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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Determinación de las frecuencias alélicas de las variantes polimórficas: intrón 3, intrón 6 y codón 72 del gen supresor de tumores tp53 en dos muestras poblacionales del departamento de Lima- Perú

Sánchez Pinto, Francisco José Melchor January 2015 (has links)
El gen TP53 codifica una proteína de 53 kDa con importante función reguladora en procesos celulares como la proliferación, muerte celular y preservación del material genético. Polimorfismos de este gen presentan una alta diversidad en la distribución de las frecuencias alélicas entre grupos étnicos y han sido relacionados con la susceptibilidad al cáncer. Utilizando la técnica de PCR-RFLP, se determinó las frecuencias alélicas de los polimorfismos intrón 3, intrón 6 y codón 72 en 58 estudiantes de la UNMSM (Lima) y 37 de la Universidad José Faustino Sánchez Carrión (Huacho). Se estimó la frecuencia génica y genotípica con el programa estadístico SPSS 11.5; y con el programa Arlequín versión 3.5, a través del índice de Nei, se estableció el grado de diferenciación genética entre ambas poblaciones al considerar el intrón 3, intrón 6 y codón 72, que resultó 1.793, 1.141 y 0.323 respectivamente. Ambas poblaciones están en equilibrio de Hardy-Weinberg (p>0.05) para los tres polimorfismos. En el codón 72, la frecuencia alélica para prolina resultó 30.1 % en la muestra de Lima y 29.7 % en la muestra de Huacho. La frecuencia del alelo para la arginina fue 69,8% para Lima y 70,2% en la de Huacho. Con relación al intrón 6, la frecuencia alélica para W en la de Lima fue 98.2 % y 81 % en la de Huacho. En contraste con el alelo M se obtuvo una frecuencia alélica de 1.7 % para la población estudiada de Lima y 18.9 % en la de Huacho. De otro lado, para el intrón 3 la frecuencia alélica W fue 94.6 % para Lima y 90 % para Huacho. En cambio la frecuencia alélica para M en los de Lima fue de 5.3 % y 10 % en los de Huacho. Se destaca el predominio del alelo Arg en el codón 72 para ambas poblaciones analizadas; así como el alelo W tanto en el intrón 6 como en el intrón 3. La comparación con las frecuencias alélicas de origen africano y asiático reveló diferencias estadísticamente significativas (p>0.001); sin embargo, se, observó una similitud con las poblaciones amerindias y caucásicas. PALABRAS CLAVE: gen TP53, polimorfismo Arg72Pro, intrón 6, intrón 3, poblaciones peruanas / --- The TP53 gene encodes a protein of 53 kDa with important regulatory role in cellular processes such as proliferation, cell death and preservation of genetic material. Polymorphisms of this gene have a high diversity in the distribution of allele frequencies between ethnic groups and have been linked to cancer susceptibility. By studying PCR-RFLP, was determined the allele frequencies of the polymorphisms, intron 3, intron 6 and codon 72 in 58 students of the University of UNMSM (Lima) and 37 at the University of Jose Faustino Sanchez Carrion. The Allelic and genotypic frequency was measured with the SPSS 11.5 statistical program; and with the Arlequin program ver. 3.5, through Nei index, was established the degree of genetic differentiation between the two populations by considering the intron 3, intron 6 and codon 72, which resulted in 1.793, 1.141 and 0.323 respectively. Both populations are in Hardy-Weinberg equilibrium (p> 0.05) for the three polymorphisms. At codon 72, the allele frequency for proline was 30.1 % in the sample of Lima and 29.7 % in the sample of Huacho. The allele frequency for arginine was 69.8 % for Lima and 70.2 % in Huacho. Regarding the intron 6, the allele frequency for W in Lima was 98.2 % and 81 % in Huacho. In contrast for the M was obtained an allelic frequency of 1.7 % for the studied population of Lima and 18.9 % in Huacho. On the other hand, for the intron 3 the allele frequency for W was 94.6 % for Lima and 90 % in Huacho. In contrast, the allele frequency for M in Lima was 5.3 % and 10 % in Huacho. The dominance of the Arg allele at codon 72 for both populations analyzed is highlighted; and the W allele both intron 6 and intron 3; and the W allele both intron 6 and intron 3. The comparison of allele frequencies of African and Asian descent revealed statistically significant differences (p <0.001); however, was observed a similarity with American and Caucasian populations. KEY WORDS: TP53 gene polymorphism Arg72Pro, intron 6, intron 3, Peruvian populations / Tesis
2

