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- Thompson, B.A., et al.
(författare)
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Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:2, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.
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- Cusminsky, Gabriela, et al.
(författare)
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Late quaternary environmental changes in Patagonia as inferred from lacustrine fossil and extant ostracods
- 2011
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Ingår i: Biological Journal of the Linnean Society. - : Oxford University Press (OUP). - 0024-4066. ; 103:2, s. 397-408
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we compare modern and Quaternary ostracods from two lacustrine basins: Laguna Cari-Laufquen (41 degrees S) and Lago Cardiel (49 degrees S) in Patagonia. Taxonomic and quantitative analyses along with isotopic and chemical studies of the extant ostracod fauna indicate that distinct ostracod associations can be identified as a function of conductivity. Three ostracod associations can be distinguished: (1) springs, ponds and small creeks, characterized by low conductivity (e. g. 1015 ms cm(-1)); (2) lakes and permanent ponds, characterized by medium conductivity (e. g. 1625 ms cm(-1)) and (3) ephemeral lacustrine environments, generally characterized by higher conductivity (e. g. 16 480 ms cm(-1)) These modern ostracod associations were also identified in older sequences from sediments outcropping in the Laguna Cari-Laufquen current shoreline, as well as in sediment cores from Lago Cardiel. The predominance of Limnocythere rionegroensis Cusminsky & Whatley in the Cari-Laufquen sections suggests the development of a saline and turbid lake during the Late Pleistocene and Early Holocene, and thus higher precipitation at these latitudes. Changes in ostracod abundance and associations have been observed in Lago Cardiel during the last approximately 16 000 calibrated years BP. Conductivity is known to change as a function of the ratio of precipitation to evaporation and a decrease in conductivity from the Late Pleistocene to the Middle Holocene suggests substantial hydrological variations (i. e. increase of the precipitation/ evaporation ratio suggests minor conductivity). These two examples show that ostracods provide an excellent proxy for interpreting palaeoclimatic and palaeoenvironmental changes in Patagonia. (C) 2011 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 103, 397-408.
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- Lundgren, Katja, et al.
(författare)
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Effects of cyclin D-1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study
- 2012
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-542X .- 1465-5411. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D-1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen. Methods: To clarify these challenging and partly contrasting treatment predictive and prognostic links for cyclin D-1 we analysed a large cohort of postmenopausal breast cancer patients randomised to receive either adjuvant anastrozole or tamoxifen, as part of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The CCND1 amplification status and protein expression of cyclin D-1 were assessed by chromogenic in situ hybridisation and immunohistochemistry, respectively, in 1,155 postmenopausal, oestrogen-receptor-positive breast cancer patients included in the TransATAC substudy. Results: Amplification of CCND1 was observed in 8.7% of the tumours and was associated with increased risk of disease recurrence (hazard ratio = 1.61; 95% confidence interval, 1.08 to 2.41) after adjustment for other clinicopathological parameters. In contrast, nuclear expression of cyclin D-1 protein was associated with decreased recurrence rate (hazard ratio = 0.6; 95% confidence interval, 0.39 to 0.92). The intensity of nuclear or cytoplasmic expression was not of prognostic value. There was no significant interaction between cyclin D-1 status and treatment efficacy, ruling out any major detrimental effect of tamoxifen in CCND1-amplified postmenopausal breast cancer. Conclusions: In summary, CCND1 amplification and low nuclear expression of cyclin D-1 predicted poor clinical outcome in postmenopausal breast cancer patients treated with either anastrozole or tamoxifen.
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- Raum, Jeffrey C, et al.
(författare)
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Islet {beta}-cell-specific MafA transcription requires the 5'-flanking conserved Region 3 control domain.
- 2010
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Ingår i: Molecular and Cellular Biology. - 0270-7306. ; 30:17, s. 4234-4244
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Tidskriftsartikel (refereegranskat)abstract
- MafA is a key transcriptional activator of islet beta cells and its exclusive expression within beta cells of the developing and adult pancreas is distinct amongst pancreatic regulators. Region 3 (base pairs -8118/-7750 relative to the transcription start site), one of six conserved 5' cis-domains of the MafA promoter, is capable of directing beta-cell-line-selective expression. Transgenic reporters of Region 3 alone (R3), sequences spanning Regions 1-6 (R1-6; base pairs -10428/+230), and R1-6 lacking Region 3 (R1-6(DeltaR3)) were generated. Only the R1-6 transgene was active in MafA(+) insulin(+) cells during development and in adults. R1-6 also mediated glucose-induced MafA expression. Conversely, pancreatic expression was not observed with the R3 or R1-6(DeltaR3) lines, although much of the non-pancreatic expression pattern was shared between the R1-6 and R1-6(DeltaR3) lines. Further support for the importance of Region 3 was shown as the islet regulators Nkx6.1 and Pax6, but not NeuroD1 activated MafA using gel shift, chromatin immunoprecipitation (ChIP), transfection assays, and in vivo mouse knockout models. Lastly ChIP demonstrated that Pax6 and Pdx-1 bound also to Regions 1 and 6, potentially functioning in pancreatic and non-pancreatic expression. These data highlight the nature of the cis- and trans-acting factors controlling the beta-3cell-specific expression of MafA.
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