| 221. |
- Adamovic, Svetlana, 1965, et al.
(författare)
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Fine mapping study in Scandinavian families suggests association between coeliac disease and haplotypes in chromosome region 5q32.
- 2008
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Ingår i: Tissue Antigens. - : Wiley. - 1399-0039 .- 0001-2815. ; 71:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- The previous genome-wide scan in Scandinavian families supported earlier evidence for linkage of a region on chromosome 5 (5q31–33) to coeliac disease. This study deals with further genetic mapping of an 18 cM region, spanning from marker GAh18A (131.87 Mb) to D5S640 (149.96 Mb). Linkage and association analyses were performed in a two-step approach. First, seven microsatellites were added. Strong evidence for linkage was obtained with a Zlr score of 3.96, Pnc = 4 × 10−5 at marker D5S436. The strongest association was with a haplotype consisting of the markers D5S2033 and D5S2490 (Pnc < 0.001). In the second step, we added 17 microsatellites and 69 single nucleotide polymorphisms (SNPs) to the analysis. These markers were located close to or within candidate genes across the region of approximately 7 Mb beneath the linkage peak marked by D5S2017 and D5S812. A substantial increase of the linkage signal with a maximum Zlr score of 4.6 at marker rs1972644 (Pnc = 2 × 10−6) was obtained and several SNPs showed association. Seven SNPs that individually showed the strongest association were genotyped in a second independent family sample set (225 trios). In the trio family sample as well as in the multiplex family sample, the strongest association was found with SNPs within the region flanked by the associated microsatellites D5S2033 and D5S2490 at 5q32.
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| 222. |
- Adamovic, Svetlana, 1965
(författare)
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Genetic linkage and association studies in celiac disease: discoveries from whole genome analysis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Celiac Disease (CD) or Gluten Sensitive Enteropathy (GSE) is a life-long disorder. It is characterized by inflammation in the small intestine of genetically predisposed individuals caused by inappropriate immune response to gluten, a protein enriched in some of our common grains (wheat, rye and barley). The toxicity of gluten is manifested by the autoimmune action of T-lymphocytes on mucosal cells in the small intestine, disrupting its vital function of absorbing nutrients from the food. The disease affects predominantly children, but it can develop later in life as well. Untreated CD involves risk for major complications: Dermatitis herpetiformis (“the celiac disease of the skin”), nutritional deficiencies, osteoporosis, anaemia, fertility problems, neurological disturbances and malignancies. The only known treatment for CD is a lifelong adherence to gluten-free diet (GFD). In a Scandinavian genome wide scan, performed by our group and published in 2001, eight chromosomal regions apart from HLA showed nominal significance (p < 0,05), among them 5q31-33. This region was previously suggested as a susceptibility region in other complex diseases: asthma, type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease. The main goal of this study was to explore the region of 18cM on 5q31-33, identify genetic risk factors and evaluate their contribution to the development of CD. In 2003 a joint analysis of four independent genome scans was performed by the European Genetics Cluster on Coeliac Disease, a collaborative work between six European research groups, including our. Data from Italian, Finnish, UK and Swedish/Norwegian cohorts, a total of 442 families, was pooled together and analysed. The meta-analysis using pooled data confirmed 5q31-33 as the second most significant region after the HLA region. After the meta-analysis, we applied a fine mapping strategy on the 18cM region on 5q31-33. The most essential result of this study was the strengthened linkage signal on 5q31-33 In 2006 we used the Illumina platform (GoldenGate assay technology) to perform an extensive screen of the region on 5q31-33. This study identified seven associated regions within 5q31-33 and a number of associated haplotypes but none of the association signals could explain the linkage peak observed in the families previously. In 2007 we performed a follow-up study of the association to the region comprising IL2/IL21 genes on 4q27, reported in the first genome-wide association study (GWAS) in celiac cases and controls. We confirmed that the IL2/IL21 region is a susceptibility region in CD. Unfortunately, the first GWAS failed to identify specific genes predisposing to CD. The GWAS as well as our own fine mapping study pointed out the difficulties scientists face in searching for the causing variants in complex diseases. It appears that causing variants may be hard to detect with association analysis alone because of the strong linkage disequilibrium in associated regions. However, the GWAS detected a number of CD associated genomic regions which remain to be explored.
