Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

3D scan to product design: Methods, techniques, and cases

3D scanning technology has derived great opportunities for ergonomic product designs. This paper is aimed to introduce various research cases and methods based on 3D scanning have conducted by an ergonomics laboratory in South Korea. Sizing systems and representative 3D models developed on anthropometric measurements and 3D scan images with technical know-how were applied to the design of various products. Head, face, ear, upper limb, and waist parts, and full body in seated were anthropometrically analyzed for the design of headwear (e.g., helmet, goggle, and headphone), oxygen mask, earphone, arm-wear (e.g., watch, armband), hip protector, and vehicle seat, Customized software for the efficient analyses such as measurement of anthropometric dimensions, analysis of sizing systems, extraction of representative models, and virtual fit evaluation between products and the body were developed and applied in the product design process with massive 3D images. Representative models (e.g., torso and head) were printed in 3D for effective usage to the design and evaluation of related products. Advanced methods and techniques such as finite element modeling, morphing, and skin deformation have been applied to 3D scanned images for an advanced design of product shapes in further researches.Industrial DesignIndustrial Design Engineerin

Comparative assessment of pressure field reconstructions from particle image velocimetry measurements and Lagrangian particle tracking

A test case for pressure field reconstruction from particle image velocimetry (PIV) and Lagrangian particle tracking (LPT) has been developed by constructing a simulated experiment from a zonal detached eddy simulation for an axisymmetric base flow at Mach 0.7. The test case comprises sequences of four subsequent particle images (representing multi-pulse data) as well as continuous time-resolved data which can realistically only be obtained for low-speed flows. Particle images were processed using tomographic PIV processing as well as the LPT algorithm ‘Shake-The-Box’ (STB). Multiple pressure field reconstruction techniques have subsequently been applied to the PIV results (Eulerian approach, iterative least-square pseudo-tracking, Taylor’s hypothesis approach, and instantaneous Vortex-in-Cell) and LPT results (FlowFit, Vortex-in-Cell-plus, Voronoi-based pressure evaluation, and iterative least-square pseudo-tracking). All methods were able to reconstruct the main features of the instantaneous pressure fields, including methods that reconstruct pressure from a single PIV velocity snapshot. Highly accurate reconstructed pressure fields could be obtained using LPT approaches in combination with more advanced techniques. In general, the use of longer series of time-resolved input data, when available, allows more accurate pressure field reconstruction. Noise in the input data typically reduces the accuracy of the reconstructed pressure fields, but none of the techniques proved to be critically sensitive to the amount of noise added in the present test case.Aerodynamic

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics