Orientador: Luis Fernando Barbisan / Banca: Thomas Prates Ong / Banca: Daniel Araki Ribeiro / Resumo: Não Disponível. / Abstract: Lemongrass (Cymbopogon citratus STAPF) has been described as a potential chemopreventive agent. Thus, the present study objectives were evaluate the protective effects of oral treatment with lemongrass essential oil (LGEO) on carcinogenesis initiation phase with N-methyl-N-nitrosurea (MNU) and post-initiation carcinogenesis phase in multipleorgans model, through 7,12-dimethylbenz(a)antracene (DMBA), 1,2-dimethylhidrazine (DMH), and N-buthyl-N-(4-hidroxibuthyl)nitrosamine (BBN) administrations in Balb/C female mice. The animals were distributed into 2 experimental protocols. Experiment 1: the animals were allocated into 3 experimental groups: G1A group (negative control), G2A group (treated with LGEO 500 mg/kg b.wt., i.g., during 5 weeks and, at the end of the 3rd and 5th weeks, received one 30 mg/kg MNU i.p. application) and G3A group (treated with the LGEO vehicle, and MNU at the end of the 3rd and 5th weeks). After 4 hours of each MNU application, blood samples were collected to perform the comet assay, and, at the end of the 5th week, all animals were euthanatized and the urinary bladder, mammary glands and colon were collected for histological analysis, apoptosis and cellular proliferation counting. Experiment 2: the animals were allocated into 3 experimental groups: G1B group (positive control, DDB-treated animals), initiated with DMBA (5x1 mg i.g. applications), DMH (4x30 mg/kg s.c. applications) and BBN (8x7.5 mg/kg i.g. applications) and treated with the LGEO vehicle, and G2B and G3B groups, similarly DDB-treated, and treated with 125 mg/kg or 500 mg/kg LGEO respectively (5x/week during 6 weeks). At the end of the experimental period, all animals were euthanatized and urinary bladder, mammary glands and colon were collected for preneoplastic and neoplastic lesions analysis. The LGEO treatment reduced DNA damage in peripheral blood leukocytes as well as mammary gland cellular proliferation index. / Mestre

Resumo: O teste de carcinogênese experimental em língua de rato Wistar que utiliza a 4- nitroquinoline 1-oxide (4NQO) como agente cancerígeno, é um excelente modelo para se estudar o carcinoma espinocelular em todas as suas fases, além das lesões pré-neoplásicas e neoplásicas induzidas serem semelhantes àquelas da cavidade bucal de seres humanos. O objetivo do presente estudo foi investigar o papel da proteína p53 e de mutações no gene supressor tumoral TP53 exons 5 a 8 durante a carcinogênese induzida pela 4NQO em língua de rato Wistar. Para isso, 30 animais foram tratados com o cancerígeno na concentração de 50 ppm, por via oral (água de beber), e sacrificados 4, 12 ou 20 semanas após o tratamento. Dez animais foram utilizados como controle negativo. Os resultados mostraram diferenças estatisticamente significativas (p<0,05) com a aumento na expressão da proteína p53 nos grupos de animais sacrificados 12 e 20 semanas após a exposição ao cancerígeno, que também apresentaram lesões pré-neoplásicas e carcinomas espinocelulares, respectivamente. Fraca expressão da proteína p53 foi encontrada nos grupos controle e de 4 semanas de exposição ao carcinógeno. O sequenciamento genético dos exons 5 a 8 do gene TP53 não indicou a presença de mutações. Concluindo, a expressão anômala da proteína p53 nas fases intermediária e final da carcinogênese bucal não pode ser relacionada à presença de mutações nos exons 5 a 8 do respectivo gene. / Abstract: The medium-term tongue carcinogenesis assay is a useful model for studying oral squamous cell carcinomas phase by phase. The aim of the present study was to investigate the expressivity of p53, as well as mutations in exons 5-8 of TP53 gene during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO) using immunohistochemistry and DNA sequencing, respectively. A total of 30 male Wistar rats were treated with 4- nitroquinoline 1-oxide in drinking water for 4, 12, and 20 weeks.Ten animals were used as negative control. Statistically differences (p<0.05) were found in p53 expression 12 and 20 weeks after treatment,i.e., pre-neoplastic lesions and squamous cell carcinomas, respectively. A weak immunoexpression was observed in the negative control and in 'normal' oral mucosa following 4 weeks after exposure to 4NQO. Regarding DNA sequencing, no mutation was found in all of the exons evaluated at all experimental periods. Taken together, our results suggest that abnormal p53 expression was present in pre-neoplastic lesions and squamous cell carcinomas of the oral cavity. However, no mutations were detected during oral cancer progression. / Orientador: Jair Cortez Montovani / Coorientador: Daisy Maria Fávero Salvatori / Coorientador: Daniel Araki Ribeiro / Banca: Maria Regina Sposto / Banca: José Vicente Tagliarini / Banca: José Humberto Damante / Banca: Magaly Machado Sales / Doutor

