Submitted by FERNANDA DA SILVA VON PORSTER (fdsvporster@univates.br) on 2016-07-28T18:50:36Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) 2016PricilaGirardi.pdf: 1029142 bytes, checksum: cabbf24ec1d0aa04a64b1668a8ac20cb (MD5) / Approved for entry into archive by Ana Paula Lisboa Monteiro (monteiro@univates.br) on 2016-08-30T11:53:59Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) 2016PricilaGirardi.pdf: 1029142 bytes, checksum: cabbf24ec1d0aa04a64b1668a8ac20cb (MD5) / Made available in DSpace on 2016-08-30T11:53:59Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) 2016PricilaGirardi.pdf: 1029142 bytes, checksum: cabbf24ec1d0aa04a64b1668a8ac20cb (MD5) Previous issue date: 2016-07 / Introdução: O transtorno de déficit de atenção e hiperatividade (TDAH) é uma desordem comportamental comum em crianças e que pode persistir na idade adulta. Ele caracteriza-se por sintomas persistentes de desatenção, hiperatividade e impulsividade. Além disso, uma proporção significativa dos pacientes com TDAH também apresenta outras comorbidades envolvidas, especialmente os transtorno por uso de álcool e nicotina. Diversos estudos moleculares têm sido realizados na busca pelos genes envolvidos com o TDAH e alguns estudos têm apontando que fatores genéticos de susceptibilidade ao TDAH são também importantes na dependência de álcool e no uso de nicotina. Objetivo: O objetivo deste estudo é investigar a influência da interação dos polimorfismos rs1799990, no gene PRNP, e rs965560, no gene NCAM1, no TDAH e nas dependências de álcool e nicotina. Metodologia: As amostras foram compostas por pacientes com TDAH, 431 crianças e 535 adultos, 130 homens dependentes de álcool, 639 indivíduos adultos da população geral e 77 crianças controles. Os polimorfismos foram genotipadas através do sistema de discriminação alélica TaqMan. As análises estatísticas envolveram o teste do qui- quadrado, ANOVA e, para o teste da interação gene-gene sobre a susceptibilidade aos transtornos, foram utilizados modelos lineares gerais. Resultados: Não foram detectadas interações significativas entre os polimorfismos investigados sobre a susceptibilidade ao TDAH e às dependências de álcool e nicotina. Foi observada uma associação entre o alelo A do polimorfismo rs1799990 com o TDAH na infância (p=0,04). Em adultos com TDAH, indivíduos heterozigotos AG apresentaram uma maior frequência de transtorno opositor desafiante (TOD) (p=0,017), assim como escores médios dos sintomas de TOD significativamente maiores (p=0,012), em comparação aos indivíduos homozigotos GG. Não foram detectadas associações significativas para o polimorfismo rs965560 com nenhuma das variáveis investigadas. Conclusão: Nossos resultados indicam que o polimorfismo rs1799990 pode estar associado com o TDAH na infância e com a presença de TOD em adultos com TDAH. Esses resultados, no entanto, são preliminares e não foram testados para múltiplos testes. / Introduction: Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder in children that can persist into adulthood. It characterized by persistent symptoms of inattention, hyperactivity and impulsivity. Moreover, a significant proportion of patients with ADHD present other comorbidities, especially alcohol dependence and nicotine use. Several molecular studies have been employed in the search for the genes involved in ADHD and some studies have pointed that susceptibility genetic factors of ADHD are also important in alcohol dependence and nicotine use. Objective: The objective of this study is to investigate the influence of the interaction between the polymorphisms rs1799990, in the PRNP gene, and rs965560, in the NCAM1 gene, on the susceptibility to ADHD and alcohol and nicotine dependence. Methods: Samples were composed by patients with ADHD, 431 children and 535 adults, 130 alcohol dependent men, 639 adults from the general population and 77 children controls. The polymorphisms were genotyped by the TaqMan allelic discrimination system. The statistical analysis involved the chi- square test, ANOVA and, for the gene-gene interaction tests, general linear models were used. Results: There were no significant interactions between the polymorphisms investigated on the susceptibility to ADHD and to alcohol and nicotine dependences. An association between the A allele of rs1799990 polymorphism and ADHD in childhood (p=0.04) was observed. In adults with ADHD, individuals heterozygous AG had a higher frequency of oppositional defiant disorder (ODD) (p=0.017) and higher mean scores of symptoms of ODD (p=0.012), when compared to homozygous GG. No significant associations were found for the rs965560 polymorphism with the investigated variables. Conclusion: Our results indicate that the polymorphism rs1799990 may be associated with ADHD in childhood and with the presence of ODD in adults with ADHD. These results, however, are preliminary and were not tested for multiple testing.

Le carcinome épidermoïde cutané (CEC) représente un enjeu important par sa fréquence et sa gravité potentielle.L’agressivité de ce cancer est liée à l’invasion péri-nerveuse (IPN), mode d’envahissement tumoral reconnu comme un facteur de mauvais pronostic.L’objectif de ce travail est de s’intéresser aux mécanismes favorisant l’IPN, en comparant 2 groupes appariés de CEC humains, avec et sans IPN.Pour cela nous avons réalisé une étude de facteurs et récepteurs neurotrophiques, de marqueurs de la transition épithélio-mésenchymateuse (TEM), et de la molécule NCAM1, par analyse immunohistochimique à partir de pièces chirurgicales de CEC et par analyse moléculaire en droplet digital PCR sur des cellules tumorales microdisséquées.L’analyse immunohistochimique a trouvé une forte expression de BDNF, TrkB, p75NGFR, Snail 1 et NCMA1 dans les cellules tumorales péri-nerveuses, contrastant avec une faible expression de ces marqueurs dans les cellules tumorales à distance du nerf. L’E-cadhérine était diminuée dans les cellules tumorales péri-nerveuses.L’analyse moléculaire en ddPCR montrait une diminution d’expression de l’E-cadhérine et une surexpression de BDNF, TrkB, p75NGFR, Snail1, Slug, Zeb2, Twist1 et NCAM1 dans les cellules tumorales péri-nerveuses par rapport aux cellules tumorales distantes du nerf.Nous avons démontré dans ce travail que l’invasion péri-nerveuse dans les CEC humains est liée aux neurotrophines, à la TEM et implique NCAM1. / Cutaneous squamous cell carcinoma (SCC) is an important issue because of its frequency and potential severity.The aggressiveness of this cancer is related to perineural invasion (PNI), a mode of tumor dissemination recognized as a poor prognosis factor.The aim of this work is to study the mechanisms of PNI, comparing 2 matched- groups of human SCC with and without PNI.For this, we studied neurotrophins, epithelial-mesenchymal transition (EMT) markers, and the NCAM1 molecule, by immunohistochemistry analysis on surgical pieces of SCC and by molecular analysis with digital-droplet PCR on laser-microdissected tumor cells.Immunohistochemistry analysis found strong expression of BDNF, TrkB, p75NGFR, Snail 1 and NCMA1 in perineural tumor cells, contrasting with weak expression of these markers in tumor cells distant from the nerves. E-cadherin was decreased in perineural tumor cells.Molecular analysis in ddPCR showed decreased expression for E-cadherin and overexpression of BDNF, TrkB, p75NGFR, Snail1, Slug, Zeb2, Twist1 and NCAM1 in perineural tumor cells compared to tumor cells distant from the nerves.We have demonstrated in this work that PNI in human SCC is linked to neurotrophins and EMT, and involves NCAM1.