Although it is fairly well accepted that Helicobacter pylori infection plays a significant role in causing gastric cancer, the exact mechanisms involved in its pathogenesis are unclear. We have examined the relationship between H. pylori infection and oncogene expression in different stages of disease progression from precursor lesions to gastric carcinoma. We used Diff-Quik stain to diagnose H. pylori infection and immunohistochemical stains against c-erbB-2, p53, ras, c-myc, and bcl-2 to determine expression of oncogenes. H. pylori infection was found in all cases of chronic gastritis, atrophic gastritis, intestinal metaplasia, and early gastric carcinoma, and in 16 of 30 (53%) cases of advanced gastric carcinoma. Overexpression of c-erbB-2 was found in 2 (7%) cases of advanced gastric carcinoma, which were H. pylori negative. Suppressor gene, p53, was overexpressed in 3 (30%) cases of intestinal metaplasia, 2 (33%) cases of early gastric carcinoma, and 18 (60%) cases of advanced gastric carcinoma. Of these 18 p53-positive advanced gastric cancer cases, 11 (61%) were H. pylori positive. Expression of ras p21 was found in 4 (40%) cases of H. pylori-negative normal mucosa, 10 (100%) cases of chronic gastritis, 1 (10%) case of atrophic mucosa, 6 (60%) cases of intestinal metaplasia, 2 (33%) cases of nonneoplastic mucosa adjacent to early gastric carcinoma, and 7 (23%) nonneoplastic mucosa adjacent to advanced gastric carcinoma, all of which showed H. pylori. No evidence of expression of either c-myc or bcl-2 was detected in any of the above-mentioned samples. The data suggest that H. pylori infection may increase expression of ras p21 proteins and induce p53 suppressor gene mutation early in the process of gastric carcinogenesis.

Orientador: Jose Barreto Campello Carvalheira / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T10:00:11Z (GMT). No. of bitstreams: 1 Oliveira_JosenilsonCamposde_D.pdf: 1237045 bytes, checksum: 1e4b99f788f9635f40a69249e72e33ba (MD5) Previous issue date: 2009 / Resumo: A regulação adequada da via de sinalização PI 3-quinase-Akt é essencial para a prevenção da carcinogênese. Dados recentes caracterizaram uma alça de retroalimentação negativa na qual a mammalian target of rapamycin (mTOR), bloqueia a ativação adicional da via Akt/mTOR por meio da inibição da função do substrato 1 do receptor de insulina (IRS-1). Entretanto, a inibição potencial do IRS-1 durante o tratamento com rapamicina não foi estudado. No presente estudo, demonstramos que um oligonucleotídeo anti-sense direcionado ao IRS-1 e a rapamicina antagonizam sinergicamente a ativação da mTOR in vivo e induzem supressão tumoral, por meio de inibição da proliferação e indução de apoptose, em enxertos de células de câncer de próstata. Estes dados demonstram que a inclusão de agentes que bloqueiam o IRS-1 potencializam o efeito da inibição da mTOR no crescimento de enxertos de células de câncer de próstata. / Abstract: Proper activation of phosphoinositide 3-kinase-Akt pathway is critical for the prevention of tumorigenesis. Recent data have characterized a negative feedback loop where in mammalian target of rapamycin (mTOR), blocks additional activation of the Akt/mTOR pathway through inhibition insulin receptor substrate 1 (IRS-1) function. However, the potential of IRS-1 inhibition during rapamycin treatment has not been examined. Herein, we show that IRS-1 antisense oligonucleotide and rapamycin synergistically antagonize the activation of mTOR in vivo and induced tumor suppression, through inhibition of proliferation and induction of apoptosis, in prostate cancer cell xenografts. These data demonstrate that the addition of agents that blocks IRS-1 potentiate the effect of mTOR inhibition in the growth of prostate cancer cell xenografts. / Doutorado / Clinica Medica / Doutor em Clínica Médica

Wang, Chengdong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 113-134). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

