Este trabalho apresenta a caracterização geoquímica e isotópica (Sr-Nd-Pb) das rochas subalcalinas diferenciadas dos diques do Enxame da Serra do Mar (ESM), localizado na costa dos estados de São Paulo e Rio de Janeiro, sendo constituído principalmente por diques básicos com altos teores de TiO2 (>3%). Os diques intermediários e ácidos, encontrados apenas na Ilha de São Sebastião e costa adjacente, foram submetidos à análise de elementos traços por ativação com nêutrons (AAN), que possibilitou a determinação de elementos terras raras (La, Ce, Nd, Sm, Eu, Tb, Yb e Lu) e outros traços incompatíveis (U, Th, Hf, Ta, Ba e Rb), além de Co e Sc. As amostras foram também analisadas por espectrometria de massa com plasma indutivamente acoplado (ICP-MS), que permitiu efetuar uma comparação entre os resultados obtidos pelos dois métodos. Foram ainda determinadas as razões isotópicas de Sr, Nd e Pb em cinco amostras representativas. Os dados obtidos por AAN indicam precisão de até 14% (maioria abaixo de 10%) e exatidão de até 4%. A comparação estatística dos dados de AAN com ICP-MS mostrou que as técnicas fornecem resultados estatisticamente concordantes para a grande maioria dos elementos analisados. Os diques diferenciados são quimicamente representados por lati-andesitos (LTA), dacitos (DAC) e riodacitos (RC). Dentre os LTA observa-se um conjunto de 4 amostras (Grupo 1) com características geoquímicas semelhantes às rochas basálticas Pitanga da Província Magmática do Paraná (PMP), embora apresentem razões isotópicas iniciais de Sr e Pb mais radiogênicas. Os demais LTA (Grupo 2) apresentam enriquecimento significativo de elementos fortemente incompatíveis. Entre as rochas mais diferenciadas dos LTA (Grupo 2) e aquelas dos DAC e RC há lacunas composicionais, sugerindo que a evolução não ocorreu por cristalização fracionada. À semelhança da gênese das rochas vulcânicas ácidas do tipo Chapecó-Ourinhos da PMP, é possível que os diques DAC e RC tenham sido originados por refusão de material de composição basáltica aprisionado na descontinuidade crosta-manto. As razões isotópicas dos diques do ESM sugerem que a gênese desse material basáltico envolveu fusão de manto litosférico subcontinental metassomatizado, conforme proposto para os diques mesozoicos do Espinhaço Meridional (Craton do São Francisco), que possuem composições isotópicas similares. Os magmas diferenciados gerados nesse processo podem ter sofrido contaminação crustal, conforme indicado também pelas composições isotópicas de Sr, Nd e Pb, requerendo, no entanto, um contaminante com características muito específicas. / The geochemical and isotopic (Sr-Nd-Pb) characterization of the subalkaline differentiated dykes from the Serra do Mar Swarm (ESM) is presented. These rocks are located at the coast of São Paulo and Rio de Janeiro states and are mainly composed by basic dikes with high contents of TiO2 (> 3%). Intermediate and acid dykes, which are found only in the São Sebastião Island and adjacent coast area were investigated by using neutron activation analysis (AAN), allowing determination of the concentrations of rare earth elements (La, Ce, Nd, Sm, Eu, Tb, Yb and Lu) and other compatible (Co and Sc) and incompatible trace elements (U, Th, Hf, Ta, Ba and Rb). The samples were also analyzed by mass spectrometry with inductively coupled plasma (ICP-MS), permitting the comparison between the results obtained by the two methods. The isotope compositions of Sr, Nd and Pb were also determined in five representative samples. The data obtained by AAN indicate precision of up to 14% (most below 10%) and accuracy of up to 4%. The statistical comparison of AAN and ICP-MS data showed that the techniques provide statistically identical results for the vast majority of the analyzed elements. The differentiated dykes are chemically represented by lati-andesites (LTA), dacites (DAC) and riodacites (RC). Four LTA samples (Group 1) have geochemical similarities with Pitanga basaltic flows from Paraná Magmatic Province (PMP), although presenting Sr and Pb initial ratios slightly more radiogenic. The remaining LTA (Group 2) rocks are enriched in highly incompatible trace elements. The compositional gap between the most evolved LTA (Group 2) and the DAC and RC suggests that the evolution of this rocks is not compatible with fractional crystallization processes. Likewise the genesis of Chapecó-Ourinhos acid volcanic rocks from PMP, it is possible that the DAC and RC have been generated by melting of basalt material, which was trapped in crust-mantle discontinuity. The isotope ratios of the ESM dykes suggest that this basaltic material was generated by melting of a metasomatized subcontinental lithospheric mantle source, due to ancient subduction processes, as proposed for the Mesozoic dykes from the Espinhaço Meridional (São Francisco Craton), whose isotope ratios are very similar. The differentiated magmas generated in this process would be affected by crustal contamination during their ascension, as also indicated by the Sr, Nd and Pb isotope compositions, requiring however, very specific characteristics for the contaminant.

Made available in DSpace on 2016-04-04T18:29:40Z (GMT). No. of bitstreams: 1 Diana Pancini Ribeiro.pdf: 3595414 bytes, checksum: 5704fc4a088f97a32ba1eaab61e87cbe (MD5) Previous issue date: 2008-02-11 / This research broaches the clinical and developing potential of the transitional use of the Thematic Story-drawing Procedure in early interviews held by undergraduate students in group supervision meetings, meant as activity which articulates knowledge transmission and holding. It is inserted, therefore, into a particular moment of the psychologist s academic development, which takes effect by means of the clinical care given to children, in the context of the psychodiagnosis. The research at issue, based on the discarding of the positivist view and the adoption of an epistemological paradigm which favors intersubjectivity, is structured according to a complex architecture, to the extent that clinical care and supervision are viewed as inseparable practices. 16 reports on the use of the Procedure, drawn up during a two-month period, along of which 16 undergraduates made twenty-four complete psychodiagnoses, were psychoanalytically evaluated, in close dialogue with the Winnicottian thought. Two of such reports are fully presented in the research. The analyses, on the whole, allow us to conclude that the transitional use of the Thematic Story-drawing Procedure seems to be heuristically important since it favors meaningful emotional communications among all the people involved in the interaction, in the contexts of the care provided for the children and the supervision provided for the students. / Este trabalho investiga o potencial cl?nico e formativo do uso transicional do Procedimento de Desenhos-Est?rias com Tema em primeiras entrevistas realizadas por alunos de gradua??o e em reuni?es de supervis?o grupal, concebida como atividade que articula transmiss?o de conhecimento e holding. Insere-se, portanto, em um particular momento da forma??o do psic?logo, que se realiza por meio do atendimento cl?nico a crian?as, no contexto do psicodiagn?stico. Pensada a partir do abandono de uma vis?o positivista e da ado??o de um paradigma epistemol?gico, que privilegia a intersubjetividade, a pesquisa se estrutura segundo arquitetura complexa, na medida em que entende o atendimento cl?nico e a supervis?o como pr?ticas indissoci?veis. Foram psicanaliticamente examinadas, em pr?xima interlocu??o com o pensamento winnicottiano, dezesseis narrativas do uso do Procedimento, elaboradas num per?odo de dois meses letivos, ao longo dos quais dezesseis alunos realizaram vinte e quatro psicodiagn?sticos completos. Duas narrativas s?o detalhadamente apresentadas na tese. O conjunto das an?lises permite afirmar que o uso transicional do Procedimento de Desenhos-Est?rias com Tema revela-se heuristicamente valioso por favorecer comunica??es emocionais significativas, entre todos os envolvidos, nos contextos do atendimento e da supervis?o.

Esse estudo apresenta o desenvolvimento de práticas psicológicas no contexto institucional. Trata-se de intervenção psicoterápica em grupo com as cuidadoras de crianças em acolhimento institucional de abrigos, por dois anos, desenvolvida no contexto da instituição. Ao realizarmos nosso estudo anterior de Mestrado, identificamos acentuado sofrimento psíquico manifestado pela equipe de cuidadoras, no qual percebemos importantes identificações da equipe com as angústias emergentes nas crianças abrigadas. Iniciamos, em março de 2006, encontros psicoterápicos grupais e semanais com as cuidadoras desse abrigo até o mês de março de 2008. Aplicamos com o grupo, no início e na finalização dos encontros, o Procedimento Desenhos-Estórias com Tema, para compreendermos a dinâmica psíquica das participantes atrelada ao relacionamento com crianças em acolhimento, e também para nos auxiliar a avaliar a intervenção realizada. Adotamos a perspectiva winnicottiana para a noção de saúde. Esta experiência nos revelou que a partir do momento em que as cuidadoras alcançaram melhor contato emocional com a interioridade puderam conter grande parte do sofrimento psíquico, apresentando-se de forma mais viva para o contato com a realidade externa e ampliando os contatos afetivos. A equipe de cuidadoras apresentou melhor contato com os próprios afetos e demonstrou avanços na capacidade de discriminação das crianças em acolhimento, o que facilitou os relacionamentos no contexto institucional. Percebemos mudanças na realidade subjetiva da equipe, embora permanecesse a mesma realidade social do contexto, o que nos possibilitou também considerar a eficácia da intervenção psicológica com o grupo de cuidadoras. Portanto, propomos esta intervenção como enquadre clínico diferenciado para atendimento de cuidadoras em abrigos / This study presents the development of the psychological practice within the institutional context. It is the psychotherapeutic group intervention with the children\'s caregivers in institutional shelters, for two