A TFD é considerada uma nova terapia minimamente invasiva destinada ao tratamento e destruição seletiva de diversos tipos de cânceres. Objetivo foi avaliar se os efeitos do azul de metileno fotoativado podem desencadear processos inflamatórios interferindo no desenvolvimento e na progressão tumoral. Os resultados demonstraram que o grupo tratado com 0.1% de azul de metileno+1J provocou um aumento estatísticamente significativo quando comparado em relação aos diferentes grupos tratados nos níveis e na expressão gênica dos diferentes marcadores inflamatórios, na geração EROS e MPO. Análise histológica complementou com os resultados anteriores, indicando que neste grupo há alterações morfológicas representadas por áreas de necrose na massa tumoral sólida com presença neutrofílica. Concluímos que há indícios que o tratamento 0.1% azul de metileno+ 1J foi capaz de gerar efeitos citotóxicos que por consequência aumentou a expressão dos mediadores inflamatórios promovendo inflamação e finalmente induzindo morte celular. / PDT is considered a new minimally invasive therapy for the treatment and selective destruction of various types of cancers. The objective was to evaluate the effects of methylene blue light activated may trigger inflammatory processes interfering with the development and tumor progression. The results showed that the group treated with 0.1 % methylene blue +1 J caused a statistically significant increase levels and gene expression of different inflammatory markers in ROS generation and MPO when compared at the different treat groups. Histological analysis complemented with previous results, indicating that there are morphological changes represented by areas of necrosis in the solid tumor mass with neutrophil presence in this group. We conclude that there is evidence that treatment 0.1 % methylene blue + 1J was able to generate cytotoxic effects therefore increased expression of inflammatory mediators, promoting inflammation and finally inducing cell death.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / IntroduÃÃo: As drogas quimioterÃpicas convencionais nÃo tÃm obtido sucesso no tratamento do cÃncer gÃstrico. O paclitaxel (TaxolÂ) mostrou ser efetivo no tratamento dos cÃnceres de ovÃrio, mama e pulmÃo. O 5-fluorouracil (5-FU) tem apresentado resultados promissores no tratamento do cÃncer de cÃlon. O Ãcido folÃnico (LeucovorinÂ) potencializa a citotoxicidade do 5-fluorouracil. Estudos desen-volvidos no JapÃo, Estados Unidos e Europa vÃm sugerindo o uso de quimioterapia associada à hiper-termia no controle da doenÃa localmente avanÃada. Objetivos: Avaliar a influÃncia do paclitaxel, 5-fluorouracil e 5-fluorouracil mais Ãcido folÃnico, isolados e associados à hipertermia, na sobrevida de ratos com tumor de Walker 256 implantados no estÃmago, e observar o comportamento do tumor de Walker 256 original implantado em estÃmagos de rato sem tratamento e submetidos aos tratamentos quimioterÃpicos propostos, associados à hipertermia. MÃtodos: Implantou-se o tumor de Walker 256 na mucosa gÃstrica de rato no 3o, 7o, e 10o dias de inoculaÃÃo do tumor. Os animais foram tratados com paclitaxel, 5-fluorouracil e 5-fluorouracil mais Ãcido folÃnico, isolados e associados à hipertermia. Foram administrados paclitaxel na dose de 25 mg/m2, 5-fluorouracil na dose de 130 mg/m2 e Ãcido folÃnico na dose de 7 mg/m2. A Hipertermia de Corpo Inteiro foi iniciada 2 horas apÃs a administraÃÃo dos quimioterÃpicos, tendo duraÃÃo de 1 hora. Resultados: Os animais inoculados com tumor apresentaram uma sobrevida de 13,25  0,53. Os animais tratados com Paclitaxel isolado apresentaram sobrevida de 28,61  0,82; 20,92  1,77 e 20,07  0,60 no 3o, 7o e 10o dias, respectivamente, e aqueles trata-dos com Paclitaxel + hipertermia apresentaram sobrevida de 19,17  1,20; 22,54  1,47 e 17,92  1,06 nos mesmos perÃodos. Os animais tratados com 5-fluorouracil isolado apresentaram sobrevida de 16,16  0,52; 15,57  0,57 e 17,94  0,46 no 3o, 7o e 10o dias, respectivamente, e aqueles tratados com 5-fluorouracil + hipertermia apresentaram sobrevida de 14,45  0,36; 16,36  0,81 e 18,37  1,86 nos mesmos perÃodos. Os animais tratados com 5-fluorouracil + Ãcido folÃnico apresentaram sobrevida de 14,89  0,71; 16,56  0,91 e 16,11  0,67 no 3o, 7o e 10o dias, respectivamente, e aqueles tratados com 5-fluorouracil + Ãcido folÃnico + hipertermia apresentaram sobrevida de 17,60  1,22; Â15,42  0,31 e 15,45  0,39 nos mesmos perÃodos. ConclusÃes: O tumor experimental de Walker 256 à um tumor de pequenas cÃlulas. A hipertermia associada à quimioterapia, com paclitaxel, 5-fluorouracil, 5-fluorouracil mais Ãcido folÃnico como tratamento do