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1
Roberti, Michele. "Sistemi esperti: Mycin come caso di studio." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amslaurea.unibo.it/8358/.
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I sistemi esperti sono programmi che cercano di riprodurre le prestazioni di esperti umani nella risoluzione di problemi specifici. Essi rappresentano il più conosciuto risultato pratico della ricerca in intelligenza artificiale. Ne vengono analizzate la struttura interna, i paragidmi su cui si basano, i componenti che ne fanno parte e i linguaggi di programmazione principali.
Viene studiato uno dei primi distemi esperti: il MYCIN. Esso opera nel campo medico ed è stato di notevole importanza e innovazione nei primi anni in cui questi sistemi venivano sviluppati.
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George, Rani Elizabeth. "Gene co-amplification with MYCN in neuroblastoma." Thesis, University of Newcastle Upon Tyne, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363879.
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Kenyon, Rebecca Margaret. "Analysis of the MYCN amplicon in neuroblastoma." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321261.
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Stermann, Alexander. "MYCN-DNA-Vakzine zur Behandlung des Neuroblastoms." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16888.
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Das Neuroblastom (NB) zählt zu den therapieresistentesten Tumoren des Kleinkindalters. Besonders NB-Patienten mit MYCN-Amplifikation sind mit einer schlechten Prognose konfrontiert. Neuere Studien legen nahe, dass eine spezifische aktive Immuntherapie gegen MYCN ein vielversprechender Ansatz zur Bekämpfung dieser malignen Erkrankung darstellen könnte. Zur Untersuchung dieser Hypothese wurde ein sogenanntes Minigen-Vakzin, welches für drei ausgewählte Epitope aus der MYCN-AS-Sequenz kodiert, generiert. Die Auswahl der Minigen-Epitope erfolgte mit dem MHC-Liganden-Vorhersageprogramm syfpeithi, welches drei starke H2-Kk-Liganden lieferte. Außerdem wurden zwei weitere Vakzine hergestellt: als Negativkontrolle MYCNLow, dessen MYCN-Peptide laut syfpeithi schlechte MHC-Klasse-I-Liganden darstellen und ein cDNA-Vakzin auf Basis der gesamten MYCN-cDNA-Sequenz. Zur Applikation der Vakzine wurden attenuierte Salmonella typhimurium SL7207 verwendet, die eine zusätzliche Stimulierung des mukosalen Immunsystems hervorrufen. Für die Untersuchung der Impfstoffe in vivo wurden zwei neuartige immunkompetente NB-Mausmodelle etabliert. Dazu wurden die syngenen NXS2/C1300 A/J-Mausmodelle soweit modifiziert, dass sie über eine induzierbare MYCN-Expression verfügten. Nach Auswahl und Charakterisierung geeigneter Transfektanten in vitro und in vivo wurde in diesen Modellen die Wirksamkeit der Vakzine untersucht. In diesen Versuchen konnte mit Hilfe der Vakzine das Primärtumorwachstum von NXS2-MYCN in geimpften Tieren signifikant im Vergleich zu Kontrollen reduziert und die Metastasierung durch C1300-MYCN Zellen signifikant verzögert werden. Mit den in-vivo-Versuchen anschließenden Analysen wurde schließlich bewiesen, dass die Immunantwort durch tumorinfiltrierende MYCN-spezifische zytotoxische CD8+ T-Zellen vermittelt wird. Zusammenfassend konnte gezeigt werden, dass eine MYCN-DNA-Vakzinierung erfolgreich zur Behandlungen MYCN-exprimierender NB im Mausmodell eingesetzt werden kann.High-level expression of MYCN protein caused by amplification of the gene characterizes a malignant phenotype of neuroblastoma (NB). Recent studies suggest that MYCN might be a promising target for immunotherapy. Therefore, we investigated the efficacy of three MYCN-specific DNA vaccines. Two minigene vaccines were generated; each encoded for three selected epitopes of the MYCN protein sequence with the highest, or as a control lowest, predicted affinity to MHC-Class-I Molecules. The third vaccine based on the cDNA of MYCN. Salmonella typhimurium SL7207 were used as oral application vehicle for the vaccines in in vivo experiments to induce an additional stimulation of the immune system. To investigate the immunotherapeutic approach NXS2- and C1300-cells syngeneic to immunocompetent A/J-mice were stably transfected with a tetracycline inducible vector system coding for MYCN. The transfectants were characterized and established in vitro and in vivo. In the MYCN-overexpressing models vaccination with the MYCN-DNA-vaccines resulted in significant reduced primary tumor growth or decelerated metastasis spread. The immune responses in the in vivo experiments followed by orally applied MYCN-DNA vaccines was mediated by tumor infiltrating cytotoxic CD8+ and CD4+ T cells. MYCN specificity of infiltrating lymphocytes was verified by MYCN-specific cytolytic activity and IFN-gamma secretion ex vivo. Finally, we showed that blocking of MHC-class I molecule H2-Kk approbated cytotoxicity mediated by CD8+ T cells, indicating MYCN specificity of the induced immune response. In summary, we showed that a MYCN based DNA vaccination strategy is effective against MYCN-expressing NB in vivo. In light of the description of MYCN-specific T cells in NB patients, the lytic action of autologous T cells on MYCN-expressing cells and the results of this study underline the possible potential of an active immunotherapy against MYCN as an alternative therapeutic approach to treat NB.
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Weber, Axel. "Identifizierung und praktische Anwendung molekularer Marker für eine Verbesserung der Prognosebeurteilung humaner Neuroblastome." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-86808.
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Die Abschätzung der Prognose für Patienten, insbesondere Kinder mit onkologischen Erkrankungen stellt eine große Herausforderung an die behandelnden Ärzte dar. Vor Beginn einer Therapie werden daher viele Informationen gesammelt, um einen Patienten möglichst gut in eine vordefinierte Risikogruppe stratifizieren und dementsprechend eine mehr oder weniger intensive Therapie anbieten zu können. Diese Einteilungen sind allerdings für keinen Malignomtyp mit 100%-iger Sicherheit möglich. Das ist die Ursache dafür, dass auch in niedrige Risikogruppen eingeteilte Patienten nicht auf die Therapie ansprechen und einen unvorhergesehen schlechten Verlauf zeigen können. Auf der anderen Seite scheint es Patienten zu geben, die trotz initial schlecht eingeschätzter Prognose einen überaschend guten Verlauf nehmen, auf die Therapie gut ansprechen und letztlich geheilt werden können.
Einen Beitrag zu leisten, um die Stratifizierung für Kinder, die an einem Neuroblastom erkrankt sind, zu verbessern und damit zu vermeiden, dass einige Patienten unter- oder andere Patienten übertherapiert werden müssen, ist das Ziel dieser Habilitationsarbeit.
Zu diesem Zweck wurden differentielle, molekulare Marker in primären humanen Neuroblastomen identifiziert und deren prognostische Bedeutung dargestellt. Einzelne dieser Marker (differentiell expremierte mRNAs) wurden in Zellkultursystemen funktionell untersucht, um deren zellbiologische Funktion, die der jeweiligen prognostischen Bedeutung zugrunde liegen kann zu erklären. Desweiteren konnten genomische Merkmale des amplifizierten genomischen Abschnittes auf Chromosom 2p25 um MYCN beschrieben werden. Darauf basierend konnte eine patientenindividuelle und tumorzellspezifische PCR entwickelt werden (AFS-PCR), die sich als Marker für den Nachweis einer minimalen Resterkrankung eignet.
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Maeshima, Ruhina. "MYCN silencing as therapeutics for neuroblastoma using RNA interference." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10043849/.
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Neuroblastoma (NB) is the most common solid tumour in childhood and accounts for 15% of childhood cancer deaths. It is known that high-risk NB is highly correlated with MYCN amplification. Overexpressed MYCN induces proliferation and cell growth and suppresses apoptosis and differentiation pathways in NB cells. Since RNA interference (RNAi) was first described, many research groups have investigated the application of RNAi with the use of short interfering RNA (siRNA). Our aim is to induce apoptosis and differentiation using RNAi as a novel therapeutic strategy for MYCN-amplified NB. Our hypothesis is that MYCN silencing by anti-MYCN siRNA induces apoptosis and differentiation at the mRNA and protein level. We are encapsulating siRNA with liposome and integrin-receptor targeting peptide to deliver MYCN siRNA into NB cells and optimising cationic and anionic polyethylene glycol (PEG)ylated receptor-targeting nanocomplexes (RTNs). In this project, we also aimed to optimise the methods to store RTNs for a long time in trehalose, which is known as a cryoprotectant. As a result, MYCN was silenced by the siRNA at both the mRNA and protein levels, and the siRNA-mediated MYCN reduction induced downstream effects, such as a neuronal differentiation marker TrkA upregulation and the morphological changes of the cells. The anti-MYCN siRNA delivered using RTNs successfully silenced MYCN mRNA in vivo as well. We used an NB cell line with non-functional p53 and resistance toward p53-pathway dependent anti-cancer drugs, probably induced by multiple sessions of chemotherapy and radiotherapy. Therefore, the results are promising for a novel therapy for relapse NB with MYCN amplification. In addition, we successfully demonstrated that trehalose maintains the biophysical properties and the function of RTNs, consisting of either DNA or siRNA at -80 °C. This allows us to make a large amount of RTN for many experiments, store it for the long term, and transport it to a place far from the laboratory.
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Solari, Valeria. "MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cells." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2003528/.
