Glioblastoma (GBM) is the most common and aggressive brain tumor in adults which is characterized by extensive cellular and genetic heterogeneity. Even with surgery, chemotherapy with temozolomide, and radiation, tumor re-growth and patient relapse are inevitable. The extensive inter- and intra-tumoral heterogeneity (ITH) of recurrent GBM emerges from dysregulation at multiple -omic levels of the tumor. ITH exits at the cellular level due to a small subpopulation of chemo- and radio-resistant cells, called brain tumor initiating cells, which may drive GBM treatment resistance. Although a wealth of literature describes the biology of primary GBM (pGBM), we currently lack an understanding of how GBM evolves through therapy to become a very different tumor at recurrence, which may explain why therapies against primary GBM fail to work in recurrent GBM (rGBM). Thus, understanding the tumor evolution from a multi-omic perspective is critical for the development of effective therapeutic approaches. The current work focuses on identification and validation of novel predictive and prognostic biomarkers for rGBM using proteomics analysis on a large cohort of patientmatched pGBM-rGBM samples. This work allowed for detailed characterization of rGBM and its cognate TIME toward a better understanding of the molecular players driving recurrence which can be further used for instructing effective targeted and personalized therapies for the treatment of therapy-resistant GBM. In another part, we developed a novel immunotherapeutic modality called dual antigen T cell engager, to target Carbonic Anhydrase 9, a highly enriched hypoxia-inducible enzyme in GBM. We demonstrated that this immunotherapeutic strategy which allows for targeting tumor cells while recruiting and triggering T cells through simultaneously, is highly effective in eliminating tumor cells and can be a complementary component of combinatorial therapy for GBM patients. Altogether, this study provided key data for instructing novel and rational combinatorial polytherapeutic approaches for the treatment of therapy-resistant GBM. / Thesis / Doctor of Philosophy (PhD) / Cancer is the leading cause of death in Canada and Glioblastoma Multiforme (GBM) is the most common type of malignant adult brain tumor which is one of the difficult human cancers to treat. In spite of the multi-model therapy including surgery, chemotherapy, and radiation, tumor re-growth and patient relapse are inevitable. A wealth of literature describes the biology of treatment-naïve or primary GBM, but we currently lack an understanding of how GBM evolves through therapy to become a very different tumor at recurrence, which may explain why therapies against primary GBM fail to work in recurrent GBM (rGBM). Clinical trials have not shown significant survival advantages for GBM patients, due not only to the lack of biological characterization of the distinct landscape of GBM recurrence, but also due to our poor understanding of the tumor immune microenvironment (TIME), the immune cells surrounding the tumor that may somehow fail to attack it due to GBM cells’ ability to suppress the immune system and evade detection. To understand how GBM cells and the TIME evolve under therapeutic pressure, we performed proteomics analysis on a large cohort of primary-recurrent GBM patient samples, to further understand treatment failure and develop effective and empirical combinatorial poly-therapies for the treatment of therapy-resistant GBM. Besides, in the next part of this study we showed existence of few cells within the tumor, termed brain tumor initiating cells (BTICs) can alone drive tumor growth and cause therapy resistance. To be able to target these population of cells, we identified treatment resistant tumor associated markers (highly expressed cell surface proteins) on these cells and developed novel treatments using a new class of biologics, Dual Antigen T cell Engagers (DATEs), to target these tumor associated markers. DATEs act like a “molecular glue” that specifically binds the patient’s own naturally circulating T-cells (soldier cells of the immune system) to cancer cells. Once bound, the T-cells attack and kill the patient’s cancer cells. In this strategy, the abnormal expression of tumor surface proteins can be used as a handle to drive T cell-mediated cell death. We predict that the dual specific antibodies through this study could be used alone or in combination with existing drugs to treat recurrent GBM.

No description available.

The Ad5 E1B antigens of MW 58000 and 19000 are known to be involved in oncogenic transformation of mammalian cells. To obtain sufficient quantities of these proteins for biochemical studies on their mechanism of action, I have attempted to express the Ad5 E1B genes in Escherichia coli. Using the strategy developed by Guarente et al. (1980), I have constructed plasmids which have the trancriptional and translational controls of the E. coli lac operon linked 5' of the 19k and 58k coding sequences. One plasmid was shown to synthesize high levels of a stable, immunoreactive 19k analogue consisting of 19k with 29 adenovirus-coded ribosome-binding sequence is functional in directing translation of this protein. Synthesis of 58k was not demonstrated, perhaps the result of [protein instability in E. coli. However, immunoreactive proteins which may correspond to the amino terminal region of 58k were demonstrated. / Thesis / Master of Science (MS)

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.

