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Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Nas últimas décadas, verificou-se diferenças nas classificações da World Health Organization (WHO) de 2001 e da European Organization for Research and Treatment of Cancer (EORTC) de 1997 para os linfomas cutâneos primários. Em 2005, representantes dessas classificações se reuniram e em consenso estabeleceram a classificação WHO-EORTC que foi adotada pela última classificação da WHO de 2008. O presente estudo visa a avaliar a aplicabilidade dessa nova classificação em casuística retrospectiva de um único centro de referência no diagnóstico e tratamento de linfomas cutâneos. Assim, todos os casos de linfoma cutâneo de células T, excluindo-se micose fungóide (MF) e síndrome de Sézary (SS), no período de 1986 a 2009, foram analisados em relação aos aspectos clínicos, histopatológicos e imunofenotípicos, incluindo-se a realização de novas reações imunoistoquímicas. Os casos foram, então, classificados de acordo com critérios estabelecidos na classificação WHO de 2008. Houve, assim, 33 casos de linfomas cutâneos de células T não-MF e não-SS, sendo 08 (24,2%) de linfoma cutâneo de grandes células anaplásicas, 05 (15,2%) de papulose linfomatóide, 06 (18,1%) de linfoma extranodal de células NK/T tipo nasal, 05 (15,2%) de neoplasia de células dendríticas plasmocitóides blásticas, 05 (15,2%) de linfoma/leucemia de células T do adulto e 04 (12,1%) de linfoma de células T periféricas, sem outra especificação. Portanto, a classificação WHO de 2008 é aplicável à maioria dos casos de linfoma cutâneo de células T não-MF e não-SS. Entretanto, permanecem casos não classificáveis, alguns dos quais com curso clínico agressivo / Recent years have witnessed differences between the World Health Organization (WHO) 2001 and the European Organization for Research and Treatment of Cancer (EORTC) 1997 classification systems of primary cutaneous lymphomas (PCLs). In 2005, a joint WHO-EORTC classification system for PCLs has been reached and was adopted by last WHO 2008 classification. This study was performed to assess the applicability of this new classification to a single referral center. All cutaneous T-cell lymphoma (CTCL) cases, excluding mycosis fungoides (MF) and Sezary syndrome (SS), who were referred from 1986 to 2009 were included. The clinical features, histological and immunohistochemical stainings were reviewed, and additional stains were performed as needed. The cases were then reclassified according to the WHO 2008 classification. There were 33 cases of non-MF and non-SS CTCL, included 08 (24.2%) CD30+ anaplastic large-cell lymphomas, 05 (15.2%) cases of lymphomatoid papulosis, 06 (18.1%) extranodal NK/T-cell lymphoma nasal type, 05 (15.2%) blastic plasmacytoid dendritic cell neoplasm, 05 (15.2%) adult T-cell lymphoma/leukemia and 04 (12.1%) peripheral T-cell lymphomas, unspecified. The new WHO 2008 classification is applicable to most nonMF and non-SS CTCL cases. However, there is still a substantial subset of T-cell PCLs which cannot be classified beyond the unspecified peripheral T-cell category, some of which may have an aggressive course

INTRODUÇÃO. Os genes da família paraoxonase (PON1, PON2 e PON3) apresentam grande homologia estrutural. PON1 está associada à molécula de HDL e possui funções fisiológicas, sendo a principal a de lactonase. PON1 também pode proteger as moléculas de LDL de modificações oxidativas. Embora o papel biológico mais conhecido das paraoxonases seja a prevenção da aterosclerose, elas também atuam sobre o estresse oxidativo envolvido na patogênese de outras condições como doenças inflamatórias, infecções e neoplasias. Toda a família PON parece estar implicada no desenvolvimento de linfomas. O polimorfismo L55M de PON1 foi relacionado a um maior risco para linfomas em indivíduos da população geral, enquanto PON3 e PON2 foram relacionadas à sobrevida de células tumorais. A Imunodeficiencia comum variável (ICV) é uma doença heterogênea caracterizada pela redução dos niveis de IgG, IgA e/ou IgM e da função de anticorpo. As manifestações clínicas incluem a presença de infecções recorrentes ou crônicas, doenças inflamatórias/autoimunes e incidência aumentada de malignidades como linfomas não-Hodgkin (LNH) e câncer