Polimorfismos do gene TP53 no linfoma de Hodgkin / TP53 Gene Polymorphisms in Hodgkin Lymphoma

Daniel de AraÃjo Viana 14 September 2007 (has links)
FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / O Linfoma de Hodgkin à uma hemopatia linfÃide pode ocorrer em qualquer faixa etÃria; no entanto, à mais comum na idade adulta jovem, dos 15 aos 40 anos. O TP53 à um gene de 20kb de comprimento que possui 11 Ãxons situado no cromossomo 17 e codifica a proteÃna p53, uma proteÃna cuja principal funÃÃo està relacionada à preservaÃÃo da integridade do cÃdigo genÃtico, e, durante o ciclo celular faz verificaÃÃo quanto à eventual ocorrÃncia de uma mutaÃÃo na seqÃÃncia do cÃdigo genÃtico. Na presenÃa dessas mutaÃÃes, impede que esta cÃlula entre em processo de mitose e complete a divisÃo celular. A maioria dos cÃnceres apresenta mutaÃÃes pontuais na seqÃÃncia do TP53. A anÃlise dos padrÃes dessas mutaÃÃes à de grande valia uma vez que o conhecimento dessas mutaÃÃes leva a um melhor entendimento das funÃÃes dos vÃrios domÃnios da proteÃna p53 e seu envolvimento com o mecanismo de supressÃo tumoral, alÃm de permitir que essas mutaÃÃes sejam utilizadas como biomarcadores para desvendar a oncogÃnese humana. Na literatura vigente, poucos trabalhos abordam a identificaÃÃo dessas mutaÃÃes em relaÃÃo ao linfoma de Hodgkin â forma clÃssica. Dessa forma, este trabalho se propÃe a investigar quantitativa e qualitativamente os padrÃes de polimorfismos existentes nesta forma do linfoma de Hodgkin. A primeira etapa do nosso experimento constou da seleÃÃo de 42 casos de linfonodos diagnosticados como linfoma de Hodgkin entre os anos de 2000 e 2006, arquivados em blocos de parafina. Os casos foram selecionados de pacientes com diagnÃstico de linfoma de Hodgkin, sem predileÃÃo por idade, sexo ou raÃa. Em seguida, o DNA foi extraÃdo das amostras selecionadas para reaÃÃo de PCR, realizada para isolar e amplificar, o fragmento de 137pb correspondente ao Ãxon 8 do gene TP53, atravÃs de primers exclusivos desenhados para o experimento: PFw8 e PRv8. ApÃs a reaÃÃo, os produtos de PCR foram purificados para reaÃÃo de SeqÃenciamento de DNA, utilizando o seqÃenciador automÃtico de DNA da marca ABI Prism 3100 de 16 capilares (Applied Biosystems). A Ãltima etapa aconteceu em laboratÃrio de bioinformÃtica â dry lab, onde as seqÃÃncias de DNA obtidas foram analisadas qualitativa- e quantitativamente. Os processos de extraÃÃo do DNA genÃmico, amplificaÃÃo do Ãxon 8, purificaÃÃo do produto de PCR foram realizadas com sucesso em todas as amostras obtidas de material parafinizado. No seqÃenciamento do DNA parafinizado foi possÃvel determinar, com seguranÃa e confiabilidades previstas em parÃmetros convencionais, a seqÃÃncia de pelo menos 32 amostras; contudo, nÃo se obteve distinÃÃo suficiente dos picos de eletroferogramas para a determinaÃÃo de eventuais polimorfismos na regiÃo analisada. NÃo foi possÃvel portanto, verificar com margem de seguranÃa razoÃvel, a presenÃa ou ausÃncia de SNPs nas amostras seqÃenciadas. Houve, contudo, uma qualificaÃÃo e competÃncia laboratorial instalada localmente (em Fortaleza), a partir da experiÃncia desenvolvida com o esforÃo deste trabalho, para continuar a investigaÃÃo molecular em prol da determinaÃÃo, em futuro breve, da ocorrÃncia ou nÃo de SNPs no exon 8 do TP53 em linfoma de Hodgkin. / Hodgkin lymphoma is a hematololgic B neoplasm occurring at patients within any age, however more likely to affect those from 15 to 40 years-old. The TP53 gene is 20kb length gene with 11 exons that encodes the p53 protein, which main function is related to the conservation and integrity of the genetic code. Most cancers show point mutations in the TP53 sequence. The analysis of these mutations allows a better understanding of the function of the diverse domains of the protein and its relationship to tumor suppression. There is only a few data about TP53 polymorphisms and Hodgkin lymphoma. In this manner, in our study we try to detect polymorphisms within the codons 272, 273, 278, 282, 306 of the exon 8 of the TP53 gene in Hodgkin lymphoma. In our survey we analyzed 42 paraffin-embedded tissues from 2000 to 2006. These samples were prepared for DNA extraction and PCR isolation and amplification of the 137bp fragment of the exon 8 of the TP53 gene, using exclusive primers specially designed to our experiment: PFw8 e PRv8. After PCR amplification, the products of the reaction were purified to the Sequencing reaction. The last part of the experiment encoded the bioinformatics analysis of sequences. DNA extraction and PCR amplification were successfully obtained in our study in all the samples. However, the DNA sequencing was only obtained in 32 samples, but there was no characteristic electropherogram of the analyzed region of the gene. Therefore, it was not possible to determine the presence or absence of SNPs in the TP53 exon 8.
3

Papiloma vírus humano e o polimorfismo do códon 72 (Alelo-G) do gene TP53 no carcinoma escamoso oral

ALMEIDA NETO, Adauto January 2007 (has links)
Made available in DSpace on 2014-06-12T23:04:13Z (GMT). No. of bitstreams: 2 arquivo8850_1.pdf: 2028888 bytes, checksum: 97a08be09d0c0592daf310c3b039a36a (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2007 / O CEC oral representa 90% de todos os tumores malignos que afetam a boca. A infecção por HPV (Papilomavírus Humano) demonstrou ser um fator relevante no desenvolvimento do carcinoma oral, assim como o polimorfismo do Códon 72 (alelo-G) do gene TP53, cuja transcrição da proteína supressora tumoral p53 é modificado. A degradação da p53 ocorre em função da interação entre a oncoproteína viral E6 junto ao sistema proteolítico ubiqütina-proteossômica. O objetivo deste trabalho foi identificar a presença do HPV no CEC oral e verificar a associação com o polimorfismo do códon 53 do gene TP53 . O grupo experimental foi composto por 24 pacientes com CEC oral , os quais freqüentavam a rotina do Hospital do Câncer de Pernambuco. O grupo controle fora composto por 21 indivíduos que apresentavam o mesmo ambiente familiar e as mesmas relações sociais dos pacientes estudados. O material biológico foi obtido pela esfoliação da mucosa oral e o DNA extraído através do método de Salting Out. A detecção do HPV foi realizada por PCR a partir da utilização dos primers GP5 + GP6 +. A identificação do polimorfismo do códon 72 (alelo-G) foi feita por PCR - RFLP. Os resultados foram negativos para a presença do HPV. Não foi observada associação entre a presença do polimorfismo alelo-G nos pacientes com CEC oral na amostra avaliada (X2 = 4,048; P = 0,132). Os resultados confirmaram que os homens (X2 = 5,88; P = 0,01) e fumantes (X2 = 8,84; P = 0,002) apresentaram uma maior freqüência de diagnóstico positivo para o CEC oral, assim como foram encontrados valores estatisticamente significativos para a idade dos indivíduos estudados (X = 5,88; P = 0,01). Os resultados não sugerem uma associação com o polimorfismo do gene TP53 (alelo-G) e da infecção por HPV com CEC oral. Os resultados para o sexo e tabagismo estão de acordo com a literatura científica
4