Resumo: O presente estudo foi delineado para investigar a possível ação quimioprotetora do quelato de zinco (ZnGly), na etapa de iniciação da carcinogênese do cólon, induzida pela 1,2- dimetilhidrazina (DMH) em ratos Wistar machos. Os animais foram distribuídos em quatro grupos experimentais e receberam três doses de 40mg/Kg, via subcutânea (sc) de DMH ou EDTA (veiculo da DMH) e 15mg/Kg de quelato de zinco (ZnGly) por gavagem durante quatro semanas. Após a narcose foram coletadas amostras de sangue e, em seguida fragmentos do cólon para dosagens de zinco. O cólon foi removido inteiro, fixado em formalina tamponada a 10%, corado com azul de metileno para análise de incidência de focos de criptas aberrantes (FCAs) e processado histologicamente para análise dos índices de proliferação celular e apoptose. A exposição à DMH aumentou significativamente os índices de proliferação celular e apoptose na mucosa do cólon. A administração do quelato de zinco (ZnGly) não alterou o número e multiplicidade de FCAs e não modificou as taxas de proliferação celular e de apoptose da mucosa do cólon, tanto no grupo tratado com DMH como no respectivo grupo controle. Os resultados deste estudo indicam o zinco não mostrou ação protetora na etapa de iniciação da carcinogênese do cólon induzida pela DMH em ratos Wistar machos / Abstract: The present study was designed to investigate the possible chemopreventive action of zinc gluconate (ZnGly) on the initiation step of colon carcinogenesis induced by 1,2- dimethylhydrazine (DMH) in male Wistar rats. The animals were divided into four groups and received three doses of DMH (40 mg/Kg, s.c) or EDTA (DMH vehicle) and 15 mg/Kg of zinc glycine (ZnGly) administered by gavage for four weeks. After the narcosis, blood and colon fragments samples were collected for zinc dosage. The entire colon was removed, fixed in buffered formalin 10%, stained with methylene blue for the analysis of ACF formation. The rates of cell proliferation and apoptosis were also analyzed in epithelial crypt cells. The exposure to DMH significantly increased the rates of cell proliferation and apoptosis in epithelial cript cells. Treatment with zinc glycine (ZnGly) did not alter the number and multiplicity of ACFs, as well as apoptosis and cell proliferation indices in both DMH-treated and control group. The present findings indicate that zinc did not present chemopreventive effects on the initiation step of DMH-induced colon carcinogenesis in male Wistar rats / Orientador: Maria Aparecida Marchesan Rodrigues / Coorientador: Luis Fernando Barbisan / Banca: Daniel Araki Ribeiro / Banca: Alaor Aparecido Almeida / Mestre

Orientador: Christiane Pienna Soares / Banca: Beatriz Maria Machado de Medeiros / Banca: Paulo Tambasco de Oliveira / Banca: Eduardo Antonio Donadi / Banca: Sérgio Mancini Nicolau / Resumo: As células tumorais infectadas pelo HPV podem apresentar estratégias para escapar da resposta imunológica resultando na persistência da infecção viral e na transformação celular maligna. O objetivo do presente estudo foi investigar o papel das células T e, indiretamente, das células Natural Killer (NK), em lesões orais causadas pelo HPV. A avaliação imunohistoquímica dos receptores de células T em infiltrado linfocitário foi realizada nas 79 biópsias de mucosa oral divididas de acordo com sua diferenciação histológica. Tipos de HPV de alto risco foram mais freqüentes em todas as lesões orais e infecções por diferentes tipos de HPV foram observados na mesma lesão. Diminuição da expressão de CD4/CD25 e CD25/CD28 ( P=0,037) foi observada nas lesões malignas e em todas as lesões com HPV. Menor expressão de CD4 e maior expressão de CD28 foram observadas em lesões orais malignas quando comparadas com as lesões benignas (P=0,005). Em 51 pacientes, elevada expressão de HLA-G foi observada em lesões orais benignas (p<0,01) e progressivamente diminuiu nas lesões pré-malignas e malignas.Correlação inversa (r = - 0,3944, p<0,05) foi observada em lesões orais com HPV, com alta expressão de HLA-G e baixa expressão de HLA-E. Em conclusão, a diminuição da expressão de receptores de células T e de moléculas HLA-E, bem