Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case–control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case–control GWAS are also associated with disease risk in HPC families

Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease

Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p≤1E−3) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may be contribute risk to aggressive disease

Robotic Laparoscopic Pyeloplasty

International audienceBackground and Objectives:We aimed to assess the feasibility and outcomes of complex ureteropelvic junction obstruction cases submitted to robotic-assisted laparoscopic pyeloplasty.Methods:The records of 131 consecutive patients who underwent robotic-assisted laparoscopic pyeloplasty were reviewed. Of this initial population of cases, 17 were considered complex, consisting of either atypical anatomy (horseshoe kidneys in 3 patients) or previous ureteropelvic junction obstruction management (14 patients). The patients were divided into 2 groups: primary pyeloplasty (group 1) and complex cases (group 2).Results:The mean operative time was 117.3 ± 33.5 minutes in group 1 and 153.5 ± 31.1 minutes in group 2 (P = .002). The median hospital stay was 5.19 ± 1.66 days in group 1 and 5.90 ± 2.33 days in group 2 (P = .326). The surgical findings included 53 crossing vessels in group 1 and 5 in group 2. One patient in group 1 required conversion to open surgery because of technical difficulties. One patient in group 2, with a history of hemorrhagic rectocolitis, presented with peritonitis postoperatively due to a small colonic injury. A secondary procedure was performed after the patient had an uneventful recovery. At 3 months, significant improvement (clinical and radiologic) was present in 93% of cases in group 1 and 88.2% in group 2. At 1 year, all patients in group 2 showed satisfactory results. At a late follow-up visit, 1 patient in group 1 presented with a recurrent obstruction.Conclusions:Robotic pyeloplasty appear to be feasible and effective, showing a consistent success rate even in complex situations. Particular care should be observed during the colon dissection in patients with previous colonic pathology

Biomietic membranes and biomolecule immobilisation strategies for nanobiotechnology applications

International audienceBiological membranes constitute a source of inspiration for making supramolecular assemblies which can be used in the design of biomimetic sensors. At the same time, the concept of using biomolecules as an elementary structure to develop self-assembled entities has received considerable attention. More particularly, the ability of amphiphilic molecules like lipids, to spontaneously organise into bilayers, is suitable to achieve biomimetic membrane models. The potential of two-dimensional molecular self-assemblies is clearly illustrated by Langmuir monolayers of lipids formed at an air/water interface, which can be used as models to acquire knowledge about the molecular recognition process occurring in biological membranes. Langmuir-Blodgett (LB) technology, based on the transfer of this interfacial monomolecular film onto a solid support, allows building up lamellar lipid stack, with an accurate control of thickness and molecular organisation. This technique offers the possibility to prepare ultrathin layers suitable for biomolecule immobilisation. We are presenting herein an overview of work performed in our group that sheds light on the formation of biomimetic LB membranes associating protein in a well-defined orientation. Two points will be addressed: investigations of protein/lipid interactions using lipid monolayers as membrane models and biosensing applications. The objectives are to highlight advantages of interfacial Langmuir monolayers and supported Langmuir-Blodgett films to investigate molecular interactions between biomolecules and lipid membrane components or to elaborate biomimetic membranes as sensing layers, respectively. The present paper also draws a general picture of non-conventional methods for biomolecule immobilisation and their applications for biochip developments. The technologies presented are based either on original solid supports or on innovative immobilisation processes. First, ''Macromolecules to PDMS transfer'' technique relying on the direct entrapment of macromolecules spots during PDMS polymerisation is proposed as an alternative for the easy and simple PDMS surface modification. Then, the electro-addressing of biomolecule-aryl diazonium adducts at the surface of conducting biochips will be presented and shown to be an interesting alternative to immobilisation processes based on surface functionalisation

A new functional membrane protein microarray based on tethered phospholipid bilayers

International audienc

Standardized multidisciplinary method for the evaluation of the effectiveness of malaria control interventions

