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Salt Lake City, UT, United States

Cohen A.L.,Huntsman Cancer Institute | Holmen S.L.,University of Utah | Colman H.,University of Utah
Current Neurology and Neuroscience Reports | Year: 2013

Mutations in isocitrate dehydrogenase (IDH) 1 and 2, originally discovered in 2008, occur in the vast majority of low-grade gliomas and secondary high-grade gliomas. These mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2-hydroxyglutarate, a possible oncometabolite, and to not produce NADPH. IDH mutations are oncogenic, although whether the mechanism is through alterations in hydroxylases, redox potential, cellular metabolism, or gene expression is not clear. The mutations also drive increased methylation in gliomas. Gliomas with mutated IDH1 and IDH2 have improved prognosis compared with gliomas with wild-type IDH. Mutated IDH can now be detected by immunohistochemistry and magnetic resonance spectroscopy. No drugs currently target mutated IDH, although this remains an area of active research. © Springer Science+Business Media New York 2013. Source

Sborov D.W.,Ohio State University | Rodgers G.M.,Huntsman Cancer Institute | Rodgers G.M.,University of Utah
British Journal of Haematology | Year: 2013

Acquired haemophilia A (AHA) is a potentially life-threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune-mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. There exists great potential for morbidity and mortality related to acute and recurrent bleeding episodes, making prompt diagnosis and treatment necessary. The two primary goals of treatment focus on cessation of bleeding and eradication of the acquired factor VIII inhibitor. No randomized clinical trials have been conducted regarding treatment, so expert clinical opinion guides therapeutic intervention. This current report provides a profile of patient characteristics, an algorithm for diagnosis, and outlines treatment recommendations based upon current guidelines and clinical experience. As first-line interventions for acute bleeding and inhibitor eradication are generally accepted, we will emphasize discussion of second-line therapeutic options. © 2013 Blackwell Publishing Ltd. Source

Meyer K.D.,University of Colorado at Boulder | Meyer K.D.,Huntsman Cancer Institute | Lin S.-C.,University of Colorado at Boulder | Bernecky C.,University of Colorado at Boulder | And 2 more authors.
Nature Structural and Molecular Biology | Year: 2010

It is not well understood how the human Mediator complex, transcription factor IIH and RNA polymerase II (Pol II) work together with activators to initiate transcription. Activator binding alters Mediator structure, yet the functional consequences of such structural shifts remain unknown. The p53 C terminus and its activation domain interact with different Mediator subunits, and we find that each interaction differentially affects Mediator structure; strikingly, distinct p53-Mediator structures differentially affect Pol II activity. Only the p53 activation domain induces the formation of a large pocket domain at the Mediator-Pol II interaction site, and this correlates with activation of stalled Pol II to a productively elongating state. Moreover, we define a Mediator requirement for TFIIH-dependent Pol II C-terminal domain phosphorylation and identify substantial differences in Pol II C-terminal domain processing that correspond to distinct p53-Mediator structural states. Our results define a fundamental mechanism by which p53 activates transcription and suggest that Mediator structural shifts trigger activation of stalled Pol II complexes. © 2010 Nature America, Inc. All rights reserved. Source

Jasperson K.W.,Huntsman Cancer Institute
Cancer Journal (United States) | Year: 2012

Hereditary colonic polyposis conditions are all characterized by high rates of cancer, but they have diverse phenotypes, genetic heterogeneity, and assorted inheritance patterns. The most well known of these conditions include familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH (MutY human homolog)-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. Early recognition of these conditions is not only vital for management in affected individuals, but also for prevention and early detection in at-risk relatives. Reviewed here are the genetic testing strategies for colonic polyposis, as well as an overview of characteristic features and management considerations for these syndromes. Copyright © 2012 by Lippincott Williams & Wilkins. Source

Ragel B.T.,Oregon Health And Science University | Jensen R.L.,Huntsman Cancer Institute
Journal of Neuro-Oncology | Year: 2010

In this article, we provide a brief description of the current understanding of aberrant signaling pathways in meningiomas. Cell signaling pathways are responsible for cellular differentiation, development, growth, growth inhibition, and death. In fact, signaling pathways can affect multiple intracellular functions, including those responsible for development, angiogenesis, and apoptosis. Ultimately, a further understanding of the signaling pathways involved in meningioma tumorigenesis will lead to the development and application of novel molecular treatments, such as small molecule inhibitors or interfering ribonucleic acid technologies. © 2010 Springer Science+Business Media, LLC. Source

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