Introdução: O melanoma mucoso de cabeça e pescoço (MMCP) é mais agressivo do que o melanoma cutâneo, marcadores prognósticos desta patologia não foram completamente esclarecidos devido a sua raridade. Em recentes estudos, algumas vias moleculares foram descritas na fisiopatologia destes tumores. Entre estas vias, existe a via da MAPK (Mitogen Activated Protein Quinase). Esta via de sinalização está envolvida no controle do crescimento celular, proliferação e migração, com um papel no desenvolvimento e progressão do melanoma. Além disso, a mutação do gene KIT foi identificada em melanomas, indicando a possibilidade de benefícios terapêuticos com o uso dos inibidores de tirosino-quinase. Objetivos: descrever a prevalência e características de mutações ativadoras do gene KIT em 28 pacientes com MMCP tratados no Instituto Nacional do Câncer-INCa; avaliar a relação entre a presença de mutação ativadora do gene KIT e evolução clínica dos pacientes tratados em relação ao estadiamento, sobrevida livre de doença e sobrevida global. Métodos: Estudo retrospectivo de coorte, foram incluídos 28 pacientes com MMCP tratados no INCA, entre 1998 e 2009. Foram analisados: estadiamento, tratamento primário, sobrevida livre de doença (SLD) e sobrevida global (SG). As curvas de sobrevida foram analisados utilizando o método de Kaplan-Meier, com software SPS 11.0. Análise KIT: O DNA foi extraído a partir de tecido incluído e fixado em parafina. O procedimento consiste de múltiplas etapas de desparafinização com xilol. Os restos celulares são precipitados por centrifugação e o DNA, no sobrenadante é utilizado nas reações de PCR (direto ou diluído). A análise mutacional do gene foi realizada utilizando-se a amplificação por PCR seguida pelo sequenciamento genômico. As análises são iniciadas pelo éxon 11, seguidas do éxon 9, 17 e 13. Resultados: Os pacientes eram predominantemente do sexo feminino (57%). A idade de apresentação variou de 27 a 85 anos. A região nasossinusal foi o sítio primário mais frequente (75%). Todos os pacientes foram submetidos a ressecção cirúrgica. Dezessete pacientes receberam radioterapia adjuvante (37%). As recorrências ocorreram em 82% dos pacientes. Presença de mutação de KIT foi encontrada em 7 casos (25%), três no éxon 9, 3 no éxon 11 e 1 no éxon 13. Fatores preditivos de recorrência foram índice mitótico (p = 0,05), invasão vascular (p = 0,043), e a disseminação perineural (p = 0,034). Não houve diferenças significativas na SLD e SG de acordo com a mutação KIT. Conclusão: A presente série incluiu 28 casos tratados. Sete casos (25%) tinham mutações ativadoras KIT. Esta descoberta sugere que existe um grupo de pacientes que poderiam se beneficiar com a terapia-alvo adequado com inibidores de tirosino-quinase / Unlike their cutaneous counterparts, head and neck mucosal malignant melanomas (HNMM) behave much more aggressively and their prognostic markers have not been fully elucidated. In recent studies, some molecular pathways have been found to be involved in the pathogenesis of melanomas. Among these, there is a proliferative MAPK pathway (\"Mitogen Activated Protein Kinase\"). This signaling pathway is involved in controlling cell growth, proliferation and migration, with a role in the development and progression of melanoma. In addition, KIT gene mutation has been identified in melanomas, indicating that there may be potential therapeutic benefits of tyrosine kinase inhibitors. Objectives: Evaluation of KIT mutation prevalence in a subset of 28 patients with HNMM treated at a single institution, establishing the relationship between different mutations and outcome (DFS and OS). The primary end-point of the study was to define the incidence of KIT mutations in HNMM, including the relationship between KIT mutations with disease-free survival (DFS) and overall survival (OS) in HNMM. Secondary end-points were correlation among therapeutic options, histopathological findings, demographic data and clinical response. Methods: This retrospective study comprised data of 28 patients with HNMM treated at Brazilian National Cancer Institute (INCA) between 2000 and 2011. Clinical analysis included patients characteristics, staging, primary and palliative treatments, disease free survival and overall survival. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method, with SPS 11.0 software. KIT analysis: paraffin blocks were selected following analyses of histologic preparations, enabling DNA extraction. Different DNA concentrations were employed in PCR amplifications, based on DNA integrity. PCR amplification of exon, 9, 11, 13 and 17 was performed. . Results: Patients were predominantly females (57%). The age of presentation ranged from 27 to 85 years. The sinonasal region was the most frequent primary site (75%). All patients underwent surgical resection. Seventeen patients received adjuvant radiotherapy (37%). Recurrences occurred in 82% patients. Oncologic mutations in KIT were found in 7 (25%) of seven tumors, 3 in exon 9, 3 in exon 11 and 1 in exon 13. Predictive factors for recurrence were mitotic rate (p=0.05), vascular invasion (p=0.043), and perineural spread (p=0.034). There were no significant differences in DFS and OS according to KIT mutation. Conclusion: HNMM remains a rare disease. The present single-institution series includes 28 cases treated in single institution. Seven cases (25%) had activating KIT mutations, which is an increased prevalence of activating KIT mutations in this specific subset of mucosal melanomas. This finding suggests that there is a group of patients who might benefit with appropriate targeted therapy with kinase inhibitors

