Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Developmental expression of DCC in the rat retina

The protein product of the deleted in colorectal cancer (DCC) gene possesses netrin-binding activity and may be involved in axonal guidance during retinal development. The temporal and spatial expression of DCC was analyzed in developing rat retina by means of immunoblotting and immunohistochemistry as well as by reverse transcription-polymerase chain reaction. Transient DCC protein expression is evident on ganglion cell axons in embryonic and neonatal retina. Double labeling experiments demonstrate DCC immunolabeling on processes that stratify in the inner plexiform layer and are derived from cholinergic amacrine cells. This pattern is maintained during the early postnatal period. DCC immunolabeling in the inner plexiform layer declines with age and is not observed in adult retina. The down-regulation of the DCC protein is confirmed by Western blot analysis. mRNA for DCC is expressed in embryonic, postnatal and adult retina and shows no correlation with the protein down-regulation. We suggest that DCC expression may be correlated with the functional segregation of the inner plexiform layer

Characterization, Analysis, and Recommendations for Exploiting the Opportunities of Cyber-Physical Systems

Leveraging on a comprehensive analysis of cyber-physical systems (CPSs) in Europe, this chapter presents overall findings focusing on (1) a characterization of CPS, (2) opportunities and challenges in representative CPS application domains, and (3) recommendations for action resulting from a cross-domain analysis. The characterization enables a high-level description of a CPS, or classes of CPS, according to their technical emphasis, cross-cutting aspects, level of automation, and life-cycle integration. We illustrate how these characteristics can be used to relate to design issues, systems, and related terms.The recommendations are to: (1) strengthen cross-disciplinary research collaboration, (2) foster CPS education and training, (3) stimulate public-private partnerships for CPS technology experimentation and to ensure dependable information and communication technology (ICT) infrastructure, (4) promote interoperability of CPS technology, (5) anticipate new business models and support open innovation, (6) ensure trustworthiness including safety and security, and (7) favor human-centered approaches to CPS.  QC 20171129</p

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH.

Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3–q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2–q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development

Thromboprophylaxis in emergency surgery

Except for hip fracture surgery, emergency surgery has been only exceptionally studied concerning thromboprophylaxis. There are, however, several reasons to believe the frequency to be fairly high and that the patient group would be in need of prophylaxis. This paper discusses various emergency situations and also gives the design for an ongoing controlled study on the effect of postoperative start of thromboprophylaxis with low molecular weight heparin in emergency abdominal surgery