Tumor metabolism is a highly dysregulated process that is identified as a unique target for therapy. Current philosophy proposes that tumor metabolism is a plastic and flexible process which sustains proliferative and survival advantages. Tumors employ an anaerobic glycolytic pathway resulting in the overproduction of lactate. Additional thinking suggests that the conversion of pyruvate to lactate regenerates the NAD+ pool in the cell, maintaining a sustainable oxidative environment. Regardless of the reasons for lactate overproduction, its excretion and build up in the microenvironment results in acidic tumor microenvironments. Tumor acidosis has been measured with several different methods, but consistently averages from pH 6.6 to 7.0. Tumor acidity can thus be measured as a biomarker for tumor metabolism. This work examines the commonly explored energy pathways available to the cancer cell and a non-invasive MRI method to measure the efficacy of the tumor metabolism targeting agent. Appendix A is an introduction to tumor metabolism pathways and the large list of candidate therapies in interfering with energy production. Glucose, fatty acid, and glutamine metabolisms are all discussed along with PI3K/AKT/mTOR and HIF growth signals and ion transport. Magnetic resonance imaging and positron emission tomography are examined as imaging methods for non-invasively interrogating tumor acidosis. Appendix B presents the findings in a study where tumor metabolism was targeted with an mTOR inhibitor, where tumor growth rate was initially decreased and accompanied by an early, acute increase in tumor extracellular pH with acidoCEST MRI. Chapter 2 discusses the combination of a lactate dehydrogenase inhibitor in conjunction with doxorubicin in a breast cancer model. Tumor extracellular pH was shown to increase when measured with acidoCEST MRI, and an increase in cell death was measured. Chapter 4 discusses the studies and experimental designs that can be done in the near future.

