排序方式: 共有175条查询结果,搜索用时 31 毫秒
101.
Testa JR Cheung M Pei J Below JE Tan Y Sementino E Cox NJ Dogan AU Pass HI Trusa S Hesdorffer M Nasu M Powers A Rivera Z Comertpay S Tanji M Gaudino G Yang H Carbone M 《Nature genetics》2011,43(10):1022-1025
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention. 相似文献
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Wyatt AR Yerbury JJ Berghofer P Greguric I Katsifis A Dobson CM Wilson MR 《Cellular and molecular life sciences : CMLS》2011,68(23):3919-3931
The extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However,
little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular
chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed
between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared
more rapidly from circulation when complexed with CLU as a result of their more efficient localization to the liver and that
this clearance is delayed by pre-injection with the scavenger receptor inhibitor fucoidan. The CLU–client complexes were found
to bind preferentially, in a fucoidan-inhibitable manner, to human peripheral blood monocytes and isolated rat hepatocytes
and in the latter cell type were internalized and targeted to lysosomes for degradation. The data suggest, therefore, that
CLU plays a key role in an extracellular proteostasis system that recognizes, keeps soluble, and then rapidly mediates the
disposal of misfolded proteins. 相似文献
103.
Bender A Krishnan KJ Morris CM Taylor GA Reeve AK Perry RH Jaros E Hersheson JS Betts J Klopstock T Taylor RW Turnbull DM 《Nature genetics》2006,38(5):515-517
Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% +/- 9.3%; individuals with Parkinson disease, 52.3% +/- 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease. 相似文献
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CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer 总被引:19,自引:0,他引:19
Weisenberger DJ Siegmund KD Campan M Young J Long TI Faasse MA Kang GH Widschwendter M Weener D Buchanan D Koh H Simms L Barker M Leggett B Levine J Kim M French AJ Thibodeau SN Jass J Haile R Laird PW 《Nature genetics》2006,38(7):787-793
Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors. 相似文献
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Rothman N Garcia-Closas M Chatterjee N Malats N Wu X Figueroa JD Real FX Van Den Berg D Matullo G Baris D Thun M Kiemeney LA Vineis P De Vivo I Albanes D Purdue MP Rafnar T Hildebrandt MA Kiltie AE Cussenot O Golka K Kumar R Taylor JA Mayordomo JI Jacobs KB Kogevinas M Hutchinson A Wang Z Fu YP Prokunina-Olsson L Burdett L Yeager M Wheeler W Tardón A Serra C Carrato A García-Closas R Lloreta J Johnson A Schwenn M Karagas MR Schned A Andriole G Grubb R Black A Jacobs EJ Diver WR Gapstur SM 《Nature genetics》2010,42(11):978-984
We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis. 相似文献
108.
Building on Norton's “material theory of induction,” this paper shows through careful historical analysis that analogy can act as a methodological principle or stratagem, providing experimentalists with a useful framework to assess data and devise novel experiments. Although this particular case study focuses on late eighteenth and early nineteenth-century experiments on the properties and composition of acids, the results of this investigation may be extended and applied to other research programs. A stage in-between what Steinle calls “exploratory experimentation” and robust theory, I argue that analogy encouraged research to substantiate why the likenesses should outweigh the differences (or vice versa) when evaluating results and designing experiments. 相似文献
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Pauline De Berdt Pauline Bottemanne John Bianco Mireille Alhouayek Anibal Diogenes Amy Llyod Jose Gerardo-Nava Gary A. Brook Véronique Miron Giulio G. Muccioli Anne des Rieux 《Cellular and molecular life sciences : CMLS》2018,75(15):2843-2856
Secondary damage following spinal cord injury leads to non-reversible lesions and hampering of the reparative process. The local production of pro-inflammatory cytokines such as TNF-α can exacerbate these events. Oligodendrocyte death also occurs, followed by progressive demyelination leading to significant tissue degeneration. Dental stem cells from human apical papilla (SCAP) can be easily obtained at the removal of an adult immature tooth. This offers a minimally invasive approach to re-use this tissue as a source of stem cells, as compared to biopsying neural tissue from a patient with a spinal cord injury. We assessed the potential of SCAP to exert neuroprotective effects by investigating two possible modes of action: modulation of neuro-inflammation and oligodendrocyte progenitor cell (OPC) differentiation. SCAP were co-cultured with LPS-activated microglia, LPS-activated rat spinal cord organotypic sections (SCOS), and LPS-activated co-cultures of SCOS and spinal cord adult OPC. We showed for the first time that SCAP can induce a reduction of TNF-α expression and secretion in inflamed spinal cord tissues and can stimulate OPC differentiation via activin-A secretion. This work underlines the potential therapeutic benefits of SCAP for spinal cord injury repair. 相似文献