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PURPOSE Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the(More)
PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers.(More)
Integrins are heterodimeric cell-surface receptors that link the extracellular matrix and the intracellular cytoskeleton and function as mechanotransducers. Signaling through integrins is important for cell growth, migration, and survival. Extracellular matrix is altered in the myocardium during hypertrophic induction and the transition to heart failure.(More)
Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of(More)
The possibility that the deleterious renal effects of positive end-expiratory pressure (PEEP) might be avoided by prevention of its attendant cardiovascular effects with increasing intravascular volume was investigated in two groups of anesthetized swine. Group 1 (12 swine) were maintained at a normovolemic state and Group 2 (11 swine) were volume expanded(More)
Topical anesthesia of oropharynx with lidocaine aerosol (6 ml of 4% for 5 min) prevented hypertension and tachycardia during laryngoscopy and tracheal intubation. In the control group (saline aerosol), systolic and mean BP as well as heart rate (HR) significantly increased during laryngoscopy and intubation. These changes were still present after 5 min. No(More)
Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by(More)
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