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Background: Development of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. MicroRNAs (miRNAs) are small regulatory RNAs that are involved in maintenance of cell homeostasis but are often altered in tumor cells., Results: In this study, we determined the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT. We used androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. We also show a correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells., Conclusions: We conclude that dynamic alterations in miRNA expression occur early on during androgen deprivation therapy, and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Furthermore our results can be used a prognostic marker of cancers with a potential to be resistant to ADT.

Background: ACCEPt, a large cluster randomized control trial, aims to determine if annual testing for 16 to 29 year olds in general practice can reduce chlamydia prevalence. ACCEPt is the first trial investigating the potential role of practice nurses (PN) in chlamydia testing. To inform the design of the ACCEPt intervention, we aimed to determine the chlamydia knowledge, attitudes, and testing practices of participating general practitioners (GPs) and PNs., Methods: GPs and PNs from 143 clinics recruited from 52 areas in 4 Australian states were asked to complete a survey at time of recruitment. Responses of PNs and GPs were compared using conditional logistic regression to account for possible intra cluster correlation within clinics., Results: Of the PNs and GPs enrolled in ACCEPt, 81% and 72% completed the questionnaire respectively. Less than a third of PNs (23%) and GPs (32%) correctly identified the two age groups with highest infection rates in women and only 16% vs 17% the correct age groups in men. More PNs than GPs would offer testing opportunistically to asymptomatic patients aged ≤25 years; women having a pap smear (84% vs 55%, P<0.01); antenatal checkup (83% vs 44%, P<0.01) and Aboriginal men with a sore throat (79% vs 33%, P<0.01), but also to patients outside of the guideline age group at the time of the survey; 26 year old males presenting for a medical check (78% vs 30%, P = <0.01) and 33 year old females presenting for a pill prescription (83% vs 55%, P<0.01). More PNs than GPs knew that retesting was recommended after chlamydia treatment (93% vs 87%, P=0.027); and the recommended timeframe was 3 months (66% vs 26%, P<0.01). A high proportion of PNs (90%) agreed that they could conduct chlamydia testing in general practice, with 79% wanting greater involvement and 89% further training., Conclusions: Our survey reveals gaps in chlamydia knowledge and management among GPs and PNs that may be contributing to low testing rates in general practice. The ACCEPt intervention is well targeted to address these and support clinicians in increasing testing rates. PNs could have a role in increasing chlamydia testing.

Introduction: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a pathogenic mechanism of depression, and genetic polymorphisms in HPA axis genes have been described to influence response to antidepressant drugs. In particular, two polymorphisms in FKBP5, a co-chaperone of the glucocorticoid receptor, were strongly associated with response to therapy. We aimed to analyze whether these findings could be reproduced in a different sample of otherwise comparable inpatients with major depression., Methods: Genotyping for the two variants within the FKBP5 gene was performed using PCR-restriction fragment length polymorphism and Taqman real-time PCR in a cohort of 179 inpatients who were monitored for the first 3 weeks of antidepressant drug treatment. The early response to antidepressant drugs was assessed as percentage of decline in Hamilton depression score after 3 weeks, responders versus nonresponders were distinguished by a 50% decrease., Results: The FKBP5 variants rs3800373 and rs1360780 were highly linked, and carriers of the FKBP5 variants had a trend towards a higher chance to respond (p = 0.04; odds ratio: 1.8; 95% CI: 0.98-3.3). When analyzing drug-specific subgroups, the effect was seen mainly in the subgroups of patients treated with antidepressant drug combinations or with venlafaxine., Conclusion: In this study, an effect of FKBP5 variants on antidepressant drug response was confirmed in an independent cohort of depressed patients; however, with an odds ratio of 1.8 the effect size was smaller than that described earlier.