1. |
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Overview of the JET results
- 2015
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In: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 55:10
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Journal article (peer-reviewed)
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2. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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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- Angelopoulos, V., et al.
(author)
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First Results from the THEMIS Mission
- 2008
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In: Space Science Reviews. - : Springer Science and Business Media LLC. - 0038-6308 .- 1572-9672. ; 141:1-4, s. 453-476
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Research review (peer-reviewed)abstract
- THEMIS was launched on February 17, 2007 to determine the trigger and large-scale evolution of substorms. During the first seven months of the mission the five satellites coasted near their injection orbit to avoid differential precession in anticipation of orbit placement, which started in September 2007 and led to a commencement of the baseline mission in December 2007. During the coast phase the probes were put into a string-of-pearls configuration at 100 s of km to 2 R-E along-track separations, which provided a unique view of the magnetosphere and enabled an unprecedented dataset in anticipation of the first tail season. In this paper we describe the first THEMIS substorm observations, captured during instrument commissioning on March 23, 2007. THEMIS measured the rapid expansion of the plasma sheet at a speed that is commensurate with the simultaneous expansion of the auroras on the ground. These are the first unequivocal observations of the rapid westward expansion process in space and on the ground. Aided by the remote sensing technique at energetic particle boundaries and combined with ancillary measurements and MHD simulations, they allow determination and mapping of space currents. These measurements show the power of the THEMIS instrumentation in the tail and the radiation belts. We also present THEMIS Flux Transfer Events (FTE) observations at the magnetopause, which demonstrate the importance of multi-point observations there and the quality of the THEMIS instrumentation in that region of space.
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4. |
- Götz, S., et al.
(author)
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Rapid extraction of short-lived isotopes from a buffer gas cell for use in gas-phase chemistry experiments, Part II : On-line studies with short-lived accelerator-produced radionuclides
- 2021
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In: Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms. - : Elsevier BV. - 0168-583X. ; 507, s. 27-35
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Journal article (peer-reviewed)abstract
- A novel combination of advanced gas-chromatography and detection systems coupled to a buffer-gas cell was characterized on-line to allow gas-phase chemical studies of accelerator-produced short-lived α-decaying mercury, francium, and astatine isotopes. These were produced in 40Ar- and 48Ca-induced nuclear fusion–evaporation reactions, subsequently isolated in the recoil separators MARS at Texas A&M University, USA, and TASCA at GSI Darmstadt, Germany, before being thermalized in a buffer-gas-stopping cell. From the latter, the nuclear reaction products were extracted into gas-phase chromatographic systems, suitable for registering α-decaying short-lived radionuclides, such as isotopes of superheavy elements. Efficiencies of 21(3)% for 204-209Fr were reached for the extraction into the optimized miniCOMPACT gas-chromatography setup, indicating that this technique enables the identification of isotopes of volatile as well as non-volatile elements. These studies guide the path towards chemical investigations of superheavy elements beyond flerovium, which are out of reach with currently used setups.
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5. |
- Johansson, T., et al.
(author)
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Observation of an inner magnetosphere electric field associated with a BBF-like flow and PBIs
- 2009
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In: Annales Geophysicae. - : Copernicus GmbH. - 0992-7689 .- 1432-0576. ; 27:4, s. 1489-1500
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Journal article (peer-reviewed)abstract
- Themis E observed a perpendicular (to the magnetic field) electric field associated with an Earthward plasma flow at XGSM=-9.6 R-E on 11 January 2008. The electric field observation resembles Cluster observations closer to Earth in the auroral region. The fast plasma flow shared some characteristics with bursty bulk flows (BBFs) but did not meet the usual criteria in maximum velocity and duration to qualify as one. Themis C observed the same flow further downtail but Themis D, separated by only 1 R-E in azimuthal direction from Themis E, did not. At the time of the electric field and ion flow event, the all-sky imager and ground-based magnetometer at Rankin Inlet observed Poleward Boundary Intensifications (PBIs) and a negative bay signature. None of the other Themis ground-based observatories recorded any significant auroral or magnetic field activity, indicating that this was a localized activity. The joint Themis in situ and ground-based observations suggest that the two observations are related. This indicates that auroral electric fields can extend to regions much farther out than previously seen in Cluster observations.
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- Neerland, B. E., et al.
(author)
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Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial
- 2022
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In: Bmj Open. - : BMJ. - 2044-6055. ; 12:6
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Journal article (peer-reviewed)abstract
- Introduction Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. Methods and analysis This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 mu g/kg/hour. The infusion rate will be decreased to 0.2 mu g/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first. Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. Ethics and dissemination This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings.
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7. |
- Northcott, Paul A, et al.
(author)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Journal article (peer-reviewed)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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9. |
- Thanabalasingham, G., et al.
(author)
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A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes
- 2011
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54:11, s. 2801-2810
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Journal article (peer-reviewed)abstract
- An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values > 10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 x 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 x 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) a parts per thousand yenaEuro parts per thousand 0.91, p a parts per thousand currency signaEuro parts per thousand 1 x 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.
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