A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth

The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA

Development and characterization of bladder cancer patient- derived xenografts for molecularly guided targeted therapy

10.1371/journal.pone.0134346PLoS ONE108e013434

Time course and recovery of arterial blood gases during exacerbations in adults with Cystic Fibrosis

AbstractIntroductionHypoxia and hypercapnia are closely linked to morbidity and mortality in patients with Cystic Fibrosis (CF). The aims of this study were to describe the changes in blood gases during and following an acute pulmonary exacerbation in adults with CF.MethodsWe performed a prospective observational study of patients with CF admitted for management of an acute exacerbation. Blood gas and spirometric analysis was performed on admission, throughout the treatment period, and 31 days after discharge (day 45).ResultsAt presentation, eight of nineteen patients had evidence of either hypoxia (PaO2<8 kPa) and/or hypercapnia (PaCO2>6.6 kPa). Blood gas parameters stabilized following two weeks of intravenous antibiotic therapy, with little difference evident in between treatment completion and subsequent review following discharge. Hypercapnia reversed in three patients, with persistent hypercapnia evident in two patients.ConclusionIn our study group, hypoxemia and hypercapnia were frequently observed at presentation of the acute exacerbation. Blood gases stabilized following two weeks of intravenous antibiotic therapy, with arterial PCO2 one month following hospital discharge generally similar to that at time of discharge