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Neuroblastoma (NBL) is the most common type of cancer diagnosed in the first year of life. It is a complex and heterogeneous disease that arises from the developing sympathetic nervous system. Despite numerous advances and the well-demonstrated role of MYCN in the pathogenesis of neuroblastoma, the mechanisms underlying its oncogenic function are not entirely understood and there is evidence that its function is, in part, dependent on the tumour microenvironment (TME). New and improved therapeutic targets are urgently required for this often lethal tumour. Heparan sulfate proteoglycans (HSPG) play a critical role in the interactions between tumour cells and the TME and their activities are dependent on the sulfation pattern, that is controlled by sulfotransferases, which add sulfate groups to the repeating disaccharide units, and sulfatases (SULFs), which selectively remove 6-O-sulfates. In this work an analysis of the expression of these enzymes in human neuroblastoma revealed higher levels of SULF2 specifically when the MYCN oncogene was amplified. Loss of expression of SULF2 in MYCN-amplified (A) cell lines was associated with a marked decrease in survival and an increase in apoptosis. Evidence is presented that SULF2 is a direct downstream target of MYCN since overexpression of MYCN in neuroblastoma cells increases SULF2 expression whereas a down regulation reduced SULF2 expression. Underlying the importance of SULF2 in neuroblastoma cell survival independently of MYCN, it is demonstrated that overexpression of SULF2 in MYCN-NA cells increases cell viability without increasing MYCN expression. Analysis of SULF2 protein expression in a large cohort of primary human neuroblastoma tumours also indicated a high level of expression in MYCN-A tumours and an almost complete absence of expression in MYCN-non A (NA) tumours. The data identify SULF2 as a new downstream target of MYCN and a key contributor to its oncogenic function in human neuroblastoma, which might have future implications for clinical therapies for high-risk NBL.
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Schulze, Franziska. "Die Telomerlänge als Prognosefaktor in MYCN nicht-amplifizierten Neuroblastomen." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-200943.
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Eines der charakteristischen Merkmale des Neuroblastoms stellt seine einzigartige biologische Heterogenität dar, die eine genaue Ausage des weiteren klinischen Verlaufes stark erschwert. Bestimmte prognostisch wirksame klinische, molekularbiologische und genetische Faktoren, wie zum Beispiel Alter bei Erstdiagnose, Tumorstadium, MYCN-Amplifikation und 1p Deletion, werden seit längerem zur Risikostratifizierung genutzt. Bereits in anderen Tumorerkrankungen konnte nun der Einfluß einer Telomerlängenveränderung auf das Gesamtüberleben von Patienten nachgewiesen werden. Telomere sichern die genomische Integrität und bestimmen maßgeblich die proliferative Kapazität jeder somatischen Zelle. Aktuelle Forschungsergebnisse legen die Vermutung nahe, dass Veränderungen der Telomerlänge auch in Neuroblastomen einen prognostischen Effekt auf das Gesamtüberleben haben.
In diesem Kontext untersucht die vorliegende Arbeit den Zusammenhang zwischen Telomerlänge und Gesamtüberleben in 420 MYCN nicht-amplifizierten primären Neuroblastomen mit Erstdiagnosen von 1983-2001. Hierfür wurden die relativen Telomerlängen mithilfe einer neu etablierten monochromen multiplex q-RT-PCR ermittelt. Anschließend wurden diese sowohl mit ausgesuchten klinischen Variablen (Alter bei Erstdiagnose, Tumorstadium, Primärlokalisation des Tumors, Histologie, Geschlecht und Rezidivauftreten) korreliert als auch auf ihren Einfluß auf das Gesamt- und ereignisfreie Überleben untersucht.
In Korrelation mit den klinischen Parametern konnte zwischen Alter bei Erstdiagnose und Telomerlänge ein eindeutiger Zusammenhang nachgewiesen werden. Je älter die Patienten bei Erstdiagnose, desto höher war sowohl der Anteil verlängerter Telomere als auch der extremer Telomerlängenveränderungen. Neuroblastome mit verlängerten Telomeren zeigten in der gleichen Altersgruppe ein verringertes Gesamtüberleben der betroffenen Patienten verglichen mit Neuroblastomen mit verkürzten Telomeren. Somit könnte eine Telomerlängenveränderung, insbesondere verlängerte Telomere, im klinischen Alltag als Hinweis auf einen prognostisch ungünstigen Verlauf genutzt werden.
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Valli, Emanuele <1983>. "The role of MYCN-mediated transcriptional repression in neuronal physiopathology." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4809/.
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MYC is a transcription factor that can activate transcription of several targets by direct binding to their promoters at specific DNA sequences (E-box).
Recent findings have also shown that it can exert its biological role by repressing transcription of other set of genes. C-MYC can mediate repression on its target genes through interaction with factors bound to promoter regions but not through direct recognition of typical E-Boxes.
In this thesis, we investigated whether MYCN can also repress gene transcription and how this is mechanistically achieved.
Moreover, expression of TRKA, P75NTR and ABCC3 is attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and transcriptional repression of these three genes.
We found that MYCN is physically associated with gene promoters in vivo in proximity of the transcriptional start sites and this association requires interactions with SP1 and/or MIZ-1.
Furthermore, we show that this interaction could interfere with SP1 and MIZ-1 activation functions by recruiting co-repressors such as DNMT3a or HDACs.
Studies in vitro suggest that MYCN interacts through distinct domains with SP1, MIZ-1 and HDAC1 supporting the idea that MYCN may form different complexes by interacting with different proteins.
Re-expression of endogenous TRKA and P75NTR with exposure to the TSA sensitizes neuroblastoma to NGF-mediated apoptosis, whereas ectopic expression of ABCC3 decreases cell motility without interfering with growth.
Finally, using shRNA whole genome library, we dissected the P75NTR repression trying to identify novel factors inside and/or outside MYCN complex for future therapeutic approaches.
Overall, our results support a model in which MYCN can repress gene transcription by direct interaction with SP1 and/or MIZ-1, and provide further lines of evidence on the importance of transcriptional repression induced by Myc in tumor biology.
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Vulcani-Freitas, Tânia Maria [UNIFESP]. "Perfil de expressão dos genes MYC, MYCN, TERT, ASPM e PRAME em Meduloblastoma." Universidade Federal de São Paulo (UNIFESP), 2010. http://repositorio.unifesp.br/handle/11600/9928.
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Previous issue date: 2010-04-28Meduloblastoma (MB) é o tumor maligno de sistema nervoso central (SNC) mais comum em criança, compreendendo 20% dos tumores primários de SNC e 40% dos tumores cerebelares da infância. Devido sua forte tendência metastática, o tratamento padrão pós-operatório inclui radio e quimioterapia, cujo impacto causa distúrbios endócrinos e de crescimento, e disfunção neurocognitiva a longo prazo. Frente a esses efeitos negativos, muitas pesquisas em meduloblastoma têm sido realizadas com intuito de obter conhecimento biológico desses tumores para tentar identificar fatores prognósticos moleculares que possam orientar os tratamentos, tornando-os mais específicos e menos agressivos. Alguns estudos em MB têm sugerido que a expressão do oncogene MYC está associada com diminuição da sobrevida e sua superexpressão com maior agressividade do tumor. Por isso, MYC pode ser um indicador importante de prognóstico, além de modulador do comportamento desta doença. Enquanto o gene MYC é expresso em uma variedade de tecidos, a expressão de MYCN, outro membro da família MYC, é restrita a estágios precoces do desenvolvimento embrionário de alguns tecidos apenas, entre eles, o sistema nervoso central e periférico, sendo um mediador importante dos efeitos de ativação na proliferação de células precursoras cerebelares. Dessa forma, quando a expressão de MYCN está desregulada, ela aumenta a tumorigenicidade dessas células podendo dar origem ao MB. Além disso, o gene MYC também é considerado importante regulador da transcrição TERT, gene que codifica uma subunidade catálica de da telomerase, enzima importante para carcinogênese e imortalização de células neoplásicas. A atividade anormal da telomerase está presente em 90% dos cânceres e o aumento de sua atividade está associado a eventos clínicos desfavoráveis. Outro gene importante é o ASPM (abnormal spindle-like microcephaly associated) que desempenha função fundamental na neurogênese e proliferação celular durante o desenvolvimento cerebral. Esse gene codifica uma proteína de centrossomo e fuso mitótico que permite a divisão celular simétrica em células neuroepiteliais durante o desenvolvimento e aumento do tamanho cerebral. Alterações em ASPM é a causa mais comum de microcefalia primária em humanos e de falha de segregação, induzindo a aneuploidias e instabilidade genética. Além desses genes, outro gene estudado recentemente, como alvo em xv imunoterapia, é o gene PRAME que codifica um antígeno tumoral que está presente em vários tumores, incluindo meduloblastoma. O gene PRAME possui baixa ou ausência de expressão em tecidos normais, por isso é pode ser um forte candidato como alvo em imunoterapia, que é um tratamento menos tóxico. OBJETIVOS: O objetivo desse estudo foi investigar a expressão dos genes MYC, MYCN, TERT, ASPM e PRAME em fragmentos tumorais de meduloblastoma de crianças e tentar correlacionar com os parâmetros clínicos e verificar se há correlação de MYC, MYCN, TERT entre si, uma vez que estão correlacionados. MÉTODOS: Análise de expressão gênica foi realizada através de PCR quantitativa em tempo real, utilizando sistema SYBR Green, em 37 amostras tumorais de crianças, com média de idade de 8 anos. Para comparação de perfil de expressão foi usada duas amostra de cérebro normal. A análise estatística foi realizada nos programas Graph Pad Prism 4 e VassarStats RESULTADOS: Todas nossas amostras superexpressaram o gene MYCN com valor de quantificação relativa (RQ) mediana igual a 31 com p=0.001; assim como, todas nossas amostras também superexpressaram o gene ASPM com mediana igual a 586, p<0.0001. Do total de amostras, 95%, 81% e 84% superexpressaram TERT, MYC e PRAME respectivamente, sendo os valores de RQ (mediana) iguais a 322, p=0.01; 9.2, p<0.0001; 33, p<0.0001. Apesar da elevada expressão dos genes estudados na maioria das amostras estudadas, houve apenas correlação estatística entre a superexpressão de MYCN (p=0.008) e os pacientes que foram a óbito, e de TERT e os pacientes que recidivaram (p=0.0431). Não encontramos outra correlação estatística entre a superexpressão dos genes e as características clínicas dos pacientes. CONCLUSÃO: Os genes MYC, MYCN e TERT estavam superexpressos nas amostras de meduloblastoma analisadas em uma freqüência muito superior ao demonstrado na literatura, o que sugere que esses três genes podem ajudar na identificação de tumores agressivos, uma vez que o pognóstico desses pacientes continua baseado apenas em parâmentros clínicos. A superexpressão de ASPM em todas as amostras estudadas sugere que este gene pode estar envolvido na origem de MB, como parte da neurogênse anormal durante o desenvolvimento embrionário, porém estudoas funcionais devem ser realizados para confirmar essa hipótese. Por fim, o gene PRAME pode ser candidato à marcador de célula tumoral em MB, podendo no futuro ser candidato como alvo em imunoterapias.