O processo da carcinogênese é provocado por múltiplos estágios, envolvendo desordens potencialmente malignas, iniciação, invasão, progressão e metástase. O prognóstico do carcinoma epidermoide de boca (CEB) ainda permanece desfavorável devido ao diagnóstico tardio. Para mitigar esta complicação, biomarcadores tem sido utilizados para ajudar no diagnóstico precoce e entender melhor a influência sobre a carcinogênese oral, onde vias de sinalização são ativadas, principalmente a PI3K/AKT. MIF foi relacionada a progressão de diversos tipos cânceres, porém pouco se sabe seu papel na evolução do CEB. Por isso, o objetivo deste estudo foi identificar e caracterizar através do padrão de expressão imuno-histoquímico proteínas participantes da via de sinalização de PI3K/AKT: AKT1 e PAKT e sua associação com a expressão de MIF em fragmento de mucosa, hiperqueratose sem e com displasia e CEB correlacionando com a progressão da doença e características clinico-demográficos. Foram utilizados 73 blocos de parafina, avaliados quanto à porcentagem da expressão de cada marcador e coletados os dados clínicos epidemiológicos referentes para correlaciona-los à imunomarcação. A imunonopositividade ocorreu nos casos de mucosa normal, sem e com displasia e CEB. Nos casos de mucosa normal foram positivos para PAKT (50%), AKT (60%), MIF (80%). Em sem displasia, foi observado imunomarcação para PAKT (50%) e MIF (50%). Com displasia houve marcação PAKT (81,81%) e MIF (81%). Nos espécimes de CEB ocorreu em PAKT(100%), AKT (95,23%) e MIF (90,5%). Todos os anticorpos tiveram alta expressão no CEB em comparação com a mucosa normal (p<0,0001), sem displasia (p<0,0001) e com displasia (p<0,0001). Observou-se também influência sobre o fator de risco como tabagismo, etilismo e etnia, respectivamente para os grupos sem displasia, CEB e com displasia. Assim, estas proteínas podem ser consideradas potenciais marcadores preditores do CEB. / The carcinogenesis process is caused by multiple stages, involving potentially malignant disorders, initiation, invasion, progression and metastasis. The prognosis of squamous cell carcinoma (CEB) remains unfavorable due to late diagnosis. To mitigate this complication, biomarkers have been used to aid in early diagnosis and better understand the influence on oral carcinogenesis, which are activated signaling pathways, particularly PI3K / AKT. MIF was related to progression of many types cancers, but its role in the evolution of CEB is little known. Therefore, the aim of this study was to identify and characterize by the expression pattern of immunohistochemical participants proteins signaling pathway PI3K / AKT: AKT1 and PAKT and its association with MIF expression in normal mucosa, hyperkeratosis with and without dysplasia and CEB correlating with the progression of the disease and clinical and demographic characteristics. 73 paraffin blocks were used, in which evaluated the percentage of expression of each marker and collected epidemiological clinical data to correlate them to immunostaining. The imunonopositividade occurred in cases of normal mucosa, hyperkeratosis with and without dysplasia. In cases of normal mucosa were positive for PAKT (50%), AKT (60%), MIF (80%). In no dysplasia, immunostaining was observed PAKT (50%) and MIF (50%). With dysplasia was marking PAKT (81.81%) and MIF (81%). In CEB specimens occurred in PAKT (100%), AKT (95.23%) and MIF (90.5%). All antibodies had high expression in the CEB compared to normal mucosa (p <0.0001) without dysplasia (p <0.0001), and dysplasia (p <0.0001). It was also observed influence on the risk factors such as smoking, alcohol consumption and the ethnicity, respectively, for with dysplasia groups, CEB and without dysplasia. Thus, these proteins can be considered potential early diagnostic markers of CEB.

