Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 122-138).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1967. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.) Veterinary Science --University of Wisconsin, 1970. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 51-57).

Orientador: Oslei Paes de Almeida / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-05T09:05:53Z (GMT). No. of bitstreams: 1 MartinezMata_Guillermo_M.pdf: 1070617 bytes, checksum: 13db66187a1a59eeaa5b18ca3a02cb9d (MD5) Previous issue date: 2005 / Resumo: O objetivo deste trabalho foi analisar as características clínicas, radiográficas, histopatológicas e perfil imunohistoquímico de 67 casos de mixomas odontogênicos (MOs), assim como relatar uma das casuísticas mais extensas da literatura mundial. Nesta pesquisa, o gênero feminino foi o mais afetado com 48 casos (71,64%) enquanto o gênero masculino foi em 19 (28,36%) (relação homem/mulher 1:2,5). A idade dos pacientes variou de 10 a 84 anos, média de 32,7. O sitio mais afetado foi a mandíbula em 27 casos (40.29%) Clinicamente, os MOs apresentaram-se como lesões assintomáticas em 29 (43,28%) casos, em 9 (13,43%) houve dor leve a moderada enquanto em outros 9 (13,43%) houve aumento de volume com evolução lenta. Radiograficamente dos 47 casos com dados disponíveis, 29 (43,28%) casos foram descritos como lesões radiolúcidas e 18 (26,86%) como mistas/multiloculares com aparência de favos de mel ou bolhas de sabão. Microscopicamente MOs apresentaram abundantes células fusiformes e estreladas homogêneas dispersas em um estroma mixóide e frouxo sem apresentar mitoses ou pleomorfismo celular. Em 6 casos (8,95%) evidenciaram presença de epitélio e 16 (23,88%) apresentaram calcificações do tipo distrófica. A reatividade de mastócitos foi positiva pela imunohistoquímica (clone AA1) em 27 casos (40,29%) e na coloração de azul de toluidina em 19 (28,35%). Treze dos 67 casos apresentaram epitélio imunoreativo para o coquetel de citoqueratinas AE1/AE3 e CK 14. Apenas 2 dos 13 casos foram positivos para CK 19 sugerindo uma possível origem odontogênica. As células fusiformes e estreladas foram reativas para vimentina em 67 casos, para a-actina músculo liso específica em 27 casos (40,29%) e para desmina em 6 (8,95%). Todos os casos foram negativos para a proteína S-100 e CK 8. O anticorpo CD-34 foi positivo em 20 (29,85%) casos, evidenciando múltiplas estruturas vasculares de diversos tamanhos. O marcador de proliferação celular Ki-67 foi positivo em apenas 2 casos apesar de sua alta taxa de recorrência. Baseado nestes achados, podemos sugerir que provavelmente os MOs sejam derivados de elementos mesenquimais, possivelmente de células fibroblásticas modificadas com características de miofibroblastos , e que outras nomenclaturas seriam mais adequadas para denominar esta lesão, tais como mixomas da região maxilar ou mixomas dos ossos gnáticos / Abstract: The aim of this study was to analyze the immunohistochemical profile and clinical, radiographical and histopathological characteristics of 67 cases of odontogenic myxoma (OM), as well as to report the greatest series related in the world literature. Females were more affected with 48 cases (71,64%) whereas males were in 19 (26.83%), male-female ratio 1:2.5. The patient¿s age ranged from 10 to 84 years (mean 32,7 years). The most frequent site affected was mandible with 27 cases (40,29%). Clinically, 29 cases (43,28%) of OM were asymptomatic, 9 cases (13,43%) presented pain and another 9 (13.43%) showed swelling. Radiographically, we disposed of clinical information in 47 cases, of which 29 (43,28%) cases were radioluced lesions and 18 (26,86%) were described as mixed/multilobular lesions of honey/comb or soap/bubble appearance. Microscopically, OM was constituted by a myxomatous background with spindle-shaped and stellate cells. Mitoses and pleomorphism were absent. Epithelium was present in 6 (8,95%) cases and 16 (23.88%) presented dystrophic calcifications. Immunohistochemical analyses revealed that 27 cases (40.29%) were positives for mast cell (clone AA1) and 19 (28,35%) positives for toluidine blue. Thirteen cases (19,47%) were positives for the antibody PAN CK AE1/AE3 and CK 14 respectively. Only 2 cases (2,98%) were positives for CK 19 suggering an possible odontogenic origin. The spindle-shaped and stellate cells showed positivity for vimentin in 67 cases, 27 cases (40,29%) for a-smooth muscle actin positives and 6 (8,95%) for desmin. All 67 cases were S-100 and CK 8 negatives. Twenty cases (29,85%) were immunopositives for CD-34, demonstring multiples blood vessels. Expression of the marker of cellular proliferation Ki-67 was low, being present only in two cases. Based on these findings, we can suggest that OM probably derives from mesenchymal elements, possibly modified fibroblasts with miofibroblastic diferentation, and that others nomenclatures as mixoma of the jaws could be suggest for this lesion / Mestrado / Patologia / Mestre em Estomatopatologia