years, developed within the context of the shelters. In our previous study for the Master\'s Degree, we identify intense psychic suffering manifested by the team of caregivers, in which we perceive important identifications between the team and the state of anguish the sheltered children are found. In March, 2006, we begin weekly psychotherapeutic gatherings with the caregivers of this shelter, until up the year 2008. Within the group, and at the beginning and the end of each gathering, we apply the Drawing- And-Story Procedure with Theme, to understand the psychic dynamics of the participants in relation with the sheltered children, and also, to help us evaluate the applied intervention. We adopt the Winnicottian Perspective for the notion of health. The experiment reveals, from the very moment the caregivers reach a better emotional contact, with the interiority, that they are able to hold back a great part of the psychic suffering, taking a more lively approach in contacting the exterior reality, expanding the affective contacts. The team of caregivers presents a better contact with their own affections; also, presents improvement in the capacity to discriminate the children under the shelter, which facilitates the relationship in the institutional context. We perceive a change in the subjective reality of the team of caregivers, even though the social reality of the context remains unchanged, and this allows us to consider the efficiency of the psychological intervention with the team of caregivers. Thus, we propose this intervention as differentiated clinical setting to aid caregivers in shelters

A tuberculose continua sendo um grave problema de saúde pública mundial. O principal agente etiológico da doença é o Mycobacterium tuberculosis, infectando entre outras células, os macrófagos. A infecção pode manter-se latente por vários anos sem causar sintomas clínicos aparentes. Para esta pesquisa, foi proposto o estudo de indução de marcadores de resposta inflamatória em células THP-1 diferenciadas em macrófagos utilizando isolados micobacterianos sensíveis, uni ou multidrogas resistentes transfectados com o plasmídeo pFPCAGFP carreando o gene da proteína verde fluorescente, como marcador de infecção celular. Objetivou também avaliar a relação entre isolados clínicos de M.tuberculosis sensíveis ou com resistência a uma ou multidrogas e sua relação à virulência. Para isso, culturas da linhagem monocítica humana (THP-1) foram mantidas para posterior infecção por isolados clínicos, genotipicamente identificados pertencentes à nossa micobacterioteca. A expressão do RNAm foi quantificada e avaliada por RTPCR e posteriormente, PCR em tempo real foi realizado. Após infecção das células THP-1 diferenciadas em macrófagos, observou-se que houve um aumento na expressão das citocinas pró-inflamatórias (IL-1β, IL-6 e TNF-α) e TLRs (TLR2 e TLR4) em relação ao controle da infecção. As análises estatísticas permitiram a correlação na expressão destas citocinas e TLRs, e através desses resultados, foi possível constatar que TLR2 regula a expressão das citocinas pró-inflamatórias (IL-1β, IL-6 e TNF-α) e que os Isolados clínicos com maior resistência, sinalizam melhor a expressão das citocinas próinflamatórias e TLRs, ao passo que isolados clínicos sensíveis, possuem uma fraca sinalização. / Tuberculosis is the major causative of death and morbidity and still is a serious problem to the health in the world. Mycobacterium tuberculosis is the major causative agent of tuberculosis disease, infecting cells like macrophages. The infection can keep dormant for several years without any clinical symptoms. For this research, the study was proposed for induction of markers of inflammatory response in cells differentiated THP-1 in macrophages by clinical isolates from sensitive or multidrug resistant mycobacteria caring pFPCAGFP plasmid that contains green fluorescent protein gene, a marker of infection cell. Also objective assesses the relationship between clinical isolates of sensitive or with resistance to one or four drugs M.tuberculosis and its relationship to virulence. For this, cultures of monocitic lineage human (THP-1) were kept for subsequent infection by clinical isolates, genotypically identified belonging to our mycobacterioteca. The expression of mRNA was quantified and evaluated by RT-PCR and subsequently, real-time PCR was performed. After infection of the THP-1 differentiated cells in macrophages, it was observed that there was an increase expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and TLRs (TLR2 and TLR4) compared to infection control. Statistical analyses allowed expression correlation of these cytokines and TLRs, and through those results, it was possible to see that TLR2 regulates pro-inflammatory cytokines (IL-1β , IL-6 and TNF-α) expression and those clinical isolates with four resistance have better signal of pro-inflammatory cytokines and TLRs expression, while sensitive clinical isolates, has a weak signal.

The aim of this thesis is to explore how young adults from ethnic minority backgrounds experience social citizenship and social participation. How do they understand their social rights and duties? What are the possibilities and obstacles for their social participation? Based on the background of different studies in Sweden, that usually focus on conditions in bigger cities, this study discusses social citizenship among ethnic minority youth in the context of a middle-sized Swedish town. In contrast to research on ethnicity and youth in Sweden, that discuss social problems and social exclusion in terms of the deficient cultural, linguistic and social competence of the individuals, this study focuses on different kinds of resources and experiences of agency among young people from migrant backgrounds. Their experiences of active social citizenship and social participation fill also a gap in the contemporary research from the perspective of social inclusion. The theoretical framework is based on the concept of social citizenship as discussed by T. H. Marshall (1950), T. Bottomore (1992) and inspired by research on the subjective dimension of social citizenship conducted by R. Lister (1997, 2003, 2007). In order to grasp the subjective dimension of social citizenship, this thesis deals with differentiated expressions of universal social citizenship in terms of agency and participation in different areas of social life. Using a qualitative approach, seventeen people have been interviewed. The interviews have been analysed from an intersectional perspective where gender, age, marital status and longevity in Sweden appear to be concurrent categories. The results point towards tendencies of enclavisation among these young adults usually articulating experience of weak social bonding in relation to the Swedish majority population. Some informants refer to their expectations of living in bigger cities or a third country, and have plans to move as a strategy for better, more integrated and less discriminated conditions of future life. In sum, the central expectations of the interviewees on the improvement of their social citizenship conditions are the following: They want to be active citizens and are willing to contribute to the development of a more inclusive Swedish society. This thesis contributes to our current understanding of how young adults from ethnic minority backgrounds, experience social citizenship and social participation within the areas of: housing, education, labour-market, leisure and policy. / Denna rapport handlar om hur unga kvinnor och män med utländsk bakgrund i en medelstor svensk stad upplever social delaktighet. I fokus står vardagslivets sociala medborgarskap och hur människor förstår sina sociala rättigheter och skyldigheter och på vilket sätt detta påverkar deras medverkan i samhällslivet. Rapporten visar att de unga kvinnorna och männen har engagemang och uttrycker ansvarskänsla och vilja till social delaktighet i det svenska samhället. Samtidig upplever de inte alltid ett fullvärdigt socialt medborgarskap på grund av etnisk diskriminering. Helene Jacobson Pettersson är doktorand i socialt arbete vid Institutionen för vårdvetenskap och socialt arbete, Växjö universitet. Hon är anställd som universitetsadjunkt i socialt arbete vid Högskolan i Kalmar. Detta är hennes licentiatavhandling.

Este trabalho apresenta a caracterização geoquímica e isotópica (Sr-Nd-Pb) das rochas subalcalinas diferenciadas dos diques do Enxame da Serra do Mar (ESM), localizado na costa dos estados de São Paulo e Rio de Janeiro, sendo constituído principalmente por diques básicos com altos teores de TiO2 (>3%). Os diques intermediários e ácidos, encontrados apenas na Ilha de São Sebastião e costa adjacente, foram submetidos à análise de elementos traços por ativação com nêutrons (AAN), que possibilitou a determinação de elementos terras raras (La, Ce, Nd, Sm, Eu, Tb, Yb e Lu) e outros traços incompatíveis (U, Th, Hf, Ta, Ba e Rb), além de Co e Sc. As amostras foram também analisadas por espectrometria de massa com plasma indutivamente acoplado (ICP-MS), que permitiu efetuar uma comparação entre os resultados obtidos pelos dois métodos. Foram ainda determinadas as razões isotópicas de Sr, Nd e Pb em cinco amostras representativas. Os dados obtidos por AAN indicam precisão de até 14% (maioria abaixo de 10%) e exatidão de até 4%. A comparação estatística dos dados de AAN com ICP-MS mostrou que as técnicas fornecem resultados estatisticamente concordantes para a grande maioria dos elementos analisados. Os diques diferenciados são quimicamente representados por lati-andesitos (LTA), dacitos (DAC) e riodacitos (RC). Dentre os LTA observa-se um conjunto de 4 amostras (Grupo 1) com características geoquímicas semelhantes às rochas basálticas Pitanga da Província Magmática do Paraná (PMP), embora apresentem razões isotópicas iniciais de Sr e Pb mais radiogênicas. Os demais LTA (Grupo 2) apresentam enriquecimento significativo de elementos fortemente incompatíveis. Entre as rochas mais diferenciadas dos LTA (Grupo 2) e aquelas dos DAC e RC há lacunas composicionais, sugerindo que a evolução não ocorreu por cristalização fracionada. À semelhança da gênese das rochas vulcânicas ácidas do tipo Chapecó-Ourinhos da PMP, é possível que os diques DAC e RC tenham sido originados por refusão de material de composição basáltica aprisionado na descontinuidade crosta-manto. As razões isotópicas dos diques do ESM sugerem que a gênese desse material basáltico envolveu fusão de manto litosférico subcontinental metassomatizado, conforme proposto para os diques mesozoicos do Espinhaço Meridional (Craton do São Francisco), que possuem composições isotópicas similares. Os magmas diferenciados gerados nesse processo podem ter sofrido contaminação crustal, conforme indicado também pelas composições isotópicas de Sr, Nd e Pb, requerendo, no entanto, um contaminante com características muito específicas. / The geochemical and isotopic (Sr-Nd-Pb) characterization of the subalkaline differentiated dykes from the Serra do Mar Swarm (ESM) is presented. These rocks are located at the coast of São Paulo and Rio de Janeiro states and are mainly composed by basic dikes with high contents of TiO2 (> 3%). Intermediate and acid dykes, which are found only in the São Sebastião Island and adjacent coast area were investigated by using neutron activation analysis (AAN), allowing determination of the concentrations of rare earth elements (La, Ce, Nd, Sm, Eu, Tb, Yb and Lu) and other compatible (Co and Sc) and incompatible trace elements (U, Th, Hf, Ta, Ba and Rb). The samples were also analyzed by mass spectrometry with inductively coupled plasma (ICP-MS), permitting the comparison between the results obtained by the two methods. The isotope compositions of Sr, Nd and Pb were also determined in five representative samples. The data obtained by AAN indicate precision of up to 14% (most below 10%) and accuracy of up to 4%. The statistical comparison of AAN and ICP-MS data showed that the techniques provide statistically identical results for the vast majority of the analyzed elements. The differentiated dykes are chemically represented by lati-andesites (LTA), dacites (DAC) and riodacites (RC). Four LTA samples (Group 1) have geochemical similarities with Pitanga basaltic flows from Paraná Magmatic Province (PMP), although presenting Sr and Pb initial ratios slightly more radiogenic. The remaining LTA (Group 2) rocks are enriched in highly incompatible trace elements. The compositional gap between the most evolved LTA (Group 2) and the DAC and RC suggests that the evolution of this rocks is not compatible with fractional crystallization processes. Likewise the genesis of Chapecó-Ourinhos acid volcanic rocks from PMP, it is possible that the DAC and RC have been generated by melting of basalt material, which was trapped in crust-mantle discontinuity. The isotope ratios of the ESM dykes suggest that this basaltic material was generated by melting of a metasomatized subcontinental lithospheric mantle source, due to ancient subduction processes, as proposed for the Mesozoic dykes from the Espinhaço Meridional (São Francisco Craton), whose isotope ratios are very similar. The differentiated magmas generated in this process would be affected by crustal contamination during their ascension, as also indicated by the Sr, Nd and Pb isotope compositions, requiring however, very specific characteristics for the contaminant.

No description available.

Differentiated instruction offers opportunities to improve student academic performance, specifically in students with learning disabilities. However, teachers' perceptions of which differentiated-instruction program works best to support differently abled students were unknown. The purpose of this qualitative case study was to explore teachers' perceptions on whether face-to-face instruction using response to intervention or computer-based learning using TenMarks works best in improving the academic performance of students who are differently abled in mathematics, specifically geometry. Constructivism, social disability theory, and Bandura's social learning theory formed the study's theoretical framework. Research questions guiding the study focused on teachers' perceptions of the advantages and challenges of traditional face-to-face instruction versus TenMarks when educating differently abled students. Data were collected through one-on-one interviews and member checking using a purposeful sample with six high school mathematic teachers. Thematic data analysis followed an open coding process to identify emergent themes. The findings showed that teachers perceived advantages and challenges with both instructional models. Further, teachers believed combining the two approaches would be most beneficial as the strengths and weaknesses of the two approaches are complementary, which correlates with disability's social and critical models. This study contributes to positive social change through school administrators and teachers in guiding school policies and practices related to differentiated-instruction approaches in classrooms that include differently abled students.

