Orientadores: Sophie Françoise Mauricette Derchain, Luis Otávio Zanatta Sarian / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T22:51:42Z (GMT). No. of bitstreams: 1 Serra_KatiaPiton_M.pdf: 1719188 bytes, checksum: fd6b0e67d77fd1b8fce08cde3c09dd45 (MD5) Previous issue date: 2010 / Resumo: Introdução: evidências laboratoriais sugerem que a enzima ciclooxigenase-2 (COX-2), é um dos principais componentes da cascata inflamatória. A enzima é responsável pela conversão do ácido araquidônico em prostaglandinas e tromboxanos. Estudos sugerem que a expressão da COX-2 correlaciona-se diretamente com o potencial maligno dos tumores de mama, e essa relação é em parte explicada pelo papel desempenhado pela COX-2 no reforço da neoangiogênese e processos de imortalização celular. Pouco se sabe, no entanto, sobre a relação da expressão da COX-2 com outros marcadores prognósticos e preditivos de tumores de mama como HER-2, p53, e receptores de hormônios (estrogênio [RE] e progesterona [RP]). Objetivos: avaliar a relação entre a expressão da COX-2 e da p53, receptores de hormônios e HER-2 nas frações in situ e invasivo de carcinomas ductais da mama. Sujeitos e métodos: foram incluídas amostras de 87 mulheres com carcinoma invasivo da mama, que tivessem áreas de carcinoma intraductal associadas. A expressão da COX-2, p53 e receptores hormonais foi avaliada por imuno-histoquímica (IHQ), a expressão de HER-2 foi avaliada por IHQ e hibridização fluorescente in situ (FISH). Nas análises estatísticas, os níveis de confiança foram ajustados para 5% (p=0,05). Na análise univariada, qui-quadrados foram calculados para comparar a expressão dos marcadores tumorais nos componentes in situ e invasivo. Coeficiente de correlação intraclasse (ICC) e qui-quadrado foram calculados para avaliar a tabulação cruzada da expressão da COX-2 nos componentes intraductal e invasor. Qui-quadrados foram utilizados para comparar as proporções de tumores in situ e invasivos que expressaram cada um dos marcadores tumorais de acordo com a expressão da COX-2. Todas as tabulações foram novamente testadas de forma multivariada, utilizando modelos de regressão logística para avaliar especificamente a expressão dos marcadores nos componentes intraductal versus invasivos e nos grupos formados pela expresão da COX-2. Resultados: a COX-2 estava expressa em 44 (61%) dos componentes in situ e em 49 (58%) dos componentes invasivos; 44% dos casos expressaram COX-2 em ambos os componentes. Dos componentes invasivos com expressão da COX-2, 17% foram negativos para a enzima no componente intraductal. Em contrapartida, nos tumores que expressaram COX-2 no componente in situ, 17% apresentaram resultados negativos para a enzima em seu componente invasivo (ICC 0,29, p=0,02). Não houve diferença estatística na expressão da COX-2 ao comparar os componentes intraductal e invasivo dos tumores (p=0,80). A expressão da p53 foi maior no componente intraductal (52%), comparada ao invasor (33%) (p<0,01). O HER-2 estava superexpresso em 21% na fração in situ e 28% no componente invasivo (p=0,49); 69% dos componentes intraductais foram positivos para RE. Aproximadamente a mesma proporção (75%) dos tumores invasivos foram também positivos para RE (p=0,36). Houve um desequilíbrio marginal na expressão de RP, com maior prevalência deste na forma in situ (59% versus 46% no componente invasivo, p=0,08). No componente intraductal, houve uma diferença estatisticamente limítrofe da expressão da p53 em tumores que também expressaram COX-2 (66% versus 44% em amostras negativas para COX-2 p=0,07). No entanto, a proporção de tumores que expressaram HER-2 (p=0,73), RE (p=0,25) e RP (p=0,57) não diferiu em tumores que expressaram ou não a COX-2. Houve uma proporção ligeiramente maior (84% versus 67%) das amostras RE positivas no grupo de tumores invasivos que expressaram COX-2 (p=0,07). Em contrapartida, a expressão de RP não foi relacionada com a da COX-2 (p=0,22) na avaliação multivariada. Conclusões: a expressão da COX-2 foi semelhante nas frações intraductal e invasora das neoplasias de mama. A expressão da p53 foi marginalmente