gástrico. OBJETIVO: estudar os polimorfismos de PON1 e PON2 bem como a atividade arilesterase de PON1 e sua relação com o perfil lipídico, morbidade, mortalidade e presença de fatores de risco para linfoma LNH em pacientes com ICV. MÉTODOS/RESULTADOS: Foram avaliadas as frequências alélicas dos polimorfismos de PON1 e PON2, o perfil lipídico e a atividade arilesterase da PON1 em 63 pacientes com ICV e 130 controles saudáveis. No grupo de pacientes foi analisada a presença de fatores de risco para LNH e parâmetros de morbidade e gravidade da doença. O polimorfismo Q192R da PON1 e os polimorfismos de PON2 (S311C e A148G) não diferiram entre os grupos e não apresentaram relação com os parâmetros analisados. O genótipo 55MM e o alelo 55M foram mais frequentes no grupo ICV em relação ao grupo controle. A atividade arilesterase foi similar em pacientes e controles apresentando correlação positiva com os níveis de HDL. Pacientes com o genótipo 55MM apresentaram menor atividade de PON1 associada a maior morbidade da doença representada pela maior frequência de infecções de vias aéreas e maior taxa de internações. O genótipo 55MM também apresentou relação com a presença de fatores de risco para LNH como hiperplasia nodular linfoide (HNL) e linfonodomegalias. Por outro lado, a análise dos alelos demonstrou que a menor morbidade da doença foi associada à presença do alelo 55L, que apresentou relação com menor frequência de HNL e linfonodomegalia e menor ocorrência de óbitos. O alelo 55M apresentou relação com história familiar de imunodeficiências e neoplasias hematológicas. CONCLUSÃO: Este constitui o primeiro relato demonstrando maior frequência do genótipo 55MM e do alelo 55M em pacientes com ICV. Nossos resultados são sugestivos de que a presença do alelo 55L possa estar associado a um melhor prognóstico da doença. Inversamente, sugerem que pacientes com o genótipo 55MM apresentem maior morbidade e, possivelmente, maior risco para LNH / INTRO: The paraoxonase gene family (PON1, PON2 and PON3) has great structural homology. PON1 is associated with the HDL molecule and possess many physiological roles, the major one being of a lactonase. PON1 also protects LDL molecules against oxidative modifications. Although the best known biological role of PONs is the prevention of atherosclerosis, they also act on the oxidative stress involved in the pathogenesis of different conditions such as inflammatory diseases, infections and malignancies. The whole PON family appears to be implicated in the development of lymphomas. The L55M polymorphism of PON1 was related with a higher risk for lymphoma in the general population while PON3 and PON2 were related to survival of tumor cells. The Common Variable Immunodeficiency (ICV) is a heterogeneous disease characterized by reduced levels of IgG, IgA and/or IgM and antibody function. Clinical manifestations include the presence of chronic or recurrent infections, inflammatory/autoimmune diseases and increased incidence of malignancies such as non-Hodgkin lymphoma (NHL) and gastric cancer. OBJECTIVE: to study the PON1 and PON2 polymorphisms and the arylesterase activity of PON1 and its correlation with the lipid profile, morbidity, mortality and the presence of risk factors for NHL in CVID patients. METHODS/RESULTS: We evaluated the allele frequencies of polymorphisms of PON1 and PON2, lipid profile and arylesterase activity of PON1 in 63 patients with CVID and 130 healthy controls. In the group of patients we analyzed the presence of risk factors for NHL and parameters of morbidity and disease severity. The Q192R polymorphism of the PON1 and PON2 polymorphisms (A148G and S311C) did not differ between groups and did not correlate with the parameters analyzed. The 55MM genotype and the 55M allele were more frequent in the CVID group than in control group. The arylesterase activity was similar in patients and controls showing a positive correlation with HDL levels. Patients with genotype 55MM had lower PON1 activity, associated with increased morbidity of the disease represented by the higher frequency of respiratory infections and a higher rate of hospitalization. The 55MM genotype also was correlated with the presence of risk factors for NHL, such as lymphoid nodular hyperplasia (HNL) and