<p>The aim of this thesis is to explore how young adults from ethnic minority backgrounds experience social citizenship and social participation. How do they understand their social rights and duties? What are the possibilities and obstacles for their social participation? Based on the background of different studies in Sweden, that usually focus on conditions in bigger cities, this study discusses social citizenship among ethnic minority youth in the context of a middle-sized Swedish town. In contrast to research on ethnicity and youth in Sweden, that discuss social problems and social exclusion in terms of the deficient cultural, linguistic and social competence of the individuals, this study focuses on different kinds of resources and experiences of agency among young people from migrant backgrounds. Their experiences of active social citizenship and social participation fill also a gap in the contemporary research from the perspective of social inclusion. The theoretical framework is based on the concept of social citizenship as discussed by T. H. Marshall (1950), T. Bottomore (1992) and inspired by research on the subjective dimension of social citizenship conducted by R. Lister (1997, 2003, 2007). In order to grasp the subjective dimension of social citizenship, this thesis deals with differentiated expressions of universal social citizenship in terms of agency and participation in different areas of social life. Using a qualitative approach, seventeen people have been interviewed. The interviews have been analysed from an intersectional perspective where gender, age, marital status and longevity in Sweden appear to be concurrent categories. The results point towards tendencies of enclavisation among these young adults usually articulating experience of weak social bonding in relation to the Swedish majority population. Some informants refer to their expectations of living in bigger cities or a third country, and have plans to move as a strategy for better, more integrated and less discriminated conditions of future life. In sum, the central expectations of the interviewees on the improvement of their social citizenship conditions are the following: They want to be active citizens and are willing to contribute to the development of a more inclusive Swedish society. This thesis contributes to our current understanding of how young adults from ethnic minority backgrounds, experience social citizenship and social participation within the areas of: housing, education, labour-market, leisure and policy.</p> / <p>Denna rapport handlar om hur unga kvinnor och män med utländsk bakgrund i en medelstor svensk stad upplever social delaktighet. I fokus står vardagslivets sociala medborgarskap och hur människor förstår sina sociala rättigheter och skyldigheter och på vilket sätt detta påverkar deras medverkan i samhällslivet. Rapporten visar att de unga kvinnorna och männen har engagemang och uttrycker ansvarskänsla och vilja till social delaktighet i det svenska samhället. Samtidig upplever de inte alltid ett fullvärdigt socialt medborgarskap på grund av etnisk diskriminering. Helene Jacobson Pettersson är doktorand i socialt arbete vid Institutionen för vårdvetenskap och socialt arbete, Växjö universitet. Hon är anställd som universitetsadjunkt i socialt arbete vid Högskolan i Kalmar. Detta är hennes licentiatavhandling.</p>

Θεωρητικό υπόβαθρο: Το οξειδωτικό στρες (ΟΣ) ορίζεται ως το παθολογικό αποτέλεσμα που προκύπτει από τη διαταραχή της ισορροπίας των κυτταρικών συγκεντρώσεων των οξειδωτικών, δραστικών ενώσεων και των αντιοξειδωτικών μορίων. Εκτός από τη βλάβη που υπόκεινται οι πρωτεΐνες και τα λιπίδια, το ΟΣ μπορεί επίσης να προκαλέσει μεταλλάξεις και επιγενετικές μεταβολές καταστρέφοντας τόσο το DNA όσο και τις πρωτεΐνες που τροποποιούν τη χρωματίνη. Παρ' όλα αυτά, στα θυρεοειδικά θυλακικά κύτταρα παράγονται σε καθημερινή βάση υψηλές ποσότητες υπεροξειδίου του υδρογόνου (H2O2), οξειδωτικής ουσίας απαραίτητης για την πραγματοποίηση της θυρεοειδικής ορμονογένεσης. Δεδομένου ότι ένα ελάχιστο ποσό οξειδωτικού φορτίου αποτελεί προϋπόθεση αφ’ενός για τη φυσιολογική λειτουργία των θυλακικών κυττάρων και αφ’ετέρου για την ανάπτυξη του θυρεοειδούς αδένα, πρόσφατα αποδείχτηκε ότι