Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Made available in DSpace on 2015-04-14T13:38:35Z (GMT). No. of bitstreams: 1 437572.pdf: 863488 bytes, checksum: 848dcb1091910bc399bd2787945a5aeb (MD5) Previous issue date: 2012-01-25 / This paper aims to describe and illustrate the general inferential theories within the semantic-linguistic internal interface, and highlight the humor as a cognitive benefit, especially when this is done through the use of rhetoric elements. The main object of this research is to study the inferential process, which resulted comic effects inside a mass media channel, as TV or internet. The theoretical framework focuses on the theories about inferential processes and rhetorical communication theories according to the External and Internal Interfaces Metatheory, developed by Costa (2008/2009), so this work uses the external interface Language / Cognition / Communication to build the survey. Thus, the interfaces are based on Grice's Inferential Theory of Communication and the Theory of Implicatures (1957/1975), the Relevance Theory by Sperber and Wilson (1986/1995/2008), the Theory of Generalized Conversational Implicatures by Levinson (2000), the Dialogue Theory by Costa (2008/2009/2010). This dissertation also considers the elucidation of the rhetoric usage from the point of view Reboul (2000) and the mass communication explanation according to Marshall McLuhan. Through the interfaces, it is possible to describe, illustrate and study the phenomenon of rhetorical humor in the Brazilian media. / Este trabalho tem como objetivo geral descrever e ilustrar as teorias inferenciais, dentro da interface interna sem?ntico-linguistica, e evidenciar o efeito humor?stico como benef?cio cognitivo, principalmente, quando este se d? por meio do uso da ret?rica. O objeto de estudo principal desta pesquisa ? o processo inferencial, do qual resultam efeitos c?micos veiculados em m?dias de comunica??o em massa, como as televisivas e as virtuais. A fundamenta??o te?rica contempla as teorias sobre os processos cognitivos inferenciais e teorias comunica??o e ret?rica segundo a Metateoria das Interfaces Externas e Internas, desenvolvida por Costa (2008/2009), assim, este trabalho parte da interface externa Lingu?stica/Cogni??o/Comunica??o para dar seguimento ? pesquisa. Assim, as interfaces s?o constru?das a partir da Teoria Inferencial das Implicaturas e Teoria da Comunica??o de Grice (1957/1975), da Teoria da Relev?ncia de Sperber e Wilson (1986/1995/2008), da Teoria das Implicaturas Conversacionais Generalizadas de Levinson (2000), de Teoria do Di?logo por Costa (2008/2009/2010); das considera??es sobre ret?rica sob o ponto de vista de Reboul (2000) e das considera??es sobre comunica??o em massa seguindo Marshall Mcluhan. Atrav?s das interfaces, ? poss?vel descrever, ilustrar e estudar o fen?meno do humor ret?rico na m?dia brasileira.

Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2016-10-17T15:56:29Z No. of bitstreams: 1 TES_FERNANDO_SIMOES_ANTUNES_JUNIOR_COMPLETO.pdf: 4144214 bytes, checksum: edb3abf928625dd33d5c42df9ad2976c (MD5) / Made available in DSpace on 2016-10-17T15:56:29Z (GMT). No. of bitstreams: 1 TES_FERNANDO_SIMOES_ANTUNES_JUNIOR_COMPLETO.pdf: 4144214 bytes, checksum: edb3abf928625dd33d5c42df9ad2976c (MD5) Previous issue date: 2016-08-30 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / This study aims to establish, with a cross and exploratory way, some interfaces between the communication theoretical foundation, systemic thinking, neuroscience and linguistics. This relationship appears to evaluate how the elicitation of emotions generated from the symbolic constructs happen. It`s produced by the mass media, especially journalism, as well as shed light on the possible effects on the formation and reinterpretation of individual and collective beliefs as from this process. Considering, with a systemic perspective, that the triad mind-body-language builds a single and indivisible system, we used theoretical assumptions of Bateson (1987), Chomsky (2005), Dam?sio (2000/2012), Ekman (2011), Krznaric (2015), Jung (1991/ 2001/ 2008/ 2011?