Tierärztl. Hochsch., Diss., 2004--Hannover.

Proefschrift Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Orientador: Luiz Carlos Spolidorio / Banca: Helio Massaiochi Tanimoto / Banca: Silvana Regina Perez Orrico / Resumo: O objetivo do presente trabalho foi validar as alterações teciduais e moleculares durante os estágios iniciais do processo de carcinogênese oral experimental em ratos, utilizando-se 4-NQO. Foram utilizados 20 ratos com aproximadamente 4 meses de idade, aleatoriamente separados em grupos controle (n=10) e tratados com solução de 50 ppm de 4-NQO dissolvido na água de beber (n=10). Os animais do grupo controle foram sacrificados no primeiro dia do experimento e os animais do grupo experimental foram sacrificados após 8 e 12 semanas de tratamento. Os cortes histológicos provenientes da língua foram corados por H&E ou submetidas à reação de imunohistoquímica para detecção de PCNA, Bcl-2, SOCS1 e -3 , e STAT3. Parte dos espécimes foi utilizada para a verificação da expressão de Vimentina, Cdh1, Cdh2 e TWIST1 por RT-qPCR. Os resultados demonstraram que o tratamento com 4-NQO após 8 semanas causou displasia epitelial severa e que houve exacerbação da atipia celular após 12 semanas de tratamento. A positividade dos anticorpos analisados, com exceção do STAT3, foi aumentada em ambos os períodos experimentais. Os resultados do presente estudo apontam que tratamento com 4-NQO por 8 ou 12 semanas viabiliza avaliar as displasias epiteliais experimentais tanto a nível morfológico quanto molecular. / Abstract: The aim of this study was to validate the tissue and molecular changes during the early stages of experimental oral carcinogenesis in rats, using 4-NQO. Were used 20 rats with approximately 4 months of age, randomly divided into control group (n = 10) and treated with 50 ppm of 4- NQO solution dissolved in drinking water (n = 10). The control group animals were sacrificed on the first day of the experiment and the experimental rats were sacrificed after 8 and 12 weeks of treatment. Histological sections from the tongue were stained with H&E or subjected to immunohistochemistry analysis for detection of PCNA, Bcl - 2, SOCS1 and -3, and STAT3. Part of the specimens was used to verify the expression of vimentin, Cdh1, Cdh2 and TWIST1 by RT - qPCR. The results showed that treatment with 4-NQO after 8 weeks caused severe dysplasia and cellular atypia was exacerbation after 12 weeks of treatment. The positivity of antibodies analyzed, with the exception of STAT3 was increased in both experimental periods. The results of this study indicate that treatment with 4-NQO for 8 or 12 weeks enables evaluating experimental epithelial dysplasias both morphological as molecular level. / Mestre

No description available.

GABA (gamma-amino butanoic acid) is the main inhibitory neurotransmitter in the mammalian central nervous system. GABA has been found to play an inhibitory role in some cancers, including colon carcinoma, cholangiocarcinoma, and lung adenocarcinoma. Growing evidence shows that GABAB receptors are involved in tumour development. The expression level of GABAB receptors was found to be upregulated in some human tumours, including the pancreas, and cancer cell lines, suggesting that GABAB receptors may be potential targets for cancer therapy and diagnosis. In this research programme, several diverse series of potential anticancer prodrugs of GABA and GABA receptor-targeting agents have been rationally designed and synthesised for selective activation in the tumour microenvironment. In one approach, a series of oligopeptide conjugate prodrugs have been synthesised as protease-activatable substrates for either the extracellular matrix metalloproteinase MMP-9 or the lysosomal endoprotease legumain; each of which are overexpressed in the tumour environment and are effectors of tumour growth and metastasis. Specifically, a novel fluorogenic, oligopeptide FRET substrate prodrug of legumain HZ101 (Rho-Pro-Ala-Asn~GABA-spacer-AQ) has been characterised and shown to have theranostic potential. Proof of principle has been demonstrated using recombinant human legumain for which HZ101 is an efficient substrate and is latently quenched until cleaved. HPLC methods have been developed to monitor prodrug activation. In another approach, cyclic prodrugs of the GABA-B receptor agonist baclofen have been designed to be activated in the acidic environment of solid tumours to exert antitumour effects through modulation of the receptor response. During the oligopeptide synthetic work, novel, coloured, anthraquinone-based reagents have been designed and evaluated as new chemical tools for amine detection and monitoring in solid phase peptide synthesis (SPPS); characterisation by spectroscopic and HPLC methods have demonstrated their advantages over existing methods and their potential applications for use on solid supported resins.