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| 223. |
- Adamovic, Tatjana, 1974, et al.
(författare)
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Nonrandom pattern of chromosome aberrations in 17beta-estradiol-induced rat mammary tumors: indications of distinct pathways for tumor development.
- 2007
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:5, s. 459-69
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens play an important role in breast cancer etiology and the ACI rat provides a novel animal model for defining the mechanisms through which estrogens contribute to mammary cancer development. In crossing experiments between the susceptible ACI strain and two resistant strains, COP (Copenhagen) and BN (Brown Norway), several quantitative trait loci (QTL) that affect development of 17beta-estradiol (E2)-induced mammary tumors have been defined. Using comparative genomic hybridization (CGH), we have analyzed cytogenetic aberrations in E2-induced mammary cancers and have found clear patterns of nonrandom chromosomal involvement. Approximately two thirds of the tumors exhibited copy number changes. Losses of rat chromosome 5 (RNO5) and RNO20 were particularly common, and it was found that these two aberrations often occurred together. A third recurrent aberration involving proximal gain and distal loss in RNO6 probably defined a distinct subgroup of tumors, since it never occurred in combination with RNO5 loss. Interestingly, QTL with powerful effects on mammary cancer development have been mapped to RNO5 and RNO6. These findings suggest that there were at least two genetic pathways to tumor formation in this rat model of E2-induced mammary cancer. By performing CGH on mammary tumors from ACI rats, F1 rats from crosses between the ACI and COP or BN strains and ACI.BN-Emca8 congenic rats, which carry the BN allele of the Emca8 QTL on RNO5 on the ACI genetic background, we were able to determine that the constitution of the germ line influences the pattern of chromosomal aberrations.
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| 224. |
- Adamovic, Tatjana, 1974, et al.
(författare)
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Oncogene amplification in the proximal part of chromosome 6 in rat endometrial adenocarcinoma as revealed by combined BAC/PAC FISH, chromosome painting, zoo-FISH, and allelotyping.
- 2005
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 44:2, s. 139-53
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Tidskriftsartikel (refereegranskat)abstract
- The inbred BDII rat is a valuable experimental model for the genetic analysis of endometrial adenocarcinoma (EAC). One common aberration detected by comparative genomic hybridization in rat EAC was gain/amplification affecting the proximal part of rat chromosome 6 (RNO6). We applied rat and mouse chromosome painting probes onto tumor cell metaphase preparations in order to detect and characterize gross RNO6 aberrations. In addition, the RNO6q11-q16 segment was analyzed by fluorescence in situ hybridization with probes representing 12 cancer-related genes in the region. The analysis revealed that seven tumors contained large RNO6-derived homogeneously staining regions (HSRs) in addition to several normal or near-normal RNO6 chromosomes. Five tumors (two of which also had HSRs) exhibited a selective increase of the RNO6q11-q16 segment, sometimes in conjunction with moderate amplification of one or a few genes. Most commonly, the amplification affected the region centered around band 6q16 and included the Mycn, Ddx1, and Rrm2 genes. A second region, centering around Slc8a1 and Xdh, also was affected by gene amplification but to a lesser extent. The aberrations in the proximal part of RNO6 were further analyzed using allelotyping of microsatellite markers in all tumors from animals that were heterozygous in the proximal RNO6 region. We could detect allelic imbalance (AI) in 12 of 20 informative tumors, 6 of which were in addition to those already analyzed by molecular cytogenetic methods as described. Our findings suggest that increase/amplification of genes in this chromosome region contribute to the development of this hormone-dependent tumor.