/ 2011b), among others, to develop circuits that explain the function of empathic process on activation of emotions, and how it can be activated by language. Field survey of transmitters and receptors of journalism's symbolic constructs has shown that there is a preference for activation of fear in the preparation of such constructs, and this preference impacts on mood, with reinterpretation's effects on collective beliefs. Quantitative data collected in random groups submitted to consumption of news, from media platforms of Zero Hora and Correio do Povo, over 14 days shown an increase in experience of some emotions such as fear, anger, and sadness, and a decrease in the joy experience. At the same time, these data showed an increase in the degree of truth for sentences representing more pessimistic beliefs about society. Field research has also enabled the development of a framework of symbolic constructs in order to, through discourse analysis, identify which specific rhetorical strategies were used in the activation of fear in the receivers. The crossing of this data with the in-depth interviews of journalists uncovered, at the end, that such phenomena, and its effects, often occur in the field of unconscious, featuring a transmission of ideology by conditioning, in which journalism play a role as a catalyst of something that Bartolli Filho (2015) calls "terror anthropology?. / O presente estudo pretende estabelecer, de forma transversal e explorat?ria, interfaces entre alguns fundamentos te?ricos da comunica??o, do pensamento sist?mico, da neuroci?ncia e da lingu?stica. Essa rela??o surge para avaliar como ocorre a elicia??o de emo??es a partir dos construtos simb?licos produzidos pelos meios de comunica??o de massa, em especial os do jornalismo, bem como lan?ar luz sobre os poss?veis efeitos na forma??o e ressignifica??o de cren?as individuais e coletivas a partir deste processo. A partir da perspectiva sist?mica de que o complexo mente-corpo-linguagem forma um sistema ?nico e indissoci?vel, utilizou-se pressupostos te?ricos de Bateson (1987), Chomsky (2005), Dam?sio (2000/2012), Ekman (2011), Krznaric (2015), Jung (1991/ 2001/ 2008/ 2011a/ 2011b), entre outros, para a elabora??o de circuitos que explicam a fun??o das emo??es na ativa??o do processo emp?tico por meio da linguagem. Pesquisas de campo junto a emissores e receptores de construtos simb?licos do jornalismo sugerem que existe uma predile??o pela ativa??o do medo na elabora??o de tais construtos, e que esta predile??o impacta no humor, com efeitos de ressignifica??o no cren??rio coletivo. Dados quantitativos coletados em uma amostragem de pessoas submetidas ao consumo de not?cias dos portais Zero Hora e Correio do Povo ao longo de 14 dias revelaram um aumento da viv?ncia de emo??es como o medo, a raiva e a tristeza, e uma diminui??o da viv?ncia da alegria. Ao mesmo tempo, tais dados demonstraram um aumento no grau de verdade para senten?as que representam cren?as mais pessimistas em rela??o ? sociedade. A pesquisa de campo tamb?m permitiu a elabora??o de um corpus demonstrativo de construtos simb?licos para que, via an?lise de discurso, fossem identificadas estrat?gias ret?ricas espec?ficas usadas para o acionamento do medo nos receptores. O cruzamento destes dados com entrevistas em profundidade realizadas junto aos construtores das not?cias revelou, por fim, que tais fen?menos, bem como seus efeitos, muitas vezes ocorrem no campo da inconsci?ncia, caracterizando uma transmiss?o de ideologia por condicionamento, na qual o jornalismo opera enquanto catalizador do que Bartolli Filho (2015) chama de ?antropologia do terror?.

The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2), and is a frequent event in sporadic thyroid carcinomas. Multiple endocrine neoplasia 2B (MEN 2B), a subtype of MEN 2, is caused primarily by a methionine to threonine substitution of residue 918 in the kinase domain of the RET receptor (2B-RET), however the molecular mechanisms that lead to the disease phenotype are unclear. In this study, we show that the M918T mutation causes a 10 fold increase in ATP binding affinity, and leads to a more stable receptor-ATP complex, relative to the wildtype receptor. We also show that 2B-RET can dimerize and become autophosphorylated in the absence of ligand. Our data suggest that multiple distinct but complementary molecular mechanisms underlie the MEN 2B phenotype and provide potential targets for effective therapeutics for this disease. In the second part of the study, we identified a novel β-catenin-RET kinase signaling pathway which is a critical contributor to the development and metastasis of human thyroid carcinoma. We show that RET binds to, and tyrosine phosphorylates, β-catenin and demonstrate that the interaction between RET and β-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, β-catenin escapes cytosolic downregulation by the APC/Axin/GSK3 complex and accumulates in the nucleus, where it can stimulate β-catenin-specific transcriptional programs in a RET-dependent fashion. We show that downregulation of β-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumour growth in nude mice. Finally, we used a structure guided approach to identify and characterize a novel, non-ATP competitive, RET inhibitor; SW-01. We show that SW-01 provides significant RET inhibition in an in vitro kinase assay using purified RET. Moreover, RET phosphorylation is blocked, or dramatically reduced, in vivo in cells overexpressing active RET. We observe a significant decrease in cell proliferation and colony formation in RET-expressing cells in the presence of SW-01. Together, our data suggest that SW-01 has potential as a novel RET kinase inhibitor with clinical utility. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2008-09-15 16:20:59.976