Submitted by Hiolanda Rêgo (hiolandarego@gmail.com) on 2016-08-18T14:47:42Z No. of bitstreams: 1 Tese_ODONTO_Leonardo de Araújo Melo.pdf: 1484624 bytes, checksum: f3ede85bed6a663ebad60c8f5126c11a (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2016-08-23T14:40:44Z (GMT) No. of bitstreams: 1 Tese_ODONTO_Leonardo de Araújo Melo.pdf: 1484624 bytes, checksum: f3ede85bed6a663ebad60c8f5126c11a (MD5) / Made available in DSpace on 2016-08-23T14:40:44Z (GMT). No. of bitstreams: 1 Tese_ODONTO_Leonardo de Araújo Melo.pdf: 1484624 bytes, checksum: f3ede85bed6a663ebad60c8f5126c11a (MD5) / Stat3 é um fator de transcrição que está envolvido em diversos processos fisiológicos incluindo proliferação e sobrevivência celular. Expressão elevada da Stat3 tem sido encontrada em diversos tipos de neoplasias de mama, pulmão, próstata, esófago, fígado e ovário. O objetivo deste estudo foi investigar a expressão da Stat3 em uma série de tumores odontogênicos para adicionar mais informações ao conhecimento do perfil biológico deste grupo de neoplasias. Para isto, nós quantificamos a expressão do gene Stat3 por qPCR em 30 amostras de tumores odontogênicos sendo 23 casos de tumor odontogênico queratocístico (TOQ) e 7 casos de ameloblastoma (AB) e comparamos esta expressão com a mucosa bucal não-neoplásica. Nós também mensuramos a expressão da proteína Stat3 por imuno-histoquímica em 43 casos de TOQ e 47 casos de AB. Transcritos de Stat3 foram encontrados em 96,6% dos tumores estudados, no entanto este gene foi subexpresso nos TOQ e AB comparado a amostra bucal não-neoplásica. TOQs esporádicos apresentaram maiores níveis de transcritos de Stat3 em relação aos TOQs sindrômicos (p=0,04). Não foi observada diferença na expressão do gene Stat3 entre TOQ e AB (p=0,88). Na imunomarcação da Stat3, não foi observada diferença estatística na proporção de células positivas, intensidade de marcação e escore final entre os TOQs esporádicos e associados a SCBCN (p=0,31; p=0,39; p=0,65, respectivamente), bem como não foi observada diferença entre ABs sólidos e unicísticos (p=0,35; p=0,13; p=0,37, respectivamente). ABs apresentaram uma significativa maior imunomarcação da Stat3 em relação aos TOQs (p=0,03). Foi evidenciado que os TOQs com inflamação tiveram uma maior proporção de células marcadas pela Stat3 (p=0,001). Em TOQs e ABs, a marcação da Stat3 foi predominantemente citoplasmática não sendo observada diferença na localização celular da Stat3 entre estes tumores (p-0,58). Nossos achados mostraram uma baixa expressão de Stat3 nos TOQs e ABs. No entanto, foi observada uma maior imunomarcação da Stat3 nos ABs em comparação aos TOQs demonstrando que Stat3 pode contribuir no comportamento mais agressivo dos ABs. A presença de inflamação parece ter influenciado numa maior imunomarcação da Stat3 nos TOQs.

Primary cardiac neoplasms (PCNs) represent the rarest form of neoplastic growths worldwide with an incidence ranging from 0.001 - 0.3% in autopsy series (Yu et al., 2014) ("Primary Cardiac Neoplasms," 2014). The rarity of these tumors has contributed to the challenges associated with their diagnosis and treatment ("Primary Cardiac Neoplasms," 2014). Primary heart tumors are generally classified as benign or malignant based on whether or not the tumors cells invade their surrounding tissue. Primary benign heart tumors can be further sub-classified as non-complicated or complicated. Non-complicated tumors are those that are stable, occur alone, and do not invade the cardiac conduction system. Conversely, complicated primary benign cardiac neoplasms are those that tend to break off into systemic circulation increasing the risk for embolization, have multicentered origins within the heart and/ or invade the cardiac conduction system which may lead to heart block and sudden death ("Cardiac Tumors: Merck Manual Professional," n.d.). These distinctions have been shown to significantly impact the efficacy of treatment. Primary tumors in general tend to involve either the myocardium, i.e. the heart muscle itself, or the endocardium; i.e. the membrane that lines the heart cavities. In either case, the tumors most often appear in the left atrium (Roberts, 2001). Among primary cardiac neoplasms, myxomas (a type of non-cancerous heart tumor) are the most common accounting for approximately 40-50% of these growths ("Primary Cardiac Neoplasms," 2014). Clinicians tend to rely heavily on imaging procedures for the diagnosis of primary heart tumors because there are no characteristic clinical signs exclusive to primary cardiac neoplasms (Bartoloni & Pucci, 2013). Further, these growths have a tendency to mimic the symptomology of other better known conditions such as heart failure, stroke, and coronary artery disease ("Cardiac Tumors: Merck Manual Professional," n.d.). The mean age of diagnosis for these tumors is approximately 50 years of age but many PCNs have been identified in children (Bartoloni & Pucci, 2013; "Primary Cardiac Neoplasms," 2014). Further, sources disagree on the relative incidence of these neoplasms among men and women. Some report a higher prevalence in women while others hold that the frequencies are equal for both sexes and across all races (Bartoloni & Pucci, 2013; "Primary Cardiac Neoplasms," 2014). The standard of care for the treatment of primary cardiac neoplasms are; as with other neoplastic conditions; radiation therapy, chemotherapy, surgical resection, and; in some instances; cardiac transplantation. However, due to the differences in tumor histology, i.e. the structure and molecular characteristics of tumor cells, many of the current treatment options available to and considered curative in patients with non-complicated benign PCNs do not confer the same survival benefits in patients with complicated benign PCNs nor in patients with malignant PCNs. With treatment, the prognosis associated with primary cardiac neoplasms is heavily dependent upon the type of tumor. Primary benign non-complicated neoplasms tend to have very positive prognoses. Even with incomplete resection, reports have shown no evidence of recurrence in patients with this tumor type (Jr et al., 1987). On the other hand, primary malignant neoplasms of the heart are associated with the poorest prognoses. The longest reported median survival time is only 16.5 - 17 months after diagnosis and surgical excision of the primary tumor (Chahinian, Gutstein, & Fuster, 2000; Ostrowski, Marcinkiewicz, Kooemider, & Jaszewski, 2014; Simpson et al., 2008). In this thesis we examine the reported outcomes of the above four forms of treatment that are regarded as the standard of care for primary cardiac neoplasms. We do this by reviewing the currently available literature characterizing the results of these respective courses of therapy. We then evaluate the efficacy of these treatments relative the definition of effective treatments developed herein. Finally, based on the evidence, we conclude that effective treatments do exist for approximately 38% of people with PCNs. This minority represents the people with primary benign non-complicated cardiac neoplasms. We also regrettably conclude that for the other 62% (37% with benign complicated cardiac neoplasms and 25% with malignant cardiac neoplasms) of people with primary cardiac tumors effective treatments do not exist. For this reason, we propose the further investigation of two promising therapies. These are cardiac autotransplantation and targeted gene therapy. We believe that elucidating the possible advantages of these therapies in the heart will lead to treatments that can be deemed effective in treating complicated primary benign cardiac neoplasms as well as primary malignant cardiac neoplasms.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Biotecnologia e Biociências, Florianópolis, 2011 / Made available in DSpace on 2012-10-26T01:26:49Z (GMT). No. of bitstreams: 1 295025.pdf: 2894933 bytes, checksum: 67593ffc68e4727beec377fc206b3a35 (MD5)

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Medicina, 2007. / Submitted by Luis Felipe Souza (luis_felas@globo.com) on 2009-01-07T12:27:13Z No. of bitstreams: 1 Dissertacao_2007_GustavoTakano.pdf: 1537047 bytes, checksum: 3781d8b3c88622c41722e039be32970e (MD5) / Approved for entry into archive by Georgia Fernandes(georgia@bce.unb.br) on 2009-02-27T15:33:14Z (GMT) No. of bitstreams: 1 Dissertacao_2007_GustavoTakano.pdf: 1537047 bytes, checksum: 3781d8b3c88622c41722e039be32970e (MD5) / Made available in DSpace on 2009-02-27T15:33:14Z (GMT). No. of bitstreams: 1 Dissertacao_2007_GustavoTakano.pdf: 1537047 bytes, checksum: 3781d8b3c88622c41722e039be32970e (MD5) / Os tumores neuroendócrinos são um conjunto de neoplasias agrupadas por características morfofuncionais em comum porém de grande variabilidade de sítios de acometimento, histogênese, apresentação clínica e prognóstico. O presente estudo afere o perfil de imunomarcação, com o objetivo de caracterização da histogênese e correlação com fatores determinantes de seu comportamento biológico. Foram selecionados 20 casos de peças cirúrgicas com o diagnóstico histopatológico de neoplasias neuroendócrinas. Reações imunoistoquímicas com anticorpos específicos para identificar as proteínas Sinaptofisina, Cromogranina, Ki67, p53, c- kit, VEGF, e- caderina, 34βE12, CD99, e S100 foram empregadas. A expressão foi medida em escalas em dois e quatro níveis, e suas frequências foram comparadas às médias ou freqüências das demais variáveis do estudo – idade, sexo, localização tumoral, classificação conforme a OMS, e classificação em dois níveis prognósticos. A avaliação dos resultados demonstra que para a Cromogranina a imunoexpressão moderada a forte foi observada em 95% dos casos, enquanto que CD99 e 34βE12 foi observada em apenas em 5% dos casos. A marcação do ki67 foi mais intensa nos tumores malignos. A expressão da proteína E-caderina foi mais frequentemente observada nas neoplasias não pertencentes aos tratos digestório e respiratório. Os tumores neuroendócrinos do aparelho digestório apresentam, respectivamente, pouca expressão para a proteína S100 e elevada expressão para Sinaptofisina. As demais variáveis não mostraram diferenças estatisticamente significativas. Estes resultados estabelecem correlação com a histogênese. Verifica-se aparente especificidade das neoplasias com a Cromogranina, e Sinaptofisina, e ki-67, além da inespecificidade para 34βE12. Verifica-se ainda que algumas destas proteínas são mais observadas em tumores de sítios específicos, como S100, e a E-caderina. VEGF, CD99, p53 e c-kit são expressos em pequenos subconjuntos destes tumores, não correlatos às variáveis estudadas. _____________________________________________________________________________________ ABSTRACT / Neuroendocrine tumours are a group of neoplasias that share morfofuncional characteristics but have a great variety of location, histogenesis, clinical presentation and prognosis. This study tests the immunohistochemistry profile of immunostaining to determine histogenetic characteristics and correlations with biological behavior determining factors. Twenty retrospective neuroendocrine tumors cases were selected and submitted to immunohistochemistry reaction with specific antibodies against synaptophysin, chromogranin, Ki67, p53, c- kit, VEGF, E-cadherin, 34βE12, CD99, e S-100. The immunoreactivity was scaled into a two and four-levels scale, and its frequencies were compared to the other variables – age, sex, location, classification according to WHO and classification in two prognostic levels. Chromogranin was the most frequent marker, with moderate to strong immunoexpression in 95% of the cases, and the least frequent markers were CD99 and 34βE12, in 5%. Ki67 reaction was stronger in malignant tumors. E-cadherin was more frequently observed in tumours outside digestive and respiratory sites. The neuroendocrine tumours of the digestive tract had, respectively, S100 low expression and synaptophysin high expression. All the other variables tested were not statistically significant. This results made a histogenetic correlation. There is apparently specificity with chromogranin, synaptophysin and ki-67, and there is not with 34βE12. Some of this proteins are more frequent in specifical sites, as S100 and E-cadherin. VEGF, CD99, p53 and c-kit are expressed in small and not correlated to the studied variables subgroups of tumours.