lymphadenopathy. Moreover, analysis of the alleles showed that less morbidity of the disease was associated with the presence of the allele 55L, which was correlated with a lower frequency of HNL and lymphadenopathies and fewer deaths. The 55M allele was correlated with a family history of immunodeficiency and hematological malignancies. CONCLUSION: This is the first report showing a greater frequency of 55MM genotype and 55M allele in patients with CVID. Our results suggest that the presence of 55L allele may be associated with a better prognosis. Conversely, these results suggest that patients with the 55MM genotype show higher morbidity and, possibly, higher risk for NHL

Orientador: Oslei Paes de Almeida / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-23T09:15:14Z (GMT). No. of bitstreams: 1 ToralRizo_VictorHugo_D.pdf: 3216317 bytes, checksum: f10b9daa311d7ae2e304dc1ea8925abf (MD5) Previous issue date: 2013 / Resumo: O linfoma difuso de grandes células B (LDGCB) é o linfoma da cavidade bucal mais comum. Alguns dos LDGCB podem apresentar células grandes morfologicamente similares às células Hodgkin e Reed/Sternberg (HRS) dos linfomas de Hodgkin clássico (LHC). O objetivo deste estudo foi comparar os LDGCB bucal que apresentem células HRS-like (LDGCB-HRS) com o linfoma de Hodgkin primário nodal, considerando os aspectos histológicos e imunoistoquímicos (IQs), angiogênese, índice de mastócitos e células dendríticas (CD), por meio de um amplo painel IQ. Quize casos foram estudados, nos quais sete eram LDGCB-HRS like e oito eram LHC nodal. Para a análise dos aspectos histológicos e IQs foram utilizados os seguintes anticorpos: CD3, CD15, CD20, CD30, CD43, LCA, CD45RO, CD79a, CD83, EMA, MUM-1, PAX-5, perforina, granzyme B, FASN, Ki-67, LMP-1; e EBER1/2. Já para a análise da angiogênese foram utilizados os anticorpos CD34, CD31, D2-40, CD105, vWF e VEGF; e para o índice de mastócitos utilizou-se o mast cell triptase. Finalmente, para avaliar a expressão IQ das CD os anticorpos CD1a, CD83, CD123, CD207, S-100 e FXIIIa foram utilizados. Todas as lâminas foram escaneadas e as células HRS-like, mastócitos e CD imunopositivas foram analisados, assim como os parâmetros morfométricos da angiogênese. Os resultados mostraram que a imunoexpressão foi postiva em 100% de casos de LHC e em 57% dos casos de LDGCB de boca, enquanto que LCA, CD20 e CD79a foram exclusivos para todos os LDGCB, e apenas CD15 foi exclusivo para os LHC. Angiogênese e o índice de mastócitos estavam aumentados em ambas as lesões, e entre elas, o LHC obteve maiores valores que o LDGCB da cavidade bucal em todos os anticorpos analisados. Por fim, o índice de CDs foram estatisticamente significante entre os grupos, exceto para CD83, que não mostrou nenhuma diferença estatística. A distribuição de CD foi reconhecida principalmente na área tumoral e ao redor das células neoplásicas em ambas as entidades. Foi possível concluir que os LDGCB com células HRS-like da cavidade bucal devem ser incluídos no diagnóstico diferencial de LHC da cavidade bucal. Quando da avaliação destes casos, a analise morfológica detalhada assim como o uso de um amplo painel de IQ são recomendados para realizar o diagnóstico correto. A angiogênese é essencial para o desenvolvimento de LDGCB da cavidade bucal, e quaisquer dos anticorpos CD34, CD31 e vWF podem ser utilizados para avaliar os parâmetros morfométricos. A presença significativa de CD nestes linfomas provavelmente desempenha um papel patologicamente relevante nos linfomas. Nossos resultados sugerem que o aumento no número de CD parece ser um fator contribuinte para a resposta imune estimulada pelo crescimento tumoral / Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common oral lymphoma. Some DLBCLs can present large cells morphologically similar to Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). The objective of this study was to compare oral DLBCL presenting HRS-like cells (DLBCL-HRS like) with primary nodal cHL, considering the following aspects: histological and immunohistochemical (IHC), angiogenesis, index of mast cells and dendritic cells (DCs); through a broad immunohistochemical panel. Fifteen cases were studied, of which, seven were DLBCL-HRS like and eight were nodal cHL. For histological and IHC aspects, immunoexpression of