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1.
Accid Anal Prev ; 55: 274-81, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23598087

ABSTRACT

Real-world retrospective evaluation of the safety benefits of new integrated safety technologies is hampered by the lack of sufficient data to assess early reliable benefits. This MUNDS study set out to examine if a "prospective" case-control meta-analysis had the potential to provide more rapid and rigorous analyses of vehicle and infrastructure safety improvements. To examine the validity of the approach, an analysis of the effectiveness of ESC using a consistent analytic strategy across 6 European and Australasian databases was undertaken. It was hypothesised that the approach would be valid if the results of the MUNDS analysis were consistent with those published earlier (this would confirm the suitability of the MUNDS approach). The findings confirm the hypothesis and also found stronger and more robust findings across the range of crash-types, road conditions, vehicle sizes and speed zones than previous. The study recommends that while a number of limitations were identified with the findings that need be addressed in future research, the MUNDS approach nevertheless should be adopted widely for the benefit of all vehicle occupants.


Subject(s)
Accidents, Traffic/prevention & control , Automobiles , Protective Devices , Technology , Australia , Case-Control Studies , Finland , Humans , Italy , New Zealand , Prospective Studies , Regression Analysis , Sweden , United Kingdom
2.
Hum Mol Genet ; 19(14): 2804-16, 2010 Jul 15.
Article in English | MEDLINE | ID: mdl-20442138

ABSTRACT

The tyrosine kinase receptor RET51 is expressed in distinct families of neurons where it promotes different functions. FKBP52 is an immunophilin with neuroprotective effects on different kinds of neurons. In this paper, we demonstrate that RET51 activation by both glial cell line-derived neurotrophic factor (GDNF) and NGF triggers the formation of RET51/FKBP52 complex. The substitution of the tyrosine 905 of RET51, a key residue phosphorylated by both GDNF and NGF, disrupts the RET51/FKBP52 complex. NGF and GDNF have a functional role in dopaminergic (DA) neurons where RET51 and FKBP52 are expressed with a yet undefined function. To clarify if RET51/FKBP52 complex should exert its function in DA neurons, we used an indirect approach by screening the genes encoding for RET51 and FKBP52 in a group of 30 Parkinson's disease patients. The degeneration of DA neurons is the main feature of PD, which is associated to a complex multifactorial aetiology combining environmental, age-related and genetic factors. We found a compound heterozygous carrying two mutations in RET and FKBP52 that are sufficient to disrupt the RET51/FKBP52 complex, indicating its potential role in PD.


Subject(s)
Parkinson Disease/etiology , Proto-Oncogene Proteins c-ret/metabolism , Proto-Oncogene Proteins c-ret/physiology , Tacrolimus Binding Proteins/metabolism , Tacrolimus Binding Proteins/physiology , Adult , Cell Line , Female , Genetic Association Studies , Genetic Testing , Glial Cell Line-Derived Neurotrophic Factor/pharmacology , Humans , Male , Middle Aged , Models, Biological , Multiprotein Complexes/chemistry , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Multiprotein Complexes/physiology , Nerve Growth Factor/pharmacology , Parkinson Disease/genetics , Parkinson Disease/metabolism , Phosphorylation , Protein Binding/drug effects , Protein Interaction Domains and Motifs/genetics , Protein Interaction Mapping , Protein Kinases/metabolism , Proto-Oncogene Proteins c-ret/chemistry , Proto-Oncogene Proteins c-ret/genetics , Tacrolimus Binding Proteins/chemistry , Tacrolimus Binding Proteins/genetics , Young Adult
3.
Hum Mol Genet ; 19(6): 1019-32, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20028790

ABSTRACT

We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors of the thyroid and kidney. We here report a high frequency of homoplasmic disruptive mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicates disassembly of respiratory complex I in vivo which in turn contributes to the inability of oncocytic tumors to stabilize HIF1alpha and to display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced the shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 gene. Such shift is associated with a profound metabolic impairment leading to the imbalance of alpha-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1alpha stabilization. We conclude that the main hallmarks of oncocytic transformation, namely the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1alpha stabilization.


