overexpression in the margin area of the tumour (M-TWIST) was related to positive surgical margin (p = 0.047), capsule invasion (p = 0.006) and biochemical recurrence (BCR) (p = 0.004). AR expression in the margin area of the tumour (M-AR) was associated with high Gleason score (p = 0.004), positive surgical margin (p = 0.004) and BCR (p = 0.05). M-TWIST overexpression was clearly associated with M-AR expression (p < 0.0001). Four parameters, i.e. M-TWIST overexpression (p < 0.0001), positive surgical margin (p = 0.003), high Gleason score (p < 0.0001) and M-AR expression (p = 0.008), predicted BFS. In the multivariate analysis, M-TWIST overexpression (p = 0.011) and Gleason score (p = 0.002) were the only independent predictors of BFS. CONCLUSIONS: M-TWIST overexpression is associated with clinicopathological prognosis factors and M-AR overexpression and is a powerful independent predictor of BFS in conjunction with the Gleason score in prostate cancer patients treated with RP.

Increased nuclear factor erythroid 2-related factor 2 expression predicts worse prognosis of prostate cancer patients treated with radical prostatectomy.

Reactive oxygen species are known to be linked with cell damage leading to carcinogenesis. Augmented levels of oxidative stress biomarkers, such as nuclear factor erythroid 2-related factor 2 (Nrf-2) and 8-hydroxydeoxyguanosine (8-OHDG), have been shown to associate with more aggressive behavior in many malignancies. The aim of this study was to determine whether Nrf-2 and 8-OHDG expression could predict the outcome in radical prostatectomy patients. Samples of 240 prostate cancer patients were analyzed for Nrf-2 and 8-OHDG expression by immunohistochemistry. The results were compared with clinicopathological data, biochemical recurrence-free survival (BFS), prostate cancer-specific survival, and overall survival (OS). Positive expression of 8-OHDG (P < .0001), Nrf-2 in cytoplasm (c-Nrf-2) (P = .015), and Nrf-2 in nucleus (n-Nrf-2) (P = .016) was more abundant in malignant tissue compared with benign, respectively. Elevated level of c-Nrf-2 expression was associated with positive surgical marginal (P = .005), extraprostatic extension (P = .031), biochemical recurrence (BCR) (P = .030), and OS (P = .002); and n-Nrf-2 expression was associated with pathologic stage class (P = .001), Gleason score (P = .026), extraprostatic extension (P = .027), BCR (P = .037), and OS (P < .0001). The increased c-Nrf-2 expression predicted shortened BFS (P = .034) and worse OS (P = .017). In the multivariate analysis, c-Nrf-2 (P = .028 and P = .019) and Gleason score (P = .001 and P = .033) were independent predictors of BFS and OS, respectively. Expression of the analyzed biomarkers was not linked with prostate cancer-specific survival. Expression of 8-OHDG was not associated with any clinicopathological factors or survival. These results reveal that increased c-Nrf-2 expression is a predictor of BFS and OS in conjunction with Gleason score in prostate cancer patients treated with radical prostatectomy.