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

Breast cancer is the most commonly diagnosed cancer in women. Despite recent advances in screening and early detection, breast cancer continues to result in a high incidence of morbidity and mortality. In its late stage the majority of patients exhibit signs of destructive skeletal metastasis. This complication is promoted by the production of growth factors by tumor cells which can induce tumor cell proliferation via their interaction with their respective receptors to initiate the vicious cycle of bone resorption. Inhibition of growth factors signaling through their receptors can therefore serve as a useful therapeutic approach to block bone metastasis. / The biological characteristics of cancer cells along with the targeting properties of immune system offer a novel approach in the treatment of breast cancer. Directed against HER-2/nue oncogene, the recombinant humanized monoclonal antibody, Trastuzumab (Herceptin), has shown significant clinical benefits for the treatment of HER-2 positive metastatic breast cancer. / In the present study, the effects of Herceptin and its molecular mechanism of action in abrogating the development and progression of osteolytic bone metastasis is investigated in an experimental mouse model of skeletal metastasis using human breast cancer cells BT-474 which are known to express high levels of HER-2. Treatment of BT-474 cells with Herceptin caused a dose dependent decrease in cell proliferation. In in vivo studies BT-474 cells were injected by into the left ventricle of female BALB/c nu/nu mice. Intraperitoneal infusion of Herceptin from the day of tumor cell inoculation or at the time of radiologically detectable skeletal metastasis either slowed the development or prevented the progression of skeletal metastasis as compared to control groups of animals receiving non-specific IgG. Bone histological analysis of long bones showed the ability of Herceptin to reduce the ratio of tumor volume to bone volume as well as mitotic index when Herceptin treatment was initiated from the day of tumor cell inoculation. Immunohistochemical analysis of long bones showed a significantly lower level of activated (phosphorylated) MAPK in bones of Herceptin treated animals. These studies demonstrate the ability of Herceptin to inhibit the development and abrogate the progression of skeletal metastasis associated with breast cancer by blocking the HER-2 mediated signaling pathways.

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A doença de Crohn é uma inflamação crônica do trato gastrointestinal. O tratamento convencional é muitas vezes desapontador. Apesar da variedade de drogas disponíveis para o tratamento da doença inflamatória intestinal, tais como: salicilatos e seus derivados, corticosteróides, antibióticos e imunossupressores, nenhuma destas mostrou ser totalmente eficaz ou definitiva para o tratamento da doença e seus surtos de exacerbação. Pesquisas têm sido desenvolvidas com o objetivo de apresentar drogas mais efetivas. Dentre estas, destacam-se as drogas biológicas. O infliximabe é um anticorpo monoclonal quimérico anti-fator de necrose tumoral alfa e está indicado na doença de Crohn refratária e fistulizante. O objetivo deste estudo visa avaliar prospectivamente os resultados e efeitos colaterais precoces e tardios do uso do anti-TNF alfa no tratamento de 60 doentes com doença de Crohn, no período de julho de 1999 a dezembro de 2005. Os doentes foram tratados com anti-TNF alfa (infliximabe), na dose de 5mg/kg de peso, aplicado por via endovenosa em intervalos de dois meses. A avaliação foi realizada por protocolo clínico que classificava os quesitos: estado geral, sintomas intestinais e doença perianal em melhor, inalterado e pior, e pelo índice de atividade da doença de Cronh. Os doentes tratados com anti-TNF alfa apresentaram mediana de duração da doença de sete anos, variando de um a 28 anos entre a data do início dos sintomas e a data de início da pesquisa. 