Subject(s)
Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Cell Hypoxia , Cell Respiration , DNA, Mitochondrial/genetics , Electron Transport Complex I/metabolism , Fumarate Hydratase/genetics , Head and Neck Neoplasms/enzymology , Head and Neck Neoplasms/genetics , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Ketoglutaric Acids/metabolism , Mutation/genetics , NADH Dehydrogenase/genetics , Phenotype , Protein Biosynthesis , Protein Stability , RNA, Transfer/genetics , Reactive Oxygen Species/metabolism , Succinate Dehydrogenase/genetics , Succinic Acid/metabolism
4.
Hum Mutat ; 30(3): 391-6, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19086058

ABSTRACT

A disruptive frameshift mtDNA mutation affecting the ND5 subunit of complex I is present in homoplasmy in a nasopharyngeal oncocytic tumor and inherited as a heteroplasmic germline mutation recurring in two of the patient's siblings. Homoplasmic ND5 mutation in the tumor correlates with lack of the ND6 subunit, suggesting complex I disassembly. A few oncocytic areas, expressing ND6 and heteroplasmic for the ND5 mutation, harbor a de novo homoplasmic ND1 mutation. Since shift to homoplasmy of ND1 and ND5 mutations occurs exclusively in tumor cells, we conclude that complex I mutations may have a selective advantage and accompany oncocytic transformation.


Subject(s)
DNA, Mitochondrial/genetics , Electron Transport Complex I/genetics , Frameshift Mutation , Nasopharyngeal Neoplasms/genetics , Aged , Amino Acid Sequence , Base Sequence , Blotting, Western , DNA Mutational Analysis , DNA, Mitochondrial/chemistry , Electron Transport Complex I/metabolism , Germ-Line Mutation , Humans , Immunohistochemistry , Male , Microscopy, Electron , Molecular Sequence Data , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/ultrastructure , Pedigree , Sequence Deletion , Sequence Homology, Amino Acid , Siblings
5.
Hum Mol Genet ; 17(7): 986-95, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18156159

ABSTRACT

Mutations in mitochondrial DNA (mtDNA) are frequent in cancers but it is not yet clearly established whether they are modifier events involved in cancer progression or whether they are a consequence of tumorigenesis. Here we show a benign tumor type in which mtDNA mutations that lead to complex I (CI) enzyme deficiency are found in all tumors and are the only genetic alteration detected. Actually renal oncocytomas are homogeneous tumors characterized by dense accumulation of mitochondria and we had found that they are deficient in electron transport chain complex I (CI, NADH-ubiquinone oxidoreductase). In this work total sequencing of mtDNA showed that 9/9 tumors harbored point mutations in mtDNA, seven in CI genes, one in complex III, and one in the control region. 7/8 mutations were somatic. All tumors were somatically deficient for CI. The clonal amplification of mutated mtDNA in 8/9 tumors demonstrates that these alterations are selected and therefore favor or trigger growth. No nuclear DNA rearrangement was detected beside mtDNA defects. We hypothesize that functional deficiency of the oxidative phosphorylation CI could create a loop of amplification of mitochondria during cell division, impair substrates oxidation and increase intermediary metabolites availability.


Subject(s)
Adenoma, Oxyphilic/genetics , DNA, Mitochondrial/genetics , Electron Transport Complex I/genetics , Kidney Neoplasms/genetics , Adenoma, Oxyphilic/metabolism , Cell Culture Techniques , Cell Nucleus/genetics , Cell Proliferation , Citrate (si)-Synthase/metabolism , DNA Mutational Analysis , DNA Polymerase gamma , DNA-Directed DNA Polymerase/genetics , Electron Transport Chain Complex Proteins/genetics , Electron Transport Chain Complex Proteins/metabolism , Electron Transport Complex I/metabolism , Gene Amplification , Glucose/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney Neoplasms/metabolism , NADH Dehydrogenase/metabolism , Nucleic Acid Hybridization , Oxidative Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Analysis, DNA
6.
Proc Natl Acad Sci U S A ; 104(21): 9001-6, 2007 May 22.
Article in English | MEDLINE | ID: mdl-17517629

ABSTRACT

Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P=0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.


Subject(s)
Biomarkers, Tumor/genetics , DNA, Mitochondrial/genetics , Electron Transport Complex I/genetics , Mutation/genetics , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Base Sequence , Humans , Oxyphil Cells/metabolism , Oxyphil Cells/pathology , Phenotype , Protein Subunits/genetics , Tumor Cells, Cultured
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