Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Process for manufacturing carbon fiber composite structures by membrane-assisted compression molding

The main objectives of this research work are to find new ways of reducing costs in the manufacture of composite materials, automate processes and improve energy efficiency by looking for alternatives to the use of autoclave, always meeting the quality requirements. For this, an out of autoclave curing process is studied through an innovative system of automatic and fast curing of composite parts for the aeronautic, automotive and construction sectors. The process allows the curing of prepregs of various materials and geometries. The process includes the provision of temperature by heating plate with electric resistances, pressure and vacuum adjustable through an air compressor, and cooling through circuit through mechanized plates. The main innovative feature of this system is the pressure supply with compressed air to the piece by means of a moldable and reusable silicone membrane, which allows to extend the field of study to complex elements saving the current limitation of hot plates presses, and without the need to place countermold. CFRP cured parts are manufactured in this new system, then their properties are compared with autoclave cured parts and similar properties are obtained, and auxiliary materials are considerably reduced. It can be concluded that this system improves energy efficiency, reduces costs and optimizes times

The effects of longitudinal chromatic aberration and a shift in the peak of the middle-wavelength sensitive cone fundamental on cone contrast.

Longitudinal chromatic aberration is a well-known imperfection of visual optics, but the consequences in natural conditions, and for the evolution of receptor spectral sensitivities are less well understood. This paper examines how chromatic aberration affects image quality in the middle-wavelength sensitive (M-) cones, viewing broad-band spectra, over a range of spatial frequencies and focal planes. We also model the effects on M-cone contrast of moving the M-cone fundamental relative to the long- and middle-wavelength (L- and M-cone) fundamentals, while the eye is accommodated at different focal planes or at a focal plane that maximizes luminance contrast. When the focal plane shifts towards longer (650 nm) or shorter wavelengths (420 nm) the effects on M-cone contrast are large: longitudinal chromatic aberration causes total loss of M-cone contrast above 10-20 c/d. In comparison, the shift of the M-cone fundamental causes smaller effects on M-cone contrast. At 10 c/d a shift in the peak of the M-cone spectrum from 560 to 460 nm decreases M-cone contrast by 30%, while a 10 nm blue-shift causes only a minor loss of contrast. However, a noticeable loss of contrast may be seen if the eye is focused at focal planes other than that which maximizes luminance contrast. The presence of separate long- and middle-wavelength sensitive cones therefore has a small, but not insignificant cost to the retinal image via longitudinal chromatic aberration. This aberration may therefore be a factor limiting evolution of visual pigments and trichromatic color vision

Patterns of Physical Activity Progression in Patients With COPD [Patrones de progresión de la actividad física en pacientes con EPOC]

Introduction: Although mean physical activity in COPD patients declines by 400–500 steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to identify distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants. Methods: We pooled data from two cohorts (usual care arm of Urban Training [NCT01897298] and PROactive initial validation [NCT01388218] studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns. Results: In 291 COPD patients (mean ± SD 68 ± 8 years, 81% male, FEV1 59 ± 19%pred) we identified three distinct physical activity progression patterns: Inactive (n = 173 [59%], baseline: 4621 ± 1757 steps/day, 12-month change (Δ): −487 ± 1201 steps/day), Active Improvers (n = 49 [17%], baseline: 7727 ± 3275 steps/day, Δ: + 3378 ± 2203 steps/day) and Active Decliners (n = 69 [24%], baseline: 11 267 ± 3009 steps/day, Δ: −2217 ± 2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR [95% CI] 0.94 [0.90–0.98] per 10 m, P =.001) and a higher mMRC dyspnea score (1.71 [1.12–2.60] per 1 point, P =.012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver. Conclusions: The natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline. © 2020 SEPA

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

International audienceGenome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes