Дисертації з теми "BRAF35"
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Carson, Robbie. "Targeting acute resistance mechanisms inhibition in BRAFMT CRC." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695267.
Повний текст джерелаBeleboni, Rafaela Cardoso [UNESP]. "Traços impressionistas nos contos de Menalton Braff." Universidade Estadual Paulista (UNESP), 2007. http://hdl.handle.net/11449/91603.
Повний текст джерелаNossa pesquisa de Mestrado procura apontar a permanência de traços impressionistas nos contos do livro premiado pelo Jabuti, em 2000, À sombra do cipreste (1999), de Menalton Braff. Para mostrar a construção dessas marcas na produção literária de Braff, recorremos a conceitos da teoria semiótica, sobretudo àqueles relacionados ao modo de presença da enunciação. A partir disso, pudemos depreender determinados elementos impressionistas presentes, sobretudo, nos contos À sombra do cipreste, No dorso do granito, O banquete e Adágio Apassionato. Dessa forma, há, na obra, do ponto de vista temático, a percepção do tempo e os ritos da memória, a relação do homem com o seu passado e o seu resgate numa situação do presente. Do ponto de vista formal, vários traços aparecem pontilhados. Sendo assim, há descrições sensoriais que dão cor, formato, som, gosto e cheiro às tensões, às dúvidas, às crises interiores das personagens que, na sua maioria, são sujeitos à flor da pele. Dentre as figuras sensoriais, a visão é predominante, figurativizada ponto-a-ponto pelos efeitos cromáticos, pelo circuito construído pelos olhares do narrador ou das personagens, pelo jogo de luz e sombra, a macro-figura impressionista recorrente na obra. A imagem criada torna-se, por meio do uso recorrente de figuras de linguagem, sugestiva. Em vários casos, há o efeito de borrão pontilhado, que indefine o objeto descrito para depois defini-lo.No entanto, esta pesquisa não se limita a desenvolver essa discussão. Procuramos, ainda, investigar, nos enunciados dos contos, as projeções da enunciação, evidenciadas nas entrevistas realizadas com o autor. Nesse sentido, procuramos contemplar quatro instâncias: a nossa leitura crítica de contos literários; a leitura do artista sobre a própria produção artística; o confronto entre essas duas leituras; o olhar do ficcionista...
Our Master research tries to indicate the permanence of impressionist traces in the tales obtained from the book A sombra do cipreste (1999) by Menalton Braff, awarded by Jabuti in 2000. We have used the concepts of semiotics theory to show these marks in Braff's work, especially those related to the way of enunciation presence. From these concepts we were able to infer some impressionist's elements present, especially in the tales, A sombra do cipreste, No dorso do granito, O banquete e Adágio Apassionato. From that, there is in the masterpiece a thematic point of view, the perception of time and rite of memory and the relation between the man with his past and its rescue to the present. From a formal point of view, many dotted traces show up. So there are many sensorial descriptions that give, color, shape, sound, taste and smell to the tensions, doubts, the characters inner crises, which are extremely evident subjects. Among the sensorial figures the predominant view symbolized point to point by the chromatics effects, the view connection built among the narrator and the characters, and by the light and shadow game, the impressionist appealing macro-figure in the masterpiece. The created image becomes significant through the use of language figures. In many cases there is the effect called dotted stain, which turns the described object indefinable to determine it later. However, this research was not limited in developing this discussion. We also tried to investigate the projection of the enunciation in the tale proposition that became evident in interviews done with the author. In those circumstances, we tried to observe four instances: our critical reading of literary tales, the authors point of view about his own work, the confrontation between these two readings and the fictionist's view facing the critics to his work. The results obtained point to agreements... (Complete abstract click electronic access below)
Beleboni, Rafaela Cardoso. "Traços impressionistas nos contos de Menalton Braff /." Araraquara : [s.n.], 2007. http://hdl.handle.net/11449/91603.
Повний текст джерелаBanca: Arnaldo Cortina
Banca: Tânia Pellegrini
Resumo: Nossa pesquisa de Mestrado procura apontar a permanência de traços impressionistas nos contos do livro premiado pelo Jabuti, em 2000, À sombra do cipreste (1999), de Menalton Braff. Para mostrar a construção dessas marcas na produção literária de Braff, recorremos a conceitos da teoria semiótica, sobretudo àqueles relacionados ao modo de presença da enunciação. A partir disso, pudemos depreender determinados elementos impressionistas presentes, sobretudo, nos contos "À sombra do cipreste", "No dorso do granito", "O banquete" e "Adágio Apassionato". Dessa forma, há, na obra, do ponto de vista temático, a percepção do tempo e os ritos da memória, a relação do homem com o seu passado e o seu resgate numa situação do presente. Do ponto de vista formal, vários traços aparecem pontilhados. Sendo assim, há descrições sensoriais que dão cor, formato, som, gosto e cheiro às tensões, às dúvidas, às crises interiores das personagens que, na sua maioria, são sujeitos à flor da pele. Dentre as figuras sensoriais, a visão é predominante, figurativizada ponto-a-ponto pelos efeitos cromáticos, pelo circuito construído pelos olhares do narrador ou das personagens, pelo jogo de luz e sombra, a macro-figura impressionista recorrente na obra. A imagem criada torna-se, por meio do uso recorrente de figuras de linguagem, sugestiva. Em vários casos, há o efeito de borrão pontilhado, que indefine o objeto descrito para depois defini-lo.No entanto, esta pesquisa não se limita a desenvolver essa discussão. Procuramos, ainda, investigar, nos enunciados dos contos, as projeções da enunciação, evidenciadas nas entrevistas realizadas com o autor. Nesse sentido, procuramos contemplar quatro instâncias: a nossa leitura crítica de contos literários; a leitura do artista sobre a própria produção artística; o confronto entre essas duas leituras; o olhar do ficcionista... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Our Master research tries to indicate the permanence of impressionist traces in the tales obtained from the book A sombra do cipreste (1999) by Menalton Braff, awarded by Jabuti in 2000. We have used the concepts of semiotics theory to show these marks in Braff's work, especially those related to the way of enunciation presence. From these concepts we were able to infer some impressionist's elements present, especially in the tales, "A sombra do cipreste", "No dorso do granito", "O banquete" e "Adágio Apassionato". From that, there is in the masterpiece a thematic point of view, the perception of time and rite of memory and the relation between the man with his past and its rescue to the present. From a formal point of view, many dotted traces show up. So there are many sensorial descriptions that give, color, shape, sound, taste and smell to the tensions, doubts, the characters inner crises, which are extremely evident subjects. Among the sensorial figures the predominant view symbolized point to point by the chromatics effects, the view connection built among the narrator and the characters, and by the light and shadow game, the impressionist appealing macro-figure in the masterpiece. The created image becomes significant through the use of language figures. In many cases there is the effect called dotted stain, which turns the described object indefinable to determine it later. However, this research was not limited in developing this discussion. We also tried to investigate the projection of the enunciation in the tale proposition that became evident in interviews done with the author. In those circumstances, we tried to observe four instances: our critical reading of literary tales, the authors point of view about his own work, the confrontation between these two readings and the fictionist's view facing the critics to his work. The results obtained point to agreements... (Complete abstract click electronic access below)
Mestre
Braff, Roseli Deienno [UNESP]. "Saramago, Braff e seus personagens duplos: uma análise comparativa." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/94006.
Повний текст джерелаCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Na leitura que fizemos dos romances O homem duplicado e Castelos de papel, guiou-nos o método comparativo de análise textual, tendo como norte a ideia de que o fato estético deve ser estudado à luz do fato histórico, em consonância com ele, e nunca dele apartado. Nessa linha de pensamento, constatamos que certo “ar do tempo” aproxima os autores José Saramago e Menalton Braff, que dialogam por meio da temática do duplo nas obras aqui investigadas. Nosso objetivo foi mostrar a existência dessa relação intertextual por meio da análise dos níveis temático, narrativo e discursivo dos romances, além do diálogo desses com a tradição literária. Ambos os autores fizeram uso, do ponto de vista da estrutura narrativa, de elementos característicos de outros gêneros, como a tragédia grega em O homem duplicado, e o drama em Castelos de papel. Além da temática do duplo, é a releitura do romance policial um dos pontos de contato mais evidente entre as duas obras, que se estruturam em torno de uma investigação. No entanto, os ficcionistas desmontam a velha fórmula: crime – investigação – desvendamento do enigma, e, na nova roupagem com que revestem esse subgênero, não há soluções tampouco culpados, mas indagações provocadoras – por essa razão a denominamos como falso romance policial. No nível temático, mostramos que o duplo como tema na literatura segue duas vertentes: o homogêneo, usualmente representado por gêmeos ou sósias idênticos, em que a identidade não é posta em questão, pois um mesmo personagem desempenha dois papéis; o heterogêneo, em que o usurpador ocupa uma forma definitiva, e tal divisão obriga o eu dilacerado a recuperar sua própria identidade. Tertuliano Máximo Afonso/ António Claro e Alberto Ribeiro/ sorveteiro são figuras do duplo heterogêneo. Exógeno, porque configurado extrinsecamente a ele, o duplicado de Tertuliano...
In our reading of the novels O homem duplicado and Castelos de papel, the comparative method of textual analysis has led us, with the idea that the aesthetic fact must be studied under the light of the historical fact, according to it and never separated from it. In this thought line, we verify that a certain “air of time” binds José Saramago and Menalton Braff in the sense of the dialogue through the way of the themes of the double, as presently in this investigated work. Our purpose was to show the existence of this intertextual relationship from the way of the analysis of the thematic, narrative and discursive levels of the novels, besides their dialogue with the literary tradition. Both the authors employed, under the point of view of narrative structure, characteristic elements of other genres, such as the Greek tragedy in O homem duplicado, and the drama in Castelos de papel. Besides the thematic of the double, it is the re-reading of the detective story one of the most evident contact points between both works that frame them around an investigation. However, the fictionists disassemble the old formula: crime − investigation − solving the enigma, and, in the new vesture in which they revest this subgenre, there are not solutions either guilty people, but provoking inquiries − due to this fact we regard them as false detective stories. In the thematic level, we show that the double as theme in literature follows two ways: the homogeneous one, habitually represented by twins or identical doubles, in which the identity is not questioned since the same character plays two roles; the heterogeneous one in which the usurper takes a definitive form, and such a division obliges the dilacerated I to pick up its own identity. Tertuliano/António Claro and Alberto/ice-cream peddler are characters of the heterogeneous double. Exogenous, because made up extrinsically to him... (Complete abstract click electronic access below)
Braff, Roseli Deienno. "Saramago, Braff e seus personagens duplos : uma análise comparativa /." Araraquara : [s.n.], 2010. http://hdl.handle.net/11449/94006.
Повний текст джерелаBanca: Ana Luiza Silva Camarani
Banca: Caio Márcio Poletti Lui Gagliardi
Resumo: Na leitura que fizemos dos romances O homem duplicado e Castelos de papel, guiou-nos o método comparativo de análise textual, tendo como norte a ideia de que o fato estético deve ser estudado à luz do fato histórico, em consonância com ele, e nunca dele apartado. Nessa linha de pensamento, constatamos que certo "ar do tempo" aproxima os autores José Saramago e Menalton Braff, que dialogam por meio da temática do duplo nas obras aqui investigadas. Nosso objetivo foi mostrar a existência dessa relação intertextual por meio da análise dos níveis temático, narrativo e discursivo dos romances, além do diálogo desses com a tradição literária. Ambos os autores fizeram uso, do ponto de vista da estrutura narrativa, de elementos característicos de outros gêneros, como a tragédia grega em O homem duplicado, e o drama em Castelos de papel. Além da temática do duplo, é a releitura do romance policial um dos pontos de contato mais evidente entre as duas obras, que se estruturam em torno de uma investigação. No entanto, os ficcionistas desmontam a velha fórmula: crime - investigação - desvendamento do enigma, e, na nova roupagem com que revestem esse subgênero, não há soluções tampouco culpados, mas indagações provocadoras - por essa razão a denominamos como falso romance policial. No nível temático, mostramos que o duplo como tema na literatura segue duas vertentes: o homogêneo, usualmente representado por gêmeos ou sósias idênticos, em que a identidade não é posta em questão, pois um mesmo personagem desempenha dois papéis; o heterogêneo, em que o usurpador ocupa uma forma definitiva, e tal divisão obriga o eu dilacerado a recuperar sua própria identidade. Tertuliano Máximo Afonso/ António Claro e Alberto Ribeiro/ sorveteiro são figuras do duplo heterogêneo. Exógeno, porque configurado extrinsecamente a ele, o duplicado de Tertuliano... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: In our reading of the novels O homem duplicado and Castelos de papel, the comparative method of textual analysis has led us, with the idea that the aesthetic fact must be studied under the light of the historical fact, according to it and never separated from it. In this thought line, we verify that a certain "air of time" binds José Saramago and Menalton Braff in the sense of the dialogue through the way of the themes of the double, as presently in this investigated work. Our purpose was to show the existence of this intertextual relationship from the way of the analysis of the thematic, narrative and discursive levels of the novels, besides their dialogue with the literary tradition. Both the authors employed, under the point of view of narrative structure, characteristic elements of other genres, such as the Greek tragedy in O homem duplicado, and the drama in Castelos de papel. Besides the thematic of the double, it is the re-reading of the detective story one of the most evident contact points between both works that frame them around an investigation. However, the fictionists disassemble the old formula: crime − investigation − solving the enigma, and, in the new vesture in which they revest this subgenre, there are not solutions either guilty people, but provoking inquiries − due to this fact we regard them as false detective stories. In the thematic level, we show that the double as theme in literature follows two ways: the homogeneous one, habitually represented by twins or identical doubles, in which the identity is not questioned since the same character plays two roles; the heterogeneous one in which the usurper takes a definitive form, and such a division obliges the dilacerated I to pick up its own identity. Tertuliano/António Claro and Alberto/ice-cream peddler are characters of the heterogeneous double. Exogenous, because made up extrinsically to him... (Complete abstract click electronic access below)
Mestre
Cheung, Lai-Kay Maggie. "Characterisation of ^L597V BRAF in cancer." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/28016.
Повний текст джерелаSugita, Juliana Sayuri. "ANÁLISE DA MUTAÇÃO V600E DO GENE BRAF EM MELANOMAS CUTÂNEOS PRIMÁRIOS." Pontifícia Universidade Católica de Goiás, 2012. http://localhost:8080/tede/handle/tede/2350.
Повний текст джерелаMelanoma comprises about 4% of skin cancers, however, more than 95% of stage IV melanoma patients will die within five years and most patients will succumb in a year. The most commonly mutated gene in melanoma is BRAF V600E mutation, described in 40-70% of cutaneous melanomas. This mutation results in the substitution of valine for glutamic acid in codon 600, resulting in the active form of the protein. The objective of this study was to investigate the frequency of BRAF V600E mutation in patients diagnosed with melanoma in Goiânia, as well as the possible associations between this mutation and clinical-pathological aspects of the cases analyzed. Seventy seven cases of melanoma from the Pathology Departament of Araújo Jorge Hospital, in Goiânia, Goiás were analized. Molecular analysis was performed by PCR and RFLP. Descriptive and comparative statistical analysis with Chi-square test were used in this study. The results demonstrated the presence of V600E mutation in 54 (70,1%) patients with cutaneous melanoma and no statistically significant association was found between the presence of mutation with other prognostics parameters such as age, gender, sun exposure, anatomic location, presence of metastasis, histological subtypes and histological parameters (Breslow thickness, presence of ulceration, signs of regression, lymphocytic infiltration and presence of satellites). Our results suggest that BRAF V600E mutation is a common event in melanomas and represents an important molecular target for therapeutic approaches in the treatment of this neoplasia.
O melanoma representa 4% das neoplasias malignas da pele, no entanto, mais de 95% dos pacientes com melanoma estágio IV irão morrer em cinco anos e a grande parte dos pacientes irá sucumbir em um ano. O gene mutado mais comumente no melanoma é o BRAF e a mutação V600E é descrita em 40 a 70% dos melanomas cutâneos. Tal mutação resulta na substituição da valina por ácido glutâmico no códon 600, resultando na forma ativa desta proteína. O objetivo desse estudo consistiu em investigar a frequência da mutação V600E do gene BRAF, em pacientes diagnosticados com melanoma em Goiânia, bem como as possíveis associações, entre tal mutação e os aspectos clinico-patológicos dos casos analisados. Para isso foram analisados 77 casos de melanoma do Setor de Anatomia Patológica do Hospital Araújo Jorge, em Goiânia, Goiás. A análise molecular foi realizada por PCR e RFLP. Análise estatística descritiva e comparativa com o teste Chi-quadrado foi usado neste estudo. A mutação V600E do gene BRAF foi encontrada em 54 (70,1%) pacientes portadores de melanoma cutâneo e nenhuma associação estatisticamente significativa foi detectada entre a presença de mutação com outros parâmetros prognósticos como idade, gênero, exposição solar, localização anatômica, presença de metástases, subtipo histológico e parâmetros histológicos (índice de Breslow, presença de ulceração, sinais de regressão, infiltração linfocitária e presença de satélites). Nossos resultados permitem concluir que a mutação V600E de BRAF é um evento comum nos melanomas e que representa um alvo molecular importante para as abordagens alvo dirigidas no tratamento desta neoplasia.
Ngeow, Kao Chin. "Post-translational modifications of BRAF and MITF." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:4f6ac084-55a7-4296-9a11-28af3979450d.
Повний текст джерелаmerante, boschin isabella. "MUTAZIONI BRAF NEL CARCINOMA PAPILLARE DELLA TIROIDE." Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3426979.
Повний текст джерелаIntroduzione Il carcinoma papillare della tiroide (CPT) è il più frequente delle neoplasie tiroidee e il suo trattamento rimane per alcuni aspetti controverso, soprattutto per le scarse informazioni preoperatorie sul livello di aggressività del tumore stesso. Scopo dello studio Questo studio si propone di verificare il ruolo prognostico della mutazione BRAFV600E e di conseguenza la ricaduta di tale mutazione sul trattamento in termini di estensione dell’intervento chirurgico e terapia radioiodometabolica. Materiali e metodi Abbiamo considerato 136 casi di CPT all’esame istologico e li abbiamo distinti in 2 gruppi BRAF + e BRAF– confrontandoli sulla base delle seguenti variabili: sesso, età, istologia definitiva, diametro della lesione, stadiazione, metastasi linfonodali, infiltrazione della capsula, Tireoglobulina (Tg) nel follow up. Abbiamo inoltre ricercato la mutazione BRAFV600E su agoaspirato tiroideo in 266 casi sottoposti a intervento chirurgico di tiroidectomia totale +/- dissezione linfonodale tra ottobre 2008 e settembre 2009 distinti nelle 5 categorie citodiagnostiche (THY1, THY2, THY3, THY4, THY5) e per ciascuna categoria abbiamo verificato la diagnosi istologica di CPT distinguendo i casi BRAF + e BRAF –. Risultati La prevalenza di BRAF mutato nei pazienti operati con diagnosi istologica di CPT è risultata pari a 69%. La mutazione BRAFV600E si è associata a una maggior età, ad una minore frequenza di istotipo papillare variante follicolare e una più elevata frequenza di variante a cellule alte, ad una prevalenza degli stadi 3 e 4 nei pazienti di età > 45 anni. La ricerca di mutazione BRAFV600E ha incrementato la sensibilità della sola citologia dall’84 all'88%. Conclusioni Si conferma una associazione statisticamente significativa tra la presenza di mutazione in BRAF e caratteristiche clinico patologiche più aggressive del CPT, quali età più elevata, varianti istologiche a prognosi peggiore (variante tall cell), stadio più avanzato di malattia. La ricerca di mutazioni BRAF migliora la sensibilità della sola indagine citologica, in particolare in nodi la cui diagnosi citologica possa essere non conclusiva.
Silva, Rosana Correa da. "ANÁLISE DA MUTAÇÃO V600E DO GENE BRAF E DETECÇÃO IMUNO-HISTOQUÍMICA DA PROTEÍNA BRAF EM CARCINOMAS PAPILÍFEROS DE TIREÓIDE." Pontifícia Universidade Católica de Goiás, 2012. http://localhost:8080/tede/handle/tede/2345.
Повний текст джерелаPapillary carcinomas are the most common tumors of the thyroid, corresponding to 80% of all tumors that affect the gland. In such tumors, a common mutation at the BRAF gene has been detected, comprising a nucleotide transversion, T1799A, at the exon 15 of gene. This mutation has been identified in about 50 % of the thyroid papillary carcinomas (TPC). Clinical and experimental studies have demonstrated important associations between BRAF mutations and different TPC clinical factors related to tumor progression, invasion and recurrence. The objective of this study was to analise BRAF protein expression, by using immunohistochemistry, and V600E BRAF mutations in a group of patients with thyroid papillary carcinoma. BRAF protein expression and V600E BRAF mutations were compared to TPC clinical and pathological aspects. The study group comprised 116 TPC patients that were selected at the Pathology Department of Hospital Araujo Jorge, in Goiânia. BRAF immunohistochemical analysis employed a labeled polymer peroxidase method and primary BRAF monoclonal antibody (clone F-7), Santa Cruz Biotechnology Inc. BRAF V600E molecular analysis was carried by PCR (Polimerase Chain Reaction) associated to RFLP (Restriction Fragment Length Polymorphism). Statistical analysis was performed by using univariate analysis (Chi-square test with Yates correction, and Fischer). Our results indicated that BRAF overexpression was detected in 54 TPC cases (46.0%), while BRAF V600E mutation was detected in 74 TPC cases (63.8%). Significant associations were detected between BRAF overexpression with distant metastasis (p=0.001) and tumor extrathyroidal extensions (p=0.0183). BRAF V600E mutations were significantly associated with lymph nodes methastasis (p=0.0385) and BRAF protein overexpression (p=0.0063).
Os carcinomas papilíferos são os tumores mais comuns da tireóide, sendo responsáveis por 80% de todos os cânceres da glândula. Nesses tumores, uma mutação comum no gene BRAF tem sido observada, compreendendo a transversão do nucleotídeo T1799A, localizado no exon 15, verificada em 50% dos carcinomas papilíferos de tireóide (CPT). Essa mutação acarreta a substituição do aminoácido valina na posição 600 da proteína, por ácido glutâmico, sendo assim designada V600E. Estudos experimentais e clínicos têm mostrado uma associação entre a mutação do gene BRAF e diferentes parâmetros clínicos de progressão, invasão e recorrência no CPT. O objetivo deste estudo foi detectar os níveis da proteína BRAF utilizando o método de imuno-histoquímica, e avaliar a mutação V600E do gene BRAF em um grupo de pacientes com carcinoma papilífero de tireóide. A detecção imuno-histoquímica da proteína BRAF e a mutação V600E do gene BRAF, foram comparadas em relação aos aspectos clínico-patológicos dos tumores. O grupo de estudo incluiu 116 pacientes com carcinoma papilífero de tireóide, selecionados no Setor de Anatomia Patológica do Hospital Araújo Jorge, em Goiânia-GO. A análise imuno-histoquímica utilizou o método da imunoperoxidase associada a polímeros e o anticorpo BRAF (clone F-7) Santa Cruz Biotechnology Inc. A análise molecular da mutação V600E do gene BRAF foi realizada por meio de PCR (reação em cadeia da polimerase) e RFLP (polimorfismo de comprimento de fragmentos de restrição). As análises estatísticas incluiram o teste do Chi-quadrado com correção de Yates e o teste exato de Fisher. Nossos resultados mostraram que a hiperexpressão de BRAF foi detectada em 54 casos (46%) e a mutação V600E do gene BRAF em 74 casos (63,8%). Dentre as associações investigadas, resultados significativos foram observados entre a hiperexpressão da proteína BRAF e extensão extra-tireoideana do tumor (p=0,0183). A presença da mutação V600E do gene BRAF foi associada as metástases linfonodais (p=0,0385) e à hiperexpressão da proteína BRAF (p=0,0063).
Boussemart, Lise. "Inhibiteurs de BRAF dans le traitement du cancer : Contribution à l’étude des mécanismes de résistance et des effets secondaires paradoxaux." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T102/document.
Повний текст джерелаBRAFV600- inhibitors, including vemurafenib, are efficient against tumors harboring this MAPK pathway activating mutation, which is the case of ~50% of melanomas. But most of the patients under treatment progress within a year, and develop paradoxical secondary tumors. Most resistance mechanisms to drugs that target the BRAF and/or MEK kinases in cancer rely on reactivation of the RAS-RAF-MEK-ERK signal transduction pathway (ERK-dependent), on activation of the alternative PI3K-AKT-mTOR pathway (ERK-independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F translation initiation complex that binds to the 7-methyl-guanine cap at the 5’ end of mRNAs, thereby modulating mRNA translation of specific mRNAs. We show here that persistent formation of the eIF4F complex, comprising the eIF4E cap binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and to anti-BRAF + anti-MEK combinations in BRAFV600- mutant melanoma, colon and thyroid cell lines. Unresponsiveness to treatment and maintenance of eIF4F complex formation is associated with either reactivation of MAPK signaling or absence of ERK-independent decreased phosphorylation of the inhibitory eiF4E binding protein 4EBP1 or increased pro-apoptotic Bcl-2 modifying factor (BMF)-dependent degradation of eIF4G. Development of an in situ method shows by proximity ligation assay (PLA) that the formation of the eIF4F complex is decreased in tumors responding to anti-BRAF therapy and increased in resistant metastases. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A with small compounds is synergistic with BRAFV600- inhibition. The other main problem arising during anti-BRAF treatment is the frequent induction of secondary cutaneous and extra-cutaneous tumors, through the formation of BRAF-CRAF dimers that we visualized in vivo for the first time. In conclusion, we have identified by PLA a novel biomarker of resistance against BRAF inhibitors, which is also a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAFV600- cancers. In parallel, we established a BRAF-CRAF PLA method in paradoxical secondary tumors induced by BRAF inhibitors, leading to the identification of several subpopulations more at risk of developing this type of tumors
López, Fauqued Marta. "Preclinical Study of PI3K and BRAF Inhibitors in Malignant Melanoma / Estudio preclínico de inhibidores de PI3K y BRAF en melanoma maligno." Doctoral thesis, Universitat de Barcelona, 2010. http://hdl.handle.net/10803/1040.
Повний текст джерелаAlthough PI-103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway was more effective. The combination of the two drugs showed a synergistic effect inhibiting RAS and PI3K pathways and in vitro melanoma cell proliferation in a cell line dependent manner. However, the combined treatment of orthotopic xenographs in immunocompetent FVB mice did not cooperate blocking tumor growth. Surprisingly, the in vivo treatment with PI-103 enhanced tumor growth. Our results also revealed that PI-103 caused immunosuppression inducing thymus atrophy and upregulating the intratumoral transcriptional levels of inmunosuppressors. In addition, PI-103 induced the antiapoptotic BH3 family proteins Mcl-1, Bcl-2 and BclXL, which correlated with the lower apoptotic rate observed within the PI-103 treated tumors.
These data indicates that due to melanoma heterogeneity, some precautions should be taken when using these inhibitors for treatment. Moreover, these results certainly make an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models before conducting clinical studies.
Silva, Natali Fabiana da Costa e. [UNESP]. "Os hábitos da memória nos conflitos dos protagonistas de Menalton Braff em Que enchente me carrega? (2000) e Bolero de Ravel (2010)." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/127843.
Повний текст джерелаCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A presente pesquisa tem como corpus dois romances do escritor contemporâneo Menalton Braff - Que enchente me carrega? (2000) e Bolero de Ravel (2010), e busca descrever, em meio ao fluxo de consciência que representa o pensamento dos protagonistas, um número incessante de memórias que se repete do início ao final das narrativas: 13 memórias são apresentadas em Que enchente me carrega? e 15 memórias em Bolero de Ravel. Entendemos que a própria estrutura da narrativa se estabelece por meio da reiterada circularidade dos processos mnemônicos presentes nas duas obras, fixando o ritmo e a coerência do texto ficcional. Além disso, torna-se possível observar que as repetições instalam o modo de olhar dos narradores para o mundo, firmando o que eles veem, como percebem o que veem e, finalmente, como lidam com o que percebem. A partir disso, a pesquisa considera a possibilidade de que a estruturação dos romances por meio de repetições de situações de memória mostra-se dotada de inegável intencionalidade estética e estabelece a maneira singular do narrador braffiano. Este, ao narrar o seu processo de desagregação social e mental, revela o seu distanciamento do mundo, medida que intitularemos de processo da esfacelamento da personagem. As obras literárias serão analisadas a partir do instrumental teórico do fluxo da consciência, trazendo à luz os conceitos propostos por Robert Humphrey e Belinda Cannone. Esta abordagem contemplará, ao mesmo tempo, os processos históricos que estão na base da crise do romance e advento da ficção do fluxo da consciência
This research has as corpus two novels of the contemporary writer Menalton Braff - Que enchente me carrega? (2000) e Bolero de Ravel (2010) and seeks to describe, amid the stream of consciousness that represents the thinking of the protagonists, an endless number of memories that are repeated from the beginning to the end of the stories: 13 memories are presented in Que enchente me carrega? and 15 memories in Bolero de Ravel. It is understood that the very structure of the narrative is established through repeated circularity of mnemonic processes present in the two works, setting the pace and consistency of the fictional text. Moreover, it is possible to observe that repetitions establish how the narrators look at the world around, determining what they see, how they perceive what they see and finally how they deal with what they perceive. The research considers that the repetitions in the novels is endowed with undeniable aesthetic intentionality and that it constitutes a characteristic of Braff's narrator. The narrator, when narrating his own process of social and mental decay, creates the image of his disengagement in the world. We named this procedure as the process of disintegration of the character. The thesis will be analyzed from the theoretical tools of the stream of consciousness, bringing to light the concepts proposed by Robert Humphrey and Belinda Cannone. This approach will include, at the same time, the historical processes that underlie the crises of the novel and the advent of the stream of consciousness fiction
Vercellino, Laetitia. "Contribution de différents biomarqueurs à l’élaboration d’une stratégie thérapeutique dans le mélanome BRAF muté." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC323/document.