No presente estudo analisou-se o metabolismo de glicose e glutamina, através da determinação da atividade enzimática, em carcinomas ductais infiltrativos de pacientes sem tratamento. As pacientes estavam na faixa etária entre 32 e 68 anos e cerca de 75% no período pós-menopausa. Os tumores estudados apresentavam graus de diferenciação e tamanho distintos; no entanto, sem metástases distantes. Os seguintes parâmetros foram analisados: a) efeito da insulina sobre o consumo de glicose em fatias tumorais, b) atividades das enzimas da via glicolítica e da glutaminase nas áreas do centro e periferia do tumor, c) parâmetros cinéticos da piruvato quinase purificada. Os resultados foram comparados entre os tumores e a glândula mamária e entre as áreas centrais e periféricas dos próprios tumores. O consumo de glicose mostrou-se maior nos carcinomas, principalmente no centro que na periferia do tumor, mas não foi alterado pela insulina. Não houve relação entre o consumo de glicose e o tamanho dos tumores, nem com o grau histológico. Inversamente, na glândula mamária, a insulina (100 µU/ml) aumentou a captação de glicose. A concentração de lactato produzida, pela incubação das fatias tumorais com glicose, foi significativamente maior nos carcinomas do que na glândula mamária, equivalente ao aumento do fluxo glicolítico. A atividade das enzimas da via glicolítica foi maior nos carcinomas em comparação ao tecido normal. A atividade foi também significativamente diferente tanto na comparação entre as áreas do centro e periferia do tumor, quanto considerando-se o grau de diferenciação dos carcinomas. Nas áreas centrais, as atividades enzimáticas foram mais elevadas, enquanto que considerando-se os graus histológicos, tumores menos diferenciados apresentaram atividades mais elevadas que os de maior grau de diferenciação. Dentre as enzimas reguladoras da glicólise, a piruvato quinase apresentou a maior atividade em comparação à hexoquinase e fosfofrutoquinase-1. Este aumento foi significativamente maior nos carcinomas associados com comprometimento de linfonodos axilares. A piruvato quinase purificada mostrou Km de 0,23 mM para fosfoenolpiruvato e 0,3 mM para ADP. ATP inibiu em 40% a atividade da enzima, enquanto que alanina, fenilalanina e cálcio inibiram em 55%, 84% e 93% a atividade da enzima, respectivamente. A frutose 1,6bifosfato induziu 36% de ativação e reverteu em 100% a inibição causada por fenilalanina, em 87% aquela da alanina e cerca de 56% para ATP, mas não reverteu a inibição por cálcio quando em concentrações saturantes e apenas em 15% em concentrações sub-saturantes. O padrão eletroforético da piruvato quinase diferiu da mama e tumores benignos (fibroadenomas), o que pode representar um marcador de malignidade. A atividade das enzimas citrato sintetase e glicerol-3-fosfato desidrogenase mostrou-se diminuída de acordo com o aumento da atividade glicolítica e relacionou-se diretamente com o grau de diferenciação dos carcinomas. Tumores diferenciados mostraram maior atividade. A atividade da glutaminase foi maior nos carcinomas em comparação à glândula mamária, sendo ainda maior nas áreas do centro do tumor que nas áreas periféricas. O grau de diferenciação também correlacionou-se com a atividade da enzima, mas não foram observadas diferenças significativas quando considerou-se o tamanho tumoral. As diferenças metabólicas observadas podem associar-se ao comportamento clínico heterogêneo entre pacientes com o mesmo tipo de carcinoma. / Glucose and glutamine metabolism of infiltrating ductal carcinomas of untreated patients was studied by determining enzyme activities. The patients were between 32 and 68 years old and about 75% were in post-menopausal period. The tumors have different histological grading and sizes but no distant metastasis. The following parameters were analysed: a) effect of insulin on glucose uptake by tumor slices, b) glycolytic (hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase) and glutaminolytic (glutaminase) enzyme activities, c) kinetic parameters of purified pyruvate kinase. The results were compared to those of mammary gland and between center and periphery regions of the tumors. Glucose, consumption was higher in the carcinomas, compared to mammary gland, specially in the solid region (center) than in the periphery, but it was not altered by insulin. No correlation was found between glucose consumption rate and the tumor size or differentiation grading. Inversely, in the mammary gland, insulin (100 µU/ml) increasead glucose uptake. Lactate production was significantly higher in the carcinomas than in the mammary gland according to the glycolytic flux. The glycolytic enzyme activities were higher in the carcinoma than in the mammary gland. The enzyme activities were more elevated in the center as compared to peripheric areas of the tumor. In the tumor center, the enzyme activities were highest in the undifferentiated carcinoma. Pyruvate kinase (PK) presented higher activity than phosphofructokinase 1 and hexokinase activities. Purified PK from the tumor presented a reduced Km for phosphoenolpyruvate (0,23 mM) and ADP(O,3 mM). ATP inhibited 40% of the enzyme activity, while alanine, phenilalanine and calcium inhibited it by 55%, 84% and 93%, respectively. Fructose 1,6 bisphosphate enhanced 36% of enzyme activity and reverted by 100% the inhibition caused by phenilalanine, 87% that of alanine and 56% that of ATP, but did not revert the inhibition by Ca+2 when at saturating concentration, having a capacity of reverting only 15% of the inhibition caused by near-saturating concentration of Ca+2. The citrate synthase and α-glycerol phosphate dehydrogenase activities were reduced according to increase in the glycolytic activity and had a direct correlation with the histological grading. Differentiated tumors had higher activities. Glutaminase activity was elevated in carcinomas as compared to mammary gland, being even higher in the central regions of the tumors. The enzyme activity was also higher in the moderate differentiated tumors than that in the differentiated tumors, but no significant differences were observed when the tumor size was considered. There was a relationship between the data and the clinicai heterogeneity of the disease.