To investigate the expression of genes MYC, MYCN and TERT in tumor fragments of pediatric medulloblastoma and correlate gene expression profiles with clinical parameters. Analysis of gene expression was performed by quantitative PCR real time in 37 tumor samples and correlated with clinical and pathological data. All 37 samples overexpressed MYCN gene (p= 0.001), 95% and 84% of the samples overexpressed TERT and MYC, respectively (p<0.0001). Twenty nine (78%) of all samples had concomitant high expression of MYC, MYCN and TERT genes together. Seventeen (59%) were high-risk classification, 10 (34%) were metastatic (M+) stage, two (7%) were anaplastic or largecell/ anaplastic subtype, eight (28%) of patients relapsed, beyond thirteen (45%) suffered partial surgical resection. and fourteen (48%) died. We found correlation between MYC, MYCN and TERT expression (p<0.0001). The identification of a subgroup with concomitant overexpression of the three investigated genes suggests the possibility of using more than one aspect of molecular indicative of unfavorable prognosis that characterizes the group with poor outcome. However, in future this may be enhanced by targeted therapy for the product TERT as proposed in some neoplasms. The identification of molecular events in the medulloblastoma categorization aims to help at-risk groups moving towards individualized medicine.
TEDE
BV UNIFESP: Teses e dissertações
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DeWitt, John. "The Role of Ciliary Neurotrophic Factor and TRKB Signaling in Neuroblastoma." ScholarWorks @ UVM, 2013. http://scholarworks.uvm.edu/graddis/67.
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Neuroblastoma is the most common pediatric cancer in infants, arising from the sympathoadrenal lineage of the neural crest. Despite recent advances in other pediatric cancers, long term survival in high risk cases of neuroblastoma remains below 40%. Therefore, to develop successful therapeutics targeting high risk tumors, further research into the mechanisms involved in high risk tumor formation is necessary. Prognosis in neuroblastoma is determined by a number of factors, including certain genetic and biological variables. The genetic variable correlated most with high risk disease is amplification of the MYCN gene, which is present in ~25% of tumors. Additionally, ~70% of these MYCN-amplified tumors express the neurotrophin receptor TrkB, and its ligand, brain-derived neurotrophic factor (BDNF), with concurrent expression of these proteins correlated with high risk disease independent of MYCN-amplification status. To better understand factors influencing MYCN-amplified tumor cell phenotype, and the role of TrkB signaling in high risk neuroblastoma, the experiments in this dissertation examined growth factor effects on MYCN-amplified tumor cells from the TH-MYCN mouse model of neuroblastoma, as well as the creation, and expression of a constitutively active TrkB receptor in a neural crest derived cell line. Overexpression of MYCN targeted to the sympathoadrenal lineage by the tyrosine hydroxylase (TH) promoter is sufficient to cause neuroblastoma in 100% of mice homozygous for the transgene (TH-MYCN mice). Screening growth factors, in vitro treatment of tumor cells from dissociated TH-MYCN tumors with ciliary neurotrophic factor (CNTF) was found to promote differentiation marked by increased neurite outgrowth, and withdrawal of actively dividing cells from the cell cycle. These effects were both concentration dependent, and specific to CNTF, as all other neurotrophic factors tested had no effect on differentiation. Furthermore, TH-MYCN tumor cells were found to highly express the receptor for CNTF, CNTFR both in vitro and in vivo. Testing the ability of CNTF to affect tumor growth in vivo, CNTF treatment attenuated subcutaneous tumor growth of the TH-MYCN tumor-derived cell line NHO1S in wild type 129/SvJ mice. Therefore, CNTF signaling may be a potential therapeutic target in MYCN-amplified neuroblastoma. In addition to being significantly correlated with a poor prognosis in neuroblastoma, the presence of activated TrkB signaling promotes a more aggressive phenotype in established neuroblastoma cell lines. However, whether TrkB signaling is sufficient to transform neural crest derived cells had not been established. To determine the role of TrkB signaling in malignant transformation, the two immunoglobulin-like (Ig) ligand binding domains were removed from a full length rat TrkB receptor. Expression of this receptor, termed IgTrkB, leads to elevated phosphorylated Erk levels in the absence of ligand, indicating the receptor is constitutively active. When expressed in the neural crest derived cell line NCM-1, constitutive TrkB signaling confers a highly transformed phenotype characterized by enhanced proliferation, anchorage-independent cell growth, anoikis resistance, and matrix invasion. Furthermore, IgTrkB NCM-1 cells upregulate transcripts for a number of cancer promoting genes, in addition to the poor prognosis marker MYCN. In vivo, IgTrkB NCM-1 cells form highly aggressive tumors, requiring euthanasia of mice by 15 days following injection, while wild type cells fail to grow. Thus, TrkB signaling is sufficient to transform cells derived from the neural crest.
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Park, Ji. "PRMT5 as a potential theraputic target for MYCN overexposing peadiatric cancers." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.743007.
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Shipillis, Nicholas. "Investigation of system properties related to MYCN oncogene expression in neuroblastoma." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/investigation-of-system-properties-related-to-mycn-oncogene-expression-in-neuroblastoma(2e3ba06b-faec-449e-85be-730213e697b9).html.
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Neuroblastoma (NB) is one the most common cancers in infancy and childhood, andpossession of amplified MYCN gene sequence (gene locus 2p24) is related toaggressive disease and poor prognosis, with a clear distinction established regardingthe survival of patients based on the gene copy-number of MYCN. However, theexpression of MYCN has been reported to vary between patients of even the sameNB subgroups and more importantly its significance in relation to NB prognosis isstill not clearly established with various reports presenting contradicting results.In this study, a bottom-up Systems Biology approach is suggested for studying boththe significance of MYCN expression, but also the distribution of control in therelated pathways that regulate this expression. An initial model was constructeddescribing the basic steps in MYCN expression and it was parameterised with valuesobtained from the literature. The results from the model simulations and analysisgenerated the hypothesis that the expression of MYCN cannot be used exclusively asa predictive factor without taking into account the relative levels of its dimerisationpartner, the protein MAX. Additionally, it was predicted that the amplification ofMYCN had a more pronounced relative effect at lower rather than at higher MYCNgene copy numbers.In order to create separate models for 4 NB cell-lines, it was necessary to performabsolute measurements for MYCN at the DNA, mRNA and protein level, as well asfor the MAX protein. The MYCN gene copy numbers were measured using theqPCR method, while a new data analysis method was suggested for performingabsolute quantification with the use of house-keeping genes, appropriate statisticalmethods and no reference samples. The relative amounts of MYCN mRNA werealso measured using qPCR and the results obtained were in agreement with thesuggested levels from the literature.The absolute measurement of the N-Myc and MAX proteins was attempted usingtwo complementary methods, western blots and ELISA. A series of optimisationexperiments and data analysis steps were taken that resulted in the refinement of theexperimental conditions to the point where they can be used for successfulquantification of the absolute levels of the N-Myc protein. Alternatively, theprocedure used for the MAX protein proved problematic and was not as successful.Overall, this study was successful in becoming the first step for an expanded bottomupsystems biology study regarding the significance of MYCN expression in NB.The combination of both the modelling and experimental parts of this workillustrated some of the potential benefits of Systems Biology approaches in studyingdisease. In this case the resulting model, once fully parameterised with experimentaldata, can be expanded in a number of suggested ways that address questions like therole and control of MYCN expression in relation to the cell-cycle deregulation ormulti-drug resistance in NB, giving in the process a better understanding regardingsuitable treatment targets for individual NB cases.
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Weiher, Moritz Adrian. "INHIBITION MYCN- VERMITTELTER ZELLZYKLUSTRANSITION DURCH THYROID CANCER 1 (TC1) IM NEUROBLASTOM – ETABLIERUNG UND CHARAKTERISIERUNG DES TC1- ÜBEREXPRESSIONSPHÄNOTYPS IN HUMANEN SH-EP NEUROBLASTOMZELLEN UNTER DEM EINFLUSS VON MYCN." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-189951.
