Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-29T14:32:15Z No. of bitstreams: 1 joselucaspereirajunior.pdf: 1221730 bytes, checksum: 46c988cc882709d3927e2736fd180ae8 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-30T11:21:22Z (GMT) No. of bitstreams: 1 joselucaspereirajunior.pdf: 1221730 bytes, checksum: 46c988cc882709d3