O processo da carcinogênese é provocado por múltiplos estágios, envolvendo desordens potencialmente malignas, iniciação, invasão, progressão e metástase. O prognóstico do carcinoma epidermoide de boca (CEB) ainda permanece desfavorável devido ao diagnóstico tardio. Para mitigar esta complicação, biomarcadores tem sido utilizados para ajudar no diagnóstico precoce e entender melhor a influência sobre a carcinogênese oral, onde vias de sinalização são ativadas, principalmente a PI3K/AKT. MIF foi relacionada a progressão de diversos tipos cânceres, porém pouco se sabe seu papel na evolução do CEB. Por isso, o objetivo deste estudo foi identificar e caracterizar através do padrão de expressão imuno-histoquímico proteínas participantes da via de sinalização de PI3K/AKT: AKT1 e PAKT e sua associação com a expressão de MIF em fragmento de mucosa, hiperqueratose sem e com displasia e CEB correlacionando com a progressão da doença e características clinico-demográficos. Foram utilizados 73 blocos de parafina, avaliados quanto à porcentagem da expressão de cada marcador e coletados os dados clínicos epidemiológicos referentes para correlaciona-los à imunomarcação. A imunonopositividade ocorreu nos casos de mucosa normal, sem e com displasia e CEB. Nos casos de mucosa normal foram positivos para PAKT (50%), AKT (60%), MIF (80%). Em sem displasia, foi observado imunomarcação para PAKT (50%) e MIF (50%). Com displasia houve marcação PAKT (81,81%) e MIF (81%). Nos espécimes de CEB ocorreu em PAKT(100%), AKT (95,23%) e MIF (90,5%). Todos os anticorpos tiveram alta expressão no CEB em comparação com a mucosa normal (p<0,0001), sem displasia (p<0,0001) e com displasia (p<0,0001). Observou-se também influência sobre o fator de risco como tabagismo, etilismo e etnia, respectivamente para os grupos sem displasia, CEB e com displasia. Assim, estas proteínas podem ser consideradas potenciais marcadores preditores do CEB. / The carcinogenesis process is caused by multiple stages, involving potentially malignant disorders, initiation, invasion, progression and metastasis. The prognosis of squamous cell carcinoma (CEB) remains unfavorable due to late diagnosis. To mitigate this complication, biomarkers have been used to aid in early diagnosis and better understand the influence on oral carcinogenesis, which are activated signaling pathways, particularly PI3K / AKT. MIF was related to progression of many types cancers, but its role in the evolution of CEB is little known. Therefore, the aim of this study was to identify and characterize by the expression pattern of immunohistochemical participants proteins signaling pathway PI3K / AKT: AKT1 and PAKT and its association with MIF expression in normal mucosa, hyperkeratosis with and without dysplasia and CEB correlating with the progression of the disease and clinical and demographic characteristics. 73 paraffin blocks were used, in which evaluated the percentage of expression of each marker and collected epidemiological clinical data to correlate them to immunostaining. The imunonopositividade occurred in cases of normal mucosa, hyperkeratosis with and without dysplasia. In cases of normal mucosa were positive for PAKT (50%), AKT (60%), MIF (80%). In no dysplasia, immunostaining was observed PAKT (50%) and MIF (50%). With dysplasia was marking PAKT (81.81%) and MIF (81%). In CEB specimens occurred in PAKT (100%), AKT (95.23%) and MIF (90.5%). All antibodies had high expression in the CEB compared to normal mucosa (p <0.0001) without dysplasia (p <0.0001), and dysplasia (p <0.0001). It was also observed influence on the risk factors such as smoking, alcohol consumption and the ethnicity, respectively, for with dysplasia groups, CEB and without dysplasia. Thus, these proteins can be considered potential early diagnostic markers of CEB.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 137-154).

Background: In addition to patient-related systemic factors directing the immune response, the pathomechanisms of appendicitis (AP) might also include insufficient drainage leading to inflammation caused by decreased peristalsis. Genetic predisposition accounts for 30%–50% of AP. M. Hirschsprung (HSCR), also characterized by disturbed peristalsis, is associated with variants in the RET proto-oncogene. We thus hypothesized that RET variants contribute to the etiology of AP. Methods: DNA from paraffin-embedded appendices and clinical data of 264 children were analyzed for the RET c.135A>G variant (rs1800858, NC_000010.11:g.43100520A>G). In 46 patients with gangrenous or perforated AP (GAP), peripheral blood DNA was used for RET sequencing. Results: Germline mutations were found in 13% of GAP, whereas no RET mutations were found in controls besides the benign variant p.Tyr791Phe (NC_000010.11:g.43118460A>T). In GAP, the polymorphic G-allele in rs2435352 (NC_000010.11:g.43105241A>G) in intron 4 was underrepresented (p = 0.0317). Conclusion: Our results suggest an impact of the RET proto-oncogene in the etiology of AP. Mutations were similar to patients with HSCR but no clinical features of HSCR were observed. The pathological phenotypes in both populations might thus represent a multigenic etiology including RET germline mutations with phenotypic heterogeneity and incomplete penetrance.