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  • 1
    Language: English
    In: The Journal of clinical investigation, April 2011, Vol.121(4), pp.1344-8
    Description: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
    Keywords: Astrocytoma -- Etiology ; Brain Neoplasms -- Etiology ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 2
    Language: German
    In: Klinische Pädiatrie, 10/2018, Vol.230(06), pp.289-290
    ISSN: 0300-8630
    E-ISSN: 1439-3824
    Source: Thieme Publishing Group (via CrossRef)
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  • 3
    In: Klinische Pädiatrie, 2018, Vol.230(06)
    In: Klinische Pädiatrie, 2018, Vol.230(06), pp.289-290
    Description: Die Fortschritte der molekularen Diagnostik haben neue Türen für die Diagnosestellung, Risikostratifizierung und Präzisionsonkologie für Kinder mit Hirntumoren aufgestoßen. Dieses Wissen konsequent und systematisch in einen klinischen Nutzen zu übertragen wird Aufgabe der kommenden Jahre sein.
    ISSN: 0300-8630
    E-ISSN: 1439-3824
    Source: Thieme Publishing Group
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 July 2013, Vol.110(28), pp.E2592-601
    Description: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
    Keywords: Hdac Inhibitor ; Childhood Tumors ; Drug Resistance ; Autophagy -- Physiology ; Cell Survival -- Physiology ; Histone Deacetylases -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: CNS oncology, July 2013, Vol.2(4), pp.359-76
    Description: Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.
    Keywords: Brain Neoplasms -- Drug Therapy ; Histone Deacetylase Inhibitors -- Therapeutic Use ; Histone Deacetylases -- Metabolism
    ISSN: 20450907
    E-ISSN: 2045-0915
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  • 6
    Language: English
    In: Brain Pathology, Nov, 2012, p.(1)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2012.00600.x/abstract Byline: Till Milde(1)(2), Thomas Hielscher(3), Hendrik Witt(2)(4), Marcel Kool(4), Stephen C. Mack(5), Hedwig E. Deubzer(1)(2), Ina Oehme(1), Marco Lodrini(1), Axel Benner(3), Michael D. Taylor(5), Andreas von Deimling(6)(7), Andreas E. Kulozik(2), Stefan M. Pfister(2)(4), Olaf Witt(1)(*), Andrey Korshunov(6)(*) Keywords: ependymoma; nestin; risk stratification; WHO grade Abstract Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low-risk tumors, whereas grade III anaplastic ependymomas are considered high-risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin-positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression-free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co-regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics. Author Affiliation: (1)Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany (2)Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany (3)Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg, Germany (4)Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany (5)Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (6)Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany (7)Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence: (*) Till Milde, MD, Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (E-mail: t.milde@dkfz.de). Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany Article Note: ([dagger]) Conflict of interest: The authors declare no conflict of interest. (*) These authors contributed equally to this work. Received 30 March 2012; Accepted 2 May 2012; Published Online Article Accepted 9 May 2012 Supporting information: Additional Supporting Information may be found in the online version of this article Figure S1. Nestin mRNA is differentially expressed in brain tumors and normal brain tissue. The database R2 was searched for nestin expression using publicly available datasets. Nestin is highly expressed in ependymoma (red) and astrocytomas and gliomas (astrocytoma, oligodendroglioma, anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma; blue), but not in medulloblastomas (blue). Normal adult tissue of varying brain regions (green) show low expression, while embryonal tissue shows high expression of nestin (green). Numbers following an underscore indicate the total numbers of samples in each dataset; in the second ependymoma dataset, letters following a83:a indicate the molecular subgroup; in the medulloblastoma, dataset letters following a120:a indicate the subgroup; in the embryogenesis, dataset numbers following a18:a indicate the week of human embryonic development; lca = large cell anaplastic; nd = not determined. Figure S2. Nestin protein is differentially expressed in ependymoma of differing location and grade. While no differences in nestin-positive and -negative ependymoma were found regarding gender or resection status, a significantly higher proportion of nestin-positive ependymoma was found in all supratentorial and WHO III ependymoma. When separated by age groups, a significantly higher proportion of pediatric supratentorial, and adult WHO III ependymoma were found to be nestin positive. infra = infratentorial; supra = supratentorial; STR = subtotal resection; GTR = gross total resection; nes = nestin; pos = positive; neg = negative; n.s. = not significant; *P 〈 0.05, **P 〈 0.005, ***P 〈 0.0001 (Fisher's exact t-test). Table S1. Cox proportional hazards model for progression-free (PFS) and overall survival (OS) estimation-univariable analysis. HR = hazard ration; CI = confidence interval. Table S2. Five-year progression-free (PFS) and overall survival (OS). infra = infratentorial; supra = supratentorial; neg = negative; pos = positive; infra = infratentorial; supra = supratentorial; PFA = posterior fossa group A; PFB = posterior fossa group B. Table S3. Genes co-regulated (correlation coefficient 〉0.5) with nestin from the Heidelberg dataset, ranked by correlation coefficient. Table S4. Genes significantly co-regulated (correlation coefficient 〉0.5) with nestin from the Toronto dataset, ranked by correlation coefficient. Table S5. Genes co-regulated with nestin found in both datasets (Heidelberg and Toronto), ranked by correlation coefficient for each dataset and displayed according to average rank. Table S6. Gene sets in the Heidelberg or Toronto dataset with significant adjusted P-value in both hypergeometric test and gene set enrichtment analysis (GSEA), with genes from the respective dataset (Supporting Table S3 or S4) in alphabetical order.
    Keywords: Gliomas -- Patient Outcomes ; Gliomas -- Analysis ; Universities And Colleges -- Analysis ; Adults -- Analysis ; Intermediate Filament Proteins -- Analysis ; Messenger Rna -- Analysis ; Stem Cell Research -- Analysis ; Transcription (Genetics) -- Analysis ; Children's Hospitals -- Analysis ; Cancer Research -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Anopheles -- Analysis ; Biometry -- Analysis ; Public Health -- Analysis ; Brain Tumors -- Patient Outcomes ; Brain Tumors -- Analysis
    ISSN: 1015-6305
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: Brain Pathology, Nov, 2012, p.(1)
    Keywords: Gliomas -- Patient Outcomes ; Gliomas -- Analysis ; Universities And Colleges -- Analysis ; Adults -- Analysis ; Intermediate Filament Proteins -- Analysis ; Messenger Rna -- Analysis ; Stem Cell Research -- Analysis ; Transcription (Genetics) -- Analysis ; Children's Hospitals -- Analysis ; Cancer Research -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Anopheles -- Analysis ; Biometry -- Analysis ; Public Health -- Analysis ; Brain Tumors -- Patient Outcomes ; Brain Tumors -- Analysis
    ISSN: 1015-6305
    Source: Cengage Learning, Inc.
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  • 8
    In: Nature, 2014, Vol.510(7506), p.537
    Description: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
    Keywords: Gene Expression Regulation, Neoplastic ; Gene Silencing ; DNA Methylation -- Genetics ; Medulloblastoma -- Genetics ; Sequence Analysis, DNA -- Methods;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 9
  • 10
    In: Nature, 2012, Vol.482(7384), p.226
    Description: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases (1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX([alpha]-thalassaemia/mental retardation syndrome X-linked) (5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres (6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
    Keywords: Gene Mutation -- Research ; Dna -- Research ; Dna -- Physiological Aspects ; Glioblastomas -- Genetic Aspects ; Glioblastomas -- Research ; Tumor Proteins -- Physiological Aspects ; Tumor Proteins -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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