tumor de Walker experimental implantado nos estÃmagos de rato Wistar, nÃo melhorou a sobrevida. / Introduction: The conventional chemotherapy drugs have not obtained success on the treatment of gastric cancer. The paclitaxel (TaxolÂ) showed to be effective on treating lung, breast and ovarian cancer. The 5-fluorouracil (5-FU) has shown promising results on the treatment of colon cancer. The folinic acid (LeucovorinÂ) reinforces the 5-FU cytotoxicity. Studies developed in Japan, United States and Europe suggest the use of chemotherapy associated with hyperthermia on the control of locally advanced disease. Objectives: Evaluate the influence of paclitaxel, 5-fluorouracil and 5-fluorouracil plus folinic acid, isolated and associated with hyperthermia, on the survival of rats with Walker 256 tumor implanted on their stomach, and observe the behavior of the original Walker 256 tumor implanted in the stomach of rats with no treatment and with the proposed chemotherapy treatments associated with hyperthermia. Methods: The Walker 256 tu-mor was implanted on the mucous layer of the rat stomach on the 3rd, 7th and 10th day after inoculation. The animals were treated with paclitaxel, 5-fluorouracil and 5-fluorourcil plus folinic acid isolated and associated with hyperthermia. Paclitaxel 25 mg/m2, 5-fluorouracil 130 mg/m2 and folinic acid 7 mg/m2 were used. The Whole-Body Hyperthermia was initiated 2 hours after the administration of the chemotherapic drugs, with 1 hour of duration. Results: The animals in-oculated with tumor showed a survival of 13.25  0.53. The animals treated with Paclitaxel isolated showed a survival of 28.61  0.82; 20.92  1.77 and 20.07  0.60 in the 3rd, 7th and 10th days, respectively, and those treated with Paclitaxel + hyperthermia showed a survival of 19.17  1.20; 22.54  1.47 and 17.92  1.06 in the same periods. The animals treated with 5-fluorouracil isolated showed a survival of 16.16  0.52; 15.57  0.57 and 17.94  0.46 in the 3rd, 7th and 10th days, respectively, and those treated with 5-fluorouracil + hyperthermia showed a survival of 14.45  0.36; 16.36  0.81 and 18.37  1.86 in the same periods. The animals treated with 5-fluorouracil + folinic acid showed a survival of 14.89  0.71; 16.56  0.91 and 16.11  0.67 in the 3rd, 7th and 10th days, respectively, and those treated with 5-fluorouracil + folinic acid + hyperthermia showed a survival of 17.60  1.22; 15.42  0.31 and 15.45  0.39 in the same periods. Conclusions: The Walker 256 is a small cell tumor. The hyperthermia associated with chemotherapy using pacli-taxel, 5-fluorouracil and 5-fluorouracil plus folinic acid as treatment of Walker experimental tu-mor implanted in Wistar rat stomachs do not improved the survival.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O cÃncer de pulmÃo tem sido, na Ãltima dÃcada, a principal causa de morte por cÃncer no mundo, apesar do surgimento de novos quimioterÃpicos e das terapias alvo-direcionadas. Por isso, faz-se necessÃrio o entendimento das alteraÃÃes moleculares e biolÃgicas envolvidas nos processos de carcinogÃnese e crescimento tumoral, bem como o desenvolvimento de modelos experimentais adequados que permitam estudar o comportamento biolÃgico dos tumores de pulmÃo e o efeito de drogas antineoplÃsicas. O objetivo desse estudo foi desenvolver um modelo de tumor no pulmÃo em ratos imunocompetentes de execuÃÃo simples e fÃcil reprodutibilidade, e avaliar a atividade de drogas antitumorais. Cento e noventa e um ratos Wistar fÃmeas, peso mÃdio de 199Â23g, foram distribuÃdos ao acaso em trÃs etapas experimentais. Todos os animais foram anestesiados com tribromoetanol 2,5% (1 ml/100g de rato) intraperitonial (ip), traqueostomizados e intubados com cateter de polietileno 16G, seguindo-o por via intrabrÃnquica (ib) atà as porÃÃes inferiores do pulmÃo para inocular cÃlulas do tumor 256 de Walker. A 1a etapa (n=32) foi feita para estabelecer a tÃcnica do implante de cÃlulas por via ib e o Ãndice de pega tumoral, inoculando-se de 105 a 5Ã105 cÃlulas. A 2a etapa (n=16) para avaliar o volume tumoral no 5o dia do implante de 4Ã105 cÃlulas e correlacionar os achados da tomografia computadorizada de alta resoluÃÃo (TCAR) de tÃrax com os da necropsia. A 3a etapa (n=143) para a avaliar o efeito de drogas e validar o modelo, sendo dividida em duas fases. A 1a fase (n=72) para avaliar o volume tumoral no 5o ou 6o dia do implante de 4Ã105 cÃlulas do tumor, composta de cinco grupos: Grupo controle (Gc), NaCl 0,9% (1ml/gavagem); Grupo celecoxib (Gclx), 15, 30 e 60 mg/kg/dia/gavagem; Grupo talidomida (Gtld), 45 mg/kg/d/sc; Grupo gefitinib (Ggfb), 25 mg/kg/dia; Grupo talidominda + gefititinib (Gtld +gfb). A 2a fase (n=71) para avaliar a sobrevida dos animais, com seis grupos: Gc, Gclx (15, 30, 60), Gtld, Ggfb, Gtld + gfb, Grupo paclitaxel (Gpcl), 8 mg/kg ip. O Ãndice geral de pega do tumor com o implante 4Ã105 cÃlulas foi de 96% (149/155), sendo 90% na 1a etapa, 100% na 2a etapa e 96% na 3a etapa. A mortalidade cirÃrgica foi de 4,2% (8/191) e 21 animais foram excluÃdos do estudo por ausÃncia de tumor no pulmÃo, morte por infecÃÃo (abscesso pulmonar) e outras causas nÃo relacionadas com o tumor. Na 2a etapa, as medidas do tumor feitas na TCAR e comparadas com a necropsia foram semelhantes (r=0, 953, p<0,0001). Na 1a fase da 3a etapa, nÃo se observou diferenÃa no volume tumoral dos animais dos grupos tratados em relaÃÃo ao controle; e na 2a fase verificou-se aumento significante da sobrevida mediana dos animais tratados com TLD, GFB e PCL (13, 13 e 29 dias, respectivamente), em relaÃÃo ao controle (11dias), teste de Log Rank: p<0,001. Conclui-se que o modelo de tumor de pulmÃo por implantaÃÃo de cÃlulas tumorais por via intrabrÃnquica mostrou-se viÃvel, com alto Ãndice de pega e mortalidade cirÃrgica desprezÃvel, de execuÃÃo simples e fÃcil reprodutibilidade. A TCAR revelou-se um mÃtodo de imagem de alta acurÃcia no diagnÃstico, localizaÃÃo e mensuraÃÃo das lesÃes tumorais. O modelo mostrou-se eficaz na avaliaÃÃo de atividade antitumoral de drogas antineoplÃsicas como o paclitaxel, antiangiogÃnicas como a talidomida, e inibidores de tirosina quinase do EGFR como o gefitinib. / Lung cancer has been the main cause of death from cancer worldwide over the past decade in spite of the appearance of new chemotherapy drugs and targeted therapies. It is therefore necessary to clarify the molecular and biological changes involved in carcinogenesis and tumor growth and to develop experimental models for the study of the biology of lung tumors and the effects of antineoplastic drugs. The objective of the study was to develop a practical and easily reproducible lung tumor model using immunocompetent rats and to evaluate the activity of antineoplastic drugs. One hundred ninety-one female Wistar rats, with an average weight of 199Â23g, were randomly assigned to one of three experimental groups. All animals were anesthetized intraperitonially (ip) with 2.5% tribromoetanol (1ml/100g live weight), tracheostomized and intubated with a polyethylene catheter (16G) guided intrabronchially (ib) to the bottom of the lung for inoculation with Walker 256 tumor cells. Group 1 (n=32) established the ib cell implant technique and the tumor take rate with inoculation of 105 to 5Ã105 cells. Group 2 (n=16) evaluated tumor volume on the fifth day of implant with 4Ã105 cells and correlated chest findings from high-resolution computerized tomography (HRCT) and necropsy. Group 3 (n=143) evaluated the effect of antineoplastic drugs and validated the model in two stages. Stage 1 (n=72) evaluated tumor volume on the fifth day of implant with 4Ã105 cells, divided into 5 groups: control (CG), 0.9% NaCl (1ml/gavage); celecoxib (Gclx), 15, 30 and 60mg/kg/day/gavage; thalidomide (Gtld), 45mg/kg/d/sc; gefitinib (Ggfb), 25mg/kg/day/gavage; and thalidomide + gefitinib (Gtld + gfb). Stage 2 (n=71) evaluted the survival of the animals divided into six groups: Gc, Gclx, Gtld, Ggfb, Gtld + gfb, and Gpcl (paclitaxel) 8mg/kg ip. The overal take rate for implants of 4Ã105 cells was 96% (149/155), specifically 90% in the first experimental group, 100% in the second and 96% in the third. Surgical mortality was 4.2% (8/191); 21 animals were excluded due to absence of tumor in the lung, death from infection (pulmonary abscess) and other causes not related to the tumor. In Group 2, measures obtained with HRCT and necropsy were similar (r=0, 953, p<0.0001). In the first stage of Group 3 no difference in tumor volume was observed between treated animals and controls; in the second stage median survival time was significantly extended in animals treated with TLD, GFB and PCL (13, 13 and 29 days, respectively) compared to controls (11 days) (Log Rank test: p<0.001). In conclusion, the present lung tumor model with intrabronchial tumor cell implantation was shown to be feasible and was associated with high tumor take rates, minor surgical mortality, simple execution and easy reproducibility. HRCT was found to be a highly accurate method of diagnosis, localization and tumor measurement. The model was efficient in the evaluation of the antitumoral activity of the antineoplastic drug paclitaxel, the antiangiogenic drug thalidomide, and the EGFR tyrosine kinase inhibitor gefitinib, making it a valid model for testing new drugs in lung cancer.