A podoplanina humana é uma glicoproteína que se expressa em várias células e tecidos normais e neoplásicos, inclusive aqueles de origem odontogênica. O objetivo deste estudo foi identificar a imunolocalização da podoplanina em tumores odontogênicos epiteliais com e sem ectomesênquima incluindo oito ameloblastomas, nove tumores odontogênicos adenomatóides, vinte tumores odontogênicos queratocísticos, cinco cistos odontogênicos ortoqueratinizados, um tumor odontogênico epitelial calcificante, dois fibromas ameloblásticos, quatro fibroodontomas ameloblásticos e cinco tumores odontogênicos císticos calcificantes. Todos os tumores odontogênicos foram submetidos a imuno-histoquímica para o anticorpo anti-podoplanina numa diluição de 1:100 e avaliados, microscopicamente, com base na distribuição tecidual e na intensidade da imunomarcação. Para os tumores odontogênicos queratocísticos e cistos odontogênicos ortoqueratinizados além da podoplanina foi determinado o índice de proliferação celular baseado na positividade nuclear das células do epitélio odontogênico imunomarcadas com o Ki-67 na diluição de 1:200 e comparados estatisticamente pelo coeficiente de correlação de Spearman. Os resultados mostraram uma forte expressão da podoplanina na membrana e no citoplasma do epitélio odontogênico da maioria dos tumores analisados, bem como, em células ectomesênquimais como os odontoblastos e suas extensões dentinárias. A ausência da podoplanina foi identificada nos ameloblastos completamente diferenciados, nas áreas de metaplasia escamosa, nas células fantasmas, nas áreas de calcificação e nos depósitos extracelulares de material eosinofílicos observados nos tumores odontogênicos. No tumor odontogênico queratocístico observou-se uma forte expressão da podoplanina na camada basal e suprabasal do epitélio, enquanto que, nos cistos odontogênicos ortoqueratinizados esta expressão estava ausente ou fracamente distribuída no epitélio. Houve uma correlação estatisticamente significativa (p=0,006) entre a expressão de podoplanina e o índice de proliferação celular dos tumores odontogênicos queratocísticos e cistos odontogênicos ortoqueratinizados. Estes resultados sugerem que a podoplanina participa dos processos de proliferação e diferenciação celular dos epitélios odontogênicos presentes nos tumores odontogênicos benignos dos ossos maxilares. / Human podoplanin is a glycoprotein expressed in various cells and normal and neoplastic tissues, including those of odontogenic origin. The aim of this study was to identify the immunolocalization of podoplanin in epithelial odontogenic tumors with and without ectomesenchyme, including eight ameloblastomas, nine adenomatoid odontogenic tumors, twenty keratocystic odontogenic tumors, five orthokeratinized odontogenic cysts, one calcifying epithelial odontogenic tumor, two ameloblastic fibromas, four ameloblastic fibro-odontomas and five calcifying cystic odontogenic tumors. All odontogenic tumors were submitted to immunohistochemistry using a podoplanin antibody at a dilution of 1:100 and evaluated microscopically, based on the tissue distribution and intensity of immunoreactivity. For keratocystic odontogenic tumors and orthokeratinized odontogenic cysts, in addition to podoplanin, the index of cell proliferation was determined based on the nuclear positivity of odontogenic epithelial cells immunostained with Ki-67 at a dilution of 1:200 and statistically compared by the Spearman correlation coefficient. The results showed strong expression of podoplanin in the membrane and cytoplasm of the odontogenic epithelium of most tumors analyzed, as well as in ectomesenchymal cells as odontoblasts and dentinal projections. Absence of podoplanin was observed in fully differentiated ameloblasts, in areas of squamous metaplasia, in ghost cells, in areas of calcification and extracellular deposits of eosinophilic material observed in odontogenic tumors. The keratocystic odontogenic tumor exhibited strong expression of podoplanin in basal and suprabasal epithelial layers, while in orthokeratinized odontogenic cysts this expression was absent or weakly distributed in the epithelium. There was statistically significant correlation (p=0,006) between the expression of podoplanin and the cellular proliferation index of odontogenic tumors and orthokeratinized odontogenic cysts. These results suggest that podoplanin participates in the processes of cell proliferation and differentiation of odontogenic epithelium present in benign odontogenic tumors of the jaws.

Os tumores odontogênicos compõem um grupo de lesões incomuns, porém interessantes, que se forma a partir dos tecidos que dão origem aos dentes. Esses tumores vêm sendo estudados há décadas por patologistas e cirurgiões que buscam entender seus mecanismos de formação e desenvolvimento, assim como desenvolver técnicas adequadas de tratamento. Inúmeras foram as tentativas realizadas até hoje para classificar esses tumores odontogênicos, sendo a última a nova Classificação de Tumores Odontogênicos da Organização Mundial da Saúde, publicada em 2005. Assim sendo, este trabalho teve por objetivo determinar a prevalência dos tumores odontogênicos diagnosticados nos Serviços de Anatomia Patológica das Faculdades de Odontologia de Bauru (USP) e de Araçatuba (UNESP) no Brasil, e das Faculdades de Odontologia da UNAM, da UAM-X e do Laboratório privado Peribact no México, compará-las e definir um perfil da ocorrência desses tumores nessas instituições e países seguindo essa nova classificação. Todos os casos diagnosticados como tumores e cistos odontogênicos passíveis de reanálise diagnóstica foram selecionados dos arquivos dessas instituições. Os dados demográficos e os aspectos clínicos de cada lesão foram obtidos a partir dos laudos e das fichas de requisição de exame anatomopatológico e as lâminas examinadas por um avaliador. Os resultados demonstraram que a inclusão do queratocisto no grupo de tumores provocou uma alteração significante na prevalência dessas lesões. O tumor odontogênico queratocístico foi a lesão mais prevalente, seguida pelo odontoma, ameloblastoma e mixoma no Brasil e no México. Quanto aos dados demográficos e localização, nossos achados corroboram com aqueles descritos na maior parte dos trabalhos realizados em todo o mundo, com diferenças pontuais em países como a China. Entretanto, a falta de maiores conhecimentos biomoleculares e genéticos dificulta a compreensão dessas diferenças. / Odontogenic tumors constitute a group of uncommon and particularly interesting lesions, arising from the odontogenic tissues. These tumors have been studied for decades by pathologists and surgeons seeking understand the mechanisms of formation and development, and trying to develop appropriate techniques of treatment. Many were the attempts made so far to classify these odontogenic tumors, the most recent being the new classification of odontogenic tumor of the World Health Organization, published in 2005. Therefore, this study aimed to determine the prevalence of odontogenic tumors diagnosed in five centers of diagnostic pathology: Laboratory of Oral Pathology, Faculty of Dentistry of Bauru USP; Laboratory of Oral Pathology, Faculty of Dentistry of Araçatuba UNESP, in Brazil; and Department of Oral Pathology, Faculty of Dentistry UNAM; Laboratory of Oral Pathology, Faculty of Dentistry of UAM-Xochimilco and Peribact Laboratory, a private laboratory of oral pathology, in Mexico; compare them and develop a profile of the occurrence of these tumors in these institutions and countries, following this new classification. All cases diagnosed as odontogenic cysts and tumors were selected for diagnostic review. The demographic and clinical features were obtained from the records when available. The cases were re-evaluated, and the diagnosis in each case was confirmed or modified when necessary. The results showed that the inclusion of keratocyst in the group of tumors caused a significant change in the prevalence of these lesions. The keratocyst odontogenic tumor was the most prevalent lesion, followed by odontoma, ameloblastoma and myxoma in Brazil and Mexico. Our findings corroborate with those reported arround the world, with occasional differences in countries, such as China. However, the lack of molecular and genetic knowledge precludes a better comprehension of these differences.