superior nas frações in situ que expressavam COX-2. Na fração invasora, houve maior proporção de tumores expressando receptores de estrógeno entre os que expressaram COX-2 / Abstract: Introduction: laboratorial evidence implicates the cyclooxygenase-2 (COX-2) enzyme as one of the major components of the inflammatory cascade. The enzyme is responsible for the conversion of aracdonic acid in prostaglandins and tromboxanes. Previous research suggests that COX-2 expression correlates directly with the malignant potential of breast tumors, and this relation is, at least in part explained by the role played by COX-2 in the enhancement of the neoangiogenesis and cell immortalization processes. Little is known, however, about the relation of COX-2 expression with other well-stablished breast tumor prognostic and predictive markers, e.g. HER-2, p53, and hormone (estrogen [ER] and progesterone [PR]) receptors. Objectives: to assess the relationship between the expression of COX-2 and that of p53, hormone receptors (estrogen (ER) and progesterone (PR)) and HER-2 in the in situ and invasive regions of ductal carcinomas of the breast. Subjects and methods: samples from 87 women with invasive carcinoma of the breast with areas of in situ carcinoma were included. The expressions of COX-2, p53 and hormone receptors were assessed with immunohistochemistry (IHC); the expression of HER-2 was assessed with IHC and Fluorescent in situ Hybridization (FISH). In statistical analyses, confidence levels were set to 5% (p 0.05). In univariate analysis, chi-squares were calculated to confront the expression of the tumor markers in the in situ and invasive components. The intraclass correlation coefficient (ICC) and chi-squares were calculated to assess the cross-tabulation of COX-2 expression in the in situ versus invasive components. Then, chi-squares were also used to compare the proportions of tumors expressing (individually for the in situ and invasive components) each of the tumor markers in the groups formed according to the COX-2 expression. All tabulations were then retested in a multivariate fashion, using logistic regression models fit specifically for the comparison of marker expression in the in situ versus the invasive components, and in the COX-2-positive and negative groups. Results: COX-2 was expressed in 44 (61%) of the in situ components and in 49 (58%) of the invasive components; 44% of the cases expressed COX-2 in both components. Of the tumors whose invasive components expressed COX-2, 17% were negative for the enzyme in the in situ component. By contrast, of the tumors that expressed COX-2 in the in situ component, 17% were negative for the enzyme in their invasive component (ICC 0.29; p=0.02). There was no statistical difference in COX-2 expression comparing the in situ and invasive components of the breast tumors (p 0.80). The p53 expression was higher in the in situ component (52%), contrasted to that in the invasive (33%) region of the tumors (p<0.01). HER-2 was expressed in 21% in the in situ component and 28% in the invasive component (p=0.49). Sixty-nine percent of the in situ components tested positive for ER, and approximately the same proportion (75%) of the invasive components were positive for ER (p=0.36). There was a marginal imbalance in PR expression, favoring the in situ component (59% versus 46% in the invasive component; p=0.08). In the in situ component, there was a statistically borderline increase in p53 expression in tumors that also expressed COX-2 (66% versus 44% in COX-2 negative specimens p=0.07). However, the proportions of tumors that expressed HER-2 (p=0.73), ER (p=0.25) and PR (p=0.57) did not differ in tumors that expressed or not COX-2 protein. There was a marginally increased proportion (83% versus 66%) of ER-positive specimens in the group of invasive tumors that expressed COX-2 (p=0.07). By contrast, PR expression was not related to that of COX-2 (p=0.22) in the multivariate assessment. Conclusions: the expression of COX-2 was similar in the in situ and invasive regions of the breast neoplasms. The expression of p53 was marginally higher in the in situ regions that were positive for COX-2. In the COX-2-positive invasive regions, there were a higher proportion of ER-positive tumors / Mestrado / Oncologia Ginecológica e Mamária / Mestre em Ciências da Saúde

