| 1. |
- Bertolotto, Corine, et al.
(författare)
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A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 480:7375, s. 94-98
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Tidskriftsartikel (refereegranskat)abstract
- So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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| 2. |
- Casanueva, Felipe F., et al.
(författare)
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Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement
- 2017
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Ingår i: Pituitary. - : Springer Science and Business Media LLC. - 1386-341X .- 1573-7403. ; 20, s. 489-498
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Forskningsöversikt (refereegranskat)abstract
- © 2017, The Author(s). Introduction: With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). Methods: To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. Results: After five years of iterative work a document with the ideal criteria for a PTCOE is presented. Conclusions: Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country.
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| 3. |
- Döscher, Ralf, et al.
(författare)
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The EC-Earth3 Earth system model for the Coupled Model Intercomparison Project 6
- 2022
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 15:7, s. 2973-3020
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Tidskriftsartikel (refereegranskat)abstract
- The Earth system model EC-Earth3 for contributions to CMIP6 is documented here, with its flexible coupling framework, major model configurations, a methodology for ensuring the simulations are comparable across different high-performance computing (HPC) systems, and with the physical performance of base configurations over the historical period. The variety of possible configurations and sub-models reflects the broad interests in the EC-Earth community. EC-Earth3 key performance metrics demonstrate physical behavior and biases well within the frame known from recent CMIP models. With improved physical and dynamic features, new Earth system model (ESM) components, community tools, and largely improved physical performance compared to the CMIP5 version, EC-Earth3 represents a clear step forward for the only European community ESM. We demonstrate here that EC-Earth3 is suited for a range of tasks in CMIP6 and beyond.
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| 4. |
- Caron, Louis-Philippe, et al.
(författare)
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Multi-year prediction skill of Atlantic hurricane activity in CMIP5 decadal hindcasts
- 2014
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Ingår i: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 42:9-10, s. 2675-2690
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Tidskriftsartikel (refereegranskat)abstract
- Using a statistical relationship between simulated sea surface temperature and Atlantic hurricane activity, we estimate the skill of a CMIP5 multi-model ensemble at predicting multi-annual level of Atlantic hurricane activity. The series of yearly-initialized hindcasts show positive skill compared to simpler forecasts such as persistence and climatology as well as non-initialized forecasts and return anomaly correlation coefficients of similar to 0.6 and similar to 0.8 for five and nine year forecasts, respectively. Some skill is shown to remain in the later years and making use of those later years to create a lagged-ensemble yields, for individual models, results that approach that obtained by the multi-model ensemble. Some of the skill is shown to come from persisting rather than predicting the climate shift that occur in 1994-1995. After accounting for that shift, the anomaly correlation coefficient for five-year forecasts is estimated to drop to 0.4, but remains statistically significant up to lead years 3-7. Most of the skill is shown to come from the ability of the forecast systems at capturing change in Atlantic sea surface temperature, although the failure of most systems at reproducing the observed slow down in warming over the tropics in recent years leads to an underestimation of hurricane activity in the later period.
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| 5. |
- Caron, Louis-Philippe, et al.
(författare)
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On the relationship between cloud-radiation interaction, atmospheric stability and Atlantic tropical cyclones in a variable-resolution climate model
- 2013
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Ingår i: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 40:5-6, s. 1257-1269
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Tidskriftsartikel (refereegranskat)abstract
- We compare two 28-year simulations performed with two versions of the Global Environmental Multiscale model run in variable-resolution mode. The two versions differ only by small differences in their radiation scheme. The most significant modification introduced is a reduction in the ice effective radius, which is observed to increase absorption of upwelling infrared radiation and increase temperature in the upper troposphere. The resulting change in vertical lapse rate is then observed to drive a resolution-dependent response of convection, which in turn modifies the zonal circulation and induces significant changes in simulated Atlantic tropical cyclone activity. The resulting change in vertical lapse rate and its implication in the context of anthropogenic climate change are discussed.
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| 6. |
- Caron, Louis-Philippe, et al.
(författare)
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Understanding and simulating the link between African easterly waves and Atlantic tropical cyclones using a regional climate model : the role of domain size and lateral boundary conditions
- 2012
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Ingår i: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 39:1-2, s. 113-135
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Tidskriftsartikel (refereegranskat)abstract
- Using a suite of lateral boundary conditions, we investigate the impact of domain size and boundary conditions on the Atlantic tropical cyclone and african easterly Wave activity simulated by a regional climate model. Irrespective of boundary conditions, simulations closest to observed climatology are obtained using a domain covering both the entire tropical Atlantic and northern African region. There is a clear degradation when the high-resolution model domain is diminished to cover only part of the African continent or only the tropical Atlantic. This is found to be the result of biases in the boundary data, which for the smaller domains, have a large impact on TC activity. In this series of simulations, the large-scale Atlantic atmospheric environment appears to be the primary control on simulated TC activity. Weaker wave activity is usually accompanied by a shift in cyclogenesis location, from the MDR to the subtropics. All ERA40-driven integrations manage to capture the observed interannual variability and to reproduce most of the upward trend in tropical cyclone activity observed during that period. When driven by low-resolution global climate model (GCM) integrations, the regional climate model captures interannual variability (albeit with lower correlation coefficients) only if tropical cyclones form in sufficient numbers in the main development region. However, all GCM-driven integrations fail to capture the upward trend in Atlantic tropical cyclone activity. In most integrations, variations in Atlantic tropical cyclone activity appear uncorrelated with variations in African easterly wave activity.
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| 7. |
- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 8. |
- Jakob, Michael, et al.
(författare)
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How trade policy can support the climate agenda
- 2022
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 376:6600, s. 1401-1404
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Tidskriftsartikel (refereegranskat)abstract
- Economic analysis has produced ample insights on how international trade and climate policy interact. Trade presents both opportunities and obstacles, and invites the question of how domestic climate policies can be effective in a global economy integrated through international trade. Particularly problematic is the potential relocation of production to regions with low climate standards. Measures to level the playing field, such as border carbon adjustments (BCAs), may be justified for specific emissions-intensive and trade-exposed sectors but need to be well-targeted, carefully navigating tensions that can arise between the desire to respect global trade rules and the need to elaborate and implement effective national climate policies. The conformity of specific trade measures with international trade and climate change law is not entirely clear. Yet, clarity is needed to ensure that the industry actors affected will find the rules predictable and be able to adhere to them.
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| 9. |
- Lavender, Sally L., et al.
(författare)
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Estimation of the maximum annual number of North Atlantic tropical cyclones using climate models
- 2018
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 4:8
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Tidskriftsartikel (refereegranskat)abstract
- Using millennia-long climate model simulations, favorable environments for tropical cyclone formation are examined to determine whether the record number of tropical cyclones in the 2005 Atlantic season is close to the maximum possible number for the present climate of that basin. By estimating both the mean number of tropical cyclones and their possible year-to-year random variability, we find that the likelihood that the maximum number of storms in the Atlantic could be greater than the number of events observed during the 2005 season is less than 3.5%. Using a less restrictive comparison between simulated and observed climate with the internal variability accounted for, this probability increases to 9%; however, the estimated maximum possible number of tropical cyclones does not greatly exceed the 2005 total. Hence, the 2005 season can be used as a risk management benchmark for the maximum possible number of tropical cyclones in the Atlantic.
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| 10. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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