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Das Neuroblastom ist der dritthäufigste maligne Tumor im Kindesalter und ist für 15% der Todesfälle durch Krebs bei Kindern unter 14 Jahren verantwortlich. Viele molekularbiologische Vorgänge, die zu der heterogenen Prognose der Patienten beitragen, sind noch nicht verstanden. Als Hauptrisikomerkmal stellt sich die Amplifikation und erhöhte Expression von MYCN dar. In Vorarbeiten der Arbeitsgruppe von Prof. Christiansen zeigte MYCN Einfluss auf die Genregion von Thyroid Cancer 1 (TC1), das als neuer Marker für maligne Schilddrüsenkarzinome erkannt wurde. In der vorliegenden Arbeit wurden erste Untersuchungen zur prognostischen Bedeutung von TC1 im Neuroblastom, sowie die Charakterisierung eines TC1 Überexpressionsphänotyps humaner Neuroblastomzelllinien unter Einfluss von MYCN durchgeführt. Es wurde ein Überexpressionsvektor von TC1 in die Neuroblastomzelllinie SH-EP eingebracht, welche über ein aktivierbares MYCN- Konstrukt verfügt. Dieser neue Phänotyp wurde bezüglich der Proliferation, des Zellzyklus und der Apoptose im Vergleich zu einer Kontrollzelllinie ohne Überexpression untersucht.
Eine In-silico Recherche in der Versteeg Neuroblastomdatenbank ergab eine deutlich bessere Überlebenswahrscheinlichkeit für Patientin mit hoher TC1 Expression.
Es konnte gezeigt werden, dass MYCN Amplifikation und Expression in einem Panel von Neuroblastom Zelllinien nicht mit der TC1 Expression korrelieren. Die spezifische Aktivierung von MYCN führte hingegen zu einer Expressionssteigerung von TC1. Weiterhin zeigte sich, dass eine TC1 Überexpression die Proliferation hemmt, indem es die MYCN induzierte G1- S- Phasen- Transition inhibiert. TC1 zeigt antiproliferative Eigenschaften im Zellkulturmodell und stellt sich als neuer prognostisch günstiger Parameter im Neuroblastom dar.
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Chowath, Rashmi. "Role of Aurora kinase in Medulloblastoma development with correlation to MYCN activity." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-255237.
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Brain tumors are abnormal tissue masses found, either malignant or benign in nature. Medulloblastoma is a brain tumor subtype found to arise in the hind region of the brain, which is highly malignant and has poor long term prospects in general. On the basis of the driving force behind the tumor, medulloblastoma is further subgrouped into 4 categories: WNT; SHH; Group 3 and Group 4 tumors. Group 3 tumors show a high expression of N-Myc protein which is seen in certain types of cancerous cells. The cell cycle is regulated at several checkpoints by cyclin/cdk inhibitors. The primary cilium is an organelle found on the cellular surface, which has functions in cell growth, differentiation and neurogenesis. Aurora kinase is a protein kinase involved in the regulation and maintainence of the cilium. Often the cilium gets deleted from the cellular surface in tumors coupled with an increase in the kinase level inside the cells. Hence aurora kinase is found to be a viable target for therapy. Aurora kinase is also involved in stabilizing the MYCN gene by protecting it from degradation. In this project, the primary cilum was studied in neural stem cells and followed by study of its presence on tumor cells in culture. The gene involved in cilium development i.e. Kif3a was mutated and its aggressive nature was compared with that of the tumor cells. Aurora kinase was commonly found to be over-expressed in both the tumors and the mutants whereas N-Myc over-expression was seen only in tumors. Experiments suggest that cilia repression in Kif3a mutants takes place via an aurora kinase dependent pathway.
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Östergren, Tiolina. "Identification of MYCN and SOX9 target genes and a study of drug treatment effects in medulloblastoma." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-262085.
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Medulloblastoma (MB) is the most common malignant brain tumor affecting children. The transcription factors MYCN and SOX9 are associated with initiation, maintenance and recurrence of MB and are also connected to more aggressive tumors. In this study, a ChIP was performed to isolate DNA from genes that are transcriptionally regulated by these proteins. Identification of these target genes will reveal new potential drug targets and help us better understand the functions of MYCN and SOX9. The ChIP was not fully optimized during this project and the target genes were not sent for sequencing and identified. To study the connection between SOX9 and recurrence, cells with different levels of SOX9 were treated with drugs, after which cell viability was measured. No significant difference in resistance could be measured. Change in expression level of MYCN, SOX9 and other relevant genes after drug treatment was also studied. The results show an increase in SOX9 and HES1, suggesting that these genes are involved in tumor recurrence.
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Nortmeyer, Maike Christine [Verfasser], and Thomas [Akademischer Betreuer] Höfer. "MYCN dependency of MYCN amplified neuroblastoma cell lines analyzed in relation to their interaction with BET proteins and in a novel orthotopic mouse model / Maike Christine Nortmeyer ; Betreuer: Thomas Höfer." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1192373022/34.
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Nortmeyer, Maike [Verfasser], and Thomas [Akademischer Betreuer] Höfer. "MYCN dependency of MYCN amplified neuroblastoma cell lines analyzed in relation to their interaction with BET proteins and in a novel orthotopic mouse model / Maike Christine Nortmeyer ; Betreuer: Thomas Höfer." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1192373022/34.
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Chen, Lindi. "An investigation of the relationship between p53 fuction, differentiation and MYCN in neuroblastoma." Thesis, University of Newcastle Upon Tyne, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.519448.
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Ryl, Tatsiana [Verfasser], and Thomas [Akademischer Betreuer] Höfer. "MYCN, proliferative heterogeneity and treatment response in neuroblastoma / Tatsiana Ryl ; Betreuer: Thomas Höfer." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1180985125/34.
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Scott, Deborah Karen. "Identification and characterisation of genes co-amplified with the MYCN oncogene in neuroblastoma." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268359.
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Cantelli, Erika <1981>. "Preclinical neuroblastoma models for a pharmacological study of a new MYCN oncogene inhibitor." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/4068/.
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Background. Neuroblastoma is the most deadly solid tumor of childhood. In the 25% of cases it is associated with MYCN amplification (MA), resulting in the disregulation of several genes involved in cancer progression, chemotherapy resistance and poor prognosis causing the disregulation of several genes involved in cancer progression and chemotherapy resistance and resulting in a poor prognosis. Moreover, in this contest, therapy-related p53 mutations are frequently found in relapsed cases conferring an even stronger aggressiveness. For this reason, the actual therapy requires new antitumor molecules. Therefore, rapid, accurate, and reproducible preclinical models are needed to evaluate the evolution of the different subtypes and the efficacy of new pharmacological strategies. Procedures. We report the real-time tumorigenesis of MA Neuroblastoma mouse models: transgenic TH-MYCN mice and orthotopic xenograft models with either p53wt or p53mut, by non-invasive micro PET and bioluminescent imaging, respectively. Characterization of MYCN amplification and expression was performed on every collected sample. We tested the efficacy of a new MYCN inhibitor in vitro and in vivo. Results. MicroPET in TH-MYCN mice permitted the identification of Neuroblastoma at an early stage and offered a sensitive method to follow metabolic progression of tumors. The MA orthotopic model harboring multitherapy-related p53 mutations showed a shorter latency and progression and a stronger aggressiveness respect to the p53wt model. The presence of MA and overexpression was confirmed in each model and we saw a better survival in the TH-MYCN homozigous mice treated with the inhibitor. Conclusions. The mouse models obtained show characteristics of non-invasiveness, rapidity and sensitivity that make them suitable for the in vivo preclinical study of MA-NB. In particular, our firstly reported p53mut BLI xenograft orthotopic mouse model offers the possibility to evaluate the role of multitherapy-related p53 mutations and to validate new p53 independent therapies for this highly aggressive Neuroblastoma subtype. Moreover, we have shown potential clinical suitability of an antigene strategy through its cellular and molecular activity, ability to specifically inhibit transcription and in vivo efficacy with no evidence of toxicity.
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Duarte, Alexandra. "The interplay between MYCN and the DNA damage response : modulation of MYCN expression, its interactions with components of the DNA damage response and cellular responses to N-myc following genotoxic stress." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9832.
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The DNA damage response (DDR) forms a signaling cascade rapidly activated upon exposure to genotoxic stress. The DDR safeguards genomic integrity by halting cell cycle progression to allow repair of damaged DNA or by inducing cell death. Myc proteins are key regulators of cell proliferation that transcriptionally control the cell cycle machinery. Amplification of N-myc in neuroblastomas (MNA-NB) is associated with abrogation of the regulatory mechanisms that normally prevent aberrant cell proliferation and the interplay between N-myc and the DDR was here analysed. Initially, an association between N-myc and the cdk inhibitor p21 was investigated in MNA-NB as a possible mechanism by which p21 is functionally suppressed in these cells. Although an N-myc/p21 interaction was not observed, MNA-NB cells appear to express short N-myc isoforms with the potential to associate with p21. Expression of N-myc rendered Rat-1 cells resistant to the cell cycle block imposed by serum starvation but these cells were not able to bypass a G1 arrest imposed by ectopic p21 suggesting N-myc does not abolish p21 activity through regulation at the protein level. Analysis of the N-myc response to DNA damage in MNA-NB cells revealed that N-myc is downregulated in a proteasome-dependent manner in response to UVC or a UV-mimetic carcinogen, 4NQO. This effect was not reproduced with other agents such as IR which like UVC were found to repress cyclin D1 expression likely indicating that alternative DDR signaling pathways differently regulate N-myc. N-myc was found to interact with the DDB2 subunit of the damaged-DNA binding (DDB) complex, a substrate receptor for the DDB1-Cul4ADDB2 E3 ligase. The DDB complex has been implicated in UV-induced protein ubiquitylation suggesting it may play a role in the N-myc response to UVC radiation. These findings highlight the complexities of the DDR and uncover potentially important mechanisms of cell cycle control through regulation of N-myc.