Adaptor proteins play a vital role in the propagation of cellular signals. Although they lack endogenous catalytic activity, they contain a variety of protein binding modules, which enable them to promote specific and efficient interactions with their binding partners. They form integrative platforms for a variety of molecules (e.g. lipids, tyrosine kinases, cytoskeletal and signaling proteins), and thereby link and coordinate key functions such as cell growth, motility and shape determination. Our laboratory has recently cloned a novel, 130 kDa adaptor protein, named XB130, as a structural homolog of actin-filament-associated-protein (AFAP-110), a stress fiber-binding Src substrate. However, the molecular interactions and functions of this novel adaptor remained to be elucidated. To characterize the function of XB130 we asked two general questions: (1) Is XB130 involved in the signal transduction pathways of tyrosine kinases? And (2) Is XB130 capable of regulating the cytoskeleton and/or is it regulated by the cytoskeleton? To address these questions first we investigated the tissue distribution of XB130 and discovered that it is abundantly expressed in thyroid. Therefore we asked whether it is a target of the thyroid-specific tyrosine kinase, RET/PTC, a genetically rearranged, constitutively active enzyme that plays a pathogenic role in papillary thyroid cancer. We found that XB130 is a RET/PTC substrate that couples RET/PTC signaling to phosphatidylinositol 3-kinase (PI3K) activation through its phosphorylation dependent interaction with the regulatory subunit p85 of PI3K. XB130 plays an important role in PI3K signaling, as downregulation of XB130 in TPC1 papillary thyroid cancer cells, harboring the RET/PTC1 kinase, strongly reduced Akt activity and concomitantly inhibited cell cycle progression and survival in suspension. In the second part we demonstrate that XB130 is a novel Rac- and cytoskeleton-regulated protein that exhibits high affinity to lamellipodial (branched) F-actin and impacts motility and invasiveness of tumor cells. In conclusion, my work characterized a novel adaptor protein and assigned two well-defined pathophysiological functions to it in the context of thyroid cancer cells.

Adaptor proteins play a vital role in the propagation of cellular signals. Although they lack endogenous catalytic activity, they contain a variety of protein binding modules, which enable them to promote specific and efficient interactions with their binding partners. They form integrative platforms for a variety of molecules (e.g. lipids, tyrosine kinases, cytoskeletal and signaling proteins), and thereby link and coordinate key functions such as cell growth, motility and shape determination. Our laboratory has recently cloned a novel, 130 kDa adaptor protein, named XB130, as a structural homolog of actin-filament-associated-protein (AFAP-110), a stress fiber-binding Src substrate. However, the molecular interactions and functions of this novel adaptor remained to be elucidated. To characterize the function of XB130 we asked two general questions: (1) Is XB130 involved in the signal transduction pathways of tyrosine kinases? And (2) Is XB130 capable of regulating the cytoskeleton and/or is it regulated by the cytoskeleton? To address these questions first we investigated the tissue distribution of XB130 and discovered that it is abundantly expressed in thyroid. Therefore we asked whether it is a target of the thyroid-specific tyrosine kinase, RET/PTC, a genetically rearranged, constitutively active enzyme that plays a pathogenic role in papillary thyroid cancer. We found that XB130 is a RET/PTC substrate that couples RET/PTC signaling to phosphatidylinositol 3-kinase (PI3K) activation through its phosphorylation dependent interaction with the regulatory subunit p85 of PI3K. XB130 plays an important role in PI3K signaling, as downregulation of XB130 in TPC1 papillary thyroid cancer cells, harboring the RET/PTC1 kinase, strongly reduced Akt activity and concomitantly inhibited cell cycle progression and survival in suspension. In the second part we demonstrate that XB130 is a novel Rac- and cytoskeleton-regulated protein that exhibits high affinity to lamellipodial (branched) F-actin and impacts motility and invasiveness of tumor cells. In conclusion, my work characterized a novel adaptor protein and assigned two well-defined pathophysiological functions to it in the context of thyroid cancer cells.

