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- Alvarez, Mariano J., et al.
(författare)
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A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
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Tidskriftsartikel (refereegranskat)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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- Baylis, Kathy, et al.
(författare)
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Mainstreaming Impact Evaluation in Nature Conservation
- 2016
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Ingår i: Conservation Letters. - : Wiley. - 1755-263X. ; 9:1, s. 58-64
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- An important part of conservation practice is the empirical evaluation of program and policy impacts. Understanding why conservation programs succeed or fail is essential for designing cost-effective initiatives and for improving the livelihoods of natural resource users. The evidence we seek can be generated with modern impact evaluation designs. Such designs measure causal effects of specific interventions by comparing outcomes with the interventions to outcomes in credible counterfactual scenarios. Good designs also identify the conditions under which the causal effect arises. Despite a critical need for empirical evidence, conservation science has been slow to adopt these impact evaluation designs. We identify reasons for the slow rate of adoption and provide suggestions for mainstreaming impact evaluation in nature conservation.
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- Hewett, D., et al.
(författare)
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Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map
- 2002
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 0888-7543. ; 79:3, s. 305-14
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Here we describe the creation of a single-nucleotide polymorphism (SNP) map spanning 900-1200 kb of chromosome 3q21, which had been previously recognized as containing a psoriasis susceptibility locus, PSORS5. We genotyped 644 individuals, from 195 Swedish psoriatic families, for 19 polymorphisms. Linkage disequilibrium (LD) between marker and disease was assessed using the transmission/disequilibrium test (TDT). In the TDT analysis, alleles of three of these SNPs showed significant association with disease (P<0.05). A 160-kb interval encompassing these three SNPs was sequenced, and a coding sequence consisting of 13 exons was identified. The predicted protein shares 30-40% homology with the family of cation/chloride cotransporters. A five-marker haplotype spanning the 3' half of this gene is associated with psoriasis to a P value of 3.8<10(-5). We have called this gene SLC12A8, coding for a member of the solute carrier family 12 proteins. It belongs to a class of genes that were previously unrecognized as playing a role in psoriasis pathogenesis.
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