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Nguyen, Tue Gia Women's & Children's Health Faculty of Medicine UNSW. "Combined transcription modulating agents to overcome MycN-mediated retinoid reistance in hish risk neuroblastoma." Publisher:University of New South Wales. Women's & Children's Health, 2007. http://handle.unsw.edu.au/1959.4/44285.
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Neuroblastoma (NB) is the most common solid tumor of early infancy. Despite a significant improvement in the general survival rate for children with cancer, the prognosis of high-risk NB remains low, at about 30%, despite the use of intensive chemo-radiotherapy followed by differentiation therapy with retinoic acid (RA). Relapses in this category of NB are often due to the emergence of multi-drug and RA-resistant minimal residual cancer cells. The use of natural 13-cis RA, as a single chemo-preventive agent, has improved the survival rate to 50% for high-risk NB patients. However, the prevalence of RA-resistance is high in high-risk NB, and in solid cancers, in general. RA-resistance in cancer cells is mediated by a number of factors. Loss of RA-induced expression of the putative tumor suppressor gene, retinoic acid receptor-beta (RARβ), is one of the most common factors that have been reported in RAresistant phenotypes of a wide range of cancer cells. The transcriptional regulation of RAR(β) gene and other retinoid responsive-genes is believed to be regulated by the ligand-dependent transactivation of the homo- or heterodimer complexes of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) subtypes, namely alpha (α), beta (β) and gamma (γ). It is believed that the anti-cancer activities of natural all-trans RA and 13-cis RA are mediated through activation of RAR-complexes. The loss of RA-induced RAR β expression can be caused by aberrant recruitment of chromatin structure modifying enzymes, histone deacetylases (HDACs), which have major roles in the global regulation of gene transcription. However, the mechanism of RA-resistance in NB cells is unclear. This thesis set out to identify the molecular mechanism of RA-resistance and to develop a new therapeutic approach to overcome RA-resistance in NB cells. The data in this thesis demonstrated that deregulation or over-expression of proto-oncogene MYCN caused a total RA-resistance in NB cells in vitro and in vivo, despite the strong induction of RARI3 expression. The data also indicated that the activation of RAR-dependent pathways by aRA or 13RA alone is not sufficient to overcome MYCN-mediated RA-resistance in NB cells. In the light of this observation, this thesis went on to examine whether combined targeting activation of RAR and RXR subtypes with receptor specific ligands could enhance the therapeutic efficacy of the retinoid signaling pathway. NB cells were treated with a panel of receptor-specific retinoids, namely aRA, l3RA, 9RA (RAR-specific), CD 417, CD 2314 (RARβ-specific), CD 666 (RARγ-specific), CD 336 (RARα-specific), CD 3640, CD 2872 (RXR-specific), as a single agent or in combination at a low concentration of 0.1 ??M. The results showed that combined targeting activation of RARα and RXR was not only the most effective combination, but also overcame MYCN-mediated RA-resistance in NB cells in vitro.Collectively, these data demonstrated the combined targeting activation of RAR and RXRs as a new approach to enhance the efficacy of retinoid therapy and overcome RA-resistance in the treatment of high-risk NB, and other cancers. The emerging therapeutic potential of HDAC inhibitors (HDACi) as front line anti-cancer agents, or adjuvants to other agents such as RA, has suggested a new approach in the treatment of cancer. However, the molecular mechanism of the remarkably specific anticancer actions of HDACi is still largely speculation. The data presented in this study was the first to demonstrate a novel sequential order and the dosage-dependent roles of basal p21Wafl expression and G2/M arrest as protective mechanisms against HDACi-induced apoptosis. In addition, this thesis also examined and compared the therapeutic efficacy of HDACi as a single agent and in combination with other anti-cancer agents such as RA, IFNα and chemotherapeutic agents. Evaluation of the therapeutic effects of combinations of aRA, IFN and HDACi showed that combination of HDACi and IFNα exhibited the strongest synergy against NB cells in vitro. Treatment of MYCN transgenic mice, which consistently develop abdominal NB tumors that closely mirror the human disease in both physiological and biological aspects, with hydroxamic acid-based HDACi, trichostatin A (TSA), alone reduced tumor growth by nearly 50%, compared to the solvent control and IFNα alone, which had no effect on NB tumor growth. The most exciting finding was that the combination of HDACi and IFNα synergistically reduced tumor mass and angiogenesis by over 80% without any apparent systemic side-effects. The therapeutic effect of treatment with HDACi correlated with the induction of acetylation of histone 4 protein (H4) in both tumor and organ tissues, indicating a wide therapeutic index for HDACi in vivo. Collectively, the data in this study have demonstrated basal p21 Wafl expression as a potential marker of sensitivity to HDACi-based therapy, and the therapeutic efficacy of a novel combination of HDACi with IFNα in vivo. These preclinical data have provided an evidence-based rationale for a clinical trial of the combination of HDACi and IFNα in the treatment of high risk NB.
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Stermann, Alexander [Verfasser], N. [Akademischer Betreuer] Lode, Lockau [Akademischer Betreuer], and Schramm [Akademischer Betreuer]. "MYCN-DNA-Vakzine zur Behandlung des Neuroblastoms / Alexander Stermann. Gutachter: N. Lode ; Lockau ; Schramm." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://d-nb.info/1047145472/34.
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Boisvilliers, Madryssa de. "Effets anti-tumoraux du VIP dans des cellules de neuroblastome." Thesis, Poitiers, 2015. http://www.theses.fr/2015POIT2283/document.
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Le neuroblastome (NB) est un cancer pédiatrique dérivé de la crête neurale. Les NB à haut risque sont des tumeurs peu différenciées présentant une amplification de MYCN et les plus agressives possèdent en plus une mutation d'ALK. Pour améliorer le traitement de ces tumeurs, les nouvelles thérapies cherchent à induire la différenciation cellulaire, l'inhibition de MYCN et la réduction de la signalisation d'ALK. Les résultats obtenus indiquent que le VIP induit une neuritogenèse dans les cellules de NB à haut risque SK-N-DZ et Kelly, et réduit en plus l'expression de MYCN dans les cellules Kelly, comme précédemment observé pour les cellules IMR-32. En parallèle, le VIP diminue l'invasion des cellules Kelly et IMR-32 et réduit également l'activité d'AKT qui est impliquée dans la signalisation d'ALK, dans les cellules Kelly qui présentent la mutation ALK F1174L. Certains effets du VIP sont dépendants de la PKA. Des analogues du PACAP, un peptide apparenté au VIP, présentent une efficacité supérieure à celle du VIP dans les cellules Kelly. Les effets du VIP sur la neuritogenèse et l'expression de MYCN dans ces cellules sont médiés par le récepteur VPAC2 qui peut avoir une localisation nucléaire dans les lignées cellulaires et les cellules de patients atteints de NB. Une délocalisation de ce récepteur nucléaire par ses propres ligands est observée. De plus, des cellules souches mésenchymateuses humaines dérivées du tissu adipeux induisent la différenciation des cellules de NB via les peptides VIP et/ou PACAP. L'ensemble de ces résultats indiquent que le VIP et des analogues du PACAP agissent sur des processus moléculaires et cellulaires qui pourraient réduire l'agressivité des NB à haut risque, et pourraient donc présenter un intérêt pour une nouvelle thérapieNeuroblastoma (NB) is a pediatric cancer derived from neural crest. High-risk NB are poorly differentiated tumors with MYCN amplification and the most aggressive forms in addition have an ALK mutation. To improve the treatment of these tumors, the new therapies aim to induce cell differentiation, inhibition of MYCN and reduction of ALK signaling. The obtained results indicate that the neuropeptide VIP induces neuritogenesis in high-risk SK-N-DZ and Kelly NB cells, and in addition reduces the expression of MYCN in Kelly cells, as previously observed in IMR-32 cells. In parallel, VIP decreases Kelly and IMR-32 cell invasion and also reduces the activity of AKT that is involved in the signaling of ALK, in Kelly cells harboring the mutation ALK F1174L. Most of these VIP effects are PKA-dependent. Analogs of PACAP, a VIP-related peptide, exhibit a higher efficiency than VIP in Kelly cells. VIP effects on neuritogenesis and MYCN expression in these cells are mediated by the VPAC2 receptor which can have a nuclear localization in the NB cell lines and in NB from patients. A relocation of this nuclear receptor by its own ligand is observed. Moreover, human mesenchymal stem cells derived from adipose tissue induce NB cells differentiation via VIP and/or PACAP peptides. Taken together, these results indicate that VIP and PACAP analogs act on molecular and cellular processes that might reduce aggressiveness of high-risk NB, and thus could be of interest for new therapy
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Boulos, Nidal. "Influence of MYCN expression and chromosome 1p deletion on responses of neuroblastoma to chemotherapeutic drugs." Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401848.
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Purgato, Stefania <1978>. "Inibizione selettiva del gene MYCN mediante PNA (acidi peptido nucleici) anti-gene nel rabdomiosarcoma umano." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2008. http://amsdottorato.unibo.it/690/.
Full textAbstract:
MYCN oncogene amplification/expression is a feature of many childhood tumors, and some adult
tumors, and it is associated with poor prognosis. While MYC expression is ubiquitary, MYCN has a
restricted expression after birth and it is an ideal target for an effective therapy. PNAs belong to the
latest class of nucleic acid-based therapeutics, and they can bind chromosomal DNA and block gene
transcription (anti-gene activity). We have developed an anti-gene PNA that targets specifically the
MYCN gene to block its transcription. We report for the first time MYCN targeted inhibition in
Rhabdomyosarcoma (RMS) by the anti-MYCN-PNA in RMS cell lines (four ARMS and four
ERMS) and in a xenograft RMS mouse model. Rhabdomyosarcoma is the most common pediatric
soft-tissue sarcoma, comprising two main subgroups [Alveolar (ARMS) and Embryonal (ERMS)].