Ma, Buig Yue Brigette. / Thesis M.D. Chinese University of Hong Kong 2014. / Includes bibliographical references (leaves 232-270). / Title from PDF title page (viewed on 18, November, 2016).

by Lui Chi Pang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 265-281). / Acknowledgements --- p.i / Abbreviations --- p.ii / Abstract --- p.iii / Table of contents --- p.vii / Introduction / Review of Literature --- p.2 / Chapter I. --- Cellular response of hyperthermia --- p.3 / Chapter A) --- Effects on macromolecules synthesis --- p.3 / Chapter B) --- Effects on glycolysis and respiration --- p.5 / Chapter C) --- "Effects on plasma membrane, intracellular ionic level and intracellular pH" --- p.6 / Chapter II. --- Physical aspects --- p.11 / Chapter A) --- Survival curves --- p.11 / Chapter B) --- Concept of thermal dose --- p.13 / Chapter III. --- Clinical thermal theraphy --- p.21 / Chapter A) --- Hyperthermia in vivo --- p.21 / Chapter B) --- Combination of hyperthermia and radiotheraphy --- p.29 / Chapter C) --- Combination of hyperthermia and chemotherapy --- p.37 / Chapter IV. --- Thermotolerance --- p.48 / Scope of study --- p.54 / Materials and Methods / Chapter I. --- Cytotoxicity tests of cells in vitro --- p.59 / Chapter II. --- Whole body hyperthermia on Ehrlich ascite tumour (EAT)-bearing mice --- p.63 / Chapter III. --- Combination of hyperthermia and drugs --- p.66 / Chapter IV. --- Measurement of intracellular pH --- p.68 / Chapter V. --- Assay for sialic acids in the plasma membrane --- p.72 / Chapter VI. --- Assays of nucleolar proteins --- p.76 / Chapter VII. --- Acetylation of nuclear proteins --- p.80 / Chapter VIII. --- Detection of 72-kD heat shock protein --- p.93 / Results and Discussion / Chapter I. --- Cytotoxicity of hyperthermia in vitro --- p.102 / Chapter II. --- Hyperthermia on EAT cells in vivo --- p.131 / Chapter III. --- Cytotoxicity of combination of hyperthermia and drugs --- p.148 / Chapter IV. --- Intracellular pH changes during hyperthermia --- p.162 / Chapter V. --- Modification of sialic acid level in plasma membrane --- p.180 / Chapter VI. --- Conformational changes of nucleolar proteins --- p.193 / Chapter VII. --- Hyperthermic effect on acetylation of nuclear proteins --- p.209 / Chapter VIII. --- Induction of 72-kD heat shock protein --- p.223 / General Discussion / Chapter A. --- Hyperthermic cytotoxicity --- p.249 / Chapter B. --- Effects on plasma membrane and control of intracellular pH --- p.253 / Chapter C. --- Effects on the nuclear proteins --- p.256 / Chapter D. --- Conclusion --- p.263 / Bibliography --- p.264