Dissertação / Submitted by Evy Augusto Salcedo Torres null (evy.salcedo.torres@ufsc.br) on 2016-09-16T19:32:49Z No. of bitstreams: 1 produtoEducacional.pdf: 1477522 bytes, checksum: 3ed089794f6871826d60c1683585ce40 (MD5) / Made available in DSpace on 2016-09-16T19:32:49Z (GMT). No. of bitstreams: 1 produtoEducacional.pdf: 1477522 bytes, checksum: 3ed089794f6871826d60c1683585ce40 (MD5) / CAPES / Efeito fotoelétrico, kit experimental

The distribution of the kit fox (Vulpes macrotis) in Utah was studied from 1974 to 1976 . A variety of methods were used, but a questionnaire sent annually to state and federal agencies, combined with interviews of fie ld personnel of these agencies, was found to be the most valuable. Kit foxes occur in western Utah and Washington County as previously reported. In addition, range extensions were noted in central Utah , and in Carbon, Emery, Grand, Wayne, and Garfield counties in east-central Utah. These range extensions total approximately 4,600- square miles (12,000 - square kilometers). The kit fox probably also inhabits San Juan County , but this was not confirmed. Stepwise discriminant analysis ~1as performed on groups of skull s representing the three nominal subspecies of y_. macrotis reported to occur in Utah (V. m nevadensis, arsipus , and neomex i cana). The skulls were judged to represent three distinct populations significantly different from each other in at least seven skull characteristics. Six specimens from eastern Utah and western Colorado were tentatively assigned to V m nevadensis.

A single tube detection kit was designed as a rapid, easy-to use and reliable test to detect Listeria spp.. Various food samples (vegetables and raw catfish fillets) were used in order to validate the performance of the detection kit. L. grayi was detected in one ready-to-eat (RTE) vegetables with the detection kit while no Listeria spp. was detected using the modified FDA-BAM method. In addition, both the detection kit and modified FDA-BAM method indicated that twelve catfish fillets were Listeria positive. The detection kit had 100% sensitivity and specificity in less detection time (24 h) than the modified FDA-BAM method (60% specificity, >72 h). There was no difference (P<0.05) between the kit and the modified FDA-BAM method on MPN for Listeria spp.

The illegal drug ecstasy, chemically known as 3,4-methylenedioxymethamphetamine (MDMA), sometimes contains additional chemicals which can pose health risks to users. This thesis examines strategies that recreational ecstasy users in Victoria, British Columbia utilize to determine the purity of their ecstasy. It also examines why they use these strategies and if they are concerned about impure ecstasy affecting their health because this information can help explain the use of these strategies. I performed a quantitative analysis of data collected by the Centre for Addictions Research of BC’s survey, the Canadian Recreational Drug Use Survey, to determine the strategies participants utilized to minimize potential harms caused by ecstasy use. This analysis revealed that 73.9% of survey participants discussed purity of ecstasy with friends, 33.3% checked drug information websites, 17.4% used an ecstasy testing kit, 2.9% asked harm reduction services for advice, and 0% owned a testing kit. In addition, the data revealed that the participants were more likely to take ecstasy from a friend than a stranger. Next, I developed an interview guide based on these findings and I interviewed 10 female recreational ecstasy users. I chose to interview women only because recreational drug use by women is underrepresented in the drug literature. The most common strategy the women utilized to determine ecstasy purity was to discuss ecstasy with friends. They preferred this strategy because it was a convenient, practical strategy. Also, they perceived their friends to be a trusted source of ecstasy and ecstasy information. Half the women analyzed how they felt after ingesting ecstasy to determine its purity because they believed different chemicals caused different effects. Others assessed the physical characteristics of their ecstasy to try to determine purity because they believed these characteristics could reveal its chemical contents. One participant used an ecstasy testing kit, but the rest cited multiple barriers to their use. Some women also had negative attitudes towards testing kits and felt no social pressure to use them. I asked the participants about their use of ecstasy testing laboratories, but none used this service because they did not know it existed. Overall, none of the women seemed concerned about ecstasy impurity harms. This could be due to four factors. First, their ecstasy use patterns made them feel safe from harms related to ecstasy use. Second, recreational ecstasy use was “normal” amongst young adults in Victoria who attend parties, raves, or clubs. Third, they primarily obtained ecstasy and ecstasy information from trusted friends. Fourth, they had never suffered significant harm caused by ecstasy impurity, even though all of the women believed they had ingested impure ecstasy. / Graduate