ARMS is associated with a poorer prognosis. MYCN amplification is a feature of both the ERMS
and ARMS, but the MYCN amplification and expression levels shows a significant correlation and
are greater in ARMS, in which they are associated with adverse outcome.
We found that MYCN mRNA and protein levels were higher in the four ARMS (RH30, RH4, RH28
and RMZ-RC2) than in the four ERMS (RH36, SMS-CTR, CCA and RD) cell lines. The potent
inhibition of MYCN transcription was highly specific, it did not affect the MYC expression, it was
followed by cell-growth inhibition in the RMS cell lines which correlated with the MYCN
expression rate, and it led to complete cell-growth inhibition in ARMS cells. We used a mutated-
PNA as control. MYCN silencing induced apoptosis. Global gene expression analysis (Affymetrix
microarrays) in ARMS cells treated with the anti-MYCN-PNA revealed genes specifically induced
or repressed, with both genes previously described as targets of N-myc or Myc, and new genes
undescribed as targets of N-myc or Myc (mainly involved in cell cycle, apoptosis, cell motility,
metastasis, angiogenesis and muscle development). The changes in the expression of the most
relevant genes were confirmed by Real-Time PCR and western blot, and their expression after the
MYCN silencing was evaluated in the other RMS cell lines. The in vivo study, using an ARMS
xenograft murine model evaluated by micro-PET, showed a complete elimination of the metabolic
tumor signal in most of the cases (70%) after anti-MYCN-PNA treatment (without toxicity),
whereas treatment with the mutated-PNA had no effect.
Our results strongly support the development of MYCN anti-gene therapy for the treatment of RMS,
particularly for poor prognosis ARMS, and of other MYCN-expressing tumors.
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Horvilleur, Emilie. "Interrelations entre les protéines de la famille p53 et MYCN dans la pathogenèse du neuroblastome." Paris 11, 2008. http://www.theses.fr/2008PA11T010.
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Okiro, Patricia Opon. "Morphological classification of childhood medulloblastomas with β-catenin immunohistochemistry and mycn fluorescent in situ hybridization." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15733.
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Medulloblastoma is the most frequently occurring childhood malignant brain tumour, affecting 1 of 5 children presenting with a brain tumour, between the ages of 0 and 9 years. The basic prognostic stratification that relies on clinical and histological findings alone has proven unsatisfactory as an outcome predictor. Distinct molecular genetic profiles have been described, with four molecular variants of medulloblastoma with specific demographic and prognostic features. These are the WNT subgroup, SHH subgroup, Group 3 and Group 4 tumours. The aim of this study was to describe the expression status of β-catenin, and MYCN, using IHC and FISH respectively, and to correlate these findings with clinico-pathological and demographic characteristics and clinical outcome. Materials and Methods This study was a nested retrospective analytical study, reviewing 54 cases of childhood medulloblastoma diagnosed between 1988 and 2014. Results Classic histology accounted for 40.7% of cases, LCA 37%, ND 16.7% and 5.6% MBEN). Based on β-catenin IHC, the WNT subgroup accounted for 16.7% of cases. This group had no mortalities or recurrences. Seven patients showed amplification of MYCN gene. The SHH group, defined by ND/MBEN histology and/or MYCN amplification, accounted for 27.7% of patients. Non-WNT/non-SHH tumours 30 patients (55.6%) showed a male predilection, and accounted for 37.5% recurrences and 50%. mortalities also falling in this group. Conclusions Nuclear β-catenin identifies WNT tumours. Nodular desmoplastic morphology is useful in identifying some, but not all cases of SHH group medulloblastomas. MYCN positive tumours also showed classical, and LCA morphology.. Patients of all the beta-catenin positive cases were free of recurrence and alive at last follow up. Patients with MYCN amplification and non-ND histology (LC/A or classic) had poorer outcomes than patients with ND histology. One patient showed both MYCN amplification and nuclear β-catenin translocation, and had good clinical outcome. This finding requires validation with other molecular techniques.
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Manoni, Eleonora. "Modellazione matematica delle dinamiche di rilevamento dell'espressione del gene N-MYC mediante un sensore biomolecolare sintetico." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amslaurea.unibo.it/10215/.
Full textAbstract:
L'espressione del gene MYCN è un importante indicatore della severità
del NBL.
Poiché il numero di copie di MYCN è un indice grezzo della sua
espressione quantificarle utilizzando tecniche come la “fluorescent in
situ hybridization” (FISH) può servire a formulare una stima del
livello di espressione MYCN [Shapiro 1993].
Tuttavia, l'espressione aberrante di MYCN nel NBL non è sempre
associata all'amplificazione genica; pertanto la valutazione diretta
del livello di espressione di questo gene sarebbe un miglior
indicatore prognostico.
Questa tesi è stata sviluppata nell'ambito di un progetto che si
propone di realizzare un sensore biomolecolare sintetico per
l'identificazione del livello di espressione di MYCN.
Di seguito saranno presentati i dettagli relativi alla progettazione
della topologia circuitale e all’analisi in silico che sono state
condotte per caratterizzare il comportamento dinamico del sistema.
Questo lavoro è stato svolto nel laboratorio di Ingegneria Cellulare e
Molecolare "S. Cavalcanti", presso la Sede di Cesena del Dipartimento
di Ingegneria dell'Energia elettrica e dell'Informazione "Guglielmo
Marconi" (DEI) dell’Ateneo di Bologna.
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Savov, Vasil. "The Role of SOX9 in Medulloblastoma." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-274630.
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Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Overall survival is about 70% and in cases where current treatment fails, the disease recurs and most often is fatal. At the molecular level, MB can be divided into four defined subgroups: WNT, SHH, Group 3 and Group 4. Amplification of MYC family genes is common in MB and correlates with poor prognosis and tumor relapse. In this thesis we showed how MYCN initiates brain tumors when transduced in neural stem cells (NSCs). Prior to transduction, NSCs were isolated from different brain regions and at various time points. While overexpression of wild-type MYCN did not generate any tumors, orthotopic transplantation of MYCNT58A-expressing forebrain, brain stem and cerebellar NSCs induced diffuse malignant glioma, PNET-like tumors and MB, respectively. Interestingly, MYCNT58A-expressing cerebellar NSCs induced SHH-dependent MB from embryonic cells but SHH-independent MB from postnatal cells. We further showed that cerebellar NSCs transduced with both MYCNT58A and transcription factor SOX9 developed tumors faster and promoted distant migration into the forebrain. The function and regulation of SOX9 in MB cells is poorly understood. We identified SOX9 protein as target of FBW7 ubiquitin ligase and demonstrated the effects of SOX9 on MB cells migration, metastasis and drug resistance. We further blocked PI3K pathway to destabilize SOX9 which sensitized cells to cytostatic treatment. We used a (TetOFF) transgenic mouse model of MYCN-induced MB (GTML) and crossed it with a (TetON) transgene which allowed us to specifically target rare SOX9-positive cells in the tumor. In this system, MB develops spontaneously and SOX9-negative tumor cells can be killed off by doxycycline. The few remaining SOX9-positive cancer cells were able to promote distant MB recurrences. Such a pattern of relapse was recently shown for Group 3 and 4 human MB where about 90% of the recurrences were distant. In summary, this thesis demonstrates that MYCN can generate various types of brain tumors depending on the timing and location of its expression. It further defines the existence of a rare population of SOX9-expressing MB cells that are involved in causing distant MB recurrences. Finally, it describes how SOX9 is stabilized in MB cells and increases MB migration and therapy resistance.
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Flórez, Amaya Andrés Felipe [Verfasser], and Thomas [Akademischer Betreuer] Höfer. "MYCN modulates the restriction point and ferroptosis in Neuroblastoma / Andrés Felipe Flórez Amaya ; Betreuer: Thomas Höfer." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1180739876/34.
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Gamble, Laura Dawn. "MYCN and the p53-MDM2/MDMX-p14ARF network in neuroblastoma amd response to MDM2-p53 antagonists." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/1350.
