Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Thesis (Ph.D.)--Murdoch University, 2004. / Thesis submitted to the Division of Health Sciences. Bibliography: leaves 214-249.

Thesis (MScIng)--University of Stellenbosch, 2005. / Accompanied by CD in end pocket of book. Bibliography. Also available via the Internet.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2008. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Wisconsin, 1951. / Typescript (carbon copy). Some charts laid in. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 51-54).

<p>Glioblastoma (GBM) is a grade IV astrocytoma in which the median overall survival is approximately 15 months at time of diagnosis. Even with the current multi- modal therapeutic approach of surgery, chemotherapy with the DNA alkylating agent temozolomide, and radiation therapy, GBM remains uniformly lethal. Immunotherapeutic interventions are a burgeoning field in many different cancer treatments. They offer the exquisite specificity endowed by the immune system with minimal toxicities and new methods are being developed to enhance the endogenous immune responses.</p><p>With the recent identification of human cytomegalovirus (CMV) present within glioblastoma tissue but void in the surrounding normal healthy parenchyma there have been significant efforts aimed at understanding the biologic implications of the presence of the virus within GBM tissues with preliminary work demonstrating several capabilities of the virus to enhance the oncogenic process. </p><p>Likewise, a key area of importance in the development and design of effective immunotherapeutic platforms is the identification and targeting of tumor-specific antigens. The success of any immunotherapy platform relies heavily on the ability to selectively target antigens present within tumors but absent on healthy tissue, regardless of its role in tumorigenesis, as well as having robust immunogenic properties.</p><p>CMV offers a plethora of possible targets, as it is the largest known DNA virus that infects humans, yet very little is known about its biological significance in glioblastoma pathogenesis as well as the most efficacious and immunogenic targets for immunotherapeutic development. </p><p>We have been able to elucidate more thoroughly the feasibility and potency of an immunologic platform targeting CMV within glioblastoma utilizing a multi-antigen multi-component peptide based strategy that demonstrated significant immunogenicity and anti-tumor activity in pre-clinical models utilizing various assays. We have also developed several sensitive and specific detection methodologies including: 1) custom gene expression microarrays, 2) multiplex real time quantitative polymerase chain reaction (RT-qPCR) assays, 3) a massively parallel RNA deep sequencing platform, and 4) immunological assays. We have also successfully determined the capacity for endogenous CMV gene expression to be maintained in primary glioblastoma cell lines as well as examining the preponderance of CMV gene expression in a subpopulation of glioma stem cell-like cells, the slow cycling GBM cells established from primary tumor tissues, in an attempt to illuminate some of the biologic underpinnings of CMV with respect to GBM pathogenesis.</p><p>Taken together, these data lay the groundwork for the development of a more efficacious vaccination strategy targeting CMV in GBM. The screening strategies employed throughout this work will allow for an accurate antigenic profile of CMV in GBM which will subsequently permit the design of a more robust peptide vaccine for the next generation of cancer vaccine. We have also begun to describe some of the interesting biologic phenomena associated with CMV in GBM, as our results demonstrate continued viral gene expression in glioma stem cell-like cell populations indicating viral tropism for certain cell types.</p> / Dissertation

Alzheimer’s disease (AD) is characterized by cognitive decline and hallmark neuropathology, including β-amyloid (Aβ). Therapeutic strategies for AD are focusing on reducing Aβ. Canines develop Aβ neuropathology and cognitive decline with age similar to AD patients. In previous studies, immunization with Aβ1-42 (VAC) in aged canines decreased brain Aβ but did not improve cognition. Behavioral enrichment (ENR) improved cognition without reducing brain Aβ. We hypothesized that VAC combined with ENR would provide cognitive benefits and reduce Aβ neuropathology, as compared individual VAC and ENR treatments. Aged beagles were placed into groups: control, VAC with fibrillar Aβ1-42, ENR, and combination treatment (VAC+ENR) for 18 months. Learning and memory was evaluated throughout the study. Serum IgG antibody titers, cerebral spinal fluid (CSF) and brain Aβ were measured. Serum anti-Aβ1-42 IgG increased significantly in VAC animals. ENR but not VAC significantly increased CSF Aβ1-40. No cognitive improvements were observed in any group. VAC significantly reduced brain Aβ1-40 and 1-42, as well as reduced plaque load. An overall slowing of plaque accumulation was seen in the ENR group. VAC and ENR were able to modify pathology when used as separate treatments; however, the combination treatment did not succeed in further reducing Aβ or improving cognition. Previous AD clinical trials using immunotherapy yielded similar outcomes to our study showing reduced Aβ pathology but little to no cognitive improvements. In combination these results suggest that future studies should focus on prevention approaches both in the canine model and in human clinical trials.