Orientador: Maria Cristina Cintra Gomes Marcondes / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T00:25:10Z (GMT). No. of bitstreams: 1 Tomasin_Rebeka_D.pdf: 4368331 bytes, checksum: 33a1f49902e0d1a423b1a4b7ebe757e9 (MD5) Previous issue date: 2014 / Resumo: Câncer é um nome genérico para um grupo de mais de cem doenças que compartilham algumas características. Talvez a característica mais marcante das neoplasias malignas seja a rápida proliferação de células anormais para além de suas fronteiras usuais, invasão de tecidos adjacentes e finalmente dispersão para órgãos distantes. Anualmente, cerca de oito milhões de pessoas morrem devido ao câncer e outros doze milhões de novos casos são diagnosticados. Dentre os eventos associados à progressão neoplásica, destacam-se as metástases e a caquexia. Metástases são tumores em sítios secundários, sendo responsáveis por cerca de 90% do total de mortes por câncer. Já a caquexia, uma síndrome paraneoplásica, é caracterizada por extensa espoliação de gordura e massa magra, fadiga e alterações metabólicas, prejudicando a qualidade de vida e a sobrevida de cerca de 50-85% dos pacientes, dependendo do tipo de tumor. Com relação às terapias, o grande desafio ainda é combater o tumor sem prejudicar o hospedeiro, o que acredita-se ser possível através de terapias-alvo para genes específicos e/ou tratamentos coadjuvantes, incluindo aqueles que empregam suplementação e/ou drogas derivadas de produtos naturais, que muitas vezes tem menor efeito tóxico ao hospedeiro. Desse modo, este trabalho teve dois objetivos: (1) avaliar a ação da administração oral de Aloe vera e mel sobre o tecido tumoral e o hospedeiro portador de carcinosarcoma de Walker 256; e (2) identificação de genes supressores de metástase através de screen funcional in vivo empregando-se biblioteca de shRNA em modelo de câncer de mama triplo negativo. Em relação ao primeiro objetivo, os resultados sugerem que a associação entre Aloe vera e mel pode modular a proteólise e o estresse oxidativo de maneira diferencial preservando o hospedeiro em detrimento do tecido tumoral. Ainda, o tratamento com Aloe vera e mel parece ser capaz de diminuir a propensão metastática das células tumorais in vivo, através de aumento na expressão de caderina-E e redução na expressão de caderina-N, bem como inibição da angiogênese. Outros experimentos sugerem que os efeitos antitumorais observados in vivo estão, em parte, relacionados à ação imunomodulatória de alguns componentes da Aloe vera. Com relação ao segundo objetivo, foram identificados dezenas de candidatos a genes supressores de metástase. Dentre esses genes, que estão sendo validados, Mnat1, Snd1, Cul5, Gabbr1, Rorb, Adk, Ccnd3, Gdnf, Nr1d1, Ptprs e Ltah4 são os genes-candidatos de maior confiabilidade por cumprirem um ou mais dos seguintes requisitos: (a) diminuição significativa do nível de DNA e RNA em canceres de mama humanos agressivos, sendo assim relacionados à pior prognostico, (b) papel biológico sugestivo, (c) fenótipo marcante durante o screen ou ainda (d) decréscimo significativo na expressão em linhagens de câncer de mama mais agressivas / Abstract: Cancer is a generic name for a group of over a hundred diseases which share some features. The most remarkable feature in cancer disease is the fast proliferation of abnormal cells beyond their usual boundaries, invasion of surrounding tissues and finally spread to distant organs. Every year, cancer is responsible for over eight million deaths and twelve million new cases are diagnosed. Among all the events associated with the neoplastic progression, metastasis and cachexia are major issues. Metastases, which are tumours growing in secondary sites, account for 90% of all cancer deaths. Cachexia, a paraneoplastic syndrome, is characterized by severe fat and lean mass waste, fatigue and metabolic alterations, jeopardizing the quality of life and reducing the survival of about 50-85% of the cancer patients, depending on the tumour type. Regarding to the therapies, the biggest challenge is still fighting the tumour without harming the host, which is believed to be possible by targeted therapies to specific genes and/or adjuvant treatments, including supplementation and drugs derived from natural compounds, which usually have lower side effects in the host. Knowing these points, this work had two aims: (1) evaluate the effects of Aloe vera and honey in both tumour and host tissues in Walker 256-tumour bearing rats; and, (2) identification of metastasis suppressor genes using a functional in vivo shRNA screen in a triple negative breast cancer syngeneic model. Regarding to the first aim, the results suggested that the combination of Aloe vera and honey selectively modulate proteolysis and oxidative stress, damaging the tumour tissue while protected the host. Moreover, the Aloe vera and honey treatment apparently decreases the metastatic potential in vivo, by simultaneous increase in E-cadherin and decrease in N-cadherin expression, while decreased tumour vascularization. Finally, our results suggested the antitumoral effects observed in vivo are, at least partially, related to the immunomodulatory activity of some Aloe vera¿s compounds. Regarding to the second aim, dozens of putative metastasis suppressor genes were identified. High confidence candidates, which would be further analysed are Mnat1, Snd1, Cul5, Gabbr1, Rorb, Adk, Ccnd3, Gdnf, Nr1d1, Ptprs e Ltah4. Their selection was based on meeting the following requirements: (a) significant decrease at DNA or RNA level in highly aggressive human breast cancer carcinomas and thus, worse prognosis, (b) suggestive biological role, (c) occurrence of a remarkable phenotype during the screen, and (d) significant decrease in expression in more aggressive cancer cell lines / Doutorado / Biologia Celular / Doutora em Biologia Celular e Estrutural

Orientadores: Hiroshi Aoyama / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-19T03:25:44Z (GMT). No. of bitstreams: 1 Camargo_CamiladeAndrade_D.pdf: 5871656 bytes, checksum: 08f82cc2064fb3997898335664c62806 (MD5) Previous issue date: 2011 / Resumo: Atualmente o câncer é um problema de saúde pública mundial, em virtude do aumento de sua incidência. A anorexia e a perda de peso involuntária são comuns em pacientes oncológicos. Esta condição, também conhecida como caquexia, afeta a capacidade funcional, a resposta ao tratamento, a qualidade de vida e a sobrevida do paciente. Estima-se que aproximadamente dois milhões de pessoas no mundo morrem anualmente devido às conseqüências da via câncer/caquexia. O modelo estudado neste trabalho é o carcinossarcoma de Walker 256 (W256), que tem como característica principal o desenvolvimento da caquexia nos animais portadores, devido ao seu comportamento biológico agressivo, crescimento invasivo e alto potencial de metástase. Os flavonóides, fitocompostos polifenólicos encontrados em plantas, apresentam diversas atividades biológicas, principalmente, devido as suas propriedades antioxidantes e habilidades em modular diversas enzimas ou receptores celulares. Estes compostos possuem efeitos protetores contra doenças relacionadas ao sistema cardiovascular, certas etiologias de câncer, doenças provocadas pela fotossensibilidade e envelhecimento, dentre outras. A proposta do presente estudo foi avaliar os efeitos dos flavonóides quercetina, narigina, morina e do composto acetoxi DMU (um derivado sintético do resveratrol e do DMU-212), na prevenção/atenuação da caquexia e inibição do crescimento do tumor em ratos portadores de W256, num estudo pré-clínico. Ratos machos sadios foram inoculados subcutaneamente, no flanco direito, com as células tumorais e tratados com diferentes doses dos compostos (10, 25 e 35mg/kg), via intraperitoneal, 5 dias consecutivos por semana, durante 50 dias ou até o óbito. A administração de 10mg/kg de quercetina e de 25mg/kg de narigina, morina e do composto acetoxi DMU inibiram cerca de 50% o crescimento do tumor (ED50) quando comparado com os animais controle inoculados com tumor, sem tratamento (grupo Tumor). A ED50 para os tratamentos com quercetina, narigina, morina e acetoxi DMU foi responsável por um aumento de 30, 70, 60 e 70%, respectivamente, na sobrevida dos ratos tratados (p < 0,05) em contraste aos 100% de mortalidade observada no grupo Tumor. Outra conseqüência da administração da ED50 foi a ocorrência de regressão tumoral em 2, 5, 2 e 3 animais, respectivamente, para os tratamentos com quercetina, narigina, morina e acetoxi DMU (n=10). O tratamento com os compostos também foi eficiente em manter os níveis das citocinas TNF-? e IL-6 (no tecido hepático e tumoral do hospedeiro), mediadores do processo caquético, semelhantes aos encontrados nos ratos controle sem tumor (grupo Controle). Já os ratos do grupo Tumor apresentaram altos níveis destas citocinas, tanto nas amostras de fígado como nas de tumor. Os tratamentos promoveram também um alto potencial anti-angiogênico, mostrado através da diminuição na expressão de VEGF e nas atividades das MMP-2 presentes nas amostras de fígado e tumor. Os níveis de VEGF encontrados nos fígados dos ratos do grupo Tumor foram significantemente maiores que os do grupo Controle. Outro efeito do tratamento com os compostos