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Sökning: WFRF:(Sjogren H.)

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  • Lindblom, P, et al. (författare)
  • Tesaglitazar, a dual PPAR-α/γ agonist, hamster carcinogenicity, investigative animal and clinical studies
  • 2012
  • Ingår i: Toxicologic pathology. - : SAGE Publications. - 1533-1601 .- 0192-6233. ; 40:1, s. 18-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Tesaglitazar was developed as a dual peroxisome proliferator–activated receptor (PPARα/γ). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with interim necropsies was performed to further elucidate these findings. Treatment with tesaglitazar resulted in changes typical for exaggerated PPARα pharmacology in rodents, such as hepatocellular hypertrophy and hepatocellular carcinoma, but not an increased frequency of hemangiosarcomas. At the highest dose level, there was an increased incidence of sinusoidal dilatation and hemangiomas. No increased endothelial cell (EC) proliferation was detected in vivo, which was confirmed by in vitro administration to ECs. Immunohistochemistry and gene expression analyses indicated increased cellular stress and vascular endothelial growth factor (VEGF) expression in the liver, which may have contributed to the sinusoidal dilatation. A two-fold increase in the level of circulating VEGF was detected in the hamster at all dose levels, whereas no effect on VEGF was observed in patients treated with tesaglitazar. In conclusion, investigations have demonstrated that tesaglitazar does not produce hemangiosarcomas in hamster despite a slight effect on vascular morphology in the liver.
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  • Johansson, A, et al. (författare)
  • Increased frequency of a new polymorphism in the cycle 2 (cdc2) gene in patients with Alzheimer's disease frontotemporal dementia
  • 2003
  • Ingår i: Neuroscience Letters. - 0304-3940. ; 340:1, s. 69-73
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies show linkage between Alzheimer's disease (AD) and two loci on chromosome 10. The cell division cycle 2 (cdc2) gene is located close to one of the chromosome 10 markers, and is a candidate gene for AD since it is involved in the pathogenesis of AD. We sequenced coding exons and flanking intronic sequences and the promoter region on the cdc2 gene and found three new single nucleotide polymorphisms (SNPs). We analyzed 272 Caucasian AD cases, 160 controls and 70 cases with frontotemporal dementia (FTD) for these SNPs. Homozygosity for one of the SNPs (Ex6 + 7I/D) was more frequent in both AD and FTD cases than in controls. In the combined tauopathy (AD and FTD) group the odds ratio (OR) was 1.77 (95% CI 1.19-2.63) for the Ex6 + 7II genotype. Our findings suggest that the Ex6 + 7I allele is associated with tauopathies, both AD and FrD. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.
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