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Made available in DSpace on 2014-12-17T15:12:10Z (GMT). No. of bitstreams: 1 LucasMO_DISEERT.pdf: 685838 bytes, checksum: ea186e065f1c9c540dfa0f0e776fcf8f (MD5) Previous issue date: 2010-03-18 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / This study presents a study on Plato's Phaedrus , with the purpose of discussing the possibility of interpreting this dialogue as a discussion on the greek notion of paideia.. We believe to find evidence to support this claim both in the cultural background of the dialogue and in its text. As background evidence, we point to the fact that Rhetoric had become the major disciplined studied in Athens in Plato's time, largely because democratic instituitions favored its practice. As text evidence, we point out that the story of the Phaedrus can be read as the story of how Socrates leads Phaedrus's soul toward philosophy. Therefore, we believe that Plato's main goal with this dialogue is to discuss Rhetoric and present the philosophical perspective on the possibility of an art of speechmaking. In order to achieve this, Plato presents an analyses of current Rhetoric, explains his conception of dialectic, and debate the relation between extemporaneous and written speech. We believe that all those elements serve the larger purpose of providing the background to discuss the cultural education of the Athenians / Essa disserta??o descreve um estudo realizado sobre o di?logo Fedro de Plat?o, com o objetivo de apresentar uma interpreta??o do mesmo a partir da hip?tese de que esse di?logo pode ser lido como uma reflex?o sobre a quest?o da paid?ia. Encontramos ind?cios para justificar essa leitura tanto no contexto cultural da ?poca do di?logo como na pr?pria narrativa do texto. Em rela??o ao contexto cultural, observamos que a ret?rica se tornara a principal disciplina na forma??o dos atenienses, em grande parte por causa das institui??es democr?ticas que favoreciam esse tipo de pr?tica. Em rela??o ? narrativa, observamos que essa ?, em larga medida, a hist?ria de como S?crates guia a alma deFedro para a filosofia. Desse modo, consideramos que o objetivo central de Plat?o ? problematizar essa disciplina e apresentar a perspectiva filos?fica sobre a possibilidade de uma arte dos discursos. Para isso, Plat?o faz uma an?lise da ret?rica, uma apresenta??o da dial?tica e discute a rela??o entre oralidade e escrita. Consideramos que todos esses elementos ganham sentido na medida em que servem para pensar a forma??o cultural dos atenienses

Made available in DSpace on 2014-12-17T15:12:13Z (GMT). No. of bitstreams: 1 Parcial_MarcosAL_DISSERT.pdf: 504349 bytes, checksum: 84d22a00f8a96e4c0fda3ede615e8317 (MD5) Previous issue date: 2010-09-08 / This research brings into focus the relationship between the work Rhetoric, from Aristotle, and the conceptions of ethics and practical wisdom of the philosopher from Stageira. Accordingly, it attempts to show that Aristotle's Rhetoric was produced to guide the construction and orientation of oratory passions of the Greek man, setting it as a reference for practices aimed at social ordering of the polis. In other words, the Aristotelian Rhetoric, designed by the author as the study of what is persuasive in every speech, is not composed with the meaning of persuasion at any cost, in another sense it is conceived by Aristotle as a useful knowledge for the improvement eupraxic (the good act in accordance with the fair and true). This research finds that such work has been prepared by Stagirite a time of strong social transformations and upheavals in ancient Greece: The skepticism expanded, with each person wanting to live their own businesses, and especially in Athens, a city that served as intellectual and political reference, there was a lack of collective spirit. In this tumultuous social environment, Aristotle, with a culture of Greeks eager Trusted reviews and socially shareable in the field of verisimilitude, sought with his Rhetoric, contributing to the development of ethics and political science; referrals for legal and organization of inter-social relations in varied environments, including seeking to provide knowledge about human passions and emotional status of active citizens in deliberative meetings / Esta pesquisa p?e em foco as rela??es entre a obra Ret?rica, de Arist?teles, e as concep??es acerca de ?tica e de sabedoria pr?tica desse mesmo autor. Nesse sentido, procura mostrar que Arist?teles produziu a Ret?rica a fim de nortear a constru??o orat?ria e a orienta??o das paix?es do