como a maior expressão de moléculas HLA-G pode ser uma estratégia do HPV para escapar da imunovigilância do hospedeiro, resultando na infecção viral persistente e na carcinogênese oral. / Abstract: HPV-infected tumor cells could present strategies to evade from the immune responses, resulting in the persistence of viral infection and to malignant cell transformation. The aim of the present study was to investigate the role of T cells, and, indirectly, natural killer cells, in HPV-infected oral lesions. To investigate T cell receptors in lymphocyte infiltrate, immunohistochemistry evaluation was performed in 79 oral biopsies, stratified according histological differentiation. High-risk HPV types were more frequent among all oral lesions and multiple HPV type infection was observed in the same oral lesions. Downregulation of CD4/CD25 and CD25/28 (P=0.037) was observed in malignant oral lesions and in all oral lesions groups HPV-infected. Lower expression of CD4 and higher expression of CD28 were observed in malignant oral lesions, when compared with benign lesions (P=0.005). In 51 patients, HLA-G overexpression was observed in benign oral lesions (p < 0.01) and progressively decreased in premalignant to malignant oral lesions. An inverse correlation (r = - 0.3944, p< 0.05) was observed in HPV-infected oral lesions, with high HLA-G expression and low HLA-E expression. We can conclude that downregulation of T cell receptors and HLA-E tissue expression as well as upregulation of HLA-G molecule might be an HPV strategy to escape from host immune surveillance, which could result in HPV persistent infection and oral carcinogenesis. / Doutor

Made available in DSpace on 2014-06-11T19:30:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-29Bitstream added on 2014-06-13T19:00:25Z : No. of bitstreams: 1 minicucci_em_dr_botfm.pdf: 755824 bytes, checksum: 476f76bec065be2e3efb743481c7ddac (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O teste de carcinogênese experimental em língua de rato Wistar que utiliza a 4- nitroquinoline 1-oxide (4NQO) como agente cancerígeno, é um excelente modelo para se estudar o carcinoma espinocelular em todas as suas fases, além das lesões pré-neoplásicas e neoplásicas induzidas serem semelhantes àquelas da cavidade bucal de seres humanos. O objetivo do presente estudo foi investigar o papel da proteína p53 e de mutações no gene supressor tumoral TP53 exons 5 a 8 durante a carcinogênese induzida pela 4NQO em língua de rato Wistar. Para isso, 30 animais foram tratados com o cancerígeno na concentração de 50 ppm, por via oral (água de beber), e sacrificados 4, 12 ou 20 semanas após o tratamento. Dez animais foram utilizados como controle negativo. Os resultados mostraram diferenças estatisticamente significativas (p<0,05) com a aumento na expressão da proteína p53 nos grupos de animais sacrificados 12 e 20 semanas após a exposição ao cancerígeno, que também apresentaram lesões pré-neoplásicas e carcinomas espinocelulares, respectivamente. Fraca expressão da proteína p53 foi encontrada nos grupos controle e de 4 semanas de exposição ao carcinógeno. O sequenciamento genético dos exons 5 a 8 do gene TP53 não indicou a presença de mutações. Concluindo, a expressão anômala da proteína p53 nas fases intermediária e final da carcinogênese bucal não pode ser relacionada à presença de mutações nos exons 5 a 8 do respectivo gene. / The medium-term tongue carcinogenesis assay is a useful model for studying oral squamous cell carcinomas phase by phase. The aim of the present study was to investigate the expressivity of p53, as well as mutations in exons 5-8 of TP53 gene during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO) using immunohistochemistry and DNA sequencing, respectively. A total of 30 male Wistar rats were treated with 4- nitroquinoline 1-oxide in drinking water for 4, 12, and 20 weeks.Ten animals were used as negative control. Statistically differences (p<0.05) were found in p53 expression 12 and 20 weeks after treatment,i.e., pre-neoplastic lesions and squamous cell carcinomas, respectively. A weak immunoexpression was observed in the negative control and in ‘normal’ oral mucosa following 4 weeks after exposure to 4NQO. Regarding DNA sequencing, no mutation was found in all of the exons evaluated at all experimental periods. Taken together, our results suggest that abnormal p53 expression was present in pre-neoplastic lesions and squamous cell carcinomas of the oral cavity. However, no mutations were detected during oral cancer progression.