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| 225. |
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| 226. |
- Adams, Kelly L., et al.
(författare)
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In Vitro Electrochemistry of Biological Systems
- 2008
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Ingår i: Annual Reviews of Analytical Chemistry. - : Annual Reviews. - 1936-1327 .- 1936-1335. ; 1, s. 329-355
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Tidskriftsartikel (refereegranskat)abstract
- This article reviews recent work involving electrochemical methods for in vitro analysis of biomolecules, with an emphasis on detection and manipulation at and of single cells and cultures of cells. The techniques discussed include constant potential amperometry, chronoamperometry, cellular electroporation, scanning electrochemical microscopy, and microfluidic platforms integrated with electrochemical detection. The principles of these methods are briefly described, followed in most cases with a short description of an analytical or biological application and its significance. The use of electrochemical methods to examine specific mechanistic issues in exocytosis is highlighted, as a great deal of recent work has been devoted to this application.
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| 227. |
- Adamsson, Jenni, 1977, et al.
(författare)
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Novel immunostimulatory agent based on CpG oligodeoxynucleotide linked to the nontoxic B subunit of cholera toxin.
- 2006
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 176:8, s. 4902-13
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we report the development of a novel, rationally designed immunostimulatory adjuvant based on chemical conjugation of CpG oligodeoxynucleotide (ODN) to the nontoxic B subunit of cholera toxin (CTB). We demonstrate that the immunostimulatory effects of CpG can be dramatically enhanced by conjugation to CTB. Thus, CpG ODN linked to CTB (CTB-CpG) was shown to be a more potent stimulator of proinflammatory cytokine and chemokine responses in murine splenocytes and human PBMCs than those of CpG ODN alone in vitro. The presence of CpG motif, but not modified phosphorothioate ODN backbone, was found to be critical for the enhanced immunostimulatory effects of CTB-CpG. Our mode-of-action studies, including studies on cells from specifically gene knockout mice suggest that similar to CpG, CTB-CpG exerts its immunostimulatory effects through a TLR9/MyD88- and NF-kappaB-dependent pathway. Surprisingly, and as opposed to CpG ODN, CTB-CpG-induced immunity was shown to be independent of endosomal acidification and resistant to inhibitory ODN. Furthermore, preincubation of CTB-CpG with GM1 ganglioside reduced the immunostimulatory effects of CTB-CpG to those of CpG ODN alone. Interestingly, conjugation of CpG ODN to CTB confers an enhanced cross-species activity to CpG ODN. Furthermore, using tetanus toxoid as a vaccine Ag for s.c. immunization, CTB-CpG markedly enhanced the Ag-specific IgG Ab response and altered the specific pattern of Ab isotypes toward a Th1 type response. To our knowledge, CTB is the first nontoxic derivative of microbial toxins discovered that when chemically linked to CpG remarkably augments the CpG-mediated immune responses.
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| 228. |
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| 229. |
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| 230. |
- Addolorato, Giovanni, et al.
(författare)
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Hormones and drinking behaviour: new findings on ghrelin, insulin, leptin and volume-regulating hormones. An ESBRA Symposium report.
- 2009
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Ingår i: Drug and alcohol review. - : Wiley. - 1465-3362 .- 0959-5236. ; 28:2, s. 160-5
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Tidskriftsartikel (refereegranskat)abstract
- There is growing evidence for a role of appetite-related peptides and volume-regulating hormones in alcoholism. In particular, recent evidence has suggested that hormones, such as ghrelin, insulin and leptin and volume-regulating hormones, could play a role in alcohol-seeking behaviour. The goal of this review is to discuss the results of recent preclinical and clinical investigations on this topic. The findings indicate that neuroendocrinological mechanisms are potentially involved in the neurobiology of alcohol craving. Accordingly, research on this topic could lead to possible development of new therapeutic approaches in the treatment of patients with alcohol problems.
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