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and toxicology Student: Lucie Rozkydalová Supervisor of Diploma thesis: Prof. PharmDr. František Štaud, PhD. Specialized supervisor: Pr. Pierre Cuq PharmD. PhD., Laure-Anaïs Vincent Title of diploma thesis: Differential resistance of melanoma to vinca-alkaloids Malignant melanoma (MM) represents the most dangerous and very aggressive skin tumor with fast development of drug resistance which is the main obstacle in successful treatment of MM. According to previous studies (microarray data analysis), KIT gene, which plays key role in melanoma pathophysiology, was chosen as one of the potential causes of failure of treatment by vinca alkaloids (VAs) because of its complete underexpression in melanoma CAL1 resistant cells (CAL1R-VAs) in comparison with parental cells (CAL1-wt). Moreover, KIT also interacted with NF-κB and cyclin D1-2 proteins involved in chemoresistance of melanoma - inside molecular network built using IPA software. Although KIT underexpression in resistant CAL1 R-VAs cell lines were confirmed (qRTPCR), KIT repression using specific siRNA transfection did not show any effect on in vitro sensibility of CAL1-wt cells to VAs. It signifies that KIT is not directly involved in melanoma resistance...

Visando a redução de poluentes emitidos pelos motores de combustão interna com ignição por compressão, que operam conforme o ciclo diesel, foram desenvolvidos nos últimos anos dispositivos para a operação destes motores com novos combustíveis, que além da redução de poluentes barateariam o custo de operação, devido à oportunidade de utilização de alguns combustíveis com boa disponibilidade. No presente estudo analisa-se a operação do motor diesel utilizando gás natural como combustível. Neste caso utiliza-se o óleo diesel apenas como combustível piloto, que será responsável pela ignição do segundo combustível, o gás natural. Em diversas publicações constata-se o ganho ambiental e econômico desta aplicação, porém nada é comentado em relação à alteração de índices de confiabilidade e surgimento de novos modos de falha. Neste trabalho verifica-se através de ferramentas de análise de confiabilidade, tais como a análise do tipo FMEA e Árvore de falhas, quais os principais modos de falha que serão inseridos no motor de combustão interna do tipo diesel quando este passa a operar como bi-combustível, com gás natural. Para tanto, necessita-se subdividir o motor diesel em subsistemas mostrando sua estruturação em árvores funcionais e integrando o kit diesel gás neste sistema. A partir da análise de confiabilidade verifica-se a probabilidade de ocorrência de novos modos de falha, que necessitarão da elaboração de novos planos de manutenção ou mesmo alterações no projeto do subsistema de injeção de gás natural. / In order to reduce pollutants emissions from internal combustion engines with compression bend ignition, designed to operate as the Diesel cycle, it has been developed in recent years devices for the addition of new fuels, which in addition to reducing pollutants could lower the cost of operation, due to the possibility of use of some fuels with good availability. In this case it is used only the diesel oil as the pilot flame, which is responsible for the ignition of the second fuel, the natural gas. Many publications discuss the environmental and the economic gain with the use of natural gas as fuel application, however nothing is said about the change of reliability indexes and the appearance of new failure modes in the engine. In this study through system reliability analysis tools such as Faillure Mode Effects and Analisys and Fault tree analysis it is analysed, which are the main failure modes that are inserted into the internal combustion engine when it comes to operate as dual fuel. For that analyses it is necessary to split the engine into subsystems showing its functional trees and integrating diesel gas kit in this system. New failure modes appear with greater severity than the existing in the traditional diesel engine system, leading to new design and maintenance practices. The end user, according to his need, will have one more parameter to choose whether to adopt a Diesel Gas system.