Folates are water-soluble B vitamins, which maintain DNA stability by regulating nucleotide synthesis and DNA methylation. Folates influence CRC risk and their ability to prevent or promote carcinogenesis may be dependent on several variables here investigated. No in vitro study has yet modelled the physiological folate status that human colon cells are exposed to in vivo. This study evaluates the ability of different forms and concentrations of folate to maintain DNA stability and normal cell function in folate-sufficient and stable human colonocytes and to modify DNA instability and the acquisition of abnormal characteristics in folate-deficient and genomically-unstable colonocytes. Non-malignant human NCM460 colonocytes cultured at physiologically-relevant concentrations of 5-methyl-THF or FA, representing the average deficient (2.5 ng/mL), sufficient (10 ng/mL) or highest post-supplementation (100 ng/mL) folate levels found in human plasma were used in this study as a model of colon-folate interaction. This work established that FA is taken up and/or retained to a lesser extent than 5-methylTHF and is less efficient at maintaining DNA stability and normal cellular characteristics in folate-sufficient and genomically-stable colonocytes at baseline, particularly at deficient and sufficient concentrations in the medium to longer term (14-21 days). During repletion of folate-deficient and genomically-unstable cells, sufficient concentrations of FA do not increase intracellular folate status and worsen the unstable phenotype, by perpetuating DNA instability and enabling the acquisition of a more pro-malignant protein expression. On the contrary, employing 5-methyl-THF sufficiency for repletion positively modifies the abnormal protein profile and morphological features of folate-deficient cells, mitigating potential progression to malignant transformation. When high post-supplementation concentrations are employed, both folate forms increase intracellular folate status, but drive a more promalignant and stress-induced proteome profile and, in the case of 5-methyl-THF, promote abnormal cell morphologies. In conclusion, the folate type, concentration employed, baseline folate status and timing of exposure to folate supplementation are important variables that should be taken into account by future studies evaluating the potential impact of mandatory FA fortification on CRC.

Orientadores: Luiz Paulo Kowalski, Oslei Paes de Almeida / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba. / Made available in DSpace on 2018-08-20T00:22:19Z (GMT). No. of bitstreams: 1 Mariano_FernandaViviane_D.pdf: 3892005 bytes, checksum: a69171d91fdd09d696a1fb4a7bc5acc0 (MD5) Previous issue date: 2009 / Resumo: O Carcinoma ex-adenoma pleomorfo (CXAP) é uma neoplasia indolente, cuja patogênese ainda não está esclarecida, embora se acredite que resulte do acúmulo de alterações genéticas em adenoma pleomorfo (AP) de longa permanência. No presente estudo, avaliamos os fatores clincopatológicos em uma série de 38 casos de CXAP provenientes de três instituições do estado de São Paulo, Brasil. Analisamos também, o índice de proliferação celular, através da imunomarcação de Ki-67 em 36 APs, 22 APs provenientes de CXAP e 36 CXAPs nas diferentes fases de progressão maligna (precoces e francamente invasivos), subdivididos quanto aos tipos histológicos, a fim de determinar uma possível ferramenta de auxílio diagnóstico. Com estes mesmos grupos de tumores, estudamos o perfil genético de ganho e perda de número de cópias e metilação de genes supressores de tumor, através da técnica de Multiplex Ligation Probe-Dependent Amplification (MLPA). Os resultados mostraram características clinicopatológicas semelhantes às descritas em grandes séries da literatura. Observamos que a marcação de Ki-67 pode ser uma útil ferramenta na distinção entre AP e CXAP, mesmo em fases precoces de transformação maligna. Este índice mostrou não ser importante para distinção dos subtipos histopatológicos. Além disso, encontramos várias alterações em genes supressores de tumor presentes durante a tumorigênese do AP e carcinogênese do CXAP, e observamos um aumento cumulativo de alterações genômicas, sendo algumas delas, específicas para cada fase / Abstract: Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive neoplasm, and its pathogenesis is still unclear, although it is believed to result from the accumulation of genetic alterations in pleomorphic adenomas (PAs) with long duration. In the present study, we evaluated the clinicopathological features in a series of 38 cases of CXPA from three institutions of the state of Sao Paulo, Brazil. We also analyzed the index of cell proliferation by labeling of Ki-67 in 36 PA, 22 PA from CXPA, and 36 CXPA in different stages of malignant progression (early and frankly invasive) subdivided in histolopathological types, to determine a possible tool to aid the diagnosis. With the same groups of tumors, it was studied also the genomic profile of gain and loss of copy number and methylation of tumor suppressor genes across Multiplex Ligation-Dependent Probe Amplification (MLPA). The results showed similar clinicopathological features to those described in large published series. We observed that Ki-67 is a useful tool in distinguishing between PA and CXPA, even in the early stages of malignant transformation. This index showed no importance for distinction among the several histological subtypes of CXPA. Furthermore, we find that various tumor suppressor genes are altered during PA tumorigenesis and CXPA carcinogenesis, and there is an accumulative increase of genomic alterations that seems to be specific for each phase / Doutorado / Patologia / Doutor em Estomatopatologia

The nucleus may be the critical site for the activation of chemical carcinogens, and subsequently the initiation of neoplasia. However, isolated nuclei may be contaminated with endoplasmic reticulum, the major site of the drug metabolizing enzymes. One of the objectives of the present study was to determine whether the enzymes in isolated rat hepatic nuclei were of nuclear origin and, if so, to compare these enzymes with those in the microsomal fraction. The selective manipulation of nuclear enzymes would be a useful tool in determining their role in cellular toxicity. Recentrifugation experiments, with aryl hydrocarbon hydroxylase (AHH) activity as a marker, showed that isolated nuclei were not contaminated with endoplasmic reticulum in the form of microsomes formed upon homogenization. However, small "tags" of endoplasmic reticulum, continuous with the nuclear membrane, and indiscernable in electron micrographs, could remain following centrifugation and account for all of the measurable enzyme activity in the isolated nuclei. It was reasoned that if endoplasmic reticulum accounted for all of the activity, then the ratio of nuclear to microsomal activity for all enzymes determined should be the same. The ratios of epoxide hydrolase and AHH were found to differ in the two fractions. The simplest interpretation of these data was that drug metabolizing enzymes existed in the nuclei. However, the distribution of drug metabolizing enzymes throughout the endoplasmic reticulum is known to be heterogeneous and these "tags" could differ from the total endoplasmic reticulum (microsomes) in their enzyme make-up. Whether these enzymes are in the nuclear membrane, nucleoplasm, or as "tags" of endoplasmic reticulum, they represent activities in close proximity to potential target sites in the nucleus. The inhibition, induction, and activation characteristics of nuclear and microsomal enzymes were studied with the goal of selective manipulation of nuclear enzymes. The enzymes in the nuclear and microsomal fractions were found to differ' only in quantitative inducibility, and were identical in all other respects. Therefore, the selective manipulation of nuclear enzymes was not achieved. The induction of hepatic drug metabolizing enzymes is a measure of altered genetic expression in the liver. Inducers of drug metabolizing enzymes have also been shown to promote neoplasia in the liver. Therefore, studying the induction of such enzymes may lead to a further understanding of the mechanism of tumour promotion. Phenobarbital, 3-methylcholanthrene and pregnenolone-16α-carbonitrile produce three distinct induction responses. In the present study, spironolactone and trans-stiIbene oxide were shown to produce distinct induction responses, also. Spironolactone was shown to be a different inducer based on the protein band patterns observed following SDS-polyacrylamide gel electrophoresis of liver microsomes. trans-Stilbene oxide was found to produce a significantly different maximal level of AHH activity. The observation of five distinct induction responses suggests at least five recognition sites (receptors) mediating the pleiotropic actions of exogenous compounds in the liver. / Pharmaceutical Sciences, Faculty of / Graduate