34 doentes (56,7%) já haviam sido submetidos a uma ou mais operações abdominais e 38 (63,3%) a operações orificiais. O software utilizado para a realização dos cálculos foi o SPSS® 9.0 for Windows, sendo estatisticamente significantes os testes com p<0,05. Foram aplicadas 225 doses de anti-TNF alfa, em média, 3,7 doses por paciente num período de aproximadamente cinco anos, variando de uma a 14 doses. No tratamento inicial 76% dos pacientes responderam a droga. As principais indicações para o emprego do anti-TNF alfa foram a presença de doença perianal em 36 casos (60%) e a intratabilidade clínica em 24 casos (40%). Observou-se que após a primeira dose da medicação, os doentes com mais de dez anos de doença e submetidos à operação abdominal tiveram resultado satisfatório semelhantemente aqueles doentes com menos de cinco anos de doença e não operados com p<0,05. O índice de atividade da doença de Crohn foi em média de 189,7 antes do início do tratamento e na primeira aplicação diminuiu em média para 135,4, e progressivamente ao longo das aplicações (115, 102, 109 e 88,4 até a quinta dose), sendo o resultado estatisticamente significativo. Houve efeito colateral em 40 aplicações (17,8%), sendo os efeitos principais: eritema cutâneo, dispnéia e dor abdominal. O tratamento com anti-fator de necrose tumoral alfa, obedecidas as indicações precisas, associou-se a baixo índice de efeitos colaterais graves tendo apresentado bons resultados na resolução da doença de Crohn perianal, na melhora da sintomatologia intestinal e no estado geral dos pacientes / Crohn´s disease is a chronic inflammatory disorder of the gastrointestinal tract. Conventional treatment is many times disappointing. Besides the great number of available medications to treat inflammatory bowel diseases, such as salicilates and derivatives, corticosteroids, antibiotics and immunosuppressive agents, none of them proved to be totally efficient or the ultimate treatment for inflammatory diseases and their exacerbation. Researches have been carried out to find more effective therapeutic drugs. Among these therapeutics, biologic treatments have been in evidence. Infliximab is a chimeric IgG1 monoclonal antibody against tumor necrosis factor-alpha, and is indicated for refractory luminal and fistulizing Crohns disease. The aim of this study is to prospectively evaluate the outcome, early and late adverse events, in 60 patients diagnosed with Crohn´s disease and treated with infliximab between July 1999 and December 2005. All patients were treated with anti-TNF-alpha (infliximab), 5mg/kg/dose, intravenously, each two months. Patients were clinically evaluated using a protocol that classified the evolution of the health status, intestinal symptoms and perianal disease, as better, worse or unchanged, during the treatment. Crohn´s disease activity index was also evaluated. Patients treated with anti-TNF-alpha presented a median disease duration of seven (range 1-28) years, between the beginning of the disease symptoms and the beginning of the research protocol. Thirty-four patients (56.7%) have been submitted to one or more abdominal surgeries before, and 38 (63.3%) to anal-rectum surgeries. All statistics tests were performed with computer software Statistical Package for the Social Sciences (SPSS® 9.0) for WindowsTM, and p values of less than 0.05 were considered statistically significant. Totals of 225 anti-TNF-alpha doses were administered. The mean doses administered per patient, in a period of approximately five years, were 3.7 (range 1-14) doses. After the initial treatment, 76% of the patients achieved a response. The most frequent indications for anti-TNF-alpha was perianal disease, occurring in 36 patients (60%), and clinical failure to the conventional treatment, happening in 24 patients (40%). After the first dose of anti-TNF-alpha, patients with more than 10 years of treatment and previously submitted to abdominal surgery presented a satisfactory outcome, similar to those with less than 5 years of disease and not submitted to surgery, p<0.05. Crohn´s disease activity index showed a mean index of 189.7 before treatment, that decreased to 135.4 after the first dose, and progressively decreased with the subsequent doses (means: 115, 102, 109 and 88.4, until the fifth dose, p<0.05). Adverse events were reported in 40 administrations (17,8%) from the total. The most prevalent adverse events were: rash, dyspnoea and abdominal pain. The treatment with anti-TNF-alpha, following precise indications, was associated with a low incidence of severe adverse events and presented good outcomes in the resolution of perianal Crohn´s disease, improving intestinal symptomatology and patients´ health status