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / COX-2 e Caderina-E participam de forma fundamental na manutenÃÃo do estado fisiolÃgico da mucosa gÃstrica e tÃm papel essencial na reaÃÃo inflamatÃria e reparo, e no cÃncer. O objetivo deste trabalho à avaliar a expressÃo das duas proteÃnas no carcinoma gÃstrico e metÃstases linfonodais e suas possÃveis participaÃÃes na progressÃo tumoral. Foram utilizados 97 casos de gastrectomias por carcinoma gÃstrico, 36 dos quais com linfonodos disponÃveis, dos arquivos do Hospital do CÃncer do CearÃ. Os casos foram classificados nos tipos intestinal (40 casos), difuso (34), mistos (16) e nÃo-classificados (7 casos) de acordo com a classificaÃÃo de Lauren (1965). Utilizou-se tÃcnica de tissue microarray associada à imunohistoquÃmica com anticorpo monoclonal anti-COX-2 e anti-Caderina-E e sistema de detecÃÃo universal estreptavidina-biotina-peroxidase. A expressÃo de COX-2 foi avaliada de acordo com os seguintes escores: Intensidade (I): 0=negativa; 1=discreta; 2= moderada; 3= acentuada; ExtensÃo (E) de cÃlulas coradas: 1= 0 a 25%; 2= >25 a 50%; 3= >50 a 75%; 4= >75 a 100%. Escore final: I x E, sendo considerados escores < 6 como COX-2 de baixa expressÃo e escores &#8805;6 de alta expressÃo. Classificou-se a expressÃo de Caderina-E nos escores: 0=negativo; 1=citoplasmÃtica; 2=citoplasmÃtica + membranar; 3= membranar-normal (Jawhari et al., 1997a). Foram comparadas expressÃo normal e anormal e membranar e nÃo membranar em cada histotipo de carcinoma, na sede primÃria e linfonodos. ExpressÃo positiva para COX-2 e anormal de Caderina-E predominaram nos diversos histotipos de carcinoma gÃstrico primÃrio, principalmente difusos e mistos. Observou-se maior expressÃo de COX-2 nas metÃstases linfonodais, em relaÃÃo Ãs lesÃes primÃrias, sobretudo nos carcinomas difusos. Carcinomas intestinais estavam associados à expressÃo membranar de Caderina-E enquanto tumores difusos se relacionaram com ausÃncia de expressÃo membranar, o que mostra a importÃncia da Caderina-E na diferenciaÃÃo do cÃncer gÃstrico. Carcinomas gÃstricos apresentam dois padrÃes de imunomarcaÃÃo citoplasmÃtica: granular (paranuclear), associado à expressÃo citoplasmÃtica exclusiva, que prevalece no componente difuso dos tumores mistos, e homogÃneo, em todo o citoplasma, correlacionado com expressÃo citoplasmÃtica-membranar, predominante nos outros histotipos. Carcinomas difusos apresentam expressÃo membranar de Caderina-E, que se expressa com maior freqÃÃncia nas metÃstases linfonodais do que nas lesÃes primÃrias e està presente em grupos celulares infiltrantes e cÃlulas isoladas, nas duas sedes anatÃmicas. Os dados sugerem que o carcinoma misto representa histotipo distinto de carcinoma gÃstrico, baseado nos aspectos peculiares da expressÃo citoplasmÃtica de Caderina-E aqui mostrados e em outros achados da literatura. NÃo houve associaÃÃo estatisticamente significativa entre expressÃo de COX-2 e de Caderina-E e demais parÃmetros clÃnico-patolÃgicos nesta amostra. Os dados aqui observados sugerem que COX-2 e Caderina-E sÃo importantes proteÃnas relacionadas com a progressÃo tumoral-linfonodal no cÃncer gÃstrico / Both COX-2 and E-Cadherin play important roles in physiological and pathological processes in the stomach, such as control of acid secretion, inflammation and cancer. The aim of this study was to analyze the relationship between COX-2 and E-Cadherin immunoexpression in human gastric adenocarcinomas and respective lymph node metastases and their possible action in tumoral progression. Tissue microarrays were prepared from paraffin embedded samples of 97 primary gastric cancers, included 36 with respective nodal metastases. Cases were classified according to Laurenâs classification as intestinal (n=40), diffuse (n=34), mixed (n=16) and undetermined (n=7). Immunoexpression of COX-2 was evaluated