Made available in DSpace on 2014-06-11T19:32:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-11-11Bitstream added on 2014-06-13T18:44:25Z : No. of bitstreams: 1 arduino_ggc_dr_jabo.pdf: 1086799 bytes, checksum: 087abbf6d5907c0059a4db75a0b3028d (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / No presente estudo, 100 fêmeas bovinas foram divididas em cinco tratamentos de 20 animais cada. Os grupos experimentais receberam quatro diferentes vacinas comerciais (B, C, D e E), e um grupo permaneceu como controle. Amostras foram colhidas no dia da aplicação da primeira dose e nos dias 3, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, 120, 150 e 180 pós-vacinação (pv). A triagem dos animais foi feita pela análise sorológica com 24 antígenos de leptospiras, escolhendo-se os animais não reagentes. Os títulos de anticorpos foram monitorados pela soroaglutinação microscópica (SAM) com os sorovares Canicola, Grippotyphosa, Hardjo, Icterohaemorrhagiae, Pomona e Wolffi. Todas as vacinas induziram, aos 3 dias pv, títulos de anticorpos aglutinantes para os sorovares Hardjo e Wolffi, que persistiram até o 150o dia pv. Os sorovares Hardjo e Wolffi induziram os maiores títulos de anticorpos aglutinantes. A vacina D, apesar de não possuir o sorovar Wolffi em sua composição, foi capaz de induzir anticorpos aglutinantes contra este sorovar. Somente foram detectados anticorpos contra o sorovar Canicola nos animais vacinados com a bacterina D. A vacina que induziu os maiores títulos médios de anticorpos, considerando todos os sorovares testados, foi a D. Há a necessidade de melhoria no poder imunogênico e na concentração dos sorovares utilizados como antígenos nas vacinas comerciais. / In this research 100 heifers were used, divided in 5 groups of 20 animals each. The four experimental groups were vaccinated using distinct commercial polyvalent bacterines: A, B, C and D, and a group was the control. Samples were collected at the days 0, 3, 7, 14, 21, 28, 35, 42, 42, 56, 63, 70, 77, 84, 91, 120, 150 and 180 from the first injection of the vaccine. The selection of the animals for the experimental groups was done based on a serological screening with 24 antigens of Leptospira sp., constituted by non-reagent animals. The vaccine titres were monitored using the microscopic agglutination test (MAT) for Canicola, Grippotyphosa, Hardjo, Icterohaemorrhagiae, Pomona and Wolffi serovars. All vaccines used were capable to product agglutinins for the Hardjo and Wolffi serovars observed at 3 days after vaccination, remaining until the 150th day; these serovars induced the highest titres of agglutinins. The vaccine D, in spite of not containing the Wolffi serovar, was able to induce the production of agglutinins to this serovar. Agglutinins to the Canicola serovar were only observed in the animals vaccinated with the D bacterine. The vaccine D induced the highest average titres of antibodies to all serovars tested. The improvement of the immunogenic power and serovars concentration utilized as antigens of the commercial vaccines are necessary.