homem grego, configurando-a como referencial de pr?ticas voltadas para a ordena??o social da p?lis. Em outras palavras, a Ret?rica aristot?lica, concebida pelo autor como sendo o estudo do que ? persuasivo em cada discurso, n?o ? composta com o significado de persuas?o a qualquer custo, pois, noutro sentido, ? idealizada pelo fil?sofo como um saber ?til ao aprimoramento da eupraxia (o bem agir em conformidade com o justo e o verdadeiro). A presente investiga??o considera que tal obra foi elaborada pelo Estagirita numa ?poca de fortes transforma??es e agita??es sociais na antiga Gr?cia: o ceticismo se expandia, com cada indiv?duo querendo viver para os seus pr?prios neg?cios e, principalmente em Atenas, uma cidade que servira como refer?ncia Intelectual e pol?tica, havia uma car?ncia do esp?rito coletivo. Nesse tumultuado ambiente social, Arist?teles, contando com uma cultura de gregos ansiosos por opini?es confi?veis e socialmente partilh?veis no campo da verossimilhan?a, buscou, com a sua Ret?rica, contribuir para o desenvolvimento da ?tica e da ci?ncia pol?tica; para os encaminhamentos judiciais e a organiza??o das inter-rela??es sociais em ambientes variados, inclusive procurando proporcionar o conhecimento sobre as paix?es humanas e o equil?brio emocional dos cidad?os atuantes em encontros deliberativos

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-04-03T21:33:40Z No. of bitstreams: 1 MauricioAlvesBezerraJunior_DISSERT.pdf: 1013357 bytes, checksum: f168e1d5e7cf4a831ae44cd78bae2bca (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-04-10T19:02:32Z (GMT) No. of bitstreams: 1 MauricioAlvesBezerraJunior_DISSERT.pdf: 1013357 bytes, checksum: f168e1d5e7cf4a831ae44cd78bae2bca (MD5) / Made available in DSpace on 2017-04-10T19:02:32Z (GMT). No. of bitstreams: 1 MauricioAlvesBezerraJunior_DISSERT.pdf: 1013357 bytes, checksum: f168e1d5e7cf4a831ae44cd78bae2bca (MD5) Previous issue date: 2016-12-15 / Esta disserta??o apresenta um estudo sobre o di?logo G?rgias, de Plat?o, interpretandoque essa obra ? uma reflex?o sobre a cr?tica plat?nica ? ret?rica sof?stica, desenvolvendoa ideia de que ela ? empeiria, produtora de lisonja (???????????). Encontramos elementos amb?guos que revelam que, apesar de criticar a persuas?o (?????), S?crates a reconhece como um requisito essencial para conduzir oelenchos(???????). No di?logo, S?crates v?-se diante de tr?s interlocutores, G?rgias, Polo e C?cicles. Este ?ltimo sendo o seu algoz principal. Reconhecemos o di?logo em seu contexto hist?rico-cultural, visto que a Ret?rica, e seu elemento de persuas?o, eram insumos constitutivos da cultura grega. Consideramos que o intuito de Plat?o ? repensar os elementos ret?ricos e persuasivos dos sofistas a fim de alhures, expor a ?verdadeira ret?rica?, ou seja, a Filosofia. Para isso, Plat?o faz uma an?lise da ret?rica persuasiva, colocando frente ao seu mestre um expoente da sof?stica, G?rgias; e procura desvelar suaarte (?????). Contudo, apesar de podermos reconhecer nele os elementos necess?rios, o di?logo finaliza sem di?logo, uma vez que n?o h? persuas?ode nenhumdos lados. Consideramos que todos esses pontos ser?o relevantes para compreendermos a persuas?o (?????) como um dos elementos basilares na oralidade grega e da dial?tica plat?nica. / This essay presents a study about the Gorgiasdialogue, by Plato, expounding that this piece is a reflection on the Platonic criticism to sophist Rhetoric, developing the idea that it is empeiria, producer of flattery (???????????). We find ambiguous elements that show that despite criticizing persuasion (?????), Socrates recognizes it as an essential requisite to conduct the elenchos (???????). In the dialogue, Socrates sees himself before three interlocutors, Gorgias, Polo and Callicles. The latter being his one chief tormentor. We acknowledge the dialogue in its historical-cultural context, since Rhetoric and its element of persuasion were Greek culture's constitutive inputs. We consider that Plato's intent is to rethink the sophists rhetorical and persuasive elements in order to expose the "true rhetoric", that it, Philosophy. For this, Plato makes an analysis of the persuasive rhetoric, placing before his master an exponent of the sophistry, Gorgias; and seeks to unveil its art (?????). However, although we can recognize in it the necessary elements, the dialogue ends without a dialogue, since there is no persuasion on either sides. We consider that all these points will be relevant to understand persuasion (?????) as one of the basic elements of Greek orality and Platonic dialectics.