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Background: MYCN-amplification is a major negative prognostic marker, occurring in 25-30% of neuroblastomas. MYCN plays contradictory roles in promoting cell growth and sensitizing cells to apoptosis, and we have recently shown that p53 is a direct transcriptional target of MYCN, and may be an important mechanism of MYCN-induced apoptosis. Although p53 mutations are rare in neuroblastoma at diagnosis, the p53/MDM2/p14ARF pathway is inactivated in 35% of cases through MDM2-amplification or p14ARF inactivation. Neuroblastoma is therefore an ideal target for p53 reactivation using MDM2-p53 antagonists. MDMX, a homologue of MDM2, is another negative regulator of p53 which is often overexpressed in cancers and has been shown to compromise the effects of MDM2-p53 antagonists in various cancer types. MDMX expression and the effect on MDM2-p53 antagonists has not been investigated in neuroblastoma. Hypotheses 1) Reactivation of p53 by inhibition of its negative regulator MDM2, using the MDM2-p53 antagonists Nutlin-3 and MI-63, will result in p53-mediated growth arrest and apoptosis preferentially in MYCN-amplified cells 2) MDMX knockdown increases and p14ARF knockdown decreases the sensitivity of neuroblastoma cell lines to MDM2-p53 antagonists. Methods: The effect of MYCN, MDM2, MDMX and p14ARF was investigated on the response to MDM2-p53 antagonists using siRNA in a panel of 21 neuroblastoma cell lines. Sensitivity was measured by growth inhibition, apoptosis assays including caspase activity and fluorescent activated cell sorting, and the effect on the p53 response measured by Western blotting. Results: Using the SHEP Tet21N MYCN regulatable system, MYCN(-) cells were more resistant to both Nutlin-3 and MI-63 mediated growth inhibition and apoptosis compared to MYCN(+) cells and siRNA mediated knockdown of MYCN in 4 MYCN-amplified cell lines resulted in decreased p53 expression and activation, as well as decreased levels of apoptosis following treatment with MDM2-p53 antagonists. In a panel of cell lines treated with Nutlin-3 and MI-63, the sub-set amplified for MYCN had a significantly lower mean GI50 value and increased caspase 3/7 activity compared to the non-MYCN-amplified group of cell lines, but p53 mutant cell lines were resistant to the antagonists regardless of MYCN status. Knockdown of MDM2 did not alter the apoptotic response to Nutlin-3 or MI-63 but surprisingly, knockdown of MDMX resulted in decreased levels of apoptosis. MDMX expression varied amongst the neuroblastoma cell lines and positively correlated with caspase 3/7 activity following MDM2-p53 antagonist treatment. p14ARF impaired cell lines underwent less apoptosis following MDM2-p53 antagonist treatment and following Nutlin-3 treatment, 3 of 4 p14ARF impaired cell lines underwent a pronounced G1 arrest. p14ARF knockdown alone resulted in decreased caspase 3/7 activity, and following MDM2-p53 antagonist treatment there was decreased caspase 3 cleavage and activity, and decreased PARP cleavage. Conclusions: Amplification or overexpression of MYCN sensitizes neuroblastoma cell lines with wildtype p53 to MDM2-p53 antagonists and these compounds may therefore be particularly effective in treating high risk MYCN-amplified disease. This data also suggests that neuroblastomas with high MDMX expression may be more susceptible to MDM2-p53 antagonist treatment, but that cells with inactivated p14ARF predominantly undergo a G1 arrest which may protect them from apoptosis. MDMX and p14ARF status may therefore be important in addition to MYCN in determining the outcome of neuroblastomas treated with MDM2-p53 antagonists.
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Fix, Anne. "Caractérisation des amplifications génomiques et des mécanismes de surexpression de la protéine MYCN dans le neuroblastome." Paris 11, 2008. http://www.theses.fr/2008PA11T005.
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Flórez, Andrés [Verfasser], and Thomas [Akademischer Betreuer] Höfer. "MYCN modulates the restriction point and ferroptosis in Neuroblastoma / Andrés Felipe Flórez Amaya ; Betreuer: Thomas Höfer." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1180739876/34.
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Dawson, Hayley Jane. "Mysin VI and binding partners in macrophages : and their roles in the endocytosis of lipoproteins during foam cell formation." Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559022.
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Röschert, Isabelle [Verfasser], Martin [Gutachter] Eilers, and Manfred [Gutachter] Gessler. "Aurora-A prevents transcription-replication conflicts in MYCN-amplified neuroblastoma / Isabelle Röschert ; Gutachter: Martin Eilers, Manfred Gessler." Würzburg : Universität Würzburg, 2021. http://d-nb.info/1239052804/34.
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Ottaviani, Daniela. "In-Depth Characterization of Human Retinoblastoma Subtype 2 and Preclinical Models." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS001.
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Le rétinoblastome, un cancer pédiatrique de la rétine en développement, est la tumeur intraoculaire la plus fréquente chez l’enfant et représente environ 4 % de tous les cancers infantiles. Bien qu'il s'agisse d'une maladie rare, l'hôpital Curie (centre de référence pour le rétinoblastome en France) accueille environ 50 à 60 nouveaux patients chaque année. Notre groupe a précédemment caractérisé deux sous-types de rétinoblastomes. Les tumeurs de type « cone-like » ou sous-type 1 sont plutôt différenciées et homogènes, présentent une surexpression des gènes liés aux cellules cônes (photorécepteurs) de la rétine, sont diagnostiquées cliniquement plus tôt et regroupent la majorité des formes héréditaires et bilatérales. Les tumeurs « mixed-type » ou sous-type 2, présentent une hétérogénéité intra-tumorale et une surexpression des gènes liés aux cellules des cônes et des cellules ganglionnaires de la rétine, sont enrichies en patients unilatéraux qui sont diagnostiqués cliniquement à des âges plus avancés. Nous avons caractérisé le paysage moléculaire et génomique de 102 rétinoblastomes provenant de trois institutions : l'Institut Curie (France), l'Hôpital Garrahan (Argentine) et l'Hôpital Sant Joan de Déu (Espagne). Le développement d'une signature de méthylation par pyroséquençage pour la classification des échantillons nous a permis d'élargir nos échantillons classés, d'une première série de 72 à notre dernière série de 102 tumeurs. L'analyse du paysage mutationnel de notre série a révélé que les tumeurs du sous-type 2 avaient plus de mutations somatiques par échantillon que les tumeurs du sous-type 1. De plus les gènes BCOR et ARID1A étaient les deux seuls gènes mutés de manière récurrente, et identifiés uniquement dans le sous-type 2. En divisant notre cohorte de tumeurs en sous-type 1 et 2, la distribution des mutations le long de RB1 était significativement différente. Par ailleurs, nous avons identifié une région de la protéine RB1 (dans le Domaine A) enrichie en mutations provenant des tumeurs du sous-type 2, avec très peu de mutations du sous-type 1. En plus, nous avons caractérisé deux événements récurrents de fusion chromosomique perturbant le gène DACH1. Les tumeurs de sous-type 2 sont caractérisées par une surexpression de TFF1, non exprimée dans la rétine normale. L'analyse par immunohistochimie de TFF1 dans des tumeurs localement invasives provenant de l'hôpital Garrahan a révélé la présence de cellules TFF1+ envahissant la région rétrolaminaire du nerf optique. Nous avons exploré un possible rôle oncogène de TFF1 dans le rétinoblastome lié à la survie cellulaire, à la migration cellulaire et à l'invasion cellulaire, qui n'a finalement pas été mis en évidence in vitro. Le sous-type moléculaire 2 regroupe les tumeurs MYCN amplifiées et les tumeurs avec une activation de la voie de signalisation MYC et des gènes cibles de MYC. L'utilisation de JQ1 et OTX015 (inhibiteurs des protéines BET) a fortement réduit la viabilité in vitro de lignées cellulaires de rétinoblastomes représentatives du sous-type 2, avec une régulation négative significative du gène et de la protéine MYC/MYCN. Nos résultats préliminaires suggèrent une nouvelle piste thérapeutique par l'inhibition des protéines BET dans le rétinoblastome. Les modèles précliniques largement utilisés dans la recherche sur le rétinoblastome n'ont pas été caractérisés ou classés au niveau moléculaire. Nous avons utilisé la même approche que pour la classification des tumeurs primaires et avons constaté que la plupart des modèles cellulaires et PDX étudiés étaient classés dans le sous-type moléculaire 2 et partageaient des caractéristiques moléculaires, génomiques et protéiques trouvés dans les tumeurs primaires de ce sous-type moléculaire. En conclusion, nous avons pu caractériser de façon plus approfondie le sous-type 2 des rétinoblastomes, qui semble présenter un phénotype plus agressif et qui est le sous-type représenté dans les modèles précliniques analysésRetinoblastoma (RB) is a rare pediatric cancer of the developing retina that represents the most common intraocular tumor in children, and accounts for about 4% of all childhood cancers. Although being a rare disease, the Curie Hospital (the referral center for retinoblastoma in France) treats about 50-60 new patients each year. Our group has previously characterized two retinoblastoma subtypes. The cone-like or subtype 1 tumors rather differentiated and homogenous, presenting an overexpression of genes related to cone photoreceptor retinal cells, clinically diagnosed earlier and grouping the majority of hereditary and bilateral forms. The mixed-type or subtype 2 tumors, displaying an intra-tumoral heterogeneity and showing overexpression of genes related to cone and retinal ganglion cells, are enriched in unilateral patients clinically diagnosed at older ages. The general goal of my thesis was to extend the molecular characterization of these subtype 2 retinoblastomas. We characterized the molecular and genomic landscape of retinoblastoma in a series of 102 primary tumors, integrating samples from three institutions: the Curie Institute (France), the Garrahan Hospital (Argentina) and Sant Joan de Déu Hospital (Spain). The development of a pyrosequencing-based tool for sample classification allowed us to enlarge our classed samples, from an initial series of 72, to our final series of 102 tumors. Analysis of the mutational landscape in our series revealed that tumors from the subtype 2 had significantly more somatic mutations per sample than tumors from the subtype 1. Besides RB1 gene, BCOR and ARID1A where the only two recurrently mutated genes, and identified only in the subtype 2. Distribution of mutations alongside the RB1 gene has so far been analyzed in terms of a single group of retinoblastomas. When splitting our cohort in subtype 1 and subtype 2 tumors, the distribution of mutations was significantly different. Besides, we identified a region of the RB1 protein (in Domain A) enriched in mutations from tumors of the subtype 2, and devoid of mutations of the subtype 1. Besides somatic mutations, we characterized two recurrent chromosomal fusion events disrupting DACH1. Subtype 2 tumors are characterized by an overexpression of TFF1, not expressed in the normal retina. Immunohistochemical analysis of TFF1 in locally invasive tumors coming from the Garrahan Hospital revealed the presence of TFF1+ cells invading the retrolaminar region of the optic nerve. We then explored a possible oncogenic role of TFF1 in retinoblastoma related to cell survival, cell migration and cell invasion, which was not fully uncovered. Molecular subtype 2 regroups the MYCN amplified tumors and tumors with MYC signaling pathway activation and upregulation of hallmark MYC target genes. The use of JQ1 and OTX015 (BET bromodomains inhibitors) strongly reduced the viability in vitro of retinoblastoma cell lines representatives of the subtype 2, together with a significant MYC/MYCN gene and protein downregulation. We provided preliminary results to explore a new therapeutic avenue of BET protein inhibition in retinoblastoma. Preclinical models widely used in retinoblastoma research has not been characterized or classified at the molecular level. We have used the same approach as for primary human tumor’s classification, and found that most cellular and PDX models studied classed in the molecular subtype 2 and shared many of the molecular, genomic and protein characteristics found in primary tumors of this molecular subtype. Taken together, we have performed a deeper characterization of subtype 2 retinoblastomas, which seems to represent a more aggressive phenotype, and is the represented subtype in the preclinical models analyzed
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Weiher, Moritz Adrian [Verfasser], Holger [Akademischer Betreuer] Christiansen, Sven [Akademischer Betreuer] Starke, Ulrich H. [Gutachter] Thóme, and Gerhard [Gutachter] Behre. "Inhibition MYCN-vermittelter Zellzyklustransition durch Thyroid Cancer 1 (TC1) im Neuroblastom – Etablierung und Charakterisierung des TC1-Überexpressionsphänotyps in HUMANEN SH-EP Neuroblastomzellen unter dem Einfluss von MYCN / Moritz Adrian Weiher ; Gutachter: Ulrich H. Thóme, Gerhard Behre ; Holger Christiansen, Sven Starke." Leipzig : Universitätsbibliothek Leipzig, 2015. http://d-nb.info/1240241445/34.