Submitted by Programa de Pós-Graduação em Odontologia Saúde (mestrodo@ufba.br) on 2017-04-03T14:12:58Z No. of bitstreams: 1 PDF Final.pdf: 4765427 bytes, checksum: ae3f93ce46ff32b7ce466869740090de (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2017-06-29T14:28:32Z (GMT) No. of bitstreams: 1 PDF Final.pdf: 4765427 bytes, checksum: ae3f93ce46ff32b7ce466869740090de (MD5) / Made available in DSpace on 2017-06-29T14:28:32Z (GMT). No. of bitstreams: 1 PDF Final.pdf: 4765427 bytes, checksum: ae3f93ce46ff32b7ce466869740090de (MD5) / FAPESB / O presente trabalho teve como objetivo estudar, por meio da imunohistoquímica, a participação de componentes celulares estromais a exemplo dos mastócitos (mast cell triptase), miofibroblastos (alfa-SMA) e macrófagos (CD163) e componentes vasculares (CD34 e D2-40) em uma série de tumores odontogênicos queratocísticos (TOQ), na tentativa de fornecer subsídios para compreender a interação entre esses componentes e o comportamento biológico distinto desta lesão. Para fins comparativos, cistos radiculares (CRs) e folículos pericoronários (FPs) também foram incluídos. A amostra foi composta por 30 TOQs, 15 CRs e 07 FPs. Para a avaliação dos mastócitos, miofibroblastos e macrófagos, foram quantificadas as células imunorreativas aos marcadores mast cell triptase, alfa-SMA e CD163, respectivamente, em 10 campos (400x). Os índices angiogênico e linfangiogênico foram avaliados por meio da densidade microvascular (MVD) e densidade microvascular linfática (MVDL) dos microvasos marcados, respectivamente, pelos marcadores CD34 e D2- 40. Foi utilizado o teste ANOVA com pós-teste de correção de Tukey, para análise estatística entre os marcadores segundo o tipo de lesão. Para a análise da correlação entre os marcadores dentro da mesma lesão, utilizamos a correlação de Pearson. Para a associação, no TOQ, entre os marcadores e a presença de inflamação, utilizamos o Teste T de Student. A análise da expressão do marcador mast cell triptase revelou existir diferenças significativas (p<0,05) entre a densidade de células mastocitárias presentes nos CRs (22,7) em relação aos FPs (1,23) e TOQs (7,39), e entre a densidade de mastócitos presentes no TOQs e FPs. Houve também diferença significativa (P<0,05) entre a densidade de miofibroblastos em TOQs (29,25) em relação aos CRs (4,66) e os FPs (1,50). A diferença da densidade de miofibroblastos entre os CRs e FPs não foi significativa (p>0,05). A respeito dos macrófagos, não houve diferenças significativas (p= 0,084) entre as densidades de macrófagos presentes nos TOQs (2,31), CRs (1,42) e FPs (0,14). Na avaliação do índice angiogênico, não houve diferenças significativas da MVD entre as três lesões estudadas. No entanto, para o índice linfangiogênico, houve diferença significativa (p<0,05) entre a MVDL presentes nos TOQs (11,64) em relação aos CRs (4,19) e aos FPs (0,167). A diferença entre a MVDL dos CRs em relação aos FPs não foi estatisticamente significante (p>0,05). Não foi encontrada associação significativa (p>0,05) entre os marcadores estudados com a presença de inflamação no TOQ. No presente trabalho, encontramos uma correlação positiva e moderada entre os marcadores mast cell triptase e o CD34 nos TOQ (p = 0,025). Já nos CRs encontramos uma correlação inversa e moderada entre os marcadores SMA x CD34 (p = 0,017). Nos FPs também encontramos uma correlação inversa entre os mesmos marcadores anteriores, porém