| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. 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 promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Cordova, R., et al.
(författare)
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Dietary intake of advanced glycation end products (AGEs) and changes in body weight in European adults
- 2020
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Ingår i: European Journal of Nutrition. - : Springer Berlin/Heidelberg. - 1436-6207 .- 1436-6215. ; 59, s. 2893-2904
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Advanced glycation end products (AGEs) can be formed in foods by the reaction of reducing sugars with proteins, and have been shown to induce insulin resistance and obesity in experimental studies. We examined the association between dietary AGEs intake and changes in body weight in adults over an average of 5 years of follow-up.Methods: A total of 255,170 participants aged 25–70 years were recruited in ten European countries (1992–2000) in the PANACEA study (Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home in relation to Anthropometry), a sub-cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition). Body weight was measured at recruitment and self-reported between 2 and 11 years later depending on the study center. A reference database for AGEs was used containing UPLC–MS/MS-measured Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) in 200 common European foods. This reference database was matched to foods and decomposed recipes obtained from country-specific validated dietary questionnaires in EPIC and intake levels of CEL, CML, and MG-H1 were estimated. Associations between dietary AGEs intake and body weight change were estimated separately for each of the three AGEs using multilevel mixed linear regression models with center as random effect and dietary AGEs intake and relevant confounders as fixed effects.Results: A one-SD increment in CEL intake was associated with 0.111 kg (95% CI 0.087–0.135) additional weight gain over 5 years. The corresponding additional weight gain for CML and MG-H1 was 0.065 kg (0.041–0.089) and 0.034 kg (0.012, 0.057), respectively. The top six food groups contributing to AGEs intake, with varying proportions across the AGEs, were cereals/cereal products, meat/processed meat, cakes/biscuits, dairy, sugar and confectionary, and fish/shellfish.Conclusion: In this study of European adults, higher intakes of AGEs were associated with marginally greater weight gain over an average of 5 years of follow-up.
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| 3. |
- Syndikus, I., et al.
(författare)
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Probing the Z = 6 spin-orbit shell gap with (p,2p) quasi-free scattering reactions
- 2020
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Ingår i: Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 809
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of the traditional nuclear magic numbers away from the valley of stability is an active field of research. Experimental efforts focus on providing key spectroscopic information that will shed light into the structure of exotic nuclei and understanding the driving mechanism behind the shell evolution. In this work, we investigate the Z=6 spin-orbit shell gap towards the neutron dripline. To do so, we employed NA(p,2p)CA−1 quasi-free scattering reactions to measure the proton component of the 21+ state of 16,18,20C. The experimental findings support the notion of a moderate reduction of the proton 1p1/2−1p3/2 spin-orbit splitting, at variance to recent claims for a prevalent Z=6 magic number towards the neutron dripline.
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| 4. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 5. |
- Forgetta, V., et al.
(författare)
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Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study
- 2020
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. Methods and findings A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N= 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r(2)= 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. Conclusions Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. Author summaryWhy was this study done? Osteoporosis screening identifies only a small proportion of the screened population to be eligible for intervention. The prediction of heritable risk factors using polygenic risk scores could decrease the number of screened individuals by reassuring those with low genetic risk. We investigated whether the genetic prediction of heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-could be incorporated into an established screening guideline to identify individuals at low risk for osteoporosis. What did the researchers do and find? Using UK Biobank, we developed a polygenic risk score (gSOS) consisting of 21,717 genetic variants that was strongly correlated with SOS ( = 23.2%). Using the National Osteoporosis Guideline Group clinical assessment guidelines in 5 validation cohorts, we estimate that reassuring individuals with a high gSOS, rather than doing further assessments, could reduce the number of clinical-risk-factor-based Fracture Risk Assessment Tool (FRAX) tests and bone-density-measurement-based FRAX tests by 37% and 41%, respectively, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. What do these findings mean? We show that genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk of osteoporotic fractures. Therefore, the potential exists to improve the efficiency of osteoporosis screening programs without large losses in sensitivity or specificity to identify individuals who should receive an intervention. Further translational studies are needed to test the clinical applications of this polygenic risk score; however, our work shows how such scores could be tested in the clinic.
