Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.

This was a retrospective, cross-sectional analysis using the Medtronic Discovery Link database. 7 All patients with CRT pacing enabled that transmitted data before September 21, 2011, were screened for inclusion. The CRT devices with the latest pacing diagnostics (eg, Concerto, Concerto II, Consulta, Protecta, Protecta XT, and Syncra; Medtronic Inc, Minneapolis, MN) were included. Patients without an atrial lead were excluded. For each patient, data were collected through remote telemetry, with information directly transferred to the Medtronic CareLink network. The information was deidentified and entered in the Discovery Link database. The most recent data transmission that included at least 24 hours of monitoring was selected for analysis. Background-The efficacy of cardiac resynchronization therapy (CRT) is associated with the amount of CRT pacing delivered. The specific causes of CRT pacing loss and their relative frequencies remain poorly defined. Methods and Results-CRT patients who transmitted device data from 2006 to 2011 were screened for inclusion. Device diagnostics were analyzed using an automated algorithm to categorize CRT loss into 10 different causes. The algorithm was validated against manual adjudications using a portion of the entire cohort. There were 80 768 patients analyzed with a median time of 594 (interquartile range, 294-1003) days from implant to time of analysis. In this cohort, 40.7% of patients had <98% pacing, and 11.5% of patients had <90% pacing. For patients with <98% pacing, device diagnostics explained 55.8% of pacing loss: 30.6% atrial tachycardia/atrial fibrillation; 16.6% premature ventricular contractions; and 8.6% captured as episodes with at least 10 consecutive beats of CRT loss (ventricular sensing episodes). Inappropriately programmed sensed and paced atrioventricular (AV) intervals (SAV/PAV) accounted for 34.5% of all ventricular sensing episodes. As the severity of CRT loss increased, the contribution of atrial tachycardia/atrial fibrillation and SAV/PAV to the loss increased. Atrial tachycardia/atrial fibrillation accounted for >50% and premature ventricular contractions accounted for <10% of CRT loss in those with <90% CRT pacing. Conclusions-CRT pacing <98% was observed in 40.7% of patients. Among those with suboptimal pacing, atrial tachycardia/ atrial fibrillation was the most common reason for CRT pacing loss. Inappropriately programmed SAV/PAV intervals was the most common reason for episodes of sustained loss of CRT pacing. This information can help in defining more effective treatments to improve CRT delivery. (Circ Arrhythm Electrophysiol. 2012;5:884-888.)

BackgroundHuman immunodeficiency virus type 2 (HIV-2) is often distinguished clinically by lower viral loads, reduced transmissibility, and longer asymptomatic periods than for human immunodeficiency virus type 1 (HIV-1). Differences in the mutation frequencies of HIV-1 and HIV-2 have been hypothesized to contribute to the attenuated progression of HIV-2 observed clinically.ResultsTo address this hypothesis, we performed Illumina sequencing of multiple amplicons prepared from cells infected with HIV-1 or HIV-2, resulting in ~4.7 million read pairs and the identification of ~200,000 mutations after data processing. We observed that: (1) HIV-2 displayed significantly lower total mutation, substitution, and transition mutation frequencies than that of HIV-1, along with a mutation spectrum markedly less biased toward G-to-A transitions, (2) G-to-A hypermutation consistent with the activity of APOBEC3 proteins was observed for both HIV-1 and HIV-2 despite the presence of Vif, (3) G-to-A hypermutation was significantly higher for HIV-1 than for HIV-2, and (4) HIV-1 and HIV-2 total mutation frequencies were not significantly different in the absence of G-to-A hypermutants.ConclusionsTaken together, these data demonstrate that HIV-2 exhibits a distinct mutational spectrum and a lower mutation frequency relative to HIV-1. However, the observed differences were primarily due to reduced levels of G-to-A hypermutation for HIV-2. These findings suggest that HIV-2 may be less susceptible than HIV-1 to APOBEC3-mediated hypermutation, but that the fidelities of other mutational sources (such as reverse transcriptase) are relatively similar for HIV-1 and HIV-2. Overall, these data imply that differences in replication fidelity are likely not a major contributing factor to the unique clinical features of HIV-2 infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0180-6) contains supplementary material, which is available to authorized users.

A long-standing question of human immunodeficiency virus (HIV) genetic variation and evolution has been whether differences exist in mutation rate and/or mutation spectra among HIV types (i.e., HIV-1 versus HIV-2) as well as among HIV groups (i.e., HIV-1 groups M-P and HIV-2 groups A-H) and HIV-1 Group M subtypes (i.e., subtypes A-D, F-H, and J-K). To address this, a new single-strand consensus sequencing assay was developed for the determination of HIV mutation frequencies and spectra using the Illumina sequencing platform. This assay enables parallel and standardized comparison of HIV mutagenesis among various viral vectors with lower background error than traditional methods of Illumina library preparation. We found significant differences in viral mutagenesis between HIV types but intriguingly no significant differences among HIV-1 Group M subtypes. More specifically, HIV-1 exhibited higher transition frequencies than HIV-2, due mostly to single G-to-A mutations and (to a lesser extent) G-to-A hypermutation. These data suggest that HIV-2 RT exhibits higher fidelity during viral replication, and, taken together, these findings demonstrate that HIV type but not subtype significantly affects viral mutation frequencies and spectra. These differences may inform antiviral and vaccine strategies.