Cancer is a deadly, complex disease with 14 million new cases diagnosed every year and the endeavour to develop a cure is a global multidisciplinary effort. The complexity of cancer and the resulting vast volume of data derived from its research necessitates a robust and cutting-edge system of mathematical and statistical modelling. This thesis proposes novel mathematical models of quantification and modelling applied to heterogeneous preclinical cancers, focusing on the translation of animal studies into patients with particular emphasis on tumour stroma. The first section of this thesis (quantification) will present different techniques of extracting and quantifying data from bioanalytical assays. The overall aim will be to present and discuss potential methods of obtaining data regarding tumour volume, stromal morphology, stromal heterogeneity, and oxygen distribution. Firstly, a 3D scanning technique will be discusses. This technique aims to assess tumour volume in mice more precisely than the current favoured method (callipers) and record any cutaneous symptoms as well, with the potential to revolutionise tumour growth analysis. Secondly, a series of image processing methods will be presented which, when applied to tumour histopathology, demonstrate that tumour stromal morphology and its microenvironment play a key role in tumour physiology. Lastly, it will be demonstrated through the integration of in-vitro data from various sources that oxygen and nutrient distribution in tumours is very irregular, creating metabolic niches with distinct physiologies within a single tumour. Tumour volume, oxygen, and stroma are the three aspects central to the successful modelling of tumour drug responses over time. The second section of this thesis (modelling) will feature a mathematical oxygen-driven model - utilising 38 cell lines and 5 patient-derived animal models - that aims to demonstrate the relationship between homogeneous oxygen distribution and preclinical tumour growth. Finally, all concepts discussed will be merged into a computational tumour-stroma model. This cellular automaton (stochastic) model will demonstrate that tumour stroma plays a key role in tumour growth and has both positive (at a molecular level) and negative (at both a molecular and tissue level) effects on cancers. This thesis contains a useful set of algorithms to help visualise, quantify, and understand tissue phenomena in cancer physiology, as well as providing a series of platforms to predict tumour outcome in the preclinical setting with clinical relevance.

High-grade serous ovarian carcinoma (HGSOC) is characterised by genomic instability, ubiquitous TP53 loss, widespread disease at diagnosis and the frequent emergence of platinum resistance. This thesis explores the use of high-throughput genomics technologies to understand if resistance could be explained by the model of tumour evolution. We performed SNP array analysis of a cell line model system of platinum resistance consisting of matched cell lines from three cases of HGSOC established before and after clinical resistance developed, the OVOl clinical study consisting of six matched pairs of tumours before and after three cycles of chemotherapy, and the OV03/0V04 study consisting of 18 cases sampled at multiple timepoints and from multiple metastatic sites. The results showed evidence of metastatic site dependent divergence. Moreover, mutually exclusive loss of heterozygosity patterns between presentation and relapse genomes, including all the cases in the cell line system and one of two OV03 cases for which relapse material was available, suggest that the relapse arises from a minor subclone of the presentation disease, while in the remaining case, the subclone with an NFJ homozygous deletion was enriched in the relapsed disease. I then asked which mutational process drives evolution. Using next-generation sequencing (NGS), I compared the structural variants between and within cases in the model system and in 6 cases of the OV03 cohort. From the genomic signatures in the cell lines, I demonstrated that a case with homologous recombination (HR) deficiency acquired numerous translocations and small deletions (median size of 13.4kb) , whereas another showed a novel tandem duplicator phenotype (median size of tandem duplications was 350kb). Mutator phenotypes in both cases arose early in progression and persisted, but the tumour with HR deficiency showed evidence of re-stabilising its ,"genome and lost platinum sensitivity after a revertant BRCA2 mutation restored its HR function. A subset of tumours from the Cancer Genome Atlas (TCGA) dataset suggested that these two phenotypes were mutually exclusive. Amongst the six OV03 cases, preliminary analysis suggests that one case showed an amplifier phenotype and three cases showed evidence of parallel evolution. Taken together, early onset of mutator phenotypes and parallel evolution may provide a mechanism by which resistance evolves. Further work should aim to identify the processes involved in tumour evolution in 'purified' populations such as cancer stem cells.

No description available.

No description available.

Tumors induce immune dysfunction through the production of soluble factors that subvert macrophage (Mf) function to favor tumor growth. Previous studies suggested that tumor-induced immune cell dysfunction may be reversible through regimens that disrupt tumor cell suppressor mechanisms and concurrently promote tumoricidal activities. Because the antineoplastic agent paclitaxel (TAXOL) activates Mf function, we studied mechanisms of paclitaxel-mediated cytotoxic and immunostimulatory responses by tumor-induced Mfs. Although tumor-derived factors, including interleukin-10 and transforming growth factor-b1, modulate Mf response to activation signals, paclitaxel partly reverses tumor-induced Mf-mediated suppression of T-cell reactivity through enhanced production of the immunostimulatory cytokine interleukin-12 (IL-12). Concurrently, paclitaxel induces Mf cytotoxic and proinflammatory molecule production, including tumor necrosis factor-a and interleukin-1b. In contrast to its apparent immunotherapeutic effect on Mf populations, paclitaxel's cytostatic mechanisms suppress lymphocyte proliferation and function. We showed that IL-12 can reverse paclitaxel-mediated suppression of T-cell responses in vitro, establishing the foundation for a novel antitumor therapy using paclitaxel in combination with IL-12. We show that the administration of paclitaxel as a chemotherapeutic agent, followed by IL-12 as an immunotherapeutic agent to alleviate paclitaxel-mediated immunosuppression, prolongs survival, reduces tumor progression, and activates immune effector populations in a murine tumor model. These results are the first experimental evidence to suggest that paclitaxel and IL-12 are an effective antitumor modality. Collectively, these studies show that paclitaxel induces multiple antitumor mechanisms that can be enhanced with proper ancillary administration of immunotherapeutic cytokines. / Ph. D.