CD3, CD15, CD20, CD30, CD43, LCA, CD45RO, CD79a, CD83, EMA, MUM-1, PAX-5, perforin, granzyme B, FASN, Ki-67, LMP-1; and EBER1/2, were assessed. As for angiogenesis analysis, the antibodies used were CD34, CD31, D2-40, CD105, vWF and VEGF; and for the index of mast cell were used the mast cell tryptase. Finally, for IHC expression of DCs, the antibodies used were CD1a, CD83, CD123, CD207, S-100, and FXIIIa. All slides were scanned and positive immunoreactive cells HRS-like, mast cell and DCs were analyzed, as well as morphometric parameters of angiogenesis. The results showed that the immunoexpression of CD30 was 100% positive in cHL and 57% in oral DLBCL HRS-like, while LCA, CD20 and CD79a were exclusive for all oral DLBCL, and only CD15 was exclusive for cHL. Angiogenesis and mast cell index values were increased in both lesions and between them, cHL was greater than oral DLBCL with all antibodies studied. Finally, DC subsets were statistically significant between groups, except CD83, which did not show statistical significance. The distribution of DCs was mainly in the tumor area, around neoplastic cells in both entities. It was possible to conclude that DLBCL-HRS should be included in the differential diagnosis of oral cHL. When evaluating these cases, a detailed morphologic and a broad IHC analyses for the correct diagnosis are recommended. Angiogenesis is essential to the development of DLBCL of the oral cavity and any of the antibodies CD34, CD31 and vWF could be used to evaluate morphometric parameters. The presence of significantly higher numbers of DCs in these lymphomas could suggest that these cells are likely to play a pathological relevant role in lymphomas. Our findings suggest that increased number of DCs in lymphomas appears to be a factor contributing to the immune response against tumor growth / Doutorado / Patologia / Doutor em Estomatopatologia

Ces travaux ont été menés dans le cadre du projet européen FACETS-ITN. Nous avons contribué à la simulation de cellules corticales grâce à des données expérimentales d'électrophysiologie comme référence et d'un circuit intégré neuromorphique comme simulateur. Les propriétés intrinsèques temps réel de nos circuits neuromorphiques à base de modèles à conductance, autorisent une exploration détaillée des différents types de neurones. L'aspect analogique des circuits intégrés permet le développement d'un simulateur matériel temps réel à l'échelle du réseau. Le deuxième objectif de cette thèse est donc de contribuer au développement d'une plate-forme mixte - matérielle et logicielle - dédiée à la simulation de réseaux de neurones impulsionnels. / This work has been supported by the European FACETS-ITN project. Within the frameworkof this project, we contribute to the simulation of cortical cell types (employingexperimental electrophysiological data of these cells as references), using a specific VLSIneural circuit to simulate, at the single cell level, the models studied as references in theFACETS project. The real-time intrinsic properties of the neuromorphic circuits, whichprecisely compute neuron conductance-based models, will allow a systematic and detailedexploration of the models, while the physical and analog aspect of the simulations, as opposedthe software simulation aspect, will provide inputs for the development of the neuralhardware at the network level. The second goal of this thesis is to contribute to the designof a mixed hardware-software platform (PAX), specifically designed to simulate spikingneural networks. The tasks performed during this thesis project included: 1) the methodsused to obtain the appropriate parameter sets of the cortical neuron models that can beimplemented in our analog neuromimetic chip (the parameter extraction steps was validatedusing a bifurcation analysis that shows that the simplified HH model implementedin our silicon neuron shares the dynamics of the HH model); 2) the fully customizablefitting method, in voltage-clamp mode, to tune our neuromimetic integrated circuits usinga metaheuristic algorithm; 3) the contribution to the development of the PAX systemin terms of software tools and a VHDL driver interface for neuron configuration in theplatform. Finally, it also addresses the issue of synaptic tuning for future SNN simulation.