ο θυρεοειδής αδένας παρουσιάζει αυξημένη αμυντική ανταπόκριση έναντι του ΟΣ. Ωστόσο, οι ακριβείς μηχανισμοί με τους οποίους τα θυλακικά κύτταρα αντιλαμβάνονται και απαντούν στο ΟΣ παραμένουν ασαφείς. Ο NFE2-related factor 2 (Nrf2), ο οποίος κωδικοποιείται από το γονίδιο NFE2L2, είναι ένας μεταγραφικός παράγοντας ο οποίος απαντά σε σήματα κυτταρικού στρες και ανταποκρίνεται επιδρώντας στη μεταγραφή γονιδίων σε διάφορους τύπους ιστών. Σε βασικές συνθήκες, ο Nrf2 οδηγείται σε πρωτεασωματική αποικοδόμηση μέσω του κυτταροπλασματικού του αναστολέα, Keap1, ενώ σε συνθήκες ΟΣ, η αποικοδόμηση του Nrf2 δεν είναι δυνατή και ο Nrf2 εισέρχεται στον πυρήνα ώστε να ενεργοποιήσει τη μεταγραφή αντιοξειδωτικών γονιδίων όπως του γονιδίου Nqo1. Καθώς η οξειδοαναγωγική ομοιοστασία κατέχει κεντρικό ρόλο στην φυσιολογία του θυρεοειδούς αδένα και ο Nrf2 πρόσφατα χαρακτηρίσθηκε ως μεσολαβητής στην αντίσταση θυρεοειδικών καρκινικών κυτταρικών σειρών σε πρωτεασωμικούς αναστολείς, το αντιοξειδωτικό μονοπάτι Nrf2 μπορεί να θεωρηθεί ως εξαιρετικός υποψήφιος της διαμεσολάβησης της απόκρισης του θυρεοειδούς αδένα στο ΟΣ. Παρ 'όλα αυτά, ο ρόλος του μονοπατιού Nrf2 στον ανθρώπινο θυρεοειδικό καρκίνο παραμένει άγνωστος. Στόχος: Στόχοι της παρούσας μελέτης ήταν η εκτίμηση της δραστηριότητας του μονοπατιού Νrf2 στο διαφοροποιημένο καρκίνωμα του θυρεοειδούς αδένα και η διερεύνηση σωματικών μεταλλάξεων των γονιδίων NFE2L2 και Keap1. Yλικά και Μέθοδοι Ασθενείς: Στη μελέτη συμμετείχαν 90 περιστατικά εκ των οποίων τα 42 αφορούσαν θηλώδη καρκινώματα (papillary thyroid carcinomas, PTCs), τα 6 θυλακιώδη καρκινώματα (follicular thyroid carcinomas, FTCs) και τα υπόλοιπα 42 καλοήθεις όγκους (24 αδενώματα και 18 οζώδης υπερπλασία). Κυτταρικές σειρές: Στα πλαίσια της παρούσας μελέτης χρησιμοποιήθηκαν κυτταρικές σειρές PTC (K1, TPC-1, XTC-1), κυτταρική σειρά φτωχά διαφοροποιημένου PTC (T243), κυτταρικές σειρές αδιαφοροποίητου καρκινώματος (C643, 8505C, Hth74) και τέλος κυτταρικές σειρές αναπλαστικού καρκινώματος (T235 , T241, T238). Μέθοδοι: Αναδρομική ανοσοϊστοχημική ανάλυση δειγμάτων PTC και FTC, παρακείμενου φυσιολογικού ιστού και καλοηθών βλαβών. Ανάλυση αλληλουχίας DNA των κυτταρικών σειρών και PTC δειγμάτων. Κύριες μετρήσεις και υπολογισμοί: Αξιολογήθηκε η ένταση της ανοσοαντίδρασης των δειγμάτων των ιστών σε αντισώματα για τα Nrf2, Nqo1, Keap1 και 4-HNE. Μελετήθηκε η αλληλουχία του εξονίου 2 του γονιδίου NFE2L2 καθώς και του γονιδίου Keap1. Αποτελέσματα: O μεταγραφικός παράγοντας Nrf2 καθώς και ο στόχος του, η πρωτεΐνη Nqo1 ήταν μη ανιχνεύσιμα σε φυσιολογικό ιστό θυρεοειδούς αδένα. Τα επίπεδά τους ήταν σημαντικά υψηλότερα στα PTC δείγματα από ό,τι στα δείγματα καλοηθών βλαβών. Η έκφραση του Keap1 εμφάνισε διακύμανση στα δείγματα PTC με τα επίπεδά του να μην εμφανίζουν συσχέτιση με τα αντίστοιχα του Nrf2, ενάντια στη θεωρία πως τα μειωμένα επίπεδα του Κeap1 συνιστούν μηχανισμό ενεργοποίησης του Nrf2. Ο δείκτης ΟΣ, 4-HNE βρέθηκε αυξημένος στη πλειοψηφία των δειγμάτων PTC σε σχέση με το φυσιολογικό ιστό αναδεικνύοντας την ύπαρξη αυξημένου ΟΣ στο PTC. Επιπλέον, όσον αφορά τα δείγματα FTC, ο μεταγραφικός παράγοντας Nrf2 και η πρωτεΐνη Nqo1 ήταν ανιχνεύσιμα σε όλα τα δείγματα, ενώ τα επίπεδα του 4-ΗΝΕ ήταν αυξημένα. Όσον αφορά την ανάλυση αλληλουχίας DNA στις καρκινικές σειρές και σε 11 δείγματα PTC με υψηλή έκφραση Nrf2, καμία μετάλλαξη δεν ανευρέθηκε στο εξόνιο 2 του γονιδίου NFE2L2 και στο γονίδιο Keap1. Συμπεράσματα: Τα αποτελέσματα της μελέτης μας σε συνδυασμό με περαιτέρω μελέτες από το εργαστήριο Ενδοκρινολογίας και Ανατομικής του Πανεπιστημίου Πατρών καθώς και από το BC κέντρο έρευνας καρκίνου (Vancouver, Canada) αποδεικνύουν ότι το μονοπάτι Nrf2 ενεργοποιείται σε PTC και κατέχει ρυθμιστικό ρόλο στην αντιοξειδωτική απόκριση και τη βιωσιμότητα των θυρεοειδικών καρκινικών κυττάρων. Συνεπώς, αναδεικνύεται το Nrf2 μονοπάτι ως νέο “σήμα κατατεθέν” του PTC. Παρά το γεγονός ότι δεν ήταν δυνατή η πραγματοποίηση στατιστικών συσχετίσεων στη μελέτη του FTC λόγω του περιορισμένου αριθμού δειγμάτων, το μονοπάτι Nrf2 φαίνεται να ενεργοποιείται επίσης στο FTC. Η σταθερή ενεργοποίηση του Nrf2 στο PTC και ενδεχομένως στο FTC δίνει το έναυσμα για περαιτέρω διερεύνηση του μονοπατιού αυτού σε όλα τα είδη θυρεοειδικού καρκίνου καθώς