regarding intensity (0-absent; 1-mild; 2-moderate; 3-strong) and extension (0-negative or rare cells; 1-<25%; 2-25-50%; 3-50-75%; 4->75% immunoreactive neoplastic cells). A combined score was calculated (intensity x extension): 0-12. A cut-off of 6 was considered to classify COX-2 expression as low (<6) or high (&#8805;6). E-Cadherin expression was evaluated according to the system proposed by Jawhari et al. (Gastroenterology, 1997) as abnormal patterns of expression: 0-no expression; 1-cytoplasmic expression; 2-heterogeneous expression, both membranous and cytoplasmic) and normal membranous pattern (3). Membranous (scores 2 and 3) and Non-membranous (scores 0 and 1) were too compared. Overall, COX-2 positive and abnormal E-Cadherin expression predominate in all types of primary gastric carcinomas. COX-2 expression was higher in lymph node metastases than in primary tumors, with a significant difference for diffuse carcinoma. A positive relationship was observed between E-Cadherin membranous expression and intestinal tumors, and absence of membranous expression and diffuse ones, which indicates the importance of E-Cadherin to gastric cancer differentiation. Granular (paranuclear) cytoplasmic immunostaining pattern was basically associated with cytoplasmic E-Cadherin expression while homogeneous pattern is frequently seen in cytoplasmic-membranous expression. Diffuse carcinomas show membranar expression more frequently in lymph nodes metastases than in gastric primary tumors in both isolated and grouped cells. The data suggest that mixed carcinoma is a distinct hystotype, based on its peculiar cytoplasmic expression of E-Cadherin shown here and other features of literature. There was no significant association linking COX-2 and E-Cadherin expression to other clinicopathological parameters. The data show that COX-2 and E-Cadherin are important proteins related to tumoral progression in gastric cancer

Orientadores: Sophie Fraçoise Mauricette Derchain, Luís Otávio Zanatta Sarian / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T00:11:32Z (GMT). No. of bitstreams: 1 Serra_KatiaPiton_D.pdf: 3794654 bytes, checksum: ce5565714883e2e12d99e6f9ed0ca141 (MD5) Previous issue date: 2014 / Resumo: Introdução: Na última década, doferentes subtipos moleculares de cancer de mama foram propostos. A classificação clinic-patológicas dos subtipos vem comprovando ser estratégica para predizer sobrevida e resposta ao tratamento. Modificação recente da classificação considera a avaliação semiquantitativa da expressão dos RP no curso clínico e resposta ao tratamento. Embora exista associação apreciável com o prognóstico e indicação de terapia citotóxica e endócrina, os subtipos parecem falhar em explicar completamente o comçortamento da doença e a resposta ao tratamento. Moléculas como as da família das cicloxigenases (COX), composta por três entidades (COX 1, 2 e 3) vem demonstrando associação com a carcinogênese mamária, e a análise da expressão da p53 nos tumores de mama pode também oferecer informações adicionais para determinação do prognóstico. Objetivos: Foi avaliada a associação entre os subtipos clinic-patológicos do cancer de mama com o prognóstico e fatores preditivos em uma relativamente grande casuística de pacientes Brasileiras com câncer de mama, que foram acompanhadas por cerca de quatro anos. Foram discutidas as vantagens e possíveis ressalvas relacionadas à nova classificação. Também foi mensurada a expressão da COX2 e da p53 em relação aos subtipos clínico-patológicos e avaliada se a expressão destas molécular poderia explicar a variabilidade no prognóstico ainda encontrada entre os subtipos clínico-patológicos do câncer de mama. Metodologia: Um total de 183 amostras de cancer de mama foram obtidas de mulheres tratadas no Hospital da Mulher da Universidade Estadual de Campinas, Campinas, Brasil, entre Junho de 2008 e Janeiro de 2011. Tissue microarrays (TMA) foram construídos dos blocos originais de parafina para realização de imunoistoquímica (IQ) e hibridização fluorescente in situ (FISH). IQ foi realizada para detecção da expressão de RE, RP, ki67, COX2 e p53; o status do HER2 foi avaliado por FISH nas 183 amostras. Os tumores foram classificados em cinco categorias de acordo com a definição correspondente clinic-patológica dos dos subtipos intrínsecos do câncer de mama, definida durante a 13th St Gallen International Breast Cancer Conference (2013). As características clínicas e patológicas das pacientes e seus tumors e a sobrevida foi avaliada em relação aos subtipos clínico-patológicos, a COX2 e a p53. O tempo médio de seguimento foi 2,94 anos (90% faixa central = 0,93 a 4,1 anos). Resultados: Aproximadamente 75% dos tumors foram classificados como luminais-like. OS HER2 positivos (não luminais) somaram 9,3% dos casos e os Triplos-negativos 13,1%. Os Luminais B-like e HER2 positivos (não luminais) foram associados a alto grau histológico quando comparados aos Luminais A-like (p<0,01). Os Luminais A-like associaram-se significativamente com melhor sobrevida global e livre de doença quando comparados aos HER2 positivos (não luminais) e Triplos-negativos. Não houve tendência à expressão de COX2 relacionada aos subtipos de Luminal A-like a Triplo-negativo. Em contraste, a p53 se expressou em cerca de 67% dos tumores Luminais A-like, 50% dos Luminais B-like HER2 positivos, 60,9% dos Luminais B-like HER2 negativos, 82% dos HER2 positivos (não luminais) e 87% dos Triplos-negativos (p para tendências = 0.06). Houve uma significativa expressão de COX2 nos tumors (66,9%) quando a p53 eram também positive, comparada àqueles tumors que não expressavam p53 (em cujo caso apenas 18,0% dos tumores foram positivos para COX2; p<0,001). Nem a COX2, nem a p53 se relacionaram à sobrevida das pacientes. Conclusões: O critério mais estrito para definer os tumors Luminais A-like aumentou a acurácia da classificação para selecionar tumors que partilhem um bom prognóstico e respondam a terapia endócrina. Parece haver uma associação positive entre a expressão da COX2 e da p53. Por outro lado, nem a expressão da COX2 nem a da p53 se associaram aos subtipos clínico-patológicos, características clínicas e do tumor e ao prognóstico. Parece ser muito cedo para eleger a detecção de COX2 usando IQ como ferramenta de prognóstico ou preditiva, mas evidências incipientes apontam para um possível papel para o marcador / Abstract: Background: In the last decade, different molecular subtypes of breast cancer have been proposed. The clinico-pathological surrogate subtypes of breast cancer classification has been proven as straightforward strategy to predict patient survival and response to treatment. Recent modifications to the classification considered the semi quantitative evaluation of the expression of PR in the clinical course and response to treatment. Although displaying appreciable association with disease prognosis and the prognostic value of cytotoxic and endocrine therapeutic modalities, the subtypes seem to fail at completely explaining disease behavior and response to treatment. Molecules such as those of the cyclocooxigenase (COX) family, currently composed of three entities (COX 1, 2 and 3) have been shown to be associated with breast carcinogenesis, and the analysis of p53 expression in breast tumors may also offer some additional prognostic clues. Objectives: We tested the association of the current clinico-pathological surrogate subtypes of breast cancer with the main prognostic and predictive factors in a relatively large dataset of breast cancer Brazilian patients, which were followed up for almost four years. We discuss the advantages and possible caveats related to this new classification. Our study also assessed COX2 and p53 expression in these clinico-pathological subtypes, and evaluated whether the expression of these molecules could help further explain the variability in prognosis still found within the surrogate molecular groups of breast cancer. Methods: A total of 183 breast cancer samples were obtained from women treated at the Women's Hospital of Campinas State University, Campinas, Brazil, between June 2008 and January 2011. Tissue microarrays (TMA) were constructed from the original paraffin blocks for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses. Immunohistochemistry was performed to detect the expression of ER, PR, ki67, COX2, and p53; the HER2 status of the 183 specimens was assessed using FISH. Tumors were subtyped into five distinct categories according to the Clinico-Pathological surrogate definitions of intrinsic subtypes of breast cancer defined during the 13th St Gallen International Breast Cancer Conference (2013). Clinical and pathological features of patients and their tumors, and patients¿ survival were assessed in relation to the surrogate subtypes, COX2 and p53. Mean follow-up time was 2.94 years (90% central range = 0.93 to 4.1 years). Results: Approximately 75% of the tumors were classified as luminal-type-like. HER2 positive (non-luminal) tumors accounted for 9.3% of the cases and Triple-negative tumors for the remainder 13.1%. Luminal B-like and HER2 positive (non-luminal) tumors were associated with higher histological grades when compared to Luminal A-like tumors (p<0.01). Luminal A-like tumors were significantly associated with better disease free and overall survival when compared to HER2 positive (non-luminal) and Triple-negative tumors. There was no trend in COX2 overexpression from Luminal A to Triple-negative subtypes. By contrast, p53 was expressed in roughly 67% of the Luminal A-like tumors, 50% of the Luminal B-like HER2 positive tumors, 60.9% of the Luminal B-like HER2 negative, approximately 82% of the HER2 positive (non-luminal) and 87% of the Triple-negative tumors (p for trends = 0.06). There was a significantly higher proportion of COX2 positive tumors (66.9%) when p53 was also positive compared to when the tumor was negative for p53 (in which case only 18.0% of the tumors were positive for COX2; p<0.001). Neither COX2 nor p53 were found to be associated with patients¿ survival. Conclusions: The more strict criteria to define Luminal A-like tumors increased the accuracy of the classification by selecting tumors that share a good prognosis and response to endocrine therapy.There seems to be a positive association between the expressions of COX2 and p53. On the other hand, neither the expression of COX nor that of p53 was associated with clinic-pathological subtypes, tumor features and prognosis. It seems to be too early to elect the detection of COX2 using IHC as prognostic or predictive tool, but incipient evidence points towards a possible role for the marker / Doutorado / Oncologia Ginecológica e Mamária / Doutora em Ciências da Saúde

No description available.

Cyclooxygenase-2 (COX-2) is a prostaglandin-generating enzyme that exhibits low basal expression levels and is upregulated in the central nervous system (CNS) in response to inflammatory stimuli. COX-2 has been implicated in the microglial-mediated neuroinflammatory and neurodegenerative processes of multiple sclerosis (MS), a demyelinating autoimmune disease. To study COX-2 activity and the role it may play in demyelination, a novel PET radiotracer specific for COX-2, [11C]BRD1158, was developed and evaluated in the lysolecithin rodent model of focal demyelination with PET-MR imaging. Preliminary results of this pilot pre-clinical study confirmed our hypothesis that the properties of [11C]BRD1158 enable visualization and monitoring of COX-2 activity under pathological conditions induced by LPC. Radiotracer uptake correlated positively with disease progression at the site of LPC injection in male rats, peaking at day 7 and resolving by day 28. Treatment with an FDA-approved MS therapy, Siponimod, diminished the increase in COX-2 activity and tracer uptake at the lesion site and throughout the brain in both male and female rats. The results from the present study will inform future pre-clinical and translational work that validates the use of [11C]BRD1158 to image COX-2 activity as a marker of underlying inflammation in MS, leading to a better understanding of pathological and inflammatory processes in MS development and progression.

No description available.

No description available.

No description available.

Chu Wai Kit. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 87-96). / Abstracts in English and Chinese. / Acknowledgments --- p.ii / Publication --- p.iii / List of Abbreviations --- p.iv / List of Tables --- p.v / List of Figures --- p.vi / Abstract --- p.vii / 摘要 --- p.x / Table of Contents --- p.xii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Epidemiology of gastric cancer --- p.1 / Chapter 1.2 --- Risk factors associated with gastric cancer --- p.7 / Chapter 1.3 --- Prevention of Gastric Cancer --- p.9 / Chapter 1.4 --- H. pylori eradication and gastric cancer development --- p.11 / Chapter 1.5 --- Non-steroidal anti-inflammatory drugs and gastric cancer prevention --- p.13 / Chapter 1.6 --- COX-2 independent pathway --- p.14 / Chapter 1.7 --- Animal model of gastric cancer --- p.15 / Chapter 1.8 --- Microarray system --- p.16 / Chapter 1.9 --- Hypothesis --- p.18 / Chapter 1.10 --- Aim of study --- p.19 / Chapter Chapter 2 --- Chemoprevention of gastric cancer by celecoxib --- p.20 / Chapter 2.1 --- Introduction --- p.20 / Chapter 2.2 --- Material and Methods --- p.22 / Chapter 2.2.1 --- Animals --- p.22 / Chapter 2.2.2 --- Chemicals --- p.22 / Chapter 2.2.3 --- Study design --- p.23 / Chapter 2.2.4 --- Cell Culture --- p.24 / Chapter 2.2.5 --- Celecoxib treatment --- p.24 / Chapter 2.2.6 --- Cell proliferation assay --- p.25 / Chapter 2.3 --- Results --- p.26 / Chapter 2.3.1 --- Chemoprevention of gastric cancer by celecoxib in rats --- p.26 / Chapter 2.3.2 --- Effects of celecoxib on growth of human gastric cancer cells --- p.29 / Chapter 2.4 --- Discussion --- p.30 / Chapter 2.4.1 --- MNNG induced gastric cancer effectively --- p.30 / Chapter 2.4.2 --- Celecoxib significantly suppressed gastric carcinogenesis in rats --- p.31 / Chapter 2.4.3 --- Celecoxib inhibited the growth of MKN 45 in a concentration-dependent manner --- p.31 / Chapter 2.4.4 --- Celecoxib may exert its anti-tumor property through COX independent pathway --- p.32 / Chapter Chapter 3 --- Gene expression profiles of celecoxib treated rat gastric tumor and human gastric cells --- p.34 / Chapter 3.1 --- Introduction --- p.34 / Chapter 3.2 --- Material and Methods --- p.34 / Chapter 3.2.1 --- RNA extraction --- p.34 / Chapter 3.2.2 --- Target preparation and Array hybridization --- p.35 / Chapter 3.2.3 --- Post-hybridization processing and Scanning --- p.36 / Chapter 3.2.4 --- Microarray data analysis --- p.36 / Chapter 3.2.5 --- Quantitative RT-PCR --- p.37 / Chapter 3.3 --- Results --- p.39 / Chapter 3.3.1 --- Gene expression profiles of rat gastric tumors --- p.39 / Chapter 3.3.1.1 --- Genes differentially expressed in MNNG induced gastric tumors --- p.39 / Chapter 3.3.1.2 --- Genes differentially expressed in celecoxib treated group --- p.42 / Chapter 3.3.1.3 --- Mechanisms underlying chemoprevention of celecoxib --- p.43 / Chapter 3.3.2 --- Verification of gene expression by quantitative RT-PCR --- p.55 / Chapter 3.3.3 --- Confirmation of the gene expression profiles in human by quantitative RT-PCR --- p.59 / Chapter 3.4 --- Discussions --- p.63 / Chapter Chapter 4 --- Effects of celecoxib on Akt pathway in gastric cancer cells --- p.68 / Chapter 4.1 --- Introduction --- p.68 / Chapter 4.2 --- Material and methods --- p.72 / Chapter 4.2.1 --- Protein extraction --- p.72 / Chapter 4.2.2 --- Western blotting --- p.72 / Chapter 4.3 --- Results --- p.74 / Chapter 4.3.1 --- Expression of the Akt pathway after treatment with celecoxib --- p.74 / Chapter 4.4 --- Discussions --- p.78 / Chapter Chapter 5 --- Conclusion --- p.82 / References --- p.87

Objective: To appraise whether adverse events following oral implant placement may be associated with peri-operative use of non-steroidal anti-inflammatory drugs (NSAIDs). Methods: All patients with recorded implant failures between 1979 and 2012 in the Implant Prosthodontics Unit were contacted to solicit additional information about potential peri-operative use of NSAIDs. Results: From a total of 168 patients with 292 implant failures between 1979 and 2012, 122 consented to participate and had intact records. Just over half (56.6%) reported no peri-operative NSAID usage. However, compared to patients who did not use peri-operative NSAIDs, four times as many had complicated medical histories and twice as many patients taking NSAIDs suffered multiple implant failures. Conclusions: Patients with a variety of systemic diseases may be adversely affected by the inhibitory effect of NSAIDs on bone healing. Further prospective clinical studies are warranted to clarify this potential causative relationship in humans.