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Frosina G.,Molecular Mutagenesis and DNA Repair Unit
European Journal of Cancer | Year: 2011

Patients with glioblastoma multiforme (GBM - WHO grade IV) seldom recover. This is due to the infiltrative nature of these tumours and the presence of cellular populations with ability to escape therapies and drive tumour recurrence and progression. In some cases, these resistant cells exhibit stem properties [glioma stem cells (GSC)]. This article aims at discussing relevant issues on GSC resistance to current therapies and outlines possible and promising avenues in regard to novel therapeutic strategies, such as pharmacological, immunological and viral interventions. © 2011 Published by Elsevier Ltd. Source

Frosina G.,Molecular Mutagenesis and DNA Repair Unit
Journal of Biomedicine and Biotechnology | Year: 2010

DNA repair is a double-edged sword in stem cells. It protects normal stem cells in both embryonic and adult tissues from genetic damage, thus allowing perpetuation of intact genomes into new tissues. Fast and efficient DNA repair mechanisms have evolved in normal stem and progenitor cells. Upon differentiation, a certain degree of somatic mutations becomes more acceptable and, consequently, DNA repair dims. DNA repair turns into a problem when stem cells transform and become cancerous. Transformed stem cells drive growth of a number of tumours (e.g., high grade gliomas) and being particularly resistant to chemo-and radiotherapeutic agents often cause relapses. The contribution of DNA repair to resistance of these tumour-driving cells is the subject of intense research, in order to find novel agents that may sensitize them to chemotherapy and radiotherapy. © 2010 Guido Frosina. Source

Capanni C.,CNR Institute of Molecular Genetics | Bruschi M.,Laboratory on Pathophysiology of Uremia | Columbaro M.,Science Laboratory of Musculoskeletal Cell Biology | Cuccarolo P.,Molecular Mutagenesis and DNA Repair Unit | And 6 more authors.
Biochimie | Year: 2013

Growing number of publication has proved an increasing of cellular function of the Fanconi anemia proteins. To chromosome stability and DNA repair new roles have been attributed to FA proteins in oxidative stress response and homeostasis, immune response and cytokines sensibility, gene expression. Our work shows a new role for FA-A protein: the organization of the cellular structure. By 2D-PAGE of FA-A and correct fibroblasts treated and untreated with H2O2 we identify different expression of protein involved in the structural organization of nucleus, intermediate filaments and mitochondria. Immunofluorescence and electronic microscopy analysis clearly show an already altered cellular structure in normal culture condition and this worsted after oxidative stress. FA-A cell appears structurally prone to physiologic stress and this could explain part of the phenotype of FA cells. © 2013 Elsevier Masson SAS. All rights reserved. Source

Raso A.,Neurosurgery Unit | Vecchio D.,Molecular Mutagenesis and DNA Repair Unit | Cappelli E.,Hematology Unit | Ropolo M.,Molecular Mutagenesis and DNA Repair Unit | And 8 more authors.
Brain Pathology | Year: 2012

Previous studies have shown that tumor-driving glioma stem cells (GSC) may promote radio-resistance by constitutive activation of the DNA damage response started by the ataxia telangiectasia mutated (ATM) protein. We have investigated whether GSC may be specifically sensitized to ionizing radiation by inhibiting the DNA damage response. Two grade IV glioma cell lines (BORRU and DR177) were characterized for a number of immunocytochemical, karyotypic, proliferative and differentiative parameters. In particular, the expression of a panel of nine stem cell markers was quantified by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. Overall, BORRU and DR177 displayed pronounced and poor stem phenotypes, respectively. In order to improve the therapeutic efficacy of radiation on GSC, the cells were preincubated with a nontoxic concentration of the ATM inhibitors KU-55933 and KU-60019 and then irradiated. BORRU cells were sensitized to radiation and radio-mimetic chemicals by ATM inhibitors whereas DR177 were protected under the same conditions. No sensitization was observed after cell differentiation or to drugs unable to induce double-strand breaks (DSB), indicating that ATM inhibitors specifically sensitize glioma cells possessing stem phenotype to DSB-inducing agents. In conclusion, pharmacological inhibition of ATM may specifically sensitize GSC to DSB-inducing agents while sparing nonstem cells. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology. Source

Leroy B.,University Pierre and Marie Curie | Fournier J.L.,University Pierre and Marie Curie | Ishioka C.,Tohoku University | Monti P.,Molecular Mutagenesis and DNA Repair Unit | And 4 more authors.
Nucleic Acids Research | Year: 2013

A novel resource centre for TP53 mutations and mutants has been developed (http://p53.fr). TP53 gene dysfunction can be found in the majority of human cancer types. The potential use of TP53 mutation as a biomarker for clinical studies or exposome analysis has led to the publication of thousands of reports describing the TP53 gene status in >10000 tumours. The UMD TP53 mutation database was created in 1990 and has been regularly updated. The 2012 release of the database has been carefully curated, and all suspicious reports have been eliminated. It is available either as a flat file that can be easily manipulated or as novel multi-platform analytical software that has been designed to analyse various aspects of TP53 mutations. Several tools to ascertain TP53 mutations are also available for download. We have developed TP53MULTLoad, a manually curated database providing comprehensive details on the properties of 2549 missense TP53 mutants. More than 100 000 entries have been arranged in 39 different activity fields, such as change of transactivation on various promoters, apoptosis or growth arrest. For several hot spot mutants, multiple gain of function activities are also included. The database can be easily browsed via a graphical user interface. © The Author(s) 2012. Source

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