Purpose: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. Methods: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. Results: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. Conclusion: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

Thesis (MSc (Biochemistry))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: The Hodgkin-Huxley model, created in 1952, was one of the first models in computational neuroscience and remains the best studied neuronal model to date. Although many other models have a more detailed system description than the Hodgkin-Huxley model, it nonetheless gives an accurate account of various high-level neuronal behaviours. The fields of computational neuroscience and Systems Biology have developed as separate disciplines for a long time and only fairly recently has the neurosciences started to incorporate methods from Systems Biology. Metabolic Control Analysis (MCA), a Systems Biology tool, has not been used in the neurosciences. This study aims to further bring these two fields together, by testing the feasibility of an MCA approach to analyse the Hodgkin-Huxley model. In MCA it is not the parameters of the system that are perturbed, as in the more traditional sensitivity analysis, but the system processes, allowing the formulation of summation and connectivity theorems. In order to determine if MCA can be performed on the Hodgkin-Huxley model, we identified all the discernable model processes of the neuronal system. We performed MCA and quantified the control of the model processes on various high-level time invariant system observables, e.g. the action potential (AP) peak, firing threshold, propagation speed and firing frequency. From this analysis we identified patterns in process control, e.g. the processes that would cause an increase in sodium current, would also cause the AP threshold to lower (decrease its negative value) and the AP peak, propagation speed and firing frequency to increase. Using experimental inhibitor titrations from literature we calculated the control of the sodium channel on AP characteristics and compared it with control coefficients derived from our model simulation. Additionally, we performed MCA on the model’s time-dependent state variables during an AP. This revealed an intricate linking of the system variables via the membrane potential. We developed a method to quantify the contribution of the individual feedback loops in the system. We could thus calculate the percentage contribution of the sodium, potassium and leak currents leading to the observed global change after a system perturbation. Lastly, we compared ion channel mutations to our model simulations and showed how MCA can be useful in identifying targets to counter the effect of these mutations. In this thesis we extended the framework of MCA to neuronal systems and have successfully applied the analysis framework to quantify the contribution of the system processes to the model behaviour. / AFRIKAANSE OPSOMMINMG: Die Hodgkin-Huxley-model, wat in 1952 ontwikkel is, was een van die eerste modelle in rekenaarmagtige neurowetenskap en is vandag steeds een van die bes-bestudeerde neuronmodelle. Hoewel daar vele modelle bestaan met ’n meer uitvoerige sisteembeskrywing as die Hodgkin-Huxley-model gee dié model nietemin ’n akkurate beskrywing van verskeie hoëvlak-sisteemverskynsels. Die twee velde van sisteembiologie en neurowetenskap het lank as onafhanklike dissiplines ontwikkel en slegs betreklik onlangs het die veld van neurowetenskap begin om metodes van sisteembiologie te benut. ’n Sisteembiologiemetode genaamd metaboliese kontrole-analise (MKA) is tot dusver nog nie in die neurowetenskap gebruik nie. Hierdie studie het gepoog om die twee velde nader aan mekaar te bring deurdat die toepasbaarheid van die MKA-raamwerk op die Hodgkin-Huxley-model getoets word. In MKA is dit nie die parameters van die sisteem wat geperturbeer word soos in die meer tradisionele sensitiwiteitsanalise nie, maar die sisteemprosesse. Dit laat die formulering van sommasie- en konnektiwiteitsteoremas toe. Om die toepasbaarheid van die MKA-raamwerk op die Hodgkin-Huxleymodel te toets, is al die onderskeibare modelprosesse van die neurale sisteem geïdentifiseer. Ons het MKA toegepas en die kontrole van die model-prosesse op verskeie hoëvlak, tydsonafhanklike waarneembare sisteemvlak-eienskappe, soos die aksiepotensiaal-kruin, aksiepotensiaal-drempel, voortplantingspoed en aksiepotensiaal-frekwensie, gekwantifiseer. Vanuit hierdie analise kon daar patrone in die proseskontrole geïdentifiseer word, naamlik dat die prosesse wat ’n toename in die natriumstroom veroorsaak, ook sal lei tot ’n afname in die aksiepotensiaal-drempel (die negatiewe waarde verminder) en tot ’n toename in die aksiepotensiaal-kruin, voortplantingspoed en aksiepotensiaalfrekwensie. Deur gebruik te maak van eksperimentele stremmer-titrasies vanuit die literatuur kon die kontrole van die natriumkanaal op die aksiepotensiaaleienskappe bereken en vergelyk word met die kontrole-koëffisiënte vanuit die modelsimulasie. Ons het ook MKA op die model se tydsafhanklike veranderlikes deur die verloop van die aksiepotensiaal uitgevoer. Die analise het getoon dat die sisteemveranderlikes ingewikkeld verbind is via die membraanpotensiaal. Ons het ’n metode ontwikkel om die bydrae van die individuele terugvoerlusse in die sisteem te kwantifiseer. Die persentasie-bydrae van die natrium-, kalium- en lekstrome wat tot die waarneembare globale verandering ná ’n sisteemperturbasie lei, kon dus bepaal word. Laastens het ons ioonkanaalmutasies met ons modelsimulasies vergelyk en getoon hoe MKA nuttig kan wees in die identifisering van teikens om die effek van hierdie mutasies teen te werk. In hierdie tesis het ons die raamwerk van MKA uitgebrei na neurale sisteme en die analise-raamwerk suksesvol toegepas om die bydrae van die sisteemprosesse tot die modelgedrag te kwantifiseer.