| 1. |
- Crowther-Swanepoel, Dalemari, et al.
(författare)
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Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 132-136
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.
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| 2. |
- den Hollander, J, et al.
(författare)
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Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 116:9, s. 1498-1505
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Tidskriftsartikel (refereegranskat)abstract
- Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant-Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function. (Blood. 2010;116(9):1498-1505)
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| 3. |
- Low, Yen Ling, et al.
(författare)
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Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility
- 2010
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:7, s. e1001012-
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Tidskriftsartikel (refereegranskat)abstract
- Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (rho(global) = 0.034) and endometrial (rho(global) = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (rho(global) = 0.008) and endometrial cancer (rho(global) = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (rho(global) = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (rho(global) = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen-estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.
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| 4. |
- Omar, Omar, et al.
(författare)
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In vivo gene expression in response to anodically oxidized versus machined titanium implants.
- 2010
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Ingår i: Journal of biomedical materials research. Part A. - : Wiley. - 1552-4965 .- 1549-3296. ; 92:4, s. 1552-1566
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Tidskriftsartikel (refereegranskat)abstract
- A quantitative polymerase chain reaction technique (qPCR) in combination with scanning electron microscopy was applied for the evaluation of early gene expression response and cellular reactions close to titanium implants. Anodically oxidized and machined titanium miniscrews were inserted in rat tibiae. After 1, 3, and 6 days the implants were unscrewed and the surrounding bone was retrieved using trephines. Both the implants and bone were analyzed with qPCR. A greater amount of cells, as indicated with higher expression of 18S, was detected on the oxidized surface after 1 and 6 days. Significantly higher osteocalcin (at day 6), alkaline phosphatase (at days 3 and 6), and cathepsin K (at day 3) expression was demonstrated for the oxidized surface. Higher expression of tumor necrosis factor-alpha (at day 1) and interleukin-1beta (at days 1 and 6) was detected on the machined surfaces. SEM revealed a higher amount of mesenchymal-like cells on the oxidized surface. The results show that the rapid recruitment of mesenchymal cells, the rapid triggering of gene expression crucial for bone remodeling and the transient nature of inflammation, constitute biological mechanisms for osseointegration, and high implant stability associated with anodically oxidized implants. (c) 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2009.
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| 5. |
- Omar, Omar, et al.
(författare)
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Integrin and chemokine receptor gene expression in implant-adherent cells during early osseointegration.
- 2010
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Ingår i: Journal of materials science. Materials in medicine. - : Springer Science and Business Media LLC. - 1573-4838 .- 0957-4530. ; 21:3, s. 969-80
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms of early cellular recruitment and interaction to titanium implants are not well understood. The aim of this study was to investigate the expression of pro-inflammatory cytokines, chemokines and adhesion markers during the first 24 h of implantation. Anodically oxidized and machined titanium implants were inserted in rat tibia. After 3, 12, and 24 h the implants were unscrewed and analyzed with quantitative polymerase chain reaction. Immunohistochemistry and scanning electron microscopy revealed different cell types, morphology and adhesion at the two implant surfaces. A greater amount of cells, as indicated by higher expression of small subunit ribosomal RNA (18S), was detected on the oxidized surface. Higher expression of CXC chemokine receptor-4 (at 12 h) and integrins, alphav (at 12 h), beta1 (at 24 h) and beta2 (at 12 and 24 h) was detected at the oxidized surfaces. Significantly higher tumor necrosis factor-alpha (at 3 h) and interleukin-1beta (at 24 h) expression was demonstrated for the machined surface. It is concluded that material surface properties rapidly modulate the expression of receptors important for the recruitment and adhesion of cells which are crucial for the inflammatory and regenerative processes at implant surfaces in vivo.
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