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Tong, Pak-ho, and 湯柏豪. "The cytotoxic effect of arsenic trioxide on human neuroblastoma cell lines and its relationship to MYCN gene status." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hdl.handle.net/10722/210315.
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Dirks, Johannes [Verfasser], and Martin [Gutachter] Eilers. "Charakterisierung der Wechselwirkung zwischen N-Myc und Aurora-A im MYCN-amplifizierten Neuroblastom / Johannes Dirks ; Gutachter: Martin Eilers." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1194836240/34.
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Brockmann, Markus [Verfasser], Martin [Gutachter] Eilers, and Manfred [Gutachter] Gessler. "Inhibition von Aurora-A als neue Therapiestrategie gegen MYCN-amplifizierte Neuroblastome / Markus Brockmann. Gutachter: Martin Eilers ; Manfred Gessler." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1112041338/34.
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Bell, Emma. "The role of MYCN in p53 activation and the downstream response to p53 after DNA damage in neuroblastoma." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437980.
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Tong, Pak-ho. "The cytotoxic effect of arsenic trioxide on human neuroblastoma cell lines and its relationship to MYCN gene status." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42841227.
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Alam, Goleeta N. "Role of the Lineage Gene Phox2B in Neuroblastoma Development." University of Toledo Health Science Campus / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1243891387.
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Samy, Mona. "Télomerase et destin des tumeurs neuroblastiques." Thesis, Paris 11, 2010. http://www.theses.fr/2011PA11T039/document.
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La télomérase est une ribonucléoprotéine, constituée d’un composant ARN (hTR) qui sert dematrice à l’addition des séquences télomériques aux extrémités des chromosomes et d’un composantprotéique catalytique à activité de transcriptase inverse (hTERT). La réactivation de la télomérasedans 90% des cancers compense le raccourcissement des télomères, permettant ainsil’immortalisation et la survie des cellules tumorales. Ce rôle canonique de la télomérase estaujourd’hui bien documenté. Cependant des travaux récents suggèrent que la télomérase pourraitavoir d'autres fonctions indépendantes de son rôle sur le maintien de la longueur des télomères dansla tumorigénèse et/ou la progression tumorale.Dans les neuroblastomes (NB), l’augmentation du niveau d’activité télomérase (AT) estassociée à un stade avancé de la maladie et à un mauvais pronostic. En effet, plusieurs études ontmontré que les neuroblastomes agressifs ont un niveau élevé d’AT alors que les tumeurs de bonpronostic, ont peu ou pas d’AT. En effet, les NB de stade 4S ayant la capacité de régresserspontanément ont un très faible niveau d'AT. Ces observations suggèrent que la télomérase peutjouer un rôle crucial dans le développement des NB.Afin de mieux comprendre l’implication de la télomérase dans le phénotype agressif desneuroblastes malins et dans la chimiorésistance, nous avons caractérisé les modificationsphénotypiques et génotypiques induites par l’inhibition de la télomérase via l’expression ectopiqued’un mutant dominant négatif catalytiquement inactif (DN-hTERT) dans la lignée IGR-N-91 induit unedifférenciation cellulaire de type stromale et une sensibilisation à l’apoptose en réponse à trois agentscytotoxiques (cisplatine, staurosporine, TRAIL). Cette chimiosensibilisation n’est pas la conséquenced’un raccourcissement des télomères mais probablement celui d’une modulation de l’expression decertains gènes impliqués dans la réponse apoptotique (ré-expression de la caspase 8 et de p53sauvage), suggérant une fonction non canonique de la télomérase. De plus, nous avons montréqu’hTERT régule activement l’expression de N-Myc. En effet, l’expression ectopique du mutanthTERT-DN entraîne une perte des copies surnuméraires de N-Myc conduisant à l’extinction del'expression de la protéine alors que la surexpression d’hTERT sauvage augmente au contraire lenombre de copies du gène. Cette élimination de la protéine N-Myc pourrait être le signe d’une pertedu caractère agressif des cellules tumorales comme en témoigne la diminution de l’expression de laNSE (marqueur de mauvais pronostique des NB) et l’induction du CD44 dans les cellules hTERT-DN.L’ensemble de nos résultats démontre donc un nouveau rôle majeur de la télomérase,indépendant de sa fonction canonique d’élongation des télomères, dans l’acquisition du phénotypemalin et dans la chimiorésistance des NB. Ces résultats sont importants en termes de connaissancede la biologie du NB et des possibilités thérapeutiques. En effet, ces résultats suggèrent quel’inhibition de la télomérase comme stratégie anti-cancéreuse est une approche qui présente un intérêttout particulier dans les cas de NB de stade 4 dans lesquels le taux de survie des patients reste trèsinsuffisant malgré les thérapeutiques les plus intensivesTelomerase is a ribonucleoprotein consisting of an RNA component (hTR) that serves as atemplate for the addition of telomeric sequences at the ends of chromosomes and a proteincomponent catalytic activity of reverse transcriptase (hTERT). The reactivation of telomerase in 90%of cancers compensates the shortening of telomeres, allowing the immortalization and survival oftumor cells. This canonical role of telomerase is now well documented. However recent studiessuggest that telomerase may have other functions beyond its role in maintaining telomere length intumorigenesis and / or tumor progression.In neuroblastoma (NB), increased levels of telomerase activity (TA) is associated withadvanced disease and poor prognosis. Indeed, several studies have shown that aggressiveneuroblastomas have a high level of TA while favourable tumors, have little or no TA. Therefore, lowtelomerase activity appears to be linked with regression or maturation of NB as it can be seen in theparticular group of 4S stage neuroblastoma. These observations suggest that telomerase may play acrucial role in the development of NB.To better understand the involvement of telomerase in the aggressive phenotype of malignantneuroblasts and drug resistance, we characterized the phenotypic and genotypic changes induced byinhibition of telomerase via ectopic expression of a mutant dominant negative catalytically inactive(DN-hTERT) in a metastatic chemoresistant NB cell line IGR-N-9. Our results show that theexpression of this mutant induces a stromal-type cell differentiation a sensitization to apoptosis inresponse to three cytotoxic agents (cisplatin, staurosporine, TRAIL). The chemosensitization is not theresult of telomere shortening but probably f a modulation of the expression of certain genes involved inthe apoptotic response (re-expression of caspase 8 and wild-type p53), suggesting a noncanonicalfunction of telomerase Furthermore, we showed that hTERT actively regulates the expression ofMYCN. Indeed, ectopic expression of the inactive mutant causes a loss of supernumerary copies ofMYCN leads to the extinction of the expression of the protein, whereas overexpression of wild hTERTincreases the number of copies of the MYCN gene. The elimination of MYCN protein could be a signof a loss of the aggressiveness of the tumor cells as evidenced by the decreased expression of NSE(a marker of poor prognosis of NB) and induction of CD44 in DN-hTERT cells.Overall, our findings thus demonstrate a new role of telomerase independent of its canonicalfunction of telomere elongation in the acquisition of the malignant phenotype and drug resistance inNB. These results are important in terms of knowledge of the biology of NB and therapeuticpossibilities. Indeed, our data suggest that inhibition of telomerase as an anticancer strategy is anapproach that has a particular interest in cases of stage 4 NB in which the survival rate of patientsremains very inadequate despite the therapeutic more intensive
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Fielitz, Kathrin [Verfasser], Alexander [Akademischer Betreuer] Schramm, and Elke [Gutachter] Cario. "Modellierung der MYCN-getriebenen Tumorgenese in vitro und in transgenen Mausmodellen / Kathrin Fielitz ; Gutachter: Elke Cario ; Betreuer: Alexander Schramm." Duisburg, 2017. http://d-nb.info/1132510597/34.
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Gogolin, Sina [Verfasser]. "MYCN-dependent and -independent mechanisms targeting drug-induced DNA damage response and chromosomal instability in neuroblastoma cells / Sina Gogolin." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/1030142882/34.
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Althoff, Kristina [Verfasser], Johannes H. [Akademischer Betreuer] Schulte, and Bertram [Akademischer Betreuer] Opalka. "Etablierung eines MYCN-vermittelten murinen Neuroblastommodells und Analyse tumorsuppressiver mikroRNAs / Kristina Althoff. Gutachter: Bertram Opalka. Betreuer: Johannes H. Schulte." Duisburg, 2014. http://d-nb.info/1046502786/34.
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