A novel steroidal antiandrogen targeting wild type and mutant androgen receptors

Prostate cancer (PCa) progression is enhanced by androgen and treatment with antiandrogens represents an alternative to castration. While patients initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years by expressing androgen receptor (AR) mutants. Such mutations, indeed, promote unfavorable agonistic behavior from classical antagonists. Here, we have synthesized and screened 37 novel compounds derived from dihydrotestosterone (DHT), cyanolutamide and hydroxyflutamide. These derivatives were tested for their potential antagonistic activity using a luciferase reporter gene assay and binding properties were determined for wild type (WT) and mutant ARs (T877A, W741C, W741L, H874Y). In the absence and presence of antiandrogens, androgen dependent cellular proliferation and prostate specific antigen (PSA) expression were assayed in the prostate cancer cell line LNCaP by crystal violet, real time PCR and by Western blots. Also, cellular proliferation and PSA expression were assayed in 22Rv1. A novel compound RB346, derived from DHT, was found to be an antagonist for all tested AR forms, preventing DHT induced proliferation and PSA expression in LNCaP and 22Rv1 cells. RB346 displayed no agonistic activity, in contrast to the non-steroidal antiandrogen bicalutamide (Casodex) with unfavorable agonistic activity for W741L-AR. Additionally, RB346 has a slightly higher binding affinity for WT-AR, T877A-AR and H874Y-AR than bicalutamide. Thus, RB346 is the first potent steroidal antiandrogen with efficacy for WT and various AR mutants.

Acute type A aortic dissection and pregnancy: a population-based study

Pregnancy has been reported to be an independent risk factor for 50% of acute aortic dissections recorded in women younger than 45 years of age. The present epidemiologic study aimed to identify whether this putative association of pregnancy and acute type A dissection could be an artifact of selective reporting.

Experimental acute type B aortic dissection: different sites of primary entry tears cause different ways of propagation

Many dissections seem to also have a retrograde component. The aim of the study was to evaluate different sites of primary entry tears and the propagation of the dissecting membrane, antegrade and retrograde, in an experimental model of acute type B aortic dissection.

Association between cam-type deformities and magnetic resonance imaging-detected structural hip damage: a cross-sectional study in young men

Objective Femoroacetabular impingement may be a risk factor for hip osteoarthritis in men. An underlying hip deformity of the cam type is common in asymptomatic men with nondysplastic hips. This study was undertaken to examine whether hip deformities of the cam type are associated with signs of hip abnormality, including labral lesions and articular cartilage damage, detectable on magnetic resonance imaging (MRI). Methods In this cross-sectional, population-based study in asymptomatic young men, 1,080 subjects underwent clinical examination and completed a self-report questionnaire. Of these subjects, 244 asymptomatic men with a mean age of 19.9 years underwent MRI. All MRIs were read for cam-type deformities, labral lesions, cartilage thickness, and impingement pits. The relationship between cam-type deformities and signs of joint damage were examined using logistic regression models adjusted for age and body mass index. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. Results Sixty-seven definite cam-type deformities were detected. These deformities were associated with labral lesions (adjusted OR 2.77 [95% CI 1.31, 5.87]), impingement pits (adjusted OR 2.9 [95% CI 1.43, 5.93]), and labral deformities (adjusted OR 2.45 [95% CI 1.06, 5.66]). The adjusted mean difference in combined anterosuperior femoral and acetabular cartilage thickness was −0.19 mm (95% CI −0.41, 0.02) lower in those with cam-type deformities compared to those without. Conclusion Our findings indicate that the presence of a cam-type deformity is associated with MRI-detected hip damage in asymptomatic young men.

Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells

Rhinoviruses are important triggers of pulmonary exacerbations and possible contributors to long-term respiratory morbidity in cystic fibrosis (CF), but mechanisms leading to rhinovirus-induced CF exacerbations are poorly understood. It is hypothesised that there is a deficient innate immune response of the airway epithelium towards rhinovirus infection in CF.

A new mechanism by which an acute type B aortic dissection is primarily complicated, becomes complicated, or remains uncomplicated

This study is to evaluate if different locations of the primary entry tear result in primary complicated, secondary complicated, or uncomplicated acute type B aortic dissection.

Repair of stent graft-induced retrograde type A aortic dissection using the E-vita open prosthesis

Stent graft-induced retrograde type A dissection is a life-threatening complication after endovascular treatment of acute aortic type B dissections.

Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations

Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.

Hexose-6-phosphate dehydrogenase modulates 11beta-hydroxysteroid dehydrogenase type 1-dependent metabolism of 7-keto- and 7beta-hydroxy-neurosteroids

BACKGROUND: The role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in the regulation of energy metabolism and immune system by locally reactivating glucocorticoids has been extensively studied. Experiments determining initial rates of enzyme activity revealed that 11beta-HSD1 can catalyze both the reductase and the dehydrogenase reaction in cell lysates, whereas it predominantly catalyzes the reduction of cortisone to cortisol in intact cells that also express hexose-6-phosphate dehydrogenase (H6PDH), which provides cofactor NADPH. Besides its role in glucocorticoid metabolism, there is evidence that 11beta-HSD1 is involved in the metabolism of 7-keto- and 7-hydroxy-steroids; however the impact of H6PDH on this alternative function of 11beta-HSD1 has not been assessed. METHODOLOGY: We investigated the 11beta-HSD1-dependent metabolism of the neurosteroids 7-keto-, 7alpha-hydroxy- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) and 7-keto- and 7beta-hydroxy-pregnenolone, respectively, in the absence or presence of H6PDH in intact cells. 3D-structural modeling was applied to study the binding of ligands in 11beta-HSD1. PRINCIPAL FINDINGS: We demonstrated that 11beta-HSD1 functions in a reversible way and efficiently catalyzed the interconversion of these 7-keto- and 7-hydroxy-neurosteroids in intact cells. In the presence of H6PDH, 11beta-HSD1 predominantly converted 7-keto-DHEA and 7-ketopregnenolone into their corresponding 7beta-hydroxy metabolites, indicating a role for H6PDH and 11beta-HSD1 in the local generation of 7beta-hydroxy-neurosteroids. 3D-structural modeling offered an explanation for the preferred formation of 7beta-hydroxy-neurosteroids. CONCLUSIONS: Our results from experiments determining the steady state concentrations of glucocorticoids or 7-oxygenated neurosteroids suggested that the equilibrium between cortisone and cortisol and between 7-keto- and 7-hydroxy-neurosteroids is regulated by 11beta-HSD1 and greatly depends on the coexpression with H6PDH. Thus, the impact of H6PDH on 11beta-HSD1 activity has to be considered for understanding both glucocorticoid and neurosteroid action in different tissues.