και της πιθανής διαγνωστικής, προγνωστικής, και/ή θεραπευτικής χρησιμότητας του μονοπατιού στο διαφοροποιημένο καρκίνο του θυρεοειδούς αδένα. / Scientific background: Oxidative stress (ΟS) is experienced by cells when pro-oxidant and electrophilic reactive species overwhelm the cell’s antioxidant and detoxification proteins. In addition to causing protein and lipid damage, oxidative stress can cause mutations and epigenetic perturbation by damaging DNA and proteins that modify chromatin. Nevertheless, in thyrocytes a daily basis high amounts of the oxidant hydrogen hyperoxide (H2O2) was generated due to the fact that H2O2 is a reactive oxygen species required for thyroid hormonogenesis. A minimal oxidative load is a prerequisite for normal thyroid cell function and development and it was recently shown that the thyroid has increased capacity for defending itself against OS. However, precise mechanisms by which thyrocytes sense and respond to OS remain obscure. NFE2-related factor 2 (Nrf2), encoded by NFE2L2 gene, is a transcription factor that integrates cellular stress signals and responds by directing transcriptional program in various tissues. In basal conditions, Nrf2 is targeted for proteasomal degradation by its cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), while in oxidative stress Nrf2 degradation is abolished and Nrf2 accumulates in the nucleus where it transactivates protective genes such as NAD(P)H dehydrogonase quinone 1 (Nqo1). As redox homeostasis plays a principal role in thyroid gland’s physiology, and Nrf2 has recently been characterised as mediator of thyroid cancer cell lines’ resistance to proteasome inhibitors, the Nrf2 antioxidant pathway seems to be an excellent candidate for mediating the antioxidant response of the thyroid gland. Nevertheless, the activity status of the Nrf2 pathway in human thyroid cancer remains unknown. Objective: The aims of this study were to assess the activity status of the Nrf2 pathway in differentiated thyroid carcinoma and investigate somatic mutations in NFE2L2 and Keap1 genes. Μethods and Materials Patients: The study included 90 individual samples; 42 papillarz thyroid carcinomas (PTCs), 6 follicular thyroid carcinomas (FTCs) and 42 benign lesions (24 adenomas and 18 nodular hyperplasias). Cell lines: Ten thyroid cell lines are used for this study: The PTC cell lines, K1, TPC-1 and XTC-1; the poorly differentiated PTC cell line, T243; the undifferentiated carcinoma cell lines, C643, 8505C and Hth74; and the anaplastic carcinoma cell lines, T235, T241 and T238. Methods: We conducted retrospective immunohistochemical analyses of PTC and FTC specimens, adjacent normal tissue, and benign lesions; DNA sequencing in cell lines and PTC samples. Main Outcome Measures: We assessed the abundance of Nrf2, Nqo1, Keap1, and 4HNE; and the sequence of NFE2L2 gene’s exon 2 and of KEAP1 gene. Results: Nrf2 and its target Nqo1 were undetectable in normal tissue; their levels were significantly higher in PTC than in benign lesions. The Nrf2 inhibitor, Keap1 was variably abundant in PTC, and its levels did not correlate with Nrf2, arguing against decreased levels as the mechanism for Nrf2 activation. The oxidized lipid 4HNE was more abundant in PTC than normal tissue indicating oxidative stress. In addition, as far as FTC samples are concerned, Nrf2 and Nqo1 were detectable in all samples as well as the levels of 4-HNE were significantly high. No mutations were detectable in exon 2 of NFE2L2 gene and in Keap1 gene. Conclusions: Our study’s results supported by further studies in laboratories of Endocrinology and Anatomy at University of Patras and BC Cancer Research Center (Vancouver, Canada) demonstrate that the Nrf2 pathway is commonly activated in PTC and that it regulates antioxidant responses and viability of cancer cells. Thus, Nrf2 is highlighted as a new hallmark of PTC. Although, statistic correlations were not possible in FTC samples’ study because of small sample size, the Nrf2 pathway seems to be also activated in FTC. The high activity of Nrf2 in PTC and possibly in FTC warrants further exploration of this pathway’s potential diagnostic, prognostic, and/or therapeutic utility in differentiated thyroid carcinoma.