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21.
Jacobs KB Yeager M Zhou W Wacholder S Wang Z Rodriguez-Santiago B Hutchinson A Deng X Liu C Horner MJ Cullen M Epstein CG Burdett L Dean MC Chatterjee N Sampson J Chung CC Kovaks J Gapstur SM Stevens VL Teras LT Gaudet MM Albanes D Weinstein SJ Virtamo J Taylor PR Freedman ND Abnet CC Goldstein AM Hu N Yu K Yuan JM Liao L Ding T Qiao YL Gao YT Koh WP Xiang YB Tang ZZ Fan JH Aldrich MC Amos C Blot WJ Bock CH Gillanders EM Harris CC Haiman CA Henderson BE Kolonel LN Le Marchand L McNeill LH 《Nature genetics》2012,44(6):651-658
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases. 相似文献
22.
Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis 总被引:25,自引:0,他引:25
Pepys MB Herbert J Hutchinson WL Tennent GA Lachmann HJ Gallimore JR Lovat LB Bartfai T Alanine A Hertel C Hoffmann T Jakob-Roetne R Norcross RD Kemp JA Yamamura K Suzuki M Taylor GW Murray S Thompson D Purvis A Kolstoe S Wood SP Hawkins PN 《Nature》2002,417(6886):254-259
The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes. 相似文献
23.
Prideaux GJ Long JA Ayliffe LK Hellstrom JC Pillans B Boles WE Hutchinson MN Roberts RG Cupper ML Arnold LJ Devine PD Warburton NM 《Nature》2007,445(7126):422-425
How well the ecology, zoogeography and evolution of modern biotas is understood depends substantially on knowledge of the Pleistocene. Australia has one of the most distinctive, but least understood, Pleistocene faunas. Records from the western half of the continent are especially rare. Here we report on a diverse and exceptionally well preserved middle Pleistocene vertebrate assemblage from caves beneath the arid, treeless Nullarbor plain of south-central Australia. Many taxa are represented by whole skeletons, which together serve as a template for identifying fragmentary, hitherto indeterminate, remains collected previously from Pleistocene sites across southern Australia. A remarkable eight of the 23 Nullarbor kangaroos are new, including two tree-kangaroos. The diverse herbivore assemblage implies substantially greater floristic diversity than that of the modern shrub steppe, but all other faunal and stable-isotope data indicate that the climate was very similar to today. Because the 21 Nullarbor species that did not survive the Pleistocene were well adapted to dry conditions, climate change (specifically, increased aridity) is unlikely to have been significant in their extinction. 相似文献