abstract: In the United States, Escherichia coli O157:H7 (E. coli O157:H7) is the most frequent cause of hemolytic uremic syndrome (HUS) and it is also the primary cause of acute renal failure in children. The most common route of the infection is ingestion of contaminated meat or dairy product originating from cattle or vegetables contaminated with bovine manure. Since cattle are the main reservoir for human infection with E. coli O157:H7, the reduction of intestinal colonization by these bacteria in cattle is the best approach to prevent human infections. Intimin is an outer membrane protein of E. coli O157:H7 that plays an important role in adhesion of the bacteria to the host cell. Hence, I proposed to express intimin protein in tomato plants to use it as a vaccine candidate to reduce or prevent intestinal colonization of cattle with E. coli O157:H7. I expressed His-tagged intimin protein in tomato plants and tested the purified plant-derived intimin as a vaccine candidate in animal trials. I demonstrated that mice immunized intranasally with purified tomato-derived intimin produced intimin-specific serum IgG1and IgG2a, as well as mucosal IgA. I further demonstrated that mice immunized with intimin significantly reduced time of the E. coli O157:H7 shedding in their feces after the challenge with these bacteria, as compared to unimmunized mice. Shiga toxin is the major virulence factor that contributes to HUS. Since Shiga toxin B subunit has an important role in the attachment of the toxin to its receptor, I fused intimin to Shiga toxin B subunit to create multivalent subunit vaccine and tested the effects upon immunization of mice with the B subunit when combined with intimin. His-tagged intimin, Shiga toxin B subunit, and Shiga toxin-intimin fusion proteins were expressed in E. coli and purified. I demonstrated that this multivalent fusion protein vaccine candidate elicited intimin- and Shiga toxin B-specific IgG1, IgG2a, and IgA antibodies in mice. I also showed a reduction in the duration of the bacterial shedding after the challenge compared to the control sham-immunized groups. / Dissertation/Thesis / Ph.D. Plant Biology 2010

Submitted by Maria Creuza Silva (mariakreuza@yahoo.com.br) on 2013-10-03T19:10:15Z No. of bitstreams: 1 Diss MP. Ieda Carvalho 2013.pdf: 743354 bytes, checksum: 86a38cc8c18f66fee690c10a1336c161 (MD5) / Approved for entry into archive by Maria Creuza Silva(mariakreuza@yahoo.com.br) on 2013-10-03T19:10:31Z (GMT) No. of bitstreams: 1 Diss MP. Ieda Carvalho 2013.pdf: 743354 bytes, checksum: 86a38cc8c18f66fee690c10a1336c161 (MD5) / Made available in DSpace on 2013-10-03T19:10:31Z (GMT). No. of bitstreams: 1 Diss MP. Ieda Carvalho 2013.pdf: 743354 bytes, checksum: 86a38cc8c18f66fee690c10a1336c161 (MD5) Previous issue date: 2013 / O câncer de colo de útero (CCU) é um importante problema de saúde em todo o mundo. O HPV é o principal fator associado a esta doença. Para a prevenção primária da infecção foi desenvolvido a vacina quadrivalente que protege contra os tipos HPV 16, 18, 11 e 6. Objetivo: este estudo analisou a relação custo-efetividade e custo-utilidade da adição da vacina contra HPV para Sistema Único de Saúde brasileiro, em comparação ao rastreamento pelo exame citopatológico, programa existente. Método: foi adaptado um modelo de Markov da história natural da infecção por HPV para estimar custo e qualidade de vida para uma coorte hipotética de meninas de 10 anos de idade acompanhadas por 70 anos. Duas estratégias foram comparadas: vacinar e rastrear (estratégia alternativa) em relação ao rastreamento (estratégia base). No modelo a cobertura para o rastreamento foi de 77,1% e para a vacina 95%. A taxa de desconto aplicada para calcular custos e efeitos futuros de saúde foi de 5%. A análise de sensibilidade foi realizada para avaliar as incertezas quanto à cobertura vacinal, a sensibilidade do exame citopatológico e o valor da vacinação. Resultados: o modelo simulou que a adição da vacina poderia reduzir em 76,18% o risco de morrer por CCU, evitando 12.072 óbitos por esta doença a um custo médio de US$ 633.559,32/óbitos evitados, com um ganho de 1.389.478 anos de vida ajustado por qualidade. Quanto aos anos de vida ganhos ajustado por qualidade (AVAQ), a estratégia base (rastreamento) representaria um custo médio de US$ 11,62/AVAQ enquanto a estratégia teste (vacina e rastreamento) teria um custo médio de 241,66 US$/ AVAQ. A razão de custo-efetividade incremental (RCEI) desta estimativa foi de US$ 5.504,46/AVAQ. Conclusão: Esta análise, apesar das limitações metodológicas, demonstra que a incorporação, pelo SUS, da vacina quadrivalente ao programa de rastreamento pode ser uma alternativa custo-efetiva para reduzir a mortalidade por CCU. / Salvador