ABSTRACT
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.
Subject(s)
DEAD-box RNA Helicases/genetics , Lung Neoplasms/genetics , MicroRNAs/genetics , Mutation , Pulmonary Blastoma/genetics , Ribonuclease III/genetics , Tumor Suppressor Protein p53/genetics , Base Sequence , Chromosomes, Human, Pair 5/genetics , DEAD-box RNA Helicases/metabolism , DNA Copy Number Variations , Exome/genetics , Female , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/chemistry , Nucleic Acid Conformation , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pulmonary Blastoma/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ribonuclease III/metabolism , Sequence Analysis, DNA/methods , Tumor Suppressor Protein p53/metabolismABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Quinazolines/therapeutic use , Receptor, ErbB-2/antagonists & inhibitors , Afatinib , Animals , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Cell Survival/drug effects , Disease Models, Animal , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Humans , Lung Neoplasms/pathology , Mice , Mice, Nude , Mice, Transgenic , NIH 3T3 Cells , Phosphorylation/drug effects , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Treatment Outcome , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Axons , Multiple Organ Failure/complications , Peripheral Nervous System Diseases/etiology , Aged , Female , Humans , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathologyABSTRACT
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.
Subject(s)
Epilepsies, Partial/diagnostic imaging , Organometallic Compounds , Oximes , Tomography, Emission-Computed , Adolescent , Adult , Aged , Child , Epilepsies, Partial/metabolism , Epilepsies, Partial/physiopathology , Female , Humans , Male , Middle Aged , Technetium Tc 99m ExametazimeABSTRACT
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.