Повний текст джерелаMetastatic melanoma has long been synonymous of dismal prognosis, due to the weak efficacy of available treatments. Numerous therapeutic innovations have profoundly modified the management of these patients, with marketing authorizations of therapies targeting the MAP Kinases pathway for patient with BRAF mutated melanoma (about 50% of patients) on the one hand and immune checkpoint inhibitors on the other hand.BRAF and MEK inhibitors result in dramatic responses, but disease control is generally short-lived, with onset of drug resistance leading to disease progression. Designing therapeutic strategies allowing delaying or bypassing this resistance phenomenon is of primary importance. Thus, in vitro and vivo biomarkers or tools predictive of response could help stratifying patients, and personalize each patient’s management.In the first part, we compared the respective value of a proliferation tracer, 18F-FLT, and of the glucose consumption tracer, 18F-FDG for therapeutic evaluation of a BRAF mutated melanoma xenograft, treated by a BRAF inhibitor. We confirmed the predominant role of 18F-FDG, and backed up the potential interest of volumetric parameters for therapeutic follow-up, especially with 18F-FLT.In a second part we assessed in vivo the ability of an intermittent schedule to delay resistance onset, compared with a continuous schedule in BRAF mutated xenografts treated by a BRAF/MEK inhibitors combination. In our experimental models, there did not seem to be any superiority for the intermittent schedule. However our experiments did not allow us to draw any final conclusions on the subject.In a third part, we tried to reproduce ex vivo the intermittent schedule with histocultures device. We also assessed the possibility for histocultures with patient derived tumours to predict response to targeted therapies in the same patients. Histocultures appear as a relevant tool to guide therapeutic choice. Determination of genetic modifications and molecular heterogeneity may also prompt tailoring therapeutic strategy depending on the supposed aggressiveness of a melanoma in a given patient
Mitra, Devarati. "The Role of Pigmentation and Oncogenic BRAF in Melanoma." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10101.
Повний текст джерелаCanto, Alan Motta do. "Análise imunohistoquímica da mutação BRAF V600E em ameloblastomas mandibulares." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/23/23139/tde-05062017-104621/.
Повний текст джерелаAmeloblastoma is an aggressive odontogenic tumour, being locally invasive and highly recurrent. Studies have demonstrated that it is the most common benign odontogenic neoplasia, sometimes exhibiting behaviour of malignant lesions. Detection of BRAF V600E mutation has been shown to be one of the main proliferation pathways of ameloblastomas. Therefore, the identification of these markers can be useful to elaborate more efficient treatment strategies for this pathology as well as to improve the patient\'s quality of life. This study investigated the BRAF V600E mutation in mandible ameloblastomas by using the immunohistochemical technique and by correlating clinical and imaging data of the patients. The sample consisted of 84 cases diagnosed as mandibular ameloblastoma, with all blocks being obtained from the Surgery Pathology Service of the FOUSP Department of Stomatology and the Maxillofacial Surgery Unit of the Erasto Gaertner Hospital, Curitiba, PR. The blocks were submitted to immunohistochemical reaction for detection of BRAF protein mutation, with clinical and imaging data such as age, gender, tumour size, mandibular location, radiographic aspect, histological type and subtype, and tumour status were collected. Statistical analysis was performed in order to establish a correlation between BRAF marker and clinical and imaging data. The results showed that, of the 84 patients, 44 were male (52.38%) and 40 female (47.62%). The median age was 25.5 years old, with 42 cases having age below the median (50%) and 42 above it (50%). With regard to the presence or absence of BRAF V600E mutation, 66 cases were found to be positive for the marker (78.57%) and 18 were negative (21.43%). The correlation between BRAF expression and variables showed statistical significances for mandibular location (P = 0.0353) and tumour size (P = 0.008), whereas no statistical significance was observed for gender (P = 0.969), age (P = 1.0), radiographic aspect (P = 0.977), histological pattern (P = 0.910), histological subtype (P = 0.5141) and tumour status (P = 0.336). The authors concluded that BRAF V600E mutation is common in mandibular ameloblastomas, with tumours larger than four cm being more frequent in the posterior region of the mandible. In addition, this pathology occurs regardless of histological type of the tumour, age, gender, radiographic aspect and tumour status.
Lundberg, Ida. "Molecular understanding of KRAS- and BRAF-mutated colorectal cancers." Doctoral thesis, Umeå universitet, Patologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-133410.
Повний текст джерелаSilva, Natalí Fabiana da Costa e. [UNESP]. "Sutiliezas entre o interno e o externo: literatura e sociedade nos contos de Menalton Braff." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/94001.
Повний текст джерелаCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Nossa pesquisa de mestrado procura apontar as relações entre a literatura e o seu condicionamento social em À sombra do cipreste (1999) e A coleira no pescoço (2006), livros de contos de Menalton Braff, autor brasileiro contemporâneo. A análise de orientação sociológica surgiu porque os contos de Menalton, ao mesmo tempo em que proporcionam uma leitura de cunho intimista pelas crises das personagens, linguagem poética, fluxo de consciência, emprego da técnica impressionista e expressionista, entre outros aspectos, integram em sua estrutura as formas com que as relações sociais, valores e orientações ideológicas interferem nas personagens e contribuem para a economia do texto. Para mostrar as imbricações entre texto e contexto, recorremos ao método analítico de Antonio Candido, a crítica sociológica, baseado nas obras Literatura e Sociedade (1965) e Formação da literatura brasileira (1997). Além disso, nosso embasamento teórico está centrado em outros autores que dialogam, direta ou indiretamente, com a crítica sociológica de Candido, como João Alexandre Barbosa, (A leitura do intervalo. Ensaios de crítica, 1990, e Alguma crítica, 2002), René Wellek e Austin Warren, (Teoria da literatura, 1965), Luiz Costa Lima (Teoria da literatura em suas fontes, 2002) e Octavio Paz, (O arco e a lira, 1982). Propusemos uma divisão do corpus em quatro frentes temáticas, Morte/Memória, Relações familiares, Abandono/Solidão e Embate social como método que auxiliasse a leitura dos contos analisados (treze no total). Essa divisão, contudo, buscou apontar o tema sobressalente em cada conto e não propor uma leitura estanque das temáticas, uma vez que, de modo geral, cada narrativa transita entre os quatro grupos. Para essa divisão utilizamos Tomachevski (“Temática”, 1973) e o Dicionário de termos literários, de Massaud Moisés, 1974...
