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- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Mayes, Maureen D, et al.
(författare)
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Immunochip analysis identifies multiple susceptibility Loci for systemic sclerosis.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:1, s. 47-61
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Tidskriftsartikel (refereegranskat)abstract
- In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
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| 4. |
- Fallani, M, et al.
(författare)
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Determinants of the human infant intestinal microbiota after the introduction of first complementary foods in infant samples from five European centres
- 2011
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Ingår i: Microbiology (Reading, England). - : Microbiology Society. - 1465-2080 .- 1350-0872. ; 157:Pt 5, s. 1385-1392
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Tidskriftsartikel (refereegranskat)abstract
- Although it is well established that early infant feeding has a major influence on the establishment of the gut microbiota, very little is understood about how the introduction of first solid food influences the colonization process. This study aimed to determine the impact of weaning on the faecal microbiota composition of infants from five European countries (Sweden, Scotland, Germany, Italy and Spain) which have different lifestyle characteristics and infant feeding practices. Faecal samples were collected from 605 infants approximately 4 weeks after the introduction of first solid foods and the results were compared with the same infants before weaning (6 weeks of age) to investigate the association with determining factors such as geographical origin, mode of delivery, previous feeding method and age of weaning. Samples were analysed by fluorescence in situ hybridization and flow cytometry using a panel of 10 rRNA targeted group- and species-specific oligonucleotide probes. The genus Bifidobacterium (36.5 % average proportion of total detectable bacteria), Clostridium coccoides group (14 %) and Bacteroides (13.6 %) were predominant after weaning. Similar to pre-weaning, northern European countries were associated with a higher proportion of bifidobacteria in the infant gut microbiota while higher levels of Bacteroides and lactobacilli characterized southern European countries. As before weaning, the initial feeding method influenced the Clostridium leptum group and Clostridium difficile+Clostridium perfringens species, and bifidobacteria still dominated the faeces of initially breast-fed infants. Formula-fed babies presented significantly higher proportions of Bacteroides and the C. coccoides group. The mode of birth influenced changes in the proportions of bacteroides and atopobium. Although there were significant differences in the mean weaning age between countries, this was not related to the populations of bifidobacteria or bacteroides. Thus, although the faecal microbiota of infants after first complementary foods was different to that before weaning commenced, many of the initial influences on microbiota composition were still evident.
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| 6. |
- Khanna, R., et al.
(författare)
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Chemical Interactions of Alumina-Carbon Refractories with Molten Steel at 1823 K (1550 degrees C) : Implications for Refractory Degradation and Steel Quality
- 2011
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Ingår i: Metallurgical and materials transactions. B, process metallurgy and materials processing science. - : Springer Science and Business Media LLC. - 1073-5615 .- 1543-1916. ; 42:4, s. 677-684
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Tidskriftsartikel (refereegranskat)abstract
- A sessile-drop study was carried out on Al(2)O(3)-10 pct C refractory substrates in contact with molten iron to investigate possible chemical reactions in the system and to determine the influence of carbon and the role, if any, played by the presence of molten iron that can act both as a reducing agent and as a metallic solvent. These investigations were carried out at 1823 K (1550 A degrees C) in argon atmosphere for times ranging between 15 minutes and 3 hours. We report the occurrence of chemical reactions in the Al(2)O(3)-10 pct C/Fe system, associated generation of CO gas, and carbon pickup by molten iron. Video images of the iron droplet started to show minor deviations after 30 minutes of contact followed by intense activity in the form of fine aluminum oxide whiskers emanating from the droplet and on the refractory substrate. The interfacial region also changed significantly over time, and the formation of small quantities of iron aluminide intermetallics was recorded after 30 minutes as a reaction product in the interfacial region. These chemical reactions also caused extensive penetration of molten iron into the refractory substrate. This study has shown that alumina cannot be treated as chemically inert at steelmaking temperatures when both carbon and molten iron are present simultaneously. These findings point to an additional reaction pathway during steelmaking that could have significant implications for refractory degradation and contamination of steel with reaction products.
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| 7. |
- Medel, Victor M., et al.
(författare)
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Robust Magnetic Moments on Impurities in Metallic Clusters : Localized Magnetic States in Superatoms
- 2013
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Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 117:20, s. 4297-4303
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Tidskriftsartikel (refereegranskat)abstract
- Introducing magnetic impurities into clusters of simplemetals can create localized states for higher angular momentum quantumnumbers (l = 2 or 3) that can breed magnetism analogous to that invirtual bound states in metallic hosts, offering a new recipe for magneticsuperatoms. In this work, we demonstrate that MnCan clusterscontaining 6−15 Ca atoms show a spin magnetic moment of 5.0 μBirrespective of the cluster size. Theoretical analysis reveals that the Mn dstates hybridize only partially with superatomic states and introduce extramajority and minority d states, largely localized at the Mn site, with alarge gap. Successive addition of Ca atoms introduces superatomic statesof varying angular momentum that are embedded in this gap, allowingcontrol over the stability of the motifs without altering the moment. Assemblies of such clusters can offer novel electronic features due to theformation of localized magnetic “quasibound states” in a confined nearlyfree electron gas.
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| 8. |
- Strand, V, et al.
(författare)
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Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial
- 2011
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70:6, s. 996-1002
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Tidskriftsartikel (refereegranskat)abstract
- To assess the impact of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in rheumatoid arthritis (RA), and to interpret these results using number needed to treat (NNT), and associations between PRO responses and longer term outcomes.MethodsA total of 619 patients with active RA were randomised to CZP 200 or 400 mg, or placebo plus methotrexate (MTX). PROs assessed included pain, patient's global assessment of disease activity (PtGA), physical function, fatigue and health-related quality of life. Treatment impact on PROs, NNT to achieve simultaneous improvements in multiple PROs and correlations between PROs were calculated. Times to onset of improvements greater than or equal to minimum clinically important differences (MCIDs) in pain as a determinant of clinical outcomes at week 24 were compared between week 6 and 12 responders, and in patients with improvements in pain ≥MCID at week 12 (week 12 responders/non-responders).ResultsCZP 200 and 400 mg plus MTX were associated with rapid, clinically meaningful improvements in all PROs. The NNT for subjects to report changes ≥MCID in up to five PROs was two to three, and five for all six PROs (pain, PtGA, physical function, fatigue and short-form 36-item Physical and Mental Component Summary Scores). More patients with improvements ≥MCID in pain at week 6 than those at week 12 had lower disease activity at week 24. Week 12 pain responders had better clinical outcomes at week 24 than non-responders.ConclusionsThe data demonstrate that CZP provides broad relief from the burden of RA.Trial registration numberNCT00160602.
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