Visando a redução de poluentes emitidos pelos motores de combustão interna com ignição por compressão, que operam conforme o ciclo diesel, foram desenvolvidos nos últimos anos dispositivos para a operação destes motores com novos combustíveis, que além da redução de poluentes barateariam o custo de operação, devido à oportunidade de utilização de alguns combustíveis com boa disponibilidade. No presente estudo analisa-se a operação do motor diesel utilizando gás natural como combustível. Neste caso utiliza-se o óleo diesel apenas como combustível piloto, que será responsável pela ignição do segundo combustível, o gás natural. Em diversas publicações constata-se o ganho ambiental e econômico desta aplicação, porém nada é comentado em relação à alteração de índices de confiabilidade e surgimento de novos modos de falha. Neste trabalho verifica-se através de ferramentas de análise de confiabilidade, tais como a análise do tipo FMEA e Árvore de falhas, quais os principais modos de falha que serão inseridos no motor de combustão interna do tipo diesel quando este passa a operar como bi-combustível, com gás natural. Para tanto, necessita-se subdividir o motor diesel em subsistemas mostrando sua estruturação em árvores funcionais e integrando o kit diesel gás neste sistema. A partir da análise de confiabilidade verifica-se a probabilidade de ocorrência de novos modos de falha, que necessitarão da elaboração de novos planos de manutenção ou mesmo alterações no projeto do subsistema de injeção de gás natural. / In order to reduce pollutants emissions from internal combustion engines with compression bend ignition, designed to operate as the Diesel cycle, it has been developed in recent years devices for the addition of new fuels, which in addition to reducing pollutants could lower the cost of operation, due to the possibility of use of some fuels with good availability. In this case it is used only the diesel oil as the pilot flame, which is responsible for the ignition of the second fuel, the natural gas. Many publications discuss the environmental and the economic gain with the use of natural gas as fuel application, however nothing is said about the change of reliability indexes and the appearance of new failure modes in the engine. In this study through system reliability analysis tools such as Faillure Mode Effects and Analisys and Fault tree analysis it is analysed, which are the main failure modes that are inserted into the internal combustion engine when it comes to operate as dual fuel. For that analyses it is necessary to split the engine into subsystems showing its functional trees and integrating diesel gas kit in this system. New failure modes appear with greater severity than the existing in the traditional diesel engine system, leading to new design and maintenance practices. The end user, according to his need, will have one more parameter to choose whether to adopt a Diesel Gas system.

En hématologie, du fait de leur évolution favorable, les tumeurs spontanément regressives comme lesmodèles myéloïde de la mastocytose, et lymphoïde de la papulose lymphomatoïde sont peu étudiés. Lamastocytose est une hémopathie myéloproliférative clonale dont les lésions cutanées peuvent régresserspontanément chez l’enfant alors que la maladie est chronique chez l’adulte. Les mutations chezl’enfant sont en partie différentes de celles retrouvées chez l’adulte. Nous avons montré in vivo dansles mastocytoses pédiatriques une expression diminuée de la télomérase, associée à des télomèrescourts. In vitro, grâce à deux modèles cellulaires comportant différents mutants de KIT de « typepédiatriques » ou de « type adulte », nous avons montré une augmentation de la longueur destélomères dans le mutant adulte, associée à une moindre sénescence comparées aux mutantspédiatriques sans pour autant mettre en évidence de différence dans l’expression et l’activité de latélomérase. Ces observations permettent en partie d’expliquer la régression des formes pédiatriques.La papulose lymphomatoïde est une lymphoprolifération cutanée T CD30+ dont les lésions régressentspontanément sans traitement. Cependant 10 à 20% des cas sont associés à un lymphome. Nous avonsétudié la physiopathologie d’expression du PDGFRβ dans les cellules tumorales via l’activation deNotch1. L’étude des télomères et de la télomérase in vivo et in vitro est préliminaire, et montrenotamment des télomères courts dans les cellules tumorales. En conclusion, nous montrons d’une partque la longueur des télomères dans les mastocytoses et la papulose lymphomatoïde est corrélée àl’évolution de la maladie, d’autre part, nous identifions un type de mutation potentiellement agressivedans les mastocytoses. Nous recommandons le génotypage systématique de cette pathologie dans lebut d’un suivi clinique attentif lorsque les lésions sont persistantes ou évolutives. / Childhood mastocytosis and lymphomatoid papulosis are mostly spontaneously regressive diseases.Mastocytosis is a clonal myeloproliferative disease; whereas cutaneous forms may regressspontaneously especially in childhood, the disease is chronic among adults. KIT mutations aredifferent between children and adults. We showed in vivo that children with mastocytosis displaydecreased telomerase expression with shorter telomere length. In vitro, using infected cells withdifferent KIT mutants, "paediatric" or "adult " one, we found longer telomere among adult mutant withdecreased senescence compared to paediatric mutant, without significant differences of telomeraseexpression and activity. These observations could explain the regression in paediatric mastocytosis.Lymphomatoid papulosis is a primary cutaneous CD30+ T-cell lymphoproliferative disorder.Cutaneous lesions are spontaneously regressive but association with a T-cell lymphoma is observed in10 to 20% of cases. We studied PDGFRβ expression to explain proliferative phase and telomerebiology to understand the regressive phase of the disease. Our result showed that PDGFRβ expressionin CD30+ cells was associated to short telomeres. In conclusion, we showed for the first time thattelomere length in mastocytosis and lymphomatoid papulosis seemed to be correlated with diseaseoutcome; on the other hand, we identify a mutation potentially aggressive. Taken together, werecommend to systematically look for KIT mutation among each patient with mastocytosis in order tocarefully monitor them when the cutaneous lesions are persistent and/or progressive.