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Taipale M.,Howard Hughes Medical Institute | Krykbaeva I.,Howard Hughes Medical Institute | Koeva M.,Howard Hughes Medical Institute | Kayatekin C.,Howard Hughes Medical Institute | And 4 more authors.
Cell | Year: 2012

HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family. © 2012 Elsevier Inc.


Mayo M.J.,UT Southwestern
Clinics in Liver Disease | Year: 2013

Primary biliary cirrhosis and primary sclerosing cholangitis share some clinical features with autoimmune hepatitis, but when features of autoimmune hepatitis are present, prognosis can be affected and immunosuppressive treatment warranted. The presence of severe interface hepatitis in primary biliary cirrhosis portends a worse prognosis and should prompt evaluation for possible autoimmune hepatitis overlap and treatment with immunosuppression. Specific models to identify which subjects benefit most from the addition of immunosuppression need to be developed. Drug-induced liver injury and IgG4 disease may masquerade as autoimmune hepatitis or primary sclerosing cholangitis and are important to consider in the differential diagnosis of the overlap or variant syndromes. © 2013 Elsevier Inc.


Dani K.A.,University of Glasgow | Warach S.,UT Southwestern
American Journal of Neuroradiology | Year: 2014

Measures of cerebral metabolism may be useful in the selection of patients for reperfusion therapies and as end points in clinical trials. However, there are currently no clinically routine techniques that provide such data directly. We review how imaging modalities in current clinical use may provide surrogate markers of metabolic activity. Promising techniques for metabolic imaging that are currently in the pipeline are reviewed.


Chhabra A.,UT Southwestern | Carrino J.,Hospital for Special Surgery
Seminars in Musculoskeletal Radiology | Year: 2015

MR neurography (MRN) techniques continue to evolve, leading to a better demonstration of peripheral nerve anatomy and pathology. This article discusses various technical perspectives and provides recommendations to obtain the best possible high-resolution imaging of the peripheral nerves in various areas of the body. We also discuss technical perspectives of whole-body MRN and its potential utility. © 2015 by Thieme Medical Publishers, Inc.


Background:Dynamic contrast-enhanced (DCE) MRI may provide prognostic insights into tumour radiation response. This study examined quantitative DCE MRI parameters in rat tumours, as potential biomarkers of tumour growth delay following single high-dose irradiation.Methods:Dunning R3327-AT1 prostate tumours were evaluated by DCE MRI following intravenous injection of Gd-DTPA. The next day tumours were irradiated (single dose of 30 Gy), while animals breathed air (n=4) or oxygen (n=4); two animals were non-irradiated controls. Growth was followed and tumour volume-quadrupling time (T4) was compared with pre-irradiation DCE assessments.Results:Irradiation caused significant tumour growth delay (T4 ranged from 28 to 48 days for air-breathing rats, and 40 to 75 days for oxygen-breathing rats) compared with the controls (T4=7 to 9 days). A strong correlation was observed between T4 and extravascular-extracellular volume fraction (ve) irrespective of the gas inhaled during irradiation. There was also a correlation between T4 and volume transfer constant (Ktrans) for the air-breathing group alone.Conclusions:The data provide rationale for expanded studies of other tumour sites, types and progressively patients, and are potentially significant, as many patients undergo contrast-enhanced MRI as part of treatment planning.British Journal of Cancer (2016) advance online publication, 3 May 2016; doi:10.1038/bjc.2016.110 www.bjcancer.com. © 2016 Cancer Research UK

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