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  • 1
    Abstract: The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (〉/=3.0-16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by 〉/=2 independent risk-factors and an extremely poor prognosis (〈15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.
    Type of Publication: Journal article published
    PubMed ID: 22139329
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  • 2
    Abstract: Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved therapeutic individualization. Tumor DNA methylation profiles were assessed, alongside molecular and clinical disease features, in 230 patients primarily from the SIOP-UKCCSG PNET3 clinical trial. We demonstrate by cross-validation in frozen training and formalin-fixed test sets that medulloblastoma comprises four robust DNA methylation subgroups (termed WNT, SHH, G3 and G4), highly related to their transcriptomic counterparts, and which display distinct molecular, clinical and pathological disease characteristics. WNT patients displayed an expected favorable prognosis, while outcomes for SHH, G3 and G4 were equivalent in our cohort. MXI1 and IL8 methylation were identified as novel independent high-risk biomarkers in cross-validated survival models of non-WNT patients, and were validated using non-array methods. Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as 'favorable risk' (〉90 % survival) compared to 13 % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.
    Type of Publication: Journal article published
    PubMed ID: 23291781
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  • 3
    ISSN: 1434-4475
    Keywords: Oxalic acid ; Phenyl phthalimide ; C-steel ; Cyclic voltammetry ; Corrosion inhibitors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Das elektrochemische Verhalten von Eisen und C-Stählen in Oxalsäurelösungen wurde mit Hilfe cyclischer Voltammetrie studiert. Dabei treten zwei Signale auf: das anodische Signal sowie ein unerwartetes reduktives Lösungssignal. Letzteres wurde im kathodischen Zweig der cyclischen Voltammogramme aller untersuchten Elektroden gefunden. Der Kohlenstoffgehalt erhöht die aktive Auflösung von Stählen und erniedrigt ihre Tendenz zur Passivierung. Die Inhibitionseffizienz von Phenylphthalimiden für die aktive Auflösung von Eisen und Stahlproben in 0.1M Oxalsäure wurde untersucht.
    Notes: Summary The electrochemical behaviour of Fe and C-steel samples in oxalic acid solutions was studied by the use of cyclic voltammetry. Two peaks were observed; the first one was the anodic peak and the second one an unexpected reductive dissolution peak which could be observed in the cathodic branch of cyclic voltammograms of all electrodes studied. The carbon content was found to increase the active dissolution of steels and to decrease their tendency towards passivation. The inhibitive efficiency of phenyl phthalimide derivatives on the active dissolution of Fe and steel samples in 0.1M oxalic acid were investigated.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2014-02-01
    Description: Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Novarino, Gaia -- Fenstermaker, Ali G -- Zaki, Maha S -- Hofree, Matan -- Silhavy, Jennifer L -- Heiberg, Andrew D -- Abdellateef, Mostafa -- Rosti, Basak -- Scott, Eric -- Mansour, Lobna -- Masri, Amira -- Kayserili, Hulya -- Al-Aama, Jumana Y -- Abdel-Salam, Ghada M H -- Karminejad, Ariana -- Kara, Majdi -- Kara, Bulent -- Bozorgmehri, Bita -- Ben-Omran, Tawfeg -- Mojahedi, Faezeh -- Mahmoud, Iman Gamal El Din -- Bouslam, Naima -- Bouhouche, Ahmed -- Benomar, Ali -- Hanein, Sylvain -- Raymond, Laure -- Forlani, Sylvie -- Mascaro, Massimo -- Selim, Laila -- Shehata, Nabil -- Al-Allawi, Nasir -- Bindu, P S -- Azam, Matloob -- Gunel, Murat -- Caglayan, Ahmet -- Bilguvar, Kaya -- Tolun, Aslihan -- Issa, Mahmoud Y -- Schroth, Jana -- Spencer, Emily G -- Rosti, Rasim O -- Akizu, Naiara -- Vaux, Keith K -- Johansen, Anide -- Koh, Alice A -- Megahed, Hisham -- Durr, Alexandra -- Brice, Alexis -- Stevanin, Giovanni -- Gabriel, Stacy B -- Ideker, Trey -- Gleeson, Joseph G -- HHSN268200782096C/PHS HHS/ -- HHSN268201100011/PHS HHS/ -- N01-CO-12400/CO/NCI NIH HHS/ -- P01 HD070494/HD/NICHD NIH HHS/ -- P01HD070494/HD/NICHD NIH HHS/ -- P30NS047101/NS/NINDS NIH HHS/ -- R01NS041537/NS/NINDS NIH HHS/ -- R01NS048453/NS/NINDS NIH HHS/ -- R01NS052455/NS/NINDS NIH HHS/ -- U54 HG006504/HG/NHGRI NIH HHS/ -- U54HG003067/HG/NHGRI NIH HHS/ -- U54HG006504/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jan 31;343(6170):506-11. doi: 10.1126/science.1247363.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/physiology ; Biological Transport/genetics ; Cohort Studies ; Exome/*genetics ; Gene Regulatory Networks ; *Genetic Association Studies ; Humans ; Motor Neuron Disease/*genetics ; Mutation ; Neurons/*metabolism ; Nucleotides/genetics/metabolism ; Pyramidal Tracts/*metabolism ; Sequence Analysis, DNA ; Spastic Paraplegia, Hereditary/*genetics ; Synapses/physiology ; Transcriptome ; Zebrafish
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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