Functional analysis of oncogenic lesions in multiple myeloma with potential significance for refractory disease / Funktionelle Analyse onkogener Läsionen beim Multiplen Myelom mit potenzieller Bedeutung für einen refraktären Krankheitsverlauf

Munawar, Umair January 2020 (has links) (PDF)
Despite the advancement in the treatment from genotoxic drugs to more targeted therapies, multiple myeloma (MM) remains incurable. MM is known for its complex genetic heterogeneity as different genetic lesion accrue over the course of the disease. The current work focuses on the functional analysis of genetic lesions found at the time of diagnosis and relapse and their potential role regarding therapy response and refractory disease. Genetic lesions involving tumor suppressor gene TP53, are found at diagnosis and tend to accrue during disease progression. Different types of mono- and biallelic TP53 alterations were emulated in the AMO1 cell line model, were functionally characterized and tested for their potential role in therapy response. Both types of single hit TP53 alteration (deletion 17p and TP53 point mutations) were found to have similar adverse effects on the functionality of the p53 system and response to genotoxic drugs which were completely abolished in the case of double hit TP53 alterations (no p53 expression, or mutant overexpression in wild type TP53 deletion background). Whereas, sensitivity to proteasome inhibitors remained unaltered. Using the clonal competition assay (CCA), single TP53 hit clones were found to have a fitness advantage over wildtype cells. Proliferative cell fitness was further enhanced in double hit TP53 clones, as they dominated wildtype and single hit TP53 clones in the CCA. Presence of external selection pressure in the form of low dose melphalan expedited the intrinsic fitness advantage. Alterations found in CUL4B, a component of CRL4-CRBN protein complex, a target of immunomodulatory drugs (IMiDs), were also functionally analyzed in the current study. Hotspot mutations and mutations found in IMiDs refractory patients were modelized in L363 cells and their role in IMiDs sensitivity was studied. CUL4B mutations were found not to be involved in providing lenalidomide resistance to the cell, whereas knocking CUL4B out was observed to provide negative fitness to the cells in CCA. In the presence of external selection pressure, these clones showed fitness, which was lost in the case of lenalidomide withdrawal. This shows that some alterations may play a role in refractory patients only in the presence of therapy, and as soon as therapy is discontinued, these altered clones may disappear such as clones with alterations in CUL4B. On the other hand, some alterations provide drug-independent intrinsic positive fitness, however, be further enhanced by drug exposure, such as seen in case of TP53 altered clones. Therefore, close monitoring and functional analysis of evolving clones is desired during disease progression, as it can be helpful in therapeutic guidance to achieve a better outcome for patients. / Das Multiple Myelom (MM) ist im Normalfall eine unheilbare Erkrankung, trotz etlicher Fortschritte hinsichtlich der Behandlung, angefangen von