published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Surgery / Master / Master of Philosophy

No description available.

Thesis (Ph. D.)--University of New South Wales, 2005. / Also available online.

Thesis (Ph.D.)--University of Western Australia, 2006.

Thesis (M.P.H.)--Georgia State University, 2008. / Title from file title page. Russ Toal, committee chair; Karen Wasilewski-Masker, committee member. Description based on contents viewed July 7, 2009. Includes bibliographical references (p. 68-72).

Thesis (Ph.D.)--Kent State University, 2006. / Title from PDF t.p. (viewed Sept. 14, 2006). Advisor: Chun-Che Tsai. Includes bibliographical references (p. 133-151).

Thesis (Ph.D.)--University of Iowa, 2006. / Supervisor: Susan K. Lutgendorf. Includes bibliographical references (leaves 121-135).

Orientador: Debora Aparecida Pires de Campos Zuccari / Coorientador: Eduardo Alves Almeida / Banca: Angelo Gustavo Zucca Matthes / Banca: Eny Maria Goloni Bertollo / Banca: Luiz Octávio Regasini / Banca: Sebastião Roberto Taboga / Resumo: O câncer de mama é a principal causa de mortes relacionadas ao câncer em mulheres e pesquisas têm sido focadas em identificar e validar biomarcadores que podem ser utilizados para confirmar o diagnóstico e determinar o prognóstico. Mudanças no ritmo circadiano podem contribuir para o desenvolvimento do câncer e sendo assim, a melatonina, um hormônio sintetizado pela glândula pineal à noite, na ausência de luz e seus metabolitos AFMK e AMK são sugeridos como potenciais biomarcadores. A melatonina pode atuar através do receptor MT1 regulando cinases e a expressão de genes específicos relacionados a proliferação, angiogênese, diferenciação celular e transporte de glicose. A expressão elevada de GLUT1 (Glucose Transporter-1) está associada ao prognóstico ruim no câncer. Os objetivos deste estudo foram comparar os níveis de melatonina, AFMK e AMK em mulheres recentemente diagnosticadas com câncer de mama, mulheres em quimioterapia adjuvante, enfermeiras que trabalham à noite em comparação com mulheres saudáveis e hábitos normais e avaliou-se a expressão do receptor MT1 e GLUT1 em tumores de mama e correlacionou com os subtipos moleculares, características patológicas e prognóstico. Foi coletado sangue de 53 mulheres com câncer de mama sendo 47 sem tratamento e 6 em quimioterapia adjuvante, 19 mulheres saudáveis sendo 1 O enfermeiras de turno noturno e 9 mulheres de hábitos normais. Os compostos foram quantificados por espectrometria de massas. Para a expressão de MT1 e GLUT1 foi... / Abstract: Breast cancer is the Jeading cause of cancer-related deaths in women and researches has been focused on identify and validate biomarkers that can be used to confirm the diagnosis and determine the prognosis. Changes in circadian rhythm may contribute to the development of cancer and thus melatonin, a hormone synthesized by the pineal gland at night, in the absence of light and its metabolites AFMK and AMK are suggested as potential biomarkers. Melatonin can act through the MT1 receptor by regulating kinases and the expression of specific genes related to proliferation, angiogenesis, ce/1 differentiation and glucose transport. High GLUT1 (Glucose Transporter-1) expression is associated with poor prognosis in cancer. The objectives of this study were to compare the leveis of melatonin, AFMK and AMK in women newly diagnosed with breast cancer, women on adjuvant chemotherapy, health nurses which work at night compared to healthy women and normal habits and the expression of MT1 receptor and GLUT1 in breast tumors and correlated with molecular subtypes, pathological features and prognosis. Blood from 53 women with breast cancer was colletcted, 47 of them without treatment and 6 in adjuvant chemotherapy, 19 healthy women, 1 O of them night shift nurses and 9 women of normal habits. Compounds were quantified by mass spectrometry. For the expression of MT1 and GLUT1, immunohistochemistry was performed in 42 breast tumors. The results showed that women with breast cancer had lower ... / Doutor

Background: High-grade serous carcinoma (HGSC) can exhibit high intratumoral heterogeneity (ITH). Despite a strong association between tumor-infiltrating lymphocytes (TIL) and survival in HGSC, ITH may have profound impacts on the anti-tumor T cell response. Yet, it is unknown how anti-tumor T cell responses contend with ITH over time in HGSC. Previous studies in melanoma and HGSC both showed tumor-reactive T cell clones emerge over time with their cognate tumor-antigens. Therefore, I hypothesized patients would share a common mechanism of T cell evolution to respond to ITH in HGSC. If so, I expect to see similar patterns of tumor recognition between primary and recurrent disease. Methods: Tumor-associated lymphocytes (TAL) were expanded from primary and recurrent ascites samples using high-dose IL-2 and a rapid-expansion protocol (REP). Following expansion, TAL were assessed for recognition of autologous tumor by IFN-γ ELISPOT and flow cytometry for CD137. CD137+ tumor-reactive TAL were FACS-purified and the tumor-reactive T cell repertoire was profiled by deep sequencing of TCRβ chains (TCRseq). Tumor-reactive TCR clonotypes were compared between primary and recurrent disease to elucidate differences in tumor-reactive populations over time in HGSC. Results: Patient TAL recognized tumor in two out of three cases. In patient IROC 060, the tumor became more immunogenic between primary and recurrent disease, which may reflect expression of new antigens and/or loss of an immunosuppressive phenotype. In patient IROC 106, the tumor remained immunogenic between primary and recurrent disease, which may reflect maintenance of stable antigen expression and an immune-sensitive phenotype. Patient IROC 034 did not exhibit any tumor-reactivity, suggesting tumor-reactivity is not ubiquitous in HGSC. FACS-purification of CD137+ T cells followed by TCRseq was successfully performed on T cell populations of both high- and low-abundance, suggesting TCRseq can be performed on populations containing very few T cells. TCRseq results that profiled the clonal repertoire of tumor-reactive TAL from primary and recurrent disease in two patients, IROC 060 and IROC 106, showed both patients had evidence of T cell loss and T cell emergence between primary and recurrent disease. Further, IROC 106 had evidence of T cell clones that were maintained between primary and recurrent disease. Conclusions: Anti-tumor T cell responses from ascites are both diverse between patients and dynamic within a patient, suggesting various mechanisms of T cell evolution to contend with ITH in HGSC. I developed a pipeline for the identification of tumor-reactive TCR sequences without the need for a priori knowledge of specific antigens. Additionally, this pipeline is feasible for very low-abundance samples, such as tumor-reactive T cells. Significance: This study provides early insights into how TAL contend with ITH in HGSC. Ultimately, these results will inform the design of adoptive T cell therapy for recurrent HGSC. / Graduate