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  • 1
    Language: English
    In: Journal of Theoretical Biology, August 7, 2014, Vol.354, p.105(8)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtbi.2014.03.028 Byline: Joanna Kawka, Dominik Sturm, Sabrina Pleier, Stefan Pfister, Anna Marciniak-Czochra Abstract: Deregulation of signaling pathways and subsequent abnormal interactions of downstream genes very often results in carcinogenesis. In this paper, we propose a two-compartment model describing intricate dynamics of the target genes of the Wnt signaling pathway in medulloblastoma. The system of nine nonlinear ordinary differential equations accounts for the formation and dissociation of complexes as well as for the transcription, translation and transport between the cytoplasm and the nucleus. We focus on the interplay between MYC and SGK1 (serum and glucocorticoid-inducible kinase 1), which are the products of Wnt/[beta]-catenin signaling pathway, and GSK3[beta] (glycogen synthase kinase). Numerical simulations of the model solutions yield a better understanding of the process and indicate the importance of the SGK1 gene in the development of medulloblastoma, which has been confirmed in our recent experiments. The model is calibrated based on the gene expression microarray data for two types of medulloblastoma, characterized by monosomy and trisomy of chromosome 6q to highlight the difference between diagnoses. Author Affiliation: (a) Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing (IWR) and BIOQUANT, University of Heidelberg, Germany (b) Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Article History: Received 2 September 2013; Revised 6 February 2014; Accepted 16 March 2014
    Keywords: Medulloblastoma -- Analysis ; Glucose Metabolism -- Analysis ; Deregulation -- Analysis ; Glucocorticoids -- Analysis ; Glycogen Synthesis -- Analysis ; Glycogen -- Analysis ; Gene Expression -- Analysis
    ISSN: 0022-5193
    Source: Cengage Learning, Inc.
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  • 2
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Tumors ; Standardization ; Data Processing ; Classification ; Methylation ; Brain Cancer ; Bioinformatics ; Cancer ; Generalized Linear Models ; DNA Methylation ; Diagnosis ; Tumors ; Genomes ; Classification ; Central Nervous System ; Central Nervous System ; Diagnosis ; Cancer ; Learning Algorithms ; Diagnostic Software ; Data Processing ; Tumors ; Central Nervous System ; Gene Expression ; Standardization ; Classification ; Cancer ; Classifiers ; Classification ; Clinical Trials ; Deoxyribonucleic Acid–DNA ; Probability ; Diagnostic Systems ; Nervous System ; Methylation ; Data Processing ; Tumors ; Data Processing ; Deoxyribonucleic Acid–DNA ; Deoxyribonucleic Acid–DNA ; World Health Organization;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    In: International Journal of Cancer, 01 February 2014, Vol.134(3), pp.703-716
    Description: Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. What's new? Medulloblastoma, the most frequent pediatric brain cancer, causes death in about 60 percent of high‐risk patients, and so there is a major need for novel, highly effective therapies. One therapy of interest is parvovirus H‐1 (H‐1PV), which was found in this study to produce marked cytotoxic effects in six medulloblastoma cell lines. Gene expression profiling revealed that H‐1PV infection causes down‐regulation of key regulatory genes involved in early neurogenesis, with significant repression of . The master regulators affected may represent putative direct or indirect H‐1PV target genes.
    Keywords: Medulloblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Cellular Targets ; Myc ; Master Regulators Of Neurogenesis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 4
    Language: English
    In: Journal of Theoretical Biology, 07 August 2014, Vol.354, pp.105-112
    Description: Deregulation of signaling pathways and subsequent abnormal interactions of downstream genes very often results in carcinogenesis. In this paper, we propose a two-compartment model describing intricate dynamics of the target genes of the Wnt signaling pathway in medulloblastoma. The system of nine nonlinear ordinary differential equations accounts for the formation and dissociation of complexes as well as for the transcription, translation and transport between the cytoplasm and the nucleus. We focus on the interplay between and (serum and glucocorticoid-inducible kinase 1), which are the products of Wnt/ -catenin signaling pathway, and (glycogen synthase kinase). Numerical simulations of the model solutions yield a better understanding of the process and indicate the importance of the gene in the development of medulloblastoma, which has been confirmed in our recent experiments. The model is calibrated based on the gene expression microarray data for two types of medulloblastoma, characterized by monosomy and trisomy of chromosome 6q to highlight the difference between diagnoses.
    Keywords: Myc ; Gsk3β ; Wnt Signaling Pathway ; Differential Equations ; Biology
    ISSN: 0022-5193
    E-ISSN: 1095-8541
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  • 5
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 6
    Article
    Article
    In: Seminars in Neurology, 2018, Vol.38(01)
    In: Seminars in Neurology, 2018, Vol.38(01), pp.121-130
    Description: Gliomas are the most common primary central nervous system (CNS) neoplasms in children and adolescents and are thought to arise from their glial progenitors or stem cells. Although the exact cells of origin for most pediatric gliomas remain to be identified, our current understanding is that specific cell populations during CNS development are susceptible to particular oncogenic events during certain time windows and thus give rise to pediatric gliomas with distinct histological, molecular, and clinical features. These may be roughly segregated into low-grade gliomas (WHO grades I or II; including most mixed glial–neuronal tumors) and high-grade gliomas (WHO grades III or IV) according to their clinical course when untreated, even though this is not yet entirely clear for some of the recently emerging groups. The genetic and epigenetic characterization of pediatric gliomas across ages and histologies has facilitated the delineation of biologically relevant subgroups and have revealed potentially targetable alterations in some of them. This review outlines diagnostic features and molecular alterations in pediatric low- and high-grade gliomas and how the latter might be exploited with future targeted therapeutic strategies.
    Keywords: Cns ; Brain tumor ; Pediatric glioma ; Astrocytoma ; Genetics ; Epigenetics ; Targeted therapy
    ISSN: 0271-8235
    E-ISSN: 1098-9021
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  • 7
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.2696-2696
    Description: CNS-primitive neuroectodermal tumors (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 323 fresh-frozen or paraffin-embedded institutionally diagnosed CNS-PNETs using DNA methylation and expression arrays. Data were compared to 211 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities.
    Keywords: Brain Tumors ; Differentiation ; Central Nervous System ; Data Processing ; Classification ; Pediatrics ; Adolescence ; DNA Methylation ; Nervous System Diseases ; Children ; Neurology & Neuropathology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 8
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.3084-3084
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.3089-3089
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 10
    Language: English
    In: Cell, 25 February 2016, Vol.164(5), pp.1060-1072
    Description: Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with activation (CNS NB- ),” “CNS Ewing sarcoma family tumor with alteration (CNS EFT- ),” “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” and “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Highly malignant primitive neuroectodermal tumors of the CNS (CNS-PNETs) have been challenging to diagnose and distinguish from other kinds of brain tumors, but molecular profiling now reveals that these cancers can be readily classified into some known tumor types and four new entities with distinct histopathological and clinical features, paving the way for meaningful clinical trials.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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