RESUMO
Oncogenic mutations in PIK3CA, which encodes the phosphoinositide-3-kinase (PI3K) catalytic subunit p110α, occur in â¼25% of human breast cancers. In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types. Whole-exome analysis of the Pik3ca(H1047R)-driven mammary tumors identified multiple mutations, including Trp53 mutations that appeared spontaneously during the development of adenocarinoma and spindle cell tumors. Further, we used this model to test the efficacy of GDC-0941, a PI3K inhibitor, in clinical development, and showed that the tumors respond to PI3K inhibition.
Assuntos
Técnicas de Introdução de Genes , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Alelos , Animais , Sequência de Bases , Classe I de Fosfatidilinositol 3-Quinases , Ativação Enzimática/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica , Humanos , Camundongos , Especificidade de Órgãos , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteína Supressora de Tumor p53/genéticaRESUMO
This study creates a compendium of gene expression in normal human tissues suitable as a reference for defining basic organ systems biology. Using oligonucleotide microarrays, we analyze 59 samples representing 19 distinct tissue types. Of approximately 7,000 genes analyzed, 451 genes are expressed in all tissue types and designated as housekeeping genes. These genes display significant variation in expression levels among tissues and are sufficient for discerning tissue-specific expression signatures, indicative of fundamental differences in biochemical processes. In addition, subsets of tissue-selective genes are identified that define key biological processes characterizing each organ. This compendium highlights similarities and differences among organ systems and different individuals and also provides a publicly available resource (Human Gene Expression Index, the HuGE Index, http://www.hugeindex.org) for future studies of pathophysiology.
Assuntos
Biologia Computacional/normas , Bases de Dados Genéticas , Perfilação da Expressão Gênica/normas , Expressão Gênica , Especificidade de Órgãos/genética , Análise por Conglomerados , Feminino , Variação Genética , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Valores de ReferênciaRESUMO
Pressure sores cause significant mortality and morbidity as well as being a financial burden on health-care services. Reduction of pressure sore incidence is a Department of Health priority. Pressure sores are accepted as largely preventable complications of illness and disability and the means to achieve prevention are available. The aim of this clinical audit was to identify potential contributing factors to pressure sore acquisition in an acute hospital setting. The results suggest that substantial changes in the approach to clinical management may be needed.
