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- Abelson, Anna-Karin, et al.
(författare)
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STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 68:11, s. 1746-1753
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
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- Dong, Lan-Feng, et al.
(författare)
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Suppression of Tumor Growth In vivo by the Mitocan alpha-tocopheryl Succinate Requires Respiratory Complex II
- 2009
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Ingår i: CLINICAL CANCER RESEARCH. - 1078-0432. ; 15:5, s. 1593-1600
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Vitamin E analogues are potent novel anticancer drugs. The purpose of this study was to elucidate the cellular target by which these agents, represented by alpha-tocopoheryl succinate (alpha-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII). Experimental Design: Chinese hamster lung fibroblasts with functional, dysfunctional, and reconstituted CII were transformed using H-Ras. The cells were then used to form xenografts in immunocompromized mice, and response of the cells and the tumors to alpha-TOS was studied. Results: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to alpha-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to alpha-TOS. Thus, growth of CII-functional and CII-reconstituted tumors was strongly suppressed by the agent, and this was accompanied by high level of apoptosis induction in the tumor cells. On the other hand, alpha-TOS did not inhibit the CII-dysfuntional tumors. Conclusions: We document in this report a novel paradigm, according to which the mitochondrial CII, which rarely mutates in human neoplasias, is a plausible target for anticancer drugs from the group of vitamin E analogues, providing support for their testing in clinical trials.
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- Korsgren, Olle, et al.
(författare)
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Optimising islet engraftment is critical for successful clinical islet transplantation
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:2, s. 227-32
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Tidskriftsartikel (refereegranskat)abstract
- Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although 'proof-of-principle' has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.
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| 5. |
- Linga Reddy, M. V. Prasad, et al.
(författare)
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Genetic association of IRF5 with SLE in Mexicans : higher frequency of the risk haplotype and its homozygozity than Europeans
- 2007
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 121:6, s. 721-727
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Tidskriftsartikel (refereegranskat)abstract
- The IRF5 gene was found to be strongly associated with SLE. We identified two functional polymorphisms and recently an insertion/deletion together with a tag SNP defining the risk haplotype in individuals of European ancestry. We now analyzed sets of Mexican patients with SLE. Three polymorphisms in the IRF5 gene were genotyped in two sets of Mexican individuals with SLE and controls as well as in families including a set of pediatric SLE patients. A set of healthy Mexican Indians was also typed. Genetic association with SLE was found for all three polymorphisms. The genetic association was very strong in the case–control analysis in both sets (for SNP rs2070197, combined P = 1.26 × 10−21) and in families (combined P = 0.000004). Compared to healthy individuals with European ancestry, the frequency of the risk haplotype in healthy Mexican individuals was significantly higher and even higher in the healthy Mexican Indian group. Further, a much higher frequency of the risk haplotype and of individual homozygote for it was found among Mexican SLE patients. The significantly higher frequency of homozygote individuals for the risk haplotype among Mexican SLE patients could be the result of genetic admixture, and suggests the possibility that IRF5 could be involved in the more active disease and organ involvement known to occur among Mexican SLE patients.
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| 7. |
- Yamada, T. K., et al.
(författare)
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Spin configuration in a frustrated ferromagnetic/antiferromagnetic thin-film system
- 2007
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Ingår i: Nanotechnology. - : IOP Publishing. - 0957-4484 .- 1361-6528. ; 18:23, s. 235702-
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Tidskriftsartikel (refereegranskat)abstract
- We have studied the magnetic configuration in ultrathin antiferromagnetic Mn films grown around monoatomic steps on an Fe( 001) surface by spin-polarized scanning tunnelling microscopy/spectroscopy and ab initio-parameterized self-consistent real-space tight-binding calculations in which the spin quantization axis is independent for each site, thus allowing noncollinear magnetism. Mn grown on Fe( 001) presents a layered antiferromagnetic structure. In the regions where the Mn films overgrows Fe steps the magnetization of the surface layer is reversed across the steps. Around these defects a frustration of the antiferromagnetic order occurs. Due to the weakened magnetic coupling at the central Mn layers, the amount of frustration is smaller than in Cr, and the width of the wall induced by the step does not change with the thickness, at least for coverages up to seven monolayers.
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