| 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. |
- Waszak, S. M., et al.
(författare)
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Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
- 2018
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Ingår i: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Tidskriftsartikel (refereegranskat)abstract
- Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 4069) and 5-year overall survival was 65% (95% CI 5281); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
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| 3. |
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| 4. |
- Nagaraja, Ch., et al.
(författare)
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Opening remarks
- 2016
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Konferensbidrag (refereegranskat)
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| 5. |
- Wang, J., et al.
(författare)
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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:11, s. 1396-1406
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Tidskriftsartikel (refereegranskat)abstract
- Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr(-/-) mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 x 10(-8)) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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| 6. |
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| 7. |
- Bartels-Rausch, T., et al.
(författare)
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A review of air-ice chemical and physical interactions (AICI): Liquids, quasi-liquids, and solids in snow
- 2014
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 14:3, s. 1587-1633
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Tidskriftsartikel (refereegranskat)abstract
- Snow in the environment acts as a host to rich chemistry and provides a matrix for physical exchange of contaminants within the ecosystem. The goal of this review is to summarise the current state of knowledge of physical processes and chemical reactivity in surface snow with relevance to polar regions. It focuses on a description of impurities in distinct compartments present in surface snow, such as snow crystals, grain boundaries, crystal surfaces, and liquid parts. It emphasises the microscopic description of the ice surface and its link with the environment. Distinct differences between the disordered air-ice interface, often termed quasi-liquid layer, and a liquid phase are highlighted. The reactivity in these different compartments of surface snow is discussed using many experimental studies, simulations, and selected snow models from the molecular to the macro-scale. Although new experimental techniques have extended our knowledge of the surface properties of ice and their impact on some single reactions and processes, others occurring on, at or within snow grains remain unquantified. The presence of liquid or liquid-like compartments either due to the formation of brine or disorder at surfaces of snow crystals below the freezing point may strongly modify reaction rates. Therefore, future experiments should include a detailed characterisation of the surface properties of the ice matrices. A further point that remains largely unresolved is the distribution of impurities between the different domains of the condensed phase inside the snowpack, i.e. in the bulk solid, in liquid at the surface or trapped in confined pockets within or between grains, or at the surface. While surface-sensitive laboratory techniques may in the future help to resolve this point for equilibrium conditions, additional uncertainty for the environmental snowpack may be caused by the highly dynamic nature of the snowpack due to the fast metamorphism occurring under certain environmental conditions. Due to these gaps in knowledge the first snow chemistry models have attempted to reproduce certain processes like the long-term incorporation of volatile compounds in snow and firn or the release of reactive species from the snowpack. Although so far none of the models offers a coupled approach of physical and chemical processes or a detailed representation of the different compartments, they have successfully been used to reproduce some field experiments. A fully coupled snow chemistry and physics model remains to be developed. © Author(s) 2014.
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| 8. |
- Charman, D. J., et al.
(författare)
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Climate-related changes in peatland carbon accumulation during the last millennium
- 2013
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4189. ; 10:2, s. 929-944
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Tidskriftsartikel (refereegranskat)abstract
- Peatlands are a major terrestrial carbon store and a persistent natural carbon sink during the Holocene, but there is considerable uncertainty over the fate of peatland carbon in a changing climate. It is generally assumed that higher temperatures will increase peat decay, causing a positive feedback to climate warming and contributing to the global positive carbon cycle feedback. Here we use a new extensive database of peat profiles across northern high latitudes to examine spatial and temporal patterns of carbon accumulation over the past millennium. Opposite to expectations, our results indicate a small negative carbon cycle feedback from past changes in the long-term accumulation rates of northern peatlands. Total carbon accumulated over the last 1000 yr is linearly related to contemporary growing season length and photosynthetically active radiation, suggesting that variability in net primary productivity is more important than decomposition in determining long-term carbon accumulation. Furthermore, northern peatland carbon sequestration rate declined over the climate transition from the Medieval Climate Anomaly (MCA) to the Little Ice Age (LIA), probably because of lower LIA temperatures combined with increased cloudiness suppressing net primary productivity. Other factors including changing moisture status, peatland distribution, fire, nitrogen deposition, permafrost thaw and methane emissions will also influence future peatland carbon cycle feedbacks, but our data suggest that the carbon sequestration rate could increase over many areas of northern peatlands in a warmer future.
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| 9. |
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| 10. |
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| 11. |
- Waszak, S. M., et al.
(författare)
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Germline Elongator mutations in Sonic Hedgehog medulloblastoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7803
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Tidskriftsartikel (refereegranskat)abstract
- Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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| 12. |
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| 13. |
- Baumeister, S, et al.
(författare)
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Processing of social and monetary rewards in autism spectrum disorders
- 2023
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Ingår i: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 222:3, s. 100-111
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Tidskriftsartikel (refereegranskat)abstract
- Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD.AimsUtilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.MethodFunctional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6–30.6 years of age) and 181 typically developing participants (7.6–30.8 years of age).ResultsAcross social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD.ConclusionsOur results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.