Our research tries to indicate the relationship between literature and society in the short stories of À sombra do cipreste (1999) and A coleira no pescoço (2006) by Menalton Braff, contemporary Brazilian author. The sociological reading arose because Menalton’s short stories, while providing an intimate reading because of the characters’ crises, poetic language, stream of consciousness, use of impressionist and expressionist technique in writing, among others characteristics, also make implicit the ways in which social relations, values and ideological orientations interfere with the characters and contribute to the economy of the text. To show the connections between text and context, we’ve used the analytical method of Antonio Candido, the sociological critic, based on the books Literatura e sociedade (1965) and Formação da literature brasileira (1997). Our theoretical framework also focuses on other authors that interact, directly or indirectly, with Candido’s sociological critic, as João Alexandre Barbosa (A leitura do intervalo. Ensaios de crítica, 1990, e Alguma crítica, 2002), René Wellek and Austin Warren, (Teoria da literatura, 1965), Luiz Costa Lima (Teoria da literatura em suas fontes, 2002) and Octavio Paz, (O arco e a lira, 1982). We have also proposed a division of the corpus into four thematic fronts, Death/Memory, Family Relationship, Abandonment/Loneliness and Social strike, as method which would help the reading of the short stories (thirteen in total). This division, however, sought to point the main theme in each story, but did not propose a reading of each theme tight, because each narrative moves among the four groups. To accomplish this division we’ve used Tomachevski (“Temática”, 1973) and the Dicionário de termos literários, by Massaud Moisés, 1974. From these theoretical assumptions, we sought to ascertain which social... (Complete abstract click electronic access below)
Silva, Natali Fabiana da Costa e. "Sutiliezas entre o interno e o externo : literatura e sociedade nos contos de Menalton Braff /." Araraquara : [s.n.], 2011. http://hdl.handle.net/11449/94001.
Повний текст джерелаBanca: Márcia Valéria Zamboni Gobbi
Banca: Tânia Pellegrini
Resumo: Nossa pesquisa de mestrado procura apontar as relações entre a literatura e o seu condicionamento social em À sombra do cipreste (1999) e A coleira no pescoço (2006), livros de contos de Menalton Braff, autor brasileiro contemporâneo. A análise de orientação sociológica surgiu porque os contos de Menalton, ao mesmo tempo em que proporcionam uma leitura de cunho intimista pelas crises das personagens, linguagem poética, fluxo de consciência, emprego da técnica impressionista e expressionista, entre outros aspectos, integram em sua estrutura as formas com que as relações sociais, valores e orientações ideológicas interferem nas personagens e contribuem para a economia do texto. Para mostrar as imbricações entre texto e contexto, recorremos ao método analítico de Antonio Candido, a crítica sociológica, baseado nas obras Literatura e Sociedade (1965) e Formação da literatura brasileira (1997). Além disso, nosso embasamento teórico está centrado em outros autores que dialogam, direta ou indiretamente, com a crítica sociológica de Candido, como João Alexandre Barbosa, (A leitura do intervalo. Ensaios de crítica, 1990, e Alguma crítica, 2002), René Wellek e Austin Warren, (Teoria da literatura, 1965), Luiz Costa Lima (Teoria da literatura em suas fontes, 2002) e Octavio Paz, (O arco e a lira, 1982). Propusemos uma divisão do corpus em quatro frentes temáticas, Morte/Memória, Relações familiares, Abandono/Solidão e Embate social como método que auxiliasse a leitura dos contos analisados (treze no total). Essa divisão, contudo, buscou apontar o tema sobressalente em cada conto e não propor uma leitura estanque das temáticas, uma vez que, de modo geral, cada narrativa transita entre os quatro grupos. Para essa divisão utilizamos Tomachevski ("Temática", 1973) e o Dicionário de termos literários, de Massaud Moisés, 1974... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Our research tries to indicate the relationship between literature and society in the short stories of À sombra do cipreste (1999) and A coleira no pescoço (2006) by Menalton Braff, contemporary Brazilian author. The sociological reading arose because Menalton's short stories, while providing an intimate reading because of the characters' crises, poetic language, stream of consciousness, use of impressionist and expressionist technique in writing, among others characteristics, also make implicit the ways in which social relations, values and ideological orientations interfere with the characters and contribute to the economy of the text. To show the connections between text and context, we've used the analytical method of Antonio Candido, the sociological critic, based on the books Literatura e sociedade (1965) and Formação da literature brasileira (1997). Our theoretical framework also focuses on other authors that interact, directly or indirectly, with Candido's sociological critic, as João Alexandre Barbosa (A leitura do intervalo. Ensaios de crítica, 1990, e Alguma crítica, 2002), René Wellek and Austin Warren, (Teoria da literatura, 1965), Luiz Costa Lima (Teoria da literatura em suas fontes, 2002) and Octavio Paz, (O arco e a lira, 1982). We have also proposed a division of the corpus into four thematic fronts, Death/Memory, Family Relationship, Abandonment/Loneliness and Social strike, as method which would help the reading of the short stories (thirteen in total). This division, however, sought to point the main theme in each story, but did not propose a reading of each theme tight, because each narrative moves among the four groups. To accomplish this division we've used Tomachevski ("Temática", 1973) and the Dicionário de termos literários, by Massaud Moisés, 1974. From these theoretical assumptions, we sought to ascertain which social... (Complete abstract click electronic access below)
Mestre
Gontijo, Antônio Paulo Machado. "ANÁLISE MOLECULAR DA MUTAÇÃO V600E DO GENE BRAF EM MICROCARCINOMA PAPILAR DE TIREÓIDE." Pontifícia Universidade Católica de Goiás, 2012. http://localhost:8080/tede/handle/tede/2363.
Повний текст джерелаThyroid cancer is the commonest endocrine malignancy, with a rising incidence all over the world. This increasing incidence is almost exclusively due to the papillary thyroid cancer (PTC) and 30% to 50% of these tumors are papillary thyroid microcarcinomas (PTMC). The many score systems for risk stratification of these patients in low and high risk have been revealed to be unsatisfactory, leading to the search of a molecular marker wich could integrate a more reliable stratification system. BRAF V600E mutation is a frequent genetic event in the papillary thyroid carcinomas, that reflects its potential as a molecular marker in the PTMC. The aim of the present study was to evaluate the prevalence of such mutation in 80 paraffin embedded PTMC samples from the Pathology Department of the Hospital Araújo Jorge of Goiânia, Goiás, Brasil, obtained from patients operated between 1999 and 2006. Molecular analysis of the BRAF V600E mutation has been achieved by PCR and RFLP techniques. Statistical analysis included Chi-squared test with Yates s correction and Fisher s exact test. From the 80 cases of PTMC analysed, 73 (91.2%) were females, 47 patients (58.7%) were less than 45 years old and 33 (41.3%) were ≥ 45 years old. Lymph node metastasis were observed in 28 patients (35.0%) and extrathyroidal extension occurred in 19 cases (23.7%). Mutation BRAF V600E was observed in 50 cases (62.5%). There was no statistically significant association between clinicalpathologic parameters and the presence of the BRAFV600E. Our results showed that the BRAFV600E is a common genetic alteration in the PTMC, and it may represent an early event in the carcinogenesis of the thyroid gland. However, implications of this mutation in the prognostic of the PTMC were not observed.