genotoxischen Medikamenten bis hin zu zielgerichteten Therapien. Eine komplexe genetische Heterogenität, bei der sich Läsionen im Verlauf der Krankheit ansammeln, ist typisch für das MM. Diese Arbeit beschäftigt sich mit der funktionellen Analyse von genetischen Läsionen zum Erstdiagnose-Zeitpunkt bzw. Rezidiv und ihrer potenziellen Bedeutung bezüglich des Ansprechens auf die Therapie und einer refraktären Verlaufsform. Genetische Veränderungen des Tumorsuppressorgens TP53 sind mitunter schon bei der Erst-Diagnose nachweisbar und nehmen im Krankheitsverlauf weiter zu. Deshalb wurden verschiedene mono- und biallelische TP53 Mutationen in AMO1 Zelllinien-Modellen nachgebildet, funktionell charakterisiert und auf ihre potenzielle Rolle im Therapie-Ansprechen getestet. Dabei wurden für beide Formen von single hit TP53 Alterationen (17p Deletionen und TP53 Punktmutationen) ähnlich nachteilige Effekte auf die Funktionalität des p53 Systems und das Ansprechen auf genotoxische Medikation gefunden. Im Falle von double hit TP53 Alterationen (keinerlei p53 Expression oder aber hohe Spiegel von mutiertem p53 bei TP53 wildtype deletierem Hintergrund) wurden diese Effekte noch weiter verstärkt. Die Sensitivität gegenüber Proteasom-Inhibitoren blieb indessen unbeeinträchtigt. Mithilfe des Clonal Competition Assays (CCA), wurde festgestellt, dass single hit TP53 Klone gegenüber wildtypischen Zellen einen Fitnessvorteil haben. In double hit TP53 Klonen war die proliferative Zell-Fitness zu dem gesteigert, sodass diese über wildtypische und single hit TP53 Klone im CCA dominierten. Die Anwesenheit eines externen Selektionsdrucks in Form von Niedrigdosis-Melphalan verstärkte zusätzlich den intrinsischen Fitnessvorteil. Aberrationen in CUL4B, einer Untereinheit des CRL4-CRBN Protein Komplexes, dem Angriffspunkt der Immunmodulatoren (IMiDs), wurden in dieser Studie ebenfalls funktionell analysiert. Hotspot Mutationen und solche Mutationen, die gehäuft in IMiD refraktären Patienten auftreten, wurden in L363 Zellen modelliert und hinsichtlich ihres Einflusses auf die IMiD Sensitivität untersucht. CUL4B Mutationen waren nicht in Lenalidomid-Resistenz involviert, ein Knockout von CUL4B äußerte sich aber in einer negativen Allgemeinzustand der Zellen im CCA. In Anwesenheit eines externen Selektionsdrucks, zeigten diese Klone einen Fitnessvorteil, der wieder verloren ging, wenn kein Lenalidomid mehr zugegeben wurde. Dies zeigt, dass manche Alterationen nur dann eine Rolle in refraktären Patienten zu spielen scheinen, wenn diese therapiert werden. Sobald die Therapie eingestellt oder unterbrochen wird, könnten solche Klone verschwinden wie z.B. CUL4B-Alterationen. Auf der anderen Seite bedingen manche Veränderungen wiederum einen Medikamenten-unabhängigen, intrinsisch Fitnessvorteil, der jedoch durch Medikamenten-Exposition noch zusätzlich verstärkt werden kann, wie beispielweise bei TP53 mutierten Klonen. Daher ist eine engmaschige Überwachung während der Krankheits-Progression sowie eine funktionelle Analyse der sich entwickelnden Klone wünschenswert. Dies könnte für die therapeutische Beratung hilfreich sein um somit ein besseres Behandlungsergebnis für die Patienten zu erzielen.
5