International audienc

Standardized multidisciplinary method for the evaluation of the effectiveness of malaria control interventions

International audienc

Durability of the deltamethrin-treated polypropylene long-lasting net LifeNet® in a pyrethroid resistance area in south western Benin: A phase III trial

International audienceBackground: Long-lasting insecticidal bed nets (LLINs) are a key measure for preventing malaria and their evaluation is coordinated by the World Health Organization Pesticide Evaluation Scheme (WHOPES). LifeNet ® was granted WHOPES time-limited interim recommendation in 2011 after successful Phase I and Phase II evaluations. Here, we evaluated the durability and community acceptance of LifeNet ® in a Phase III trial from June 2014 to June 2017 in Benin rural area.Methods: A prospective longitudinal, cluster-randomized, controlled trial with households as the unit of observation was designed to assess the performance of LifeNet® over a three-year period, using a WHOPES fully recommended LLIN (PermaNet® 2.0) as a positive control. The primary outcomes were the bioassay performance using WHO cone assays and tunnel tests, the insecticide content and physical integrity.Results: At baseline, 100% of LLINs were within the tolerance limits of their target deltamethrin concentrations. By 36 months only 17.3% of LifeNet® and 8.5% of PermaNet® LLINs still were within their target deltamethrin concentrations. Despite these low rates, 100% of both LLINs meet WHO efficacy criteria (≥ 80% mortality or ≥ 95% knockdown or tunnel test criteria of ≥ 80% mortality or ≥ 90% blood-feeding inhibition) after 36 months using WHO cone bio-assays and tunnel tests. The proportion of LLINs in good physical condition was 33% for LifeNet® and 29% for PermaNet® after 36 months. After 36 M the survivorship was 21% and 26% for LifeNet® and PermaNet® respectively. Although both LLINs were well accepted by the population, complaints of side effects were significantly higher among LifeNet® users than PermaNet® ones.Conclusion: LifeNet® LLINs did meet WHO criteria for bio-efficacy throughout the study period and were well accepted by the population. This is an important step towards getting a full WHO recommendation for use in malaria endemic countrie

Survivorship of LifeNet and PermaNet LLINs.

BackgroundLong-lasting insecticidal bed nets (LLINs) are a key measure for preventing malaria and their evaluation is coordinated by the World Health Organization Pesticide Evaluation Scheme (WHOPES). LifeNet® was granted WHOPES time-limited interim recommendation in 2011 after successful Phase I and Phase II evaluations. Here, we evaluated the durability and community acceptance of LifeNet® in a Phase III trial from June 2014 to June 2017 in Benin rural area.MethodsA prospective longitudinal, cluster-randomized, controlled trial with households as the unit of observation was designed to assess the performance of LifeNet® over a three-year period, using a WHOPES fully recommended LLIN (PermaNet® 2.0) as a positive control. The primary outcomes were the bioassay performance using WHO cone assays and tunnel tests, the insecticide content and physical integrity.ResultsAt baseline, 100% of LLINs were within the tolerance limits of their target deltamethrin concentrations. By 36 months only 17.3% of LifeNet® and 8.5% of PermaNet® LLINs still were within their target deltamethrin concentrations. Despite these low rates, 100% of both LLINs meet WHO efficacy criteria (≥ 80% mortality or ≥ 95% knockdown or tunnel test criteria of ≥ 80% mortality or ≥ 90% blood-feeding inhibition) after 36 months using WHO cone bio-assays and tunnel tests. The proportion of LLINs in good physical condition was 33% for LifeNet® and 29% for PermaNet® after 36 months. After 36 M the survivorship was 21% and 26% for LifeNet® and PermaNet® respectively. Although both LLINs were well accepted by the population, complaints of side effects were significantly higher among LifeNet® users than PermaNet® ones.ConclusionLifeNet® LLINs did meet WHO criteria for bio-efficacy throughout the study period and were well accepted by the population. This is an important step towards getting a full WHO recommendation for use in malaria endemic countries.</div