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| 6. |
- Callaghan, Terry V., et al.
(författare)
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Improving dialogue among researchers, local and indigenous peoples and decision-makers to address issues of climate change in the North
- 2020
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Ingår i: Ambio: a Journal of the Human Environment. - : Springer Science and Business Media LLC. - 0044-7447. ; 49:6, s. 1161-1178
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Tidskriftsartikel (refereegranskat)abstract
- The Circumpolar North has been changing rapidly within the last decades, and the socioeconomic systems of the Eurasian Arctic and Siberia in particular have displayed the most dramatic changes. Here, anthropogenic drivers of environmental change such as migration and industrialization are added to climate-induced changes in the natural environment such as permafrost thawing and increased frequency of extreme events. Understanding and adapting to both types of changes are important to local and indigenous peoples in the Arctic and for the wider global community due to transboundary connectivity. As local and indigenous peoples, decision-makers and scientists perceive changes and impacts differently and often fail to communicate efficiently to respond to changes adequately, we convened a meeting of the three groups in Salekhard in 2017. The outcomes of the meeting include perceptions of how the three groups each perceive the main issues affecting health and well-being and recommendations for working together better.
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| 7. |
- Gobel, K., et al.
(författare)
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Coulomb dissociation of 16O into 4He and 12C
- 2020
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 1668:1
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(a,?)16O fusion reaction and to reach lower center-ofmass energies than measured so far. The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-To-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
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| 8. |
- Johansson, J., et al.
(författare)
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Machinability evaluation of low-lead brass alloys
- 2020
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Ingår i: Procedia Manufacturing. - : Elsevier BV. - 2351-9789. ; 38, s. 1723-1730
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Tidskriftsartikel (refereegranskat)abstract
- The machinability of brass is considered to increase with the addition of lead as an alloying element. Due to both environmental and health reasons, the decrease of lead in brass components is of high importance. Several mechanical and thermal material properties control a materials machinability, in combination with the chosen machining system. To evaluate the difference in machinability between a traditional free-machining leaded alloy and brass alloys with low lead content, material properties influencing the machinability have been measured. Results of machining, such as burr formation and difference in cutting forces and cutting resistance has been studied. The presented results indicates that alloys with lower lead content do not show as good machinability as leaded brass. However, investigations show that the machinability for some of the alloys with low lead content is not considerably worse compared to alloys with a high lead content, making them viable options for a more sustainable production.
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| 9. |
- Laakso, Sampsa V.A., et al.
(författare)
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There is logic in logit - Including wear rate in Colding's tool wear model
- 2020
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Ingår i: Procedia Manufacturing. - : Elsevier BV. - 2351-9789. ; 38, s. 1066-1073
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Tidskriftsartikel (refereegranskat)abstract
- Modelling of tool wear in metal cutting processes has been the foundation of the field since the famous Taylor's tool life model. Tool wear models have been developed for planning machining operations and calculating production costs. Most wear models do not include wear rate in the model but rather just the final wear at end of tool life, i.e. the limiting wear. This is a major disadvantage of Taylor's model, and practically all the other experimental models of tool wear. The wear progression over time is lost with the selection the limiting wear. This paper proposes a new logit-function based model for wear rate that can be included in the existing models. In this work, in addition to Taylor's model, Colding's model is used with the proposed wear rate model. The outcome is a model that can predict the tool wear at a given cutting speed, feed and at any given time within the tool life range, without selection the limiting tool wear. The model can be also used inversely so that the output is the tool life at a given cutting parameters and wear. The results show good fit to the experiment data (~10 %) and the model captures the typical wear rate shape well.
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| 10. |
- Li, Constance H., et al.
(författare)
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Sex differences in oncogenic mutational processes
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
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