O câncer de tireoide é a neoplasia maligna endócrina mais comum, com incidência crescente em todo o mundo. Esse crescimento é quase que exclusivamente às custas do carcinoma papilar da tireóide (CPT) e, atualmente, 30-50% desses tumores são microcarcinomas papilares de tireóide (MCPT). Os diversos sistemas de estratificação para classificação desses pacientes em baixo e alto risco têm se revelado insatisfatórios, levando à procura de um marcador molecular que possa compor uma estratificação mais efetiva. A mutação V600E do gene BRAF constitui um evento genético frequente dos carcinomas papilares da tireóide, refletindo seu potencial como marcador tumoral nos MCPT. O objetivo do presente estudo foi avaliar a prevalência dessa mutação em 80 espécimes de MCPT, oriundas do Serviço de Patologia do Hospital Araújo Jorge de Goiânia, de pacientes operados entre 1999 a 2006. A análise molecular da mutação V600E do gene BRAF foi realizada por meio das técnicas de Reação em Cadeia de Polimerase (PCR) e Polimorfismo de Comprimento de Fragmento de Restrição (RFLP). As análises estatísticas incluíram o teste do Qui-quadrado com correção de Yates e o teste exato de Fisher. Dentre os 80 casos de MCPT analisados, 73 (91,2%) eram do sexo feminino; 47 pacientes (58,7%) tinham idades abaixo de 45 anos e 33 (41,3%) tinham idades ≥ 45 anos. Metástases linfonodais foram observadas em 28 pacientes (35%) e 19 tumores (23,7%) apresentaram extensão extratiroidiana. A mutação V600E do gene BRAF foi observada em 50 casos (62,5%). Dentre os parâmetros clínicos e histopatológicos investigados no grupo de pacientes deste estudo, nenhuma associação estatisticamente significativa foi detectada em relação à presença da mutação V600E do gene BRAF. Nossos resultados demonstraram que a mutação V600E do gene BRAF é uma alteração genética comum nos MCPT, podendo representar um evento precoce na carcinogênese da glândula tireóide. Entretanto, implicações desta mutação no prognóstico dos microcarcinomas papilíferos de tiróide não foram observadas.
Richardson, Jennifer. "Zebrafish as a model of BRAFV600E melanoma subtypes and Nevus biology." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6493.
Повний текст джерелаLiu, Tianyi. "BRAF Inhibitors Stimulate CAFs to Drive Drug Resistance in Melanoma." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin162324201258474.
Повний текст джерелаCarlino, Matteo Salvatore. "BRAF mutant melanoma: prognosis; response and resistance to targeted therapy." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14010.
Повний текст джерелаKeil, Philipp [Verfasser]. "BRAF V600 Mutationen in spindelzelligen und desmoplastischen Melanomen / Philipp Keil." Ulm : Universität Ulm, 2018. http://d-nb.info/115193819X/34.
Повний текст джерелаMoka, Nagaishwarya, Kelley cross, Marianne Brannon, Janet Lightner, Megan Dycus, William Stone, Victoria Palau, and Koyamangalath Krishnan. "Delta-tocotrienol and simvastatin induces differential cytotoxicity and synergy in BRAF wild-type SK-MEL-2 and mutant BRAF SK-MEL-28 melanoma cancer cells." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/215.
Повний текст джерелаLo, Chi-chuen Evans. "A study of BRAF and RAS genes in papillary thyroid carcinoma." Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31972007.
Повний текст джерелаGrasse, Katinka. "KRAS/BRAF-Mutationsanalysen und die immunhistologische Expression von p53 und p16." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-151228.
Повний текст джерелаLo, Chi-chuen Evans, and 盧致泉. "A study of BRAF and RAS genes in papillary thyroid carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31972007.
Повний текст джерелаSamuel, Jesvin John. "Translational studies in B-cell malignancies : studies on TP53 and BRAF." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/36233.
Повний текст джерелаMedina-Pérez, Paula Andrea. "Functional characterization of cancer- and RASopathies-associated SHP2 and BRAF mutations." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2016. http://dx.doi.org/10.18452/17420.
Повний текст джерелаDeregulation of the Ras/MAPK signaling is implicated in a variety of human diseases, including cancer and developmental disorders. The RASopathies are characterized by an overlapping phenotype in patients and result from germline mutations in key regulators of the MAPK signaling cascade. Although the incidence of solid tumors is rather low, reports on different leukemia forms have increased. In this work, a group of mutations in the genes PTPN11 and BRAF were selected for expression in cell lines for a comprehensive molecular and phenotypic characterization. Non-tumorigenic human cell lines and the rat 208F fibroblasts were transduced with lentiviral particles with SHP2/BRAF wildtype (wt), Noonan (NS)-, NS- and leukemia- or LS–associated SHP2 mutations (mut) and CFC-associated BRAF mutations to identify their potential roles in neoplastic transformation. Mutations in both genes promoted cell morphology alterations, cell proliferation, density- and anchorage-independent growth in rat fibroblasts. These results suggested that RASopathies-associated mutations in both genes confer a transformation phenotype in vitro similar to the classical oncogenes. To investigate whether mutations in SHP2 contribute to tumor growth in vivo, 208F cells expressing wt/mut SHP2 were injected in nude mice. Both wt/mut SHP2 expressing cells promoted tumor growth. Additionally, RASopathies-associated mutant SHP2 and BRAF proteins constitutively activate the MAPK signaling in a moderate manner compared to oncogenic BRAF. To identify modifications in the protein interaction of mut-SHP2, TAP assays were performed. Mut-SHP2 proteins showed an increased binding strength to GAB1 compared to wt. Finally, a microarray analysis revealed a gene cluster commonly regulated in both RASopathies and the oncogenic BRAF. The findings of this work might be useful for a better understanding of the downstream mechanisms of RASopathies-related signaling and their involvement in cancer progression.
Vergani, E. "BRAF AND MAPK PATHWAY MOLECULES FOR TARGETED THERAPY OF MALIGNANT MELANOMA." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/173422.
Повний текст джерелаArnoux, Fanny. "Origine de l'apparition d'auto-anticorps dans la polyarthrite rhumatoïde." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4095.
Повний текст джерелаRheumatoid Arthritis (RA) is a chronic inflammatory autoimmune joint disease. RA most specific autoantibodies (AAb) recognize citrulline proteins (ACPA). 30% of patients with RA have anti-B-Raf AAb. ACPA are IgG that arise in the absence of associated T cell responses. PAD enzymes, responsible for the citrullination, are also targets of AAb in RA. We thus propose a mechanism to explain the emergence of ACPA. We hypothesize that anti-citrullinated protein immunization arises because, at first, PAD is recognized by T cells, which, in turn help the production of AAb to neighbor proteins citrullinated by PAD. To test this model, we primed mice with PAD proteins and looked for immune response to PAD and citrullinated proteins. We found that PAD immunization leads to T cell response, Ab anti-PAD as well as anti-citrullinated fibrinogen peptides Ab production. Anti-PAD immunization could induce anti-citrullinated protein immunization.B-Raf, a ser-thr kinase of the MAPK signalling pathway, is involved in inflammation and in T cell activation. An overexpression of B-Raf is observed in T cells from RA patients increasing T cell activation to autoantigens. Our hypothesis is that BRAF gene mutations could trigger a rupture of tolerance and AAb production in RA. We have identified a BRAF mutation, a valine residue at position 600 is substituted by an alanine (V600A). V600A is found more often and at greater quantities in patients with RA, noteworthy in their T cells. This mutation does not correlate with Anti-B-Raf AAb presence but this is a strong enhancer of B-Raf kinase activity. This could lead to abnormal T cells activation and explain tolerance rupture in RA
Neyra, Jennifer Eliana Montoya. "Modulação dos efeitos citotóxicos dos vemurafenibe pela cloroquina em células de melanoma maligno G-361: papel da dermicidina." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-30012018-101101/.
Повний текст джерелаIn this study we evaluated the pharmacological effects of vemurafenib ( inhibitor BRAFV600E) and chloroquine (autophagy inhibitor) in cell viability and tumor growth of two melanoma cell lines identified as G-361 pLKO, which expresses dermcidin, and G361 IBC I which silenced DCD expression. G-361 melanoma cells responded to vemurafenib (1-2 μM) and chloroquine (50-100 μM) alone or combined, with increased apoptosis rates, while decreasing senescent cells. Vemurafenib (50 mg/kg / 21 days) inhibited melanoma growth in immunodeficient mice independent of dermicidin. Chloroquine (30 mg/kg) in combination with vemurafenib, accelerated (at 24 hour interval), and reduced (at 72 hours interval), melanoma growth. Tumor tissues showed atypical cell morphology and nuclear histological patterns and melanocytic differentiation biomarkers S100, HMB-45, Melan-A or pancytokeratins were not. This work confirms the efficacy of vemurafenib and suggests potential adjuvant effect of chloroquine. It also confirms the role of dermcidin as growth factor and oncogene for melanoma cells.