forte (p=0,049). Embora os componentes celulares estromais e microvasculares aqui representados por mastócitos, miofibroblastos, macrófagos CD163 positivos e vasos CD34 e D240, respectivamente, sejam importantes para manutenção do arcabouço estrutural do TOQ e CR, existiu uma interação significante entre mast cell triptase e CD34 no TOQ e entre CD34 e o alfa –SMA no CR. / The present study aimed to investigate, by immunohistochemistry, the participation of stromal cell components such mast cell (mast cell tryptase), myofibroblasts (alpha- SMA) and macrophages (CD163) and vascular components (CD34 and D2-40) in a series of keratocysts odontogenic tumors (OKT) in an attempt to provide information to understand the interaction between these components and the biological behavior of this lesion. For comparative purposes, radicular cysts (RCs) and pericoronal follicles (PFs) were also included. The sample comprised 30 OKTs, 15 RCs and 07 PFs. For the evaluation of mast cells, myofibroblasts and macrophages, the cells immunoreactive with biomarkers mast cell tryptase, alpha- SMA and CD163 were quantified, respectively, in 10 fields (400x). The angiogenic and lymphangiogenic index were assessed by microvessel density (MVD) and lymphatic microvessel density (MVDL) of microvessels marked respectively by for CD34 and D2-40. ANOVA with post-test Tukey correction for statistical analysis between markers was used according to the type of injury. To analyze the correlation between markers within the same lesion, we used the Pearson correlation. For the association, the OKT between markers and the presence of inflammation, we used the Student's t test. The analysis of expression of mast cell tryptase shows any significant differences (p < 0.05) between the density of mast cells present in RCs (22.7) than FPs (1.23) and TOQs (7.39) and the density of mast cells present in TOQs and FPs. There was also a significant difference (P < 0.05) between the density of myofibroblasts in TOQs (29.25) compared to CRs (4.66) and FPs (1.50). The difference in density between the RCs of myofibroblasts and PFs was not significant (p> 0.05). With respect to macrophages, no significant differences (p = 0.084) between the densities of macrophages present in TOQs (2.31), CR (1.42) and FPs (0.14). With respect to the angiogenic index, there were no significant differences in MVD between the three lesions studied. However, for the lymphangiogenic index, a significant difference (p < 0.05) between MVDL present in TOQs (11.64) compared to CRs (4.19) and FPs (0.167). The difference between MVDL of CRs compared to FPs was not statistically significant (p > 0.05). No significant association (p > 0.05) between the biomarkers studied in the presence of inflammation in the OKT was found. In the present study, we found a moderate positive correlation between mast cell tryptase and CD34 markers in OKT (p = 0.025). Have the CR and found an inverse correlation between moderate SMA x CD34 (p = 0.017). In PFs also found an inverse correlation between the SMA x CD34, but strong (p = 0.049). Although stromal microvascular and cellular components represented here by mast cells, myofibroblasts, and CD163 positive macrophages and vessels CD34 and D240 are important for maintaining the structural framework of the OKT and RC, a significant interaction between mast cell tryptase x CD34 existed in OKT and between CD34 x alpha- SMA in RC.