TP53 Mutationen und Polymorphismen bei erwachsenen Patienten mit Nebennierenrindenkarzinom / TP53 mutations and polymorphisms in adult patients with adrenocortical carcinoma

Herrmann, Leonie Judith Maria January 2012 (has links) (PDF)
Das Nebennierenrindenkarzinom (NNR-Ca) gehört mit einer Inzidenz von 1-2/1000000 zu den seltenen malignen Neubildungen. Neben Sarkomen, Hirntumoren, Brustkrebs und Leukämie gehört das NNR-Ca zu den Kerntumoren, durch die das selten vorkommende autosomal dominante Tumor-Prädispositions Syndrom, das Li Fraumeni Syndrom (LFS) gekennzeichnet ist. Das LFS wird mit Keimbahnmutationen im Tumorsuppressor Gen TP53 in Verbindung gebracht. Die vorliegende Arbeit untersucht TP53 Keimbahnmutationen und -polymorphismen und ihre Auswirkung auf klinische Faktoren bei einem großen Kollektiv von erwachsenen NNR-Ca Patienten. Es wurde DNS aus Blut und teilweise aus Tumorgewebe von Patienten aus dem Deutschen Nebennierenrindenkarzinom Register extrahiert und die Exons 2 bis 11 von TP53 sequenziert. Darüber hinaus wurde der Nachweis der Mutationen und eines Loss of Heterozgosity von TP53 im Tumorgewebe und die immunhistochemische Färbung von p53 vorgenommen. Die anschließende Auswertung der Daten erfolgte unter Einbeziehung des klinischen Verlaufs der Krankheit bei den Patienten. In dieser Arbeit konnten vier NNR-Ca Patienten (3,9 %) mit mindestens einer Keimbahnmutation im TP53 identifiziert werden, bei den unter 40-jährigen entspricht dies einem Anteil von 13,0 %. Unter der Altersgrenze von 40 Jahren sollte daher ein TP53 Mutationsscreening erwogen werden. Die Auswertung der Polymorphismen zeigte, dass diese einen Einfluss auf die Entstehung und den klinischen Verlauf des NNR-Cas zu haben scheinen, jedoch weitere Studien nötig sind. / Adrenocortical cancer (ACC) is a rare malignancy with an incidence of 1-2 cases per million population. Li Fraumeni Syndrom (LFS) is a rare autosomal dominant cancer predisposition syndrome that is characterized by sarcoma, brain tumor, breast cancer, leukaemia, and ACC. LFS is associated with germline mutations in the tumor supressor gene TP53. This study investigates TP53 germline mutations and polymorphisms and their impact on clinical characteristics of a large cohort of adult patients with ACC. DNA was extracted from peripheral blood and tumor tissue derived from patients from the German ACC registry and sequencing was performed on exons 2-11 and adjacent introns. Tumor tissue was analyzed for loss of heterozygosity of TP53 and p53 immunohistochemitry. Analysis was performed by taking clinical characteristics of ACC patients into consideration. Four ACC patients (3.9%) were carriers of at least one TP53 germline mutation corresponding to 13% below the age of 40 years. In younger adults (<40 yr) with ACC screening for TP53 mutations should be considered. While further studies are needed to validate the data, the analysis of TP53 polymorphisms showed possible impact of polymorphisms on development and course of ACC.
6

Prognostic and Therapeutic Implications of Biological Behavior of TP53 Mutations in WNT and Sonic-Hedgehog Medulloblastomas

Zhukova, Nataliya 27 November 2012 (has links)
Recent discoveries enabled us to divide medulloblastoma into molecular sub-groups and uncover novel mutations in these tumors. However, except for superior survival of the WNT sub-group, the prognostic and therapeutic implications of these observations remain unclear. TP53 mutations which confer radioresistance revealed conflicting clinical relevance in different studies. We hypothesized that the effect of TP53 mutations on survival is modulated through molecular sub-grouping. This is especially important since therapeutic targeting of WNT can be achieved with administration of lithium. Here we first confirmed that TP53 mutant tumors confers unfavorable outcome only in SHH subgroup, but not in WNT. We demonstrated that while TP53 mutations cause radioresistance, activation of WNT/β-catenin signaling radiosensitizes medulloblastoma cells. We demonstrated that lithium activates the WNT pathway and effectively sensitize medulloblastoma cells to radiation. Furthermore, lithium did not sensitize normal neural stem cells to radiation, suggesting its potential as an effective radiosensitizer for medulloblastoma.
7

Prognostic and Therapeutic Implications of Biological Behavior of TP53 Mutations in WNT and Sonic-Hedgehog Medulloblastomas

Zhukova, Nataliya 27 November 2012 (has links)
Recent discoveries enabled us to divide medulloblastoma into molecular sub-groups and uncover novel mutations in these tumors. However, except for superior survival of the WNT sub-group, the prognostic and therapeutic implications of these observations remain unclear. TP53 mutations which confer radioresistance revealed conflicting clinical relevance in different studies. We hypothesized that the effect of TP53 mutations on survival is modulated through molecular sub-grouping. This is especially important since therapeutic targeting of WNT can be achieved with administration of lithium. Here we first confirmed that TP53 mutant tumors confers unfavorable outcome only in SHH subgroup, but not in WNT. We demonstrated that while TP53 mutations cause radioresistance, activation of WNT/β-catenin signaling radiosensitizes medulloblastoma cells. We demonstrated that lithium activates the WNT pathway and effectively sensitize medulloblastoma cells to radiation. Furthermore, lithium did not sensitize normal neural stem cells to radiation, suggesting its potential as an effective radiosensitizer for medulloblastoma.
8

