Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation.

Abstract: BackgroundGenetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. MethodsWe performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse. ResultsTP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P<0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with...

Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis.

Abstract: Effector T cell responses can be modulated by competing positive or negative signals transduced by natural killer (NK) cell receptors. This raises the possibility that dominant T cell stimulation might promote autoimmune reactions. In rheumatoid arthritis (RA), the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4+CD28– T cells, which are scarce in healthy individuals. For poorly defined reasons, these T cells are autoreactive, implying that they may contribute to disease manifestations. CD4+CD28– T cells in peripheral blood and synovial tissue of RA patients were found to express NKG2D, a costimulatory receptor that is absent on normal CD4 T cells. NKG2D was induced by tumor necrosis factor α and IL-15, which are abundant in inflamed synovia and RA patient sera. RA synoviocytes aberrantly expressed the stress-inducible MIC ligands of NKG2D, which stimulated autologous CD4+CD28– T cell cytokine and proliferative responses. Peripheral blood serum samples of RA patients contained substantial amounts of synoviocyte-derived soluble MICA, which failed to induce down-modulation of NKG2D because of the opposing activity of tumor necrosis factor α and IL-15. These results suggest that a profound dysregulation of NKG2D and its MIC ligands may cause autoreactive T cell stimulation, thus promoting the self-perpetuating pathology in RA and possibly other autoimmune diseases.

RNA splicing factors as oncoproteins and tumour suppressors

Abstract: This Review discusses the current genetic and functional links between dysregulated and/or mutated RNA splicing factors and cancer, as well as the therapeutic opportunities presented by alterations in alternative splicing in cancer. The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these 'spliceosomal mutations' suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic and biological effects of spliceosomal mutations are crucial for the development of cancer therapies targeted at these mutations.