Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

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

Phytotoxicity of silver nanoparticles on Vicia faba: evaluation of particle size effects on photosynthetic performance and leaf gas exchange

Nanotechnology is an emerging field in science and engineering, which presents significant impacts on the economy, society and the environment. The nanomaterials’ (NMs) production, use, and disposal is inevitably leading to their release into the environment where there are uncertainties about its fate, behaviour, and toxicity. Recent works have demonstrated that NMs can penetrate, translocate, and accumulate in plants. However, studies about the effects of the NMs on plants are still limited because most investigations are carried out in the initial stage of plant development. The present study aimed to evaluate and characterize the photochemical efficiency of photosystem II (PSII) of broad bean (Vicia faba) leaves when subjected to silver nanoparticles (AgNPs) with diameters of 20, 51, and 73 nm as well as to micrometer-size Ag particles (AgBulk). The AgNPs were characterized by transmission electron microscopy and dynamic light scattering. The analyses were performed by injecting the leaves with 100 mg L-1 aqueous solution of Ag and measuring the chlorophyll fluorescence imaging, gas exchange, thermal imaging, and reactive oxygen species (ROS) production. In addition, silver ion (Ag+) release from Ag particles was determined by dialysis. The results revealed that AgNPs induce a decrease in the photochemical efficiency of photosystem II (PSII) and an increase in the non-photochemical quenching. The data also revealed that AgNPs affected the stomatal conductance (gs) and CO2 assimilation. Further, AgNPs induced an overproduction of ROS in Vicia faba leaves. Finally, all observed effects were particle diameter-dependent, increasing with the reduction of AgNPs diameter and revealing that AgBulk caused only a small or no changes on plants. In summary, the results point out that AgNPs may negatively affect the photosynthesis process when accumulated in the leaves, and that the NPs themselves were mainly responsible since negligible Ag+ release was detected

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

Defining Advance Care Planning for Adults: A Consensus Definition From a Multidisciplinary Delphi Panel

Context Despite increasing interest in advance care planning (ACP) and previous ACP descriptions, a consensus definition does not yet exist to guide clinical, research, and policy initiatives. Objective The aim of this study was to develop a consensus definition of ACP for adults. Methods We convened a Delphi panel of multidisciplinary, international ACP experts consisting of 52 clinicians, researchers, and policy leaders from four countries and a patient/surrogate advisory committee. We conducted 10 rounds using a modified Delphi method and qualitatively analyzed panelists’ input. Panelists identified several themes lacking consensus and iteratively discussed and developed a final consensus definition. Results Panelists identified several tensions concerning ACP concepts such as whether the definition should focus on conversations vs. written advance directives; patients’ values vs. treatment preferences; current shared decision making vs. future medical decisions; and who should be included in the process. The panel achieved a final consensus one-sentence definition and accompanying goals statement: “Advance care plannin