Orientadores: José Murilo Robilotta Zeitune, Sandra Cecília Botelho Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-18T12:37:01Z (GMT). No. of bitstreams: 1 Roesler_BrunaMaria_D.pdf: 2549394 bytes, checksum: 8534c8dd497e83d0a6b58932dcf0c4cf (MD5) Previous issue date: 2011 / Resumo: O entendimento acerca da carcinogênese gástrica, que é um processo multifatorial, avançou consideravelmente nas últimas décadas, especialmente no que diz respeito ao papel do Helicobacter pylori no desenvolvimento das lesões pré-cancerosas e na neoplasia propriamente dita, tanto em seu estágio precoce quanto avançado. O H. pylori é uma bactéria gram-negativa, classificada como carcinógeno tipo I pela IARC e que possui um alto grau de diversidade genética, assim como importantes fatores de virulência, o que pode ser verificado através das diferentes cepas encontradas nas doenças do trato gastrointestinal. A determinação, portanto, das cepas mais virulentas, responsáveis, pelo menos teoricamente, pelo desenvolvimento das doenças gástricas mais graves, é de vital importância tanto para estudos epidemiológicos quanto para a determinação de quais são os pacientes com maior probabilidade de desenvolvimento do câncer gástrico, que permanece como um grave problema de saúde pública. No presente estudo foram comparadas cepas da bactéria prevalentes em amostras de tecido gástrico provenientes de pacientes com diagnóstico de adenocarcinoma gástrico distal do tipo intestinal precoce e avançado através do uso de técnicas de biologia molecular para avaliar diferentes regiões genômicas da bactéria: genes ureaseC, vacA (regiões s e m), cagA, cagT e dupA (regiões jhp0917 e jhp0918). Os resultados obtidos foram semelhantes tanto para os casos precoces quanto avançados da doença, porém, uma relação estatisticamente significativa foi encontrada entre o gene cagA e o adenocarcinoma avançado. Em geral, as cepas foram classificadas como vacA s1m1, cagA positivas, cagT positivas e dupA negativas, concluindo-se que cepas com o genótipo vacA s1m1 cagA positivo e cagT positivas podem ser consideradas mais virulentas. Além disso, conclui-se que o gene dupA, apesar de pouco presente nas amostras de câncer gástrico estudadas, não pode ser considerado um marcador exclusivo da úlcera duodenal, como descrito inicialmente / Abstract: The understanding of gastric carcinogenesis, that is a multifactorial process, has advanced considerably in recent decades, especially with regard to the role of Helicobacter pylori in the development of precancerous lesions and cancer, both in its early or advanced stage. H. pylori is a gram-negative bacteria, classified as a group I carcinogen by the IARC and it has a high degree of genetic diversity, as well as important virulence factors, which can be verified through the different strains present in gastrointestinal diseases. Therefore, determination of the most virulent strains, responsible, at least theoretically, for the development of the most severe diseases, as gastric adenocarcinoma, is of fundamental importance for epidemiological studies and for determination of the patients with high probability for development of the disease, which remains as a serious public health problem. In the present study they were compared strains of the bacteria prevalent in early and advanced gastric distal type intestinal adenocarcinoma through molecular biology techniques to evaluate different regions of bacterium genoma: urease C, vacA (regions s and m), cagA, cagT and dupA (jhp0917 and jhp0918 regions) genes. The results were similar for both early and advanced cases of the disease, however, a statistically significant relationship was found between the cagA gene and advanced adenocarcinoma. In general, the strains were classified as vacA s1m1, cagA positive, cagT positive and dupA negative, conducting that strains with the genotype vacA s1m1, cagA positive and cagT positive may be considered more virulent. Moreover, it is concluded that the dupA gene, although found in a little proportion of the gastric cancer H. pylori strains, can not be considered an exclusive marker for duodenal ulcer, as described earlier / Doutorado / Ciencias Basicas / Doutor em Clínica Médica

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22373号 / 医博第4614号 / 新制||医||1043(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武田 俊一, 教授 小川 誠司, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM