Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

An Inspiring Journey of Hope and Persistence: Life Lessons with Françoise Barré-Sinoussi

Three early-career female virologists sat down with a distinguished Nobel laureate to discuss two pandemics, 39 years apart [...

Predicting and Preventing The Theft Of Electronic Products

The research presented within this paper was conducted as part of a two-year project (Project MARC) to develop and render operational a mechanism to assess the risk of theft of electronic products. Clarke and Newman (2002) proposed the use of two checklists – one to measure vulnerability the other to measure security, as a means of categorising products according to their vulnerability to theft. Consultation with key stakeholders yielded the common view that such a mechanism was worth pursuing, but that it must reflect the language of those who would use it. An extensive consultation with stakeholders from ten European member states ensued. Participants were asked to rate a range of electronic products in terms of vulnerability and security and to explain their ratings. Their responses were used to develop two checklists which incorporate a variety of factors, weighted according to the frequency with which they were expressed. The crime vulnerability checklist developed within this paper is judged fit for purpose as a provisional measurement but urge caution in relation to the security checklist

Design and Crime: Proofing Electronic Products and Services against Theft

This paper introduces the work of Project Marc (an EU funded project to develop Mechanisms for Assessing the Risk of Crime) and discusses both difficulties encountered throughout the project and progress made since the project ended. The authors introduce the papers contained within this special edition and summarise their relevance to crime proofing. The paper discusses progress made within this field in the decade prior to Project Marc and makes recommendations to ensure that the ideas move forward

Sustaining the crime reduction impact of designing out crime: Re-evaluating the Secured by Design scheme 10 years on

Secured by Design (SBD) is an award scheme that aims to encourage housing developers to design out crime at the planning or concept stage. The scheme is managed by the Association of Chief Police Officers Crime Reduction Initiatives (ACPO CPI) while the day-to-day delivery of the scheme is conducted by Architectural Liaison Officers (ALOs) or Crime Prevention Design Advisors (CPDAs) working for individual police forces throughout the United Kingdom. The scheme sets standards for compliance that developments must meet to be awarded SBD status. This article presents the findings of research conducted over a 10-year period (1999–2009) into the effectiveness of the SBD scheme as a crime reduction measure. Utilising a variety of methods, the research aims to establish whether residents living within SBD developments experience less crime and fear of crime than their non-SBD counterparts; whether SBD developments show less visual signs of crime and disorder than their non-SBD counterparts; and finally, whether properties built to the SBD standard are able to sustain any crime reduction benefits over a 10-year period

Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency.

BackgroundOne strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed.MethodsWe quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat.FindingsIn total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA.InterpretationFollowing administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal.FundingNHMRC, NIH DARE collaboratory

Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency.

BackgroundOne strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed.MethodsWe quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat.FindingsIn total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA.InterpretationFollowing administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal.FundingNHMRC, NIH DARE collaboratory