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- Bandopadhayay, Pratiti, et al.
(författare)
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BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
- 2014
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.Experimental Design:We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.Results:Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.Conclusion:JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
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| 2. |
- McMahon, Barry J., et al.
(författare)
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Genetic variation among endangered Irish red grouse (Lagopus lagopus hibernicus) populations : implications for conservation and management
- 2012
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Ingår i: Conservation Genetics. - : Springer Science and Business Media LLC. - 1566-0621 .- 1572-9737. ; 13:3, s. 639-647
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Tidskriftsartikel (refereegranskat)abstract
- Extant populations of Irish red grouse (Lagopus lagopus hibernicus) are both small and fragmented, and as such may have an increased risk of extinction through the effects of inbreeding depression and compromised adaptive potential. Here we used 19 microsatellite markers to assay genetic diversity across 89 georeferenced samples from putatively semi-isolated areas throughout the Republic of Ireland and we also genotyped 27 red grouse from Scotland using the same markers. The genetic variation within Ireland was low in comparison to previously published data from Britain and the sample of Scottish red grouse, and comparable to threatened European grouse populations of related species. Irish and Scottish grouse were significantly genetically differentiated (F-ST = 0.07, 95% CI = 0.04-0.10). There was evidence for weak population structure within Ireland with indications of four distinct genetic clusters. These correspond approximately to grouse populations inhabiting suitable habitat patches in the North West, Wicklow Mountains, Munster and Cork, respectively, although some admixture was detected. Pair-wise F-ST values among these populations ranged from 0.02 to 0.04 and the overall mean allelic richness was 5.5. Effective population size in the Munster area was estimated to be 62 individuals (95% CI = 33.6-248.8). Wicklow was the most variable population with an AR value of 5.4 alleles/locus. Local (Munster) neighbourhood size was estimated to 31 individuals corresponding to an average dispersal distance of 31 km. In order to manage and preserve Irish grouse we recommend that further fragmentation and destruction of habitats need to be prevented in conjunction with population management, including protection of the integrity of the existing population by refraining from augmenting it with individuals from mainland Britain to maximise population size.
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| 3. |
- Mulchrone, Kieran F., et al.
(författare)
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Constraining the strain ellipsoid and deformation parameters using deformed single layers : A computational approach assuming pure shear and isotropic volume change
- 2014
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Ingår i: Journal of Structural Geology. - : Elsevier BV. - 0191-8141 .- 1873-1201. ; 62, s. 194-206
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Tidskriftsartikel (refereegranskat)abstract
- If the deformation history of individual layers in a deformed rock mass can be appropriately analysed and categorised then the surface of no elongation (snoe) and the surface of no infinitesimal elongation (snoie) may be identified. A computational approach to automatically identify the polar snoe and snoie is presented and tested on synthetic and natural examples. Additionally the equations that allow extraction of parameter values, which quantify the deformation, are derived here. Two fundamental assumptions are made: 1) the progressive deformation is pure shear and 2) the associated volume change is isotropic. The proposed method is tested using data generated from known deformation sequences and is found to work reasonably well. However, as is the case with most methods of analysis, suitable data with a wide range of orientations is required for reliable results.
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