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| 14. |
- Matyschok, J., et al.
(författare)
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Compact, few-cycle OPCPA system with ultralow CEP noise
- 2013
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Ingår i: Advanced Solid State Lasers, ASSL 2013. - 9781557529824
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Konferensbidrag (refereegranskat)abstract
- A compact, high-repetition rate OPCPA system with CEP-stable 6.3 fs pulses duration and 10 μJ of pulse energy is presented together with results from numerical simulations. First results of high harmonic generation will be shown.
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| 15. |
- Matyschok, J., et al.
(författare)
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Ultra-stable fiber pumped CEP-stabilized dual stage OPCPA system
- 2013
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Ingår i: 2013 Conference on Lasers & Electro-Optics Europe & International Quantum Electronics Conference CLEO EUROPE/IQEC. - 9781479905942
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Konferensbidrag (refereegranskat)abstract
- For the generation of intense few-cycle laser pulses with stable carrier envelope phase (CEP), the approach of optical parametric chirped pulse amplification (OPCPA) is well established. In this contribution we present a compact and robust CEP-stable OPCPA system emitting pulses with energy above 10 μJ at 200 kHz repetition rate and pulse durations of 6.3 fs. Additionally, we present the results of (2+1)-dimensional numerical simulations [1] for a better understanding of the parametric amplification process.
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| 16. |
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| 17. |
- Rahnev, D, et al.
(författare)
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The Confidence Database
- 2020
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 4:3, s. 317-325
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Tidskriftsartikel (refereegranskat)
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| 18. |
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| 19. |
- Ritschl, Valentin, et al.
(författare)
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Educational readiness among health professionals in rheumatology: low awareness of EULAR offerings and unfamiliarity with the course content as major barriers-results of a EULAR-funded European survey
- 2023
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Ingår i: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOngoing education of health professionals in rheumatology (HPR) is critical for high-quality care. An essential factor is education readiness and a high quality of educational offerings. We explored which factors contributed to education readiness and investigated currently offered postgraduate education, including the European Alliance of Associations for Rheumatology (EULAR) offerings.Methods and participantsWe developed an online questionnaire, translated it into 24 languages and distributed it in 30 European countries. We used natural language processing and the Latent Dirichlet Allocation to analyse the qualitative experiences of the participants as well as descriptive statistics and multiple logistic regression to determine factors influencing postgraduate educational readiness. Reporting followed the Checklist for Reporting Results of Internet E-Surveys guideline.ResultsThe questionnaire was accessed 3589 times, and 667 complete responses from 34 European countries were recorded. The highest educational needs were professional development, prevention and lifestyle intervention. Older age, more working experience in rheumatology and higher education levels were positively associated with higher postgraduate educational readiness. While more than half of the HPR were familiar with EULAR as an association and the respondents reported an increased interest in the content of the educational offerings, the courses and the annual congress were poorly attended due to a lack of awareness, comparatively high costs and language barriers.ConclusionsTo promote the uptake of EULAR educational offerings, attention is needed to increase awareness among national organisations, offer accessible participation costs, and address language barriers.
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| 20. |
- Singh, A K, et al.
(författare)
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CFTR and its key role in in vivo resting and luminal acid-induced duodenal HCO3-secretion
- 2008
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 193:4, s. 357-365
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: We investigated the role of the recently discovered, villous-expressed anion exchanger Slc26a6 (PAT1) and the predominantly crypt-expressed cystic fibrosis transmembrane regulator (CFTR) in basal and acid-stimulated murine duodenal HCO3− secretion in vivo, and the influence of blood HCO3− concentration on both.Methods: The proximal duodenum of anaesthetized mice was perfused in situ, and HCO3− secretion was determined by back-titration. Duodenal mucosal permeability was assessed by determining 51Cr-EDTA leakage from blood to lumen.Results: Compared with wild type (WT) littermates basal duodenal HCO3− secretory rates were slightly reduced in Slc26-deficient mice at low (∼21 mm), and markedly reduced at high blood HCO3− concentration (∼29 mm). In contrast, basal HCO3− secretion was markedly reduced in CFTR-deficient mice compared with WT littermates both at high and low blood HCO3− concentration. A short-term application of luminal acid increased duodenal HCO3− secretory rate in Slc26a6-deficient and WT mice to the same degree, but had no stimulatory effect in the absence of CFTR. Luminal acidification to pH 2.5 did not alter duodenal permeability.Conclusions: The involvement of Slc26a6 in basal HCO3− secretion in murine duodenum in vivo is critically dependent on the systemic acid/base status, and this transporter is not involved in acid-stimulated HCO3− secretion. The presence of CFTR is essential for basal and acid-induced HCO3− secretion irrespective of acid/base status. This suggests a coupled action of Slc26a6 with CFTR for murine basal duodenal HCO3− secretion, but not acid-stimulated secretion, in vivo.
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