RESUMO
Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.
Assuntos
RNA Helicases DEAD-box/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Mutação , Blastoma Pulmonar/genética , Ribonuclease III/genética , Proteína Supressora de Tumor p53/genética , Sequência de Bases , Cromossomos Humanos Par 5/genética , RNA Helicases DEAD-box/metabolismo , Variações do Número de Cópias de DNA , Exoma/genética , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/química , Conformação de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Blastoma Pulmonar/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonuclease III/metabolismo , Análise de Sequência de DNA/métodos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Afatinib , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Células NIH 3T3 , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Complications involving the peripheral nervous system known as CIP have been reported during the course of prolonged sepsis and MOFS. These may be differentiated from Guillain-Barré's syndrome by their electrophysiological characteristics of axonal neuronal damage and the normality of spinal fluid tests. The Authors report and discuss a case which was brought to their attention.
Assuntos
Axônios , Insuficiência de Múltiplos Órgãos/complicações , Doenças do Sistema Nervoso Periférico/etiologia , Idoso , Feminino , Humanos , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologiaRESUMO
We used 99mTc HM-PAO SPECT to study 50 patients with partial epilepsy: 47 interictally and 3 during a seizure. All 3 patients studied during a seizure presented an area of increased tracer uptake. Of those in whom recordings were taken during seizure-free intervals 35 (74%) showed perfusion asymmetries: 27 (57%) with decreased and 8 (17%) with increased uptake. We discuss the findings and compare them with those of similar studies using SPECT and positron emission tomography.
Assuntos
Epilepsias Parciais/diagnóstico por imagem , Compostos Organometálicos , Oximas , Tomografia Computadorizada de Emissão , Adolescente , Adulto , Idoso , Criança , Epilepsias Parciais/metabolismo , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tecnécio Tc 99m ExametazimaRESUMO
A descriptive epidemiological survey conducted in Turin on a population of 1,065,304 in Jan. 1-June 30 1984, produced preliminary data on the incidence of MS. Given the restricted area and brief duration of the survey, such data are however purely indicative. Primarily clinical criteria supported by instrumental and laboratory tests (P., Ev., liquor) were uniformly adopted.
