ABSTRACT
Several operations in cardiothoracic surgery have been accurately modeled with tissue-based simulations. These have been shown to be beneficial in the training of residents. Cardiac transplantation has not been simulated. We describe a high-fidelity, tissue-based simulation that can be used to teach trainees to perform a cardiac transplant. We modified the existing Ramphal Cardiac Surgery Simulator to accommodate cardiac transplantation. An attending cardiac surgeon successfully performed the simulated transplant, demonstrating each of the component tasks of the operation. We believe our simulation will enhance the training of cardiothoracic surgery residents.
Subject(s)
Clinical Competence , Education, Medical, Graduate/methods , Heart Transplantation/education , Internship and Residency/methods , Simulation Training/methods , Thoracic Surgery/education , Curriculum , HumansABSTRACT
Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.
Subject(s)
Janus Kinase 2/physiology , Polycythemia/etiology , Suppressor of Cytokine Signaling Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Animals , Disease Models, Animal , Humans , Janus Kinase 2/antagonists & inhibitors , Mice , Mutation/genetics , Polycythemia/genetics , Protein Multimerization/genetics , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins/physiology , Ubiquitin-Protein Ligases/physiology , Von Hippel-Lindau Tumor Suppressor Protein/physiologyABSTRACT
Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2alpha levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2alpha is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2alpha and a mutant form of Kras (KrasG12D) that induces lung tumors. Mice expressing both Hif2a and KrasG12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only KrasG12D. Additionally, tumors expressing both KrasG12D and Hif2a were more invasive, demonstrated features of epithelial- mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2alpha causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2alpha can promote expression of markers of EMT, and define HIF2alpha as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2alpha and prognosis in patients with NSCLC.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , Lung Neoplasms/etiology , Proto-Oncogene Proteins p21(ras)/physiology , Animals , Cell Differentiation , Endothelium/pathology , Gene Expression Profiling , Humans , Lung Neoplasms/blood supply , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Mesoderm/pathology , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness , Organic Cation Transport Proteins/geneticsABSTRACT
After decades of therapeutic nihilism in the treatment of advanced renal cell carcinoma, remarkable therapeutic strides have been made over the last few years. Early forays into molecularly targeted therapy for this difficult-to-treat disease were based around the inhibition of gene products of the hypoxia-inducible factor (HIF) transcription factor (i.e., VEGF). Recent data suggest that inhibition of mTOR results in clinical benefit in patients with poor prognostic features, and in preclinical models this therapeutic effect involves downregulation of HIF. Intriguingly, patients with nonclear cell histology appeared to obtain clinical benefit when treated with mTOR inhibitors. This review will highlight the mTOR pathway, its relevance to both clear cell and nonclear cell renal cell carcinoma, and its place in the host of quickly expanding treatment options.