| 1. |
- Barrett, Jennifer H., et al.
(författare)
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Genome-wide association study identifies three new melanoma susceptibility loci
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1108-1113
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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| 2. |
- Iles, Mark M., et al.
(författare)
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A variant in FTO shows association with melanoma risk not due to BMI
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:4, s. 428-432
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Tidskriftsartikel (refereegranskat)abstract
- We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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| 4. |
- Malmström, Rickard E., et al.
(författare)
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Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs
- 2013
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Ingår i: Frontiers in Pharmacology. - : FRONTIERS RESEARCH FOUNDATION. - 1663-9812. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
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| 5. |
- Rafnar, Thorunn, et al.
(författare)
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
- 2011
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 20:21, s. 4268-81
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Tidskriftsartikel (refereegranskat)abstract
- Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
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| 7. |
- Gebrehiwot, Solomon, et al.
(författare)
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Hydrological change detection using modeling : Half a century of runoff from four rivers in the Blue Nile Basin
- 2013
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Ingår i: Water resources research. - : American Geophysical Union (AGU). - 0043-1397 .- 1944-7973. ; 49:6, s. 3842-3851
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Tidskriftsartikel (refereegranskat)abstract
- Land cover changes can have significant impacts on hydrological regime. The objective of this study was to detect possible hydrological changes of four watersheds in the Blue Nile Basin using a model-based method for hydrological change detection. The four watersheds, Birr, Upper-Didesa, Gilgel Abbay, and Koga range in size from 260 to 1800 km(2). The changes were assessed based on model parameters, model residuals, and in the overall function of the watersheds in transferring rainfall into runoff. The entire time series (1960-2004) was divided into three periods based on political and land management policy changes. A conceptual rainfall-runoff model, the HBV (Hydrologiska Byrans Vattenbalansavdelning) model, was used for the analysis, and suitable parameter sets for each period were found based on a Monte Carlo approach. The values of six out of nine parameters changed significantly between the periods. Model residuals also showed significant changes between the three periods in three of the four watersheds. On the other hand, the overall functioning of the watersheds in processing rainfall to runoff changed little. So even though the individual parameters and model residuals were changing, the integrated functioning of the watersheds showed minimal changes. This study demonstrated the value of using different approaches for detecting hydrological change and highlighted the sensitivity of the outcome to the applied modeling and statistical methods.
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| 10. |
- Grabs, Thomas, et al.
(författare)
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Riparian zone hydrology and soil water total organic carbon (TOC) : implications for spatial variability and upscaling of lateral riparian TOC exports
- 2012
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 9:10, s. 3901-3916
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Tidskriftsartikel (refereegranskat)abstract
- Groundwater flowing from hillslopes through riparian (near-stream) soils often undergoes chemical transformations that can substantially influence stream water chemistry. We used landscape analysis to predict total organic carbon (TOC) concentration profiles and groundwater levels measured in the riparian zone (RZ) of a 67 km2 catchment in Sweden. TOC exported laterally from 13 riparian soil profiles was then estimated based on the riparian flow-concentration integration model (RIM). Much of the observed spatial variability of riparian TOC concentrations in this system could be predicted from groundwater levels and the topographic wetness index (TWI). Organic riparian peat soils in forested areas emerged as hotspots exporting large amounts of TOC. These TOC fluxes were subject to considerable temporal variations caused by a combination of variable flow conditions and changing soil water TOC concentrations. Mineral riparian gley soils, on the other hand, were related to rather small TOC export rates and were characterized by relatively time-invariant TOC concentration profiles. Organic and mineral soils in RZs constitute a heterogeneous landscape mosaic that potentially controls much of the spatial variability of stream water TOC. We developed an empirical regression model based on the TWI to move beyond the plot scale and to predict spatially variable riparian TOC concentration profiles for RZs underlain by glacial till.
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