foi uma diminuição significativa na expressão da proteína tirosina fosfatase de baixa massa molecular (nas amostras de fígado e tumor), que havia sido super-expressa em animais do grupo Tumor. As análises dos pesos dos testículos e órgãos reprodutivos acessórios (epidídimo, vesícula seminal, glândula de coagulação e próstata) foram feitas para os animais tratados com narigina e acetoxi DMU. Os resultados indicaram uma redução significativa nos órgãos dos animais do grupo Tumor em comparação com o grupo Controle. Pelo contrário, o tratamento terapêutico de ratos com tumor com a narigina e o acetoxi DMU se mostrou eficaz em proteger a morfologia destes órgãos e inibir esta redução. De acordo com os resultados obtidos, o melhor tratamento foi obtido com o acetoxi DMU. Os resultados obtidos neste trabalho confirmam o efeito dos flavonóides e de acetoxi DMU em diminuir os sintomas da caquexia no modelo tumoral utilizado para experimentação e em inibir o crescimento tumoral, contribuindo, assim, para uma melhor compreensão da ação in vivo destes compostos, tanto no organismo sadio como na presença do tumor / Abstract: Currently, cancer is a public health problem worldwide in virtue of the increase in incidence. Anorexia and involuntary weight loss are common in cancer patients. This condition, also known as cachexia, affects the functional capacity, response to treatment, quality of life and patient survival. It is estimated that approximately two million people worldwide die annually because of cancer cachexia consequences. In this work the Walker 256 carcinosarcoma (W256) is used as an experimental model to establish cancer cachexia in infected animals. Furthermore, it presents an aggressive biological behavior, local invasive growth and high metastasis potential. Flavonoids are polyphenolic compounds with several biological activities mainly due to its antioxidant properties and ability to modulate several enzymes or cellular receptors. These characteristics are associated with the protective effect attributed to these compounds against cardiovascular system diseases, some causes of cancer, diseases caused by photosensitivity and aging, among other. The aim of this study was to evaluate the effects of the flavonoids quercetin, naringin and morin and the compound acetoxy DMU (a synthetic derivative of resveratrol and DMU-212) in the cachexia prevention/attenuation and inhibition of tumor growth in rats bearing W256, in a preclinical study. Healthy male rats were inoculated with tumor cells and treated with different doses of quercetin, naringin, morin and acetoxy DMU (10, 25 and 35mg/kg) intraperitoneally administered, 5 consecutive times a week, during 50 days or until death. The administration of 10 mg/kg quercetin and 25mg/kg naringin, morin and acetoxy DMU inhibited about 50% of tumor growth (ED50) compared with Tumor group (untreated). The ED50 values for the treatment with quercetin, naringin, morin and acetoxy DMU were responsible for a survival increase about 30, 50, 40 and 60%, respectively, in contrast to 100% mortality observed in the tumor group. Another consequence of the ED50 administration was the tumor regression in 2, 5, 2 and 3 animals, respectively, for treatment with quercetin, naringin, morin and acetoxy DMU (n=10). The effect of treatment with these compounds on cytokines mediators of the cachectic process (in liver and tumor tissue) was efficient in maintaining the TNF-? and IL-6 levels similar to those found in control rats (Control group). Tumor group presented high levels of these cytokines in both liver and tumor samples. The treatments also promoted a high potential anti-angiogenic, shown by the decrease in VEGF expression and MMP-2 activity of liver and tumor samples. The VEGF levels found in Tumor group (liver samples) were significantly higher than the Control group. Another effect of treatment with the compounds was a significant decrease in the low molecular weight protein tyrosine phosphatase expression (in liver and tumor tissue), which had been over-expressed in Tumor group. Analyses of testes and accessory reproductive organs weights (epididymis, seminal vesicle, coagulating gland and prostate) were made for animals treated with narigina and acetoxy DMU. The results indicated a significant reduction in Tumor group organs compared with the Control group. On the other hand, the naringin and acetoxi DMU therapeutic treatments of rats with tumor have been proven effective in protecting the morphology of these organs and inhibiting its reduction. According to the results, the best treatment was obtained with the acetoxy DMU. The results of this work confirm the effect of these flavonoids and acetoxi DMU on reducing the cachexia symptoms and tumor growth inhibition, contributing to a better understanding of the action of these compounds in vivo, both in healthy and in tumor organisms / Doutorado / Bioquimica / Doutor em Biologia Funcional e Molecular

Orientador: Maria Cristina Cintra Gomes Marcondes / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-04T06:14:31Z (GMT). No. of bitstreams: 1 Ventrucci_Gislaine_D.pdf: 735812 bytes, checksum: 9ccc59181ffe68918015bc1467e83a50 (MD5) Previous issue date: 2005 / Resumo: Caquexia, presente na maioria dos hospedeiros com câncer, é um estado caracterizado pela perda involuntária de peso. Pacientes com caquexia apresentam expectativa de vida muito reduzida e menor qualidade de vida. Nos pacientes com câncer-caquexia há intensa mobilização de substratos dos tecidos da carcaça do organismo hospedeiro ocorrendo, preferencialmente, depleção de proteína muscular em função da redução da síntese e/ou aumento da degradação protéica no músculo. Este aumento da taxa de proteólise muscular tem como função prover aminoácidos para síntese de glutamina, bem como para a demanda de síntese das células neoplásicas. Trabalhos da literatura mostram que o desenvolvimento de câncer dá-se de forma mais agressiva e severa quanto mais jovem for o paciente. Pacientes acometidos pelo crescimento de neoplasia maligna concomitante à gravidez sofrem da mesma agressividade desta doença, com um agravante maior tratam se de dois pacientes: mãe e feto. Neste trabalho analisamos os efeitos de uma dieta rica em leucina sobre o metabolismo protéico em animais jovens prenhes portadores ou não do carcinossarcoma de Walker 256. Ratas Wistar foram distribuídas em grupos experimentais de acordo com a inoculação ou não do carcinossarcoma de Walker 256 e submetidas ou não a dieta rica em leucina. Após 20 dias de experimento foi realizado ensaios com o músculo esquelético (gastrocnêmio) a fim de elucidar o mecanismo de catabolismo tecidual que ocorre durante o processo de câncer-caquexia. Os grupos apresentaram aumento da taxa de proteólise muscular e redução da taxa de síntese protéica muscular. Porém, o grupo inoculado com tumor e tratado com dieta rica em leucina apresentou aumento da síntese protéica e menor espoliação de proteína muscular quando comparado com o grupo inoculado com tumor e não tratado com leucina na dieta. A suplementação de leucina na dieta, uma vez que este aminoácido é utilizado como fonte energética pelo músculo esquelético pode prevenir a depleção da carcaça, preservar a massa protéica corpórea e impedir o estado caquético do animal / Doutorado / Fisiologia / Doutor em Biologia Funcional e Molecular

Satellite constellation design has been a well-studied problem since the beginning of the space age. In recent years new concepts and approaches tried to solve it with fewer satellites whilst guaranteeing coverage to the areas of interest, whether globally or regionally. This thesis introduces a novel approach based on the repeating ground track concept. It then links and converts the constellation design problem to a Set Cover problem. Although it is NP-hard, the Greedy Algorithm is capable to approximate the solution in a polynomial time with a logarithm ratio. An application of the non-symmetric strategy is illustrated with in 36 different scenarios, where altitude, sensor swath and time requirement are varied. In addition to that, a comparison with the Walker constellation on 6 scenarios is analyzed and discussed. In most cases the non-symmetric strategy produces constellations with significantly less satellites required. / Satellitkonstellationsdesign har varit ett väl studerat problem sedan början av rymdåldern. Under de senaste åren har nya koncept och tillvägagångssätt försökt lösa det med färre satelliter samtidigt som de garanterar täckning till intresseområdena, globalt eller regionalt. Detta examensarbete introducerar ett nytt tillvägagångssätt baserat på konceptet med återkommande markspår. Den länkar sedan och konverterar konstellationsdesignproblemet till ett Set Cover-problem. Även om problemet är NP-hårt, är den giriga algoritmen kapabel att approximera lösningen under polynomtid med ett logaritmförhållande. En tillämpning av den icke-symmetriska strategin illustreras med i 36 olika scenarier, där höjd, sensorsvep och tidsbehov varieras. Utöver det analyseras och diskuteras en jämförelse med Walker-konstellationen på 6 scenarier. I de allra flesta fall producerar den icke-symmetriska strategin konstellationer med betydligt färre satelliter.

The home should represent safety and security for the person who lives there, and this is an important factor for independence and autonomy in very old age. With aging populations, the needs for long-term care increase, care provided by spouses and/or from the growing home care sector. Injuries among these groups are common. In this study, an ergonomics perspective was applied in the analysis of some basic daily activities performed by old persons and by home care workers, assisting. The postures and movements of home care staff assisting at toilet visits, and transferring persons from wheelchair to toilet, were measured and analysed. Some daily activities related to making food and washing clothes, performed by a group of persons between the age of 75 and 100, were measured and analysed. The task of getting up from the floor – on your own and with the help of a walker equipped with a lifting device – was analysed with the help of older persons and nursing staff. The design was built on the knowledge gained from analysing how older people get up from floor. Requirements for access with a four-wheeled walker in the local built environment were investigated. Observations were made with the help of video recording. Postures were recorded with the CUELA measurement system. The VIDAR ergonomics evaluation instrument was used to register the participants’ experiences of discomfort and pain during getting up from the floor with or without the walker with a lifting device. Structured interviews were used to find out about older peoples’ experience of using the four-wheel walker. It is concluded that ageing at home requires improved architectural and technical bathroom design and improved access in the local built environment. / <p>QC 20140124</p>

A good work environment is important for the individual, for industry and for society. The work environment research has, predominantly, targeted identification of problems and the measurement of the size of these problems. Innovations to reduce the incidence of musculoskeletal disorder, MSD, have been introduced in different branches of industry, but with limited success. Few of the ergonomic innovations developed for the building and construction industry have reached a sufficient level of adoption. Ergonomic innovations in the health care sector are of an incremental character and seem to have similar problems of adoption as the ones in the building and construction industry. Three examples of ergonomic innovation are examined in the thesis: a glue spreader for floor layers a four-wheel walker with a lifting device a sonographer’s scanning support device The studies show that an ergonomic innovation is not adopted for prevention of occupational injury unless the innovation also has other relative advantages apart from the ergonomic ones. For the group who already has sustained an injury, it is enough that the ergonomic problems are solved, while the other, symptom-free group, requires other advantages in order to adopt the innovation; increased production economy seems to be the most prominent potential advantage. / <p>QC 20150114</p>

The thesis investigates the ways in which James Baldwin, Alice Walker and Toni Morrison’s fictional portrayals of forms of love, eroticism and sexuality that are excluded or prohibited by social norms, destabilise heteronormativity as the only legitimate option for non-harmful and pleasurable sensual and sexual expression. It aims to situate Baldwin, Walker and Morrison in a continuum of African American authors, beginning with Harlem Renaissance writer Bruce Nugent – the first African American writer to openly explore the relationship between homosexuality and Blackness – that have examined the intertwining issues of transgressive sexuality and race in increasingly explicit ways. By highlighting the ways in which Baldwin, Walker and Morrison decentre heteronormativity, the project aims to uncover how their novels expose the systems of power and knowledge by which racial forms of oppression are maintained, thereby debunking both the notion of Black “authenticity” and Black sexual stereotypes. Finally, the project hopes to show how the process of “queering” heteronormativity in these ways effectively serves to legitimise all forms of love, eroticism and sexuality that are non-harmful, opening up a new trajectory for contemporary twentieth-century authors who delve into these themes. Theoretical Approach: The thesis will argue for a queer reading of Baldwin, Walker and Morrison’s novels that underscores the writers’ treatment of sexuality as a discursive construct. Specifically, this theoretical perspective looks to their legitimisation of alternative forms of love, eroticism and sexuality that are non-harmful – a process that, in each case, serves to counteract and denaturalise White heteronormativity as the only rightful option for sexual desire and practice. Through this approach, the thesis strives to reveal how by working to legitimise such taboo expressions, these writers deconstruct the idea of the “other” as aberrant, thus calling attention to the specific political and moral systems by which love, eroticism and sexuality are judged in the modern Western world. Chapter Break Down: Chapters one and two of the project situate my argument in the context of critical earlier American writing encompassing canonical fiction, including political protest and African American folklorist novels, political polemics, Puritan captivity narratives, slave narratives, political essays, and experimentalist fiction. Together, these chapters provide a detailed overview of discourses surrounding sexuality, considering what is socially determined to be sexually “perverse” as a shifting concept, the meaning of which changes in tandem with changes in social and historical context. They also extensively analyse Black cultural specificity, examining both the sociological genesis of Black sexual stereotypes that led in part to the justification of the modern slave trade and the subsequent impact of slavery on African American sexual practices. In chapter three, the literary analysis begins with a consideration of the broadened possibilities of sexual acceptability Baldwin puts forth in his anti-protest style of fiction, by examining relationships between characters that do not fit conventional racial or sexual stereotypes, their social contexts, and the narrative perspectives employed by the author. Chapter four examines how Walker’s work carries forward Baldwin’s ideas, by further opening up the spectrum of socially acceptable forms of love, eroticism and sexuality through her presentation of an even wider array of erotically transgressive characters, and her effort to write about them during sustained periods of American conservatism. In chapter five, I examine how Morrison complicates the traditional understanding of what constitutes legitimate sexuality by infusing positive elements into sensual and sexual acts that appear to be nothing other than violent, illegal or psychologically regressive, thereby exposing the impact of social and historical context on the individual, further emphasising the changing and discursive nature of sexuality. The thesis finally argues that Baldwin, Walker and Morrison’s particular depictions of alternative sexuality roll back into a bigger idea of human experience that claims as necessary a re-thinking of social norms based on ethical considerations, rather than arbitrary social codes of morality that lead to both racial and sexual discrimination. Their novels thus ultimately involve us in human issues of justice and responsibility beyond the boundaries of race and sexuality.