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

Design and Build of Swarm Quadrotor UAVs at UGS

At the University of Glasgow, we have been developing the swarm of autonomous micro-unmanned aerial vehicle (?-UAVs), as a part of team projects of the final yearproject design course: Aerospace Systems Design Project 4for our BEng in Aerospace Systems program. For our Singapore campus, where similar course is conducted, the platform chosen is the quadrotor. In this paper, we present the conceptual design, construction, flight test, swarm behaviour and lessons learnt

Flame-made amorphous solid acids with tunable acidity for the aqueous conversion of glucose to levulinic acid

Solid acids of amorphous silica-alumina (a-SA) and amorphous silica-alumina-phosphate (a-SAPO) were prepared by flame spray pyrolysis (FSP). Careful tuning of the acidity of the solid acids was enabled by capitalizing on the advantage of FSP in preserving the metal stoichiometry (i.e., Si, Al, P) in the product nanoparticles. Although the amount of acids on these non-porous solid acids is an order of magnitude lower than the well-recognized strong acidic ZSM-5 zeolite, both exhibit comparable acid strengths. The a-SA and a-SAPO were characterized by a mixture of Brønsted (B) and Lewis (L) acids, and the B/L ratios were composition-tunable. The highest B/L ratios were recorded for a-SA (Al/(Al + Si) = 0.4) and a-SAPO (Si/(P + Si) = 0.25), giving the highest yields of levulinic acid (≥40% carbon yield) from the conversion of glucose in the aqueous phase without requiring the addition of liquid acids or metal halides. Under the same conditions, the almost exclusive Brønsted acid ZSM-5 yielded only 17% levulinic acid. The FSP-made solid acid catalyst exhibited good reusability over at least 4 consecutive runs.ChemE/Catalysis Engineerin

COSMIC (Cohort Studies of Memory in an International Consortium): An international consortium to identify risk and protective factors and biomarkers of cognitive ageing and dementia in diverse ethnic and sociocultural groups.

International audienceBACKGROUND: A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders.Methods/design: Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress. DISCUSSION: The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing

Measurement of the diffractive cross-section in deep inelastic scattering

Diffractive scattering of $\gamma^* p \to X + N$, where $N$ is either a proton or a nucleonic system with $M_N~<~4$~GeV has been measured in deep inelastic scattering (DIS) at HERA. The cross section was determined by a novel method as a function of the $\gamma^* p$ c.m. energy $W$ between 60 and 245~GeV and of the mass $M_X$ of the system $X$ up to 15~GeV at average $Q^2$ values of 14 and 31~GeV$^2$. The diffractive cross section $d\sigma^{diff} /dM_X$ is, within errors, found to rise linearly with $W$. Parameterizing the $W$ dependence by the form d\sigma^{diff}/dM_X \propto (W^2)^{(2\overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} -2)} the DIS data yield for the pomeron trajectory \overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} = 1.23 \pm 0.02(stat) \pm 0.04 (syst) averaged over $t$ in the measured kinematic range assuming the longitudinal photon contribution to be zero. This value for the pomeron trajectory is substantially larger than \overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} extracted from soft interactions. The value of \overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} measured in this analysis suggests that a substantial part of the diffractive DIS cross section originates from processes which can be described by perturbative QCD. From the measured diffractive cross sections the diffractive structure function of the proton F^{D(3)}_2(\beta,Q^2, \mbox{x_{_{I\hspace{-0.2em}P}}}) has been determined, where $\beta$ is the momentum fraction of the struck quark in the pomeron. The form F^{D(3)}_2 = constant \cdot (1/ \mbox{x_{_{I\hspace{-0.2em}P}}})^a gives a good fit to the data in all $\beta$ and $Q^2$ intervals with $a = 1.46 \pm 0.04 (stat) \pmComment: 45 pages, including 16 figure

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