I established the phage antibody library platform for the identification of specific antibodies. In the first part of my study, I tried to identify antibody against SARS-CoV. Two fragments on the spike protein, which is responsible for inducing viral entry, was chosen as target for the selection of antibody. An antibody was identified which can selectively recognize the SARS-CoV infected cells, but not non-infected cells. Although this antibody was found to retain no neutralizing ability, this specific antibody may have potential to develop for diagnostic purpose. / I utilized the phage system-based cloning method as an attractive approach to screen and identify virus-specific antibodies that can be encoded by the human genome. Once a useful phage clone is identified, unlimited amounts of human monoclonal virus-specific antibodies can be manufactured, and potentially applied clinically for prophylactic and therapeutic uses. The study focuses on two of these new infections, both of which cause severe respiratory disease: SARS and avian influenza. / Identification of specific antibodies, either for diagnostic or therapeutic use, was successfully demonstrated in the two infectious disease models. The phage antibody platform offers a fast and cost-effective method to identify phage antibodies, which can easily be converted to human viral specific monoclonal antibodies for clinical use. / In the 21st century, a number of novel infectious diseases emerged suddenly and spread rapidly, endangering the lives and well-being of people around the world. Severe acute respiratory syndrome (SARS) is a life threatening form of atypical pneumonia that ravaged Hong Kong, Taiwan, China, Canada and many cities in 2003. In the same year, novel avian influenza viruses infected human beings on two continents. Both of these diseases originated in animals and crossed over into the human population. These emerging diseases pose significant public health threats while providing a chilling reminder that another influenza pandemic could occur at any time. Thus, the development of effective therapeutics to control the disease is of paramount importance. Although several vaccines against SARS and avian influenza are available nowadays, the poor clinical performance and frequent mutation of viral strains may limit the practical use and value of the vaccines. Moreover, there are no promising antiviral drugs available for the treatment. Therefore, I aimed to develop an immunotherapy as an alternative treatment option against these diseases. / In the second part of my study, the extracellular domain of matrix protein of avian influenza virus was chosen as target for the selection of antibody. I successfully identified an antibody which can neutralize the avian influenza virus infection. This promising result indicated this antibody has potential to develop for therapeutic use and these antibodies can be easily manufactured in unlimited amounts for clinical application. / Leung, Ka Man. / Adviser: Kwok Pui Fung. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0212. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 112-123). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

A doença de Crohn é uma inflamação crônica do trato gastrointestinal. O tratamento convencional é muitas vezes desapontador. Apesar da variedade de drogas disponíveis para o tratamento da doença inflamatória intestinal, tais como: salicilatos e seus derivados, corticosteróides, antibióticos e imunossupressores, nenhuma destas mostrou ser totalmente eficaz ou definitiva para o tratamento da doença e seus surtos de exacerbação. Pesquisas têm sido desenvolvidas com o objetivo de apresentar drogas mais efetivas. Dentre estas, destacam-se as drogas biológicas. O infliximabe é um anticorpo monoclonal quimérico anti-fator de necrose tumoral alfa e está indicado na doença de Crohn refratária e fistulizante. O objetivo deste estudo visa avaliar prospectivamente os resultados e efeitos colaterais precoces e tardios do uso do anti-TNF alfa no tratamento de 60 doentes com doença de Crohn, no período de julho de 1999 a dezembro de 2005. Os doentes foram tratados com anti-TNF alfa (infliximabe), na dose de 5mg/kg de peso, aplicado por via endovenosa em intervalos de dois meses. A avaliação foi realizada por protocolo clínico que classificava os quesitos: estado geral, sintomas intestinais e doença perianal em melhor, inalterado e pior, e pelo índice de atividade da doença de Cronh. Os doentes tratados com anti-TNF alfa apresentaram mediana de duração da doença de sete anos, variando de um a 28 anos entre a data do início dos sintomas e a data de início da pesquisa. 