Baxter, Eva Louise. "Investigating the association between BRAFV600E and methylation in sporadic colon cancer." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6525.
Повний текст джерелаGonzález, Sánchez Elena. "Study of the cooperative effect of UVR, BRAF and LKB1 in melanoma." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667375.
Повний текст джерелаUnderstanding the molecular mechanisms related with melanomagenesis is key in order to find new preventive and therapeutical approaches against this lethal disease. Epidemiology indicates that there are genetic- and environmental-factors associated with melanoma development and progression. In this study, we have generated the B/L/UV animal model that allows us to study the cooperation between the oncogene, BrafV600E, the environmental insult, ultraviolet radiation (UVR), and the loss of a tumor suppressor, Lkb1. In summary, the B/L/UV animal model presented here is a strong system to study the melanoma pathogenesis. This animal model demonstrates the important role of UVR in preventing the BrafV600E-induced senescence, a requisite in melanoma progression in this specific mutational context. Moreover, a patent fact is the importance of Lkb1 in in vivo induction of this disease, which has a relevant effect in the tumors, affecting its onset, its genetic instability, and its histological heterogeneity. The genetic analysis of tumors highlights the important role of Rho-, Netrin1- and SAPK/JNK-signaling pathway in melanomagenesis.
Safaee, Ardekani Gholamreza. "Prognostic role of BRAF in human cutaneous melanoma : gene versus protein expression." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54855.
Повний текст джерелаMedicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
Rebecca, Vito William. "Potential Targeted Therapeutic Strategies for Overcoming Resistance in BRAF Wild Type Melanoma." Scholar Commons, 2014. http://scholarcommons.usf.edu/etd/5112.
Повний текст джерелаBraune, Jan [Verfasser], and Nikolas von [Akademischer Betreuer] Bubnoff. "Zirkulierende Tumor DNA erlaubt Therapiemonitoring in BRAF und NRAS mutiertem malignem Melanom." Freiburg : Universität, 2021. http://d-nb.info/1231232560/34.
Повний текст джерелаDarp, Revati A. "Insights into the Role of Oncogenic BRAF in Tetraploidy and Melanoma Initiation." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1129.
Повний текст джерелаYuan, Long. "Role of Reactive Oxygen Species and Therapeutic Implications in BRAF Mutant Melanoma." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595847645348909.
Повний текст джерелаDinges, Hanns-Christian [Verfasser]. "Validierung eines Protokolls zur manuellen, mutationsspezifischen BRAF V600E Immunhistochemie / Hanns-Christian Dinges." Ulm : Universität Ulm, 2017. http://d-nb.info/1125528176/34.
Повний текст джерелаBubolz, Anna-Maria [Verfasser]. "Potentielle klinische Implikationen von BRAF Mutationen in histiozytären Proliferationen / Anna-Maria Bubolz." Ulm : Universität Ulm, 2017. http://d-nb.info/1132713137/34.
Повний текст джерелаAnastasaki, Korina. "MAPK pathway : a role in development, disease and behaviour." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5955.
Повний текст джерелаPapadogeorgakis, Eftychios. "Development of malignant melanoma is dependent on a switch in Embryonic Transcription Factors orchestrated by the BRAF-MAPK pathway." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/28138.
Повний текст джерелаCurley, David. "Characterizing the Roles of BRAF, PTEN and Cdkn2a in Novel Mouse Models of Melanoma Formation and Progression." ScholarWorks @ UVM, 2008. http://scholarworks.uvm.edu/graddis/62.
Повний текст джерелаWojciechowska, Sonia. "The conditional control of MITF reveals cellular subpopulations essential for melanoma survival and recurrence in new zebrafish models." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/29645.
Повний текст джерелаSteck, Mirjam [Verfasser], Luitpold [Akademischer Betreuer] Distel, and Luitpold [Gutachter] Distel. "Interaktion von BRAF-Inhibitoren und ionisierender Strahlung bei Behandlung von Fibroblasten und einer BRAF-mutierten und einer Wildtyp-Zelllinie des Malignen Melanoms / Mirjam Steck ; Gutachter: Luitpold Distel ; Betreuer: Luitpold Distel." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1220506028/34.
Повний текст джерелаSeitz-Alghrouz, Ruth Christin [Verfasser], and Paul [Akademischer Betreuer] Fisch. "BRAF V600E mutations in nevi and melanocytic tumors of uncertain malignant potential (MELTUMPs)." Freiburg : Universität, 2019. http://d-nb.info/1188195891/34.
Повний текст джерелаL'hôte, Valentin. "Senolytic drug discovery and mechanisms of action in BRAF-V600E oncogene-induced senescence." Thesis, université Paris-Saclay, 2022. http://www.theses.fr/2022UPASL042.
Повний текст джерелаIn response to oncogene expression (such as BRAF-V600E), genotoxic insults, or other stresses, eukaryotic cells can suppress apoptosis and enter senescence. Senescence is a cell fate characterized by a quasi-irreversible proliferative arrest and deep transcriptional reprogramming, notably leading to an important secretion of inflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). Due to increased secretory demands and chronic stress, proteostasis may be challenged in senescence. As it limits the proliferation of cells possibly bearing pre-neoplastic potential, senescence is an essential tumor suppressing process; however, the accumulation of senescent cells during aging, in pathological contexts, or following chemotherapy or radiotherapy, is detrimental and leads to tissue dysfunction. Senolytics are drugs that selectively induce apoptosis in senescent cells while sparing normal cells, and their therapeutical application has proved a valuable pharmacological strategy in pathological contexts in which senescence plays a driving role. The aim of this project was to identify novel senolytic compounds, notably in BRAF-V600E-induced senescence, and to characterize their mechanisms of action, thereby adding to the understanding of cell survival pathways regulation in senescence. Cardioglycosides constitute a class of drugs that were identified as potent senolytics in the screen of a repurposing library. We showed that BRAF-V600E senescent cells were remarkably sensitive to senolysis induced by cardioglycosides. We demonstrated that BRAF-V600E senescent cells have a heightened autophagy flux that is essential to their survival, and that cardioglycosides acted as senolytics by inhibiting autophagy through Na,K-ATPase signal transduction. Accordingly, blocking autophagy through other routes such as with chloroquine was also senolytic. To gain insight into the regulation of autophagy and proteostasis in senescence and identify new senolytic targets, we then assessed endoplasmic reticulum stress and the unfolded protein response (UPR) in different senescence models. In parallel, we screened various chemical libraries, in which we identified potential senolytics targeting different facets of proteostasis. Interestingly, we found that UPR sensor Ire1 was upregulated in oncogene-induced senescence. Ire1 regulates cell fate through several pathways, and many small compounds that differentially modulate its activity are available. We thus employed a panel of Ire1 modulators to begin characterizing its role in senescence, and establish novel senolytic strategies. Collectively, our results highlight the senolytic potential of targeting autophagy and proteostasis in oncogene-induced senescence, and the importance of deciphering the mechanisms of action of senolytics to identify new targets and regulatory pathways
Menzies, Alexander Maxwell. "The biology of BRAF-‐mutant melanoma and biomarkers of response to targeted therapy." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13804.
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