Etude des facteurs de chimiorésistance de la leucémie lymphoïde chronique / Determinants of chemoresistance in chronic lymphocytic leukemia

Guièze, Romain 15 June 2017 (has links)
La leucémie lymphoïde chronique (LLC) est décrite comme la plus fréquente forme de leucémie de l’adulte dans les pays occidentaux. Elle est caractérisée par l’envahissement de la moelle osseuse, du sang et parfois des organes lymphoïdes secondaires par des lymphocytes B matures à l’immunophénotype spécifique. Son évolution clinique est très variable selon les patients. Des progrès thérapeutiques majeurs permettent des réponses profondes et durables sans pour autant être à l’origine d’authentiques guérisons. Nous proposons dans ce travail d’explorer différents mécanismes de chimiorésistance. L’altération de TP53 est le facteur le plus reconnu de résistance mais les mécanismes qui lui sont possiblement associés sont peu documentés. Une première partie portant sur 115 patients a décrit une perte d’intégrité des télomères significativement plus importante en cas d’altération de TP53 (raccourcissement télomérique, ré-expression d’hTERT, répression des gènes codant le complexe shelterin). Ces 2 perturbations pouvant coopérer en aggravant l’instabilité génomique comme en témoignent des données cytogénétiques. Une autre analyse par séquençage ciblé nouvelle génération de 114 patients présentant une LLC en rechute a révélé la présence et le pronostic défavorable des combinaisons récurrentes de mutations géniques impliquant TP53, SF3B1 et ATM, gènes disposant d’un rôle crucial dans la réponse aux dommages à l’ADN. Une seconde partie s’est intéressée au rôle de TCL1A, une protéine co-activatrice d’AKT et de la voie NF-Kappa B. Alors que son hyperexpression est à l’origine du principal modèle murin de LLC, son rôle chez les patients restait peu connu. Nous avons montré qu’un niveau élevé d’expression de TCL1A était associé à des caractéristiques clinico-biologiques de maladie agressive et à un pronostic plus sombre. Le transcriptome dépendant de TCL1A généré chez des patients et dans une lignée lymphoïde B par une stratégie de shRNA est en faveur d’une signature MYC. Les inhibiteurs des protéines à BET bromodomaine ont précédemment été identifiés comme une stratégie efficace pour cibler cette voie. Cette approche thérapeutique (molécule JQ1) s’est avérée très efficace in vitro sur des cellules primaires de LLC.Ces travaux ont ainsi identifié des coopérations génomiques pouvant être à l’origine d’une résistance à l’immunochimiothérapie et ont aussi montré qu’une hyperexpression de TCL1A pouvait expliquer certains cas de résistance pour lesquels une stratégie de traitement épigénétique doit être évaluée dans des essais cliniques. / Résumé indisponible.
9

Vývoj inovativního biosenzoru pro elektrochemickou detekci tumor supresorového genu TP53

Navrátil, Jiří January 2019 (has links)
The theoretical part of the diploma thesis deals with tumour diseases and a general description of tumour suppressor genes. Special attention is paid to the TP53 gene and its influence on the functioning of the organism, including its production of the p53 protein. Based on an analysis and synthesis of findings from specialised sources, the current methods of detecting the aforesaid gene, in particular immunological and elec-trochemical, were described. The last chapter of the theoretical part is devoted to bio-sensors and their classification, with a special focus on electrochemical biosensors. The practical part involves the construction and optimisation of the biosensor, from the cleaning of electrodes, the deposition of gold nanoparticles, the ssDNA bond, the blocking of free binding points and a synthesis of the complementary chain to the resulting measurement and quality testing. This part also presents the concept of an innovative biosensor that offers an easier and more reliable alternative for the detec-tion of the TP53 gene. The last chapter of this part analyses and comments on the aforesaid results.
10

A STUDY OF MICRORNAS ASSOCIATED WITH MULTIPLE MYELOMA PATHOGENESIS AND MICORRNAS/TP53 FEEDBACK CIRCUIT IN HUMAN CANCERS, MULTIPLE MYELOMA AND GLIOBLASTOMA MULTIFORME

Suh, Sung-Suk 17 July 2012 (has links)
No description available.

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