34 doentes (56,7%) já haviam sido submetidos a uma ou mais operações abdominais e 38 (63,3%) a operações orificiais. O software utilizado para a realização dos cálculos foi o SPSS® 9.0 for Windows, sendo estatisticamente significantes os testes com p<0,05. Foram aplicadas 225 doses de anti-TNF alfa, em média, 3,7 doses por paciente num período de aproximadamente cinco anos, variando de uma a 14 doses. No tratamento inicial 76% dos pacientes responderam a droga. As principais indicações para o emprego do anti-TNF alfa foram a presença de doença perianal em 36 casos (60%) e a intratabilidade clínica em 24 casos (40%). Observou-se que após a primeira dose da medicação, os doentes com mais de dez anos de doença e submetidos à operação abdominal tiveram resultado satisfatório semelhantemente aqueles doentes com menos de cinco anos de doença e não operados com p<0,05. O índice de atividade da doença de Crohn foi em média de 189,7 antes do início do tratamento e na primeira aplicação diminuiu em média para 135,4, e progressivamente ao longo das aplicações (115, 102, 109 e 88,4 até a quinta dose), sendo o resultado estatisticamente significativo. Houve efeito colateral em 40 aplicações (17,8%), sendo os efeitos principais: eritema cutâneo, dispnéia e dor abdominal. O tratamento com anti-fator de necrose tumoral alfa, obedecidas as indicações precisas, associou-se a baixo índice de efeitos colaterais graves tendo apresentado bons resultados na resolução da doença de Crohn perianal, na melhora da sintomatologia intestinal e no estado geral dos pacientes / Crohn´s disease is a chronic inflammatory disorder of the gastrointestinal tract. Conventional treatment is many times disappointing. Besides the great number of available medications to treat inflammatory bowel diseases, such as salicilates and derivatives, corticosteroids, antibiotics and immunosuppressive agents, none of them proved to be totally efficient or the ultimate treatment for inflammatory diseases and their exacerbation. Researches have been carried out to find more effective therapeutic drugs. Among these therapeutics, biologic treatments have been in evidence. Infliximab is a chimeric IgG1 monoclonal antibody against tumor necrosis factor-alpha, and is indicated for refractory luminal and fistulizing Crohns disease. The aim of this study is to prospectively evaluate the outcome, early and late adverse events, in 60 patients diagnosed with Crohn´s disease and treated with infliximab between July 1999 and December 2005. All patients were treated with anti-TNF-alpha (infliximab), 5mg/kg/dose, intravenously, each two months. Patients were clinically evaluated using a protocol that classified the evolution of the health status, intestinal symptoms and perianal disease, as better, worse or unchanged, during the treatment. Crohn´s disease activity index was also evaluated. Patients treated with anti-TNF-alpha presented a median disease duration of seven (range 1-28) years, between the beginning of the disease symptoms and the beginning of the research protocol. Thirty-four patients (56.7%) have been submitted to one or more abdominal surgeries before, and 38 (63.3%) to anal-rectum surgeries. All statistics tests were performed with computer software Statistical Package for the Social Sciences (SPSS® 9.0) for WindowsTM, and p values of less than 0.05 were considered statistically significant. Totals of 225 anti-TNF-alpha doses were administered. The mean doses administered per patient, in a period of approximately five years, were 3.7 (range 1-14) doses. After the initial treatment, 76% of the patients achieved a response. The most frequent indications for anti-TNF-alpha was perianal disease, occurring in 36 patients (60%), and clinical failure to the conventional treatment, happening in 24 patients (40%). After the first dose of anti-TNF-alpha, patients with more than 10 years of treatment and previously submitted to abdominal surgery presented a satisfactory outcome, similar to those with less than 5 years of disease and not submitted to surgery, p<0.05. Crohn´s disease activity index showed a mean index of 189.7 before treatment, that decreased to 135.4 after the first dose, and progressively decreased with the subsequent doses (means: 115, 102, 109 and 88.4, until the fifth dose, p<0.05). Adverse events were reported in 40 administrations (17,8%) from the total. The most prevalent adverse events were: rash, dyspnoea and abdominal pain. The treatment with anti-TNF-alpha, following precise indications, was associated with a low incidence of severe adverse events and presented good outcomes in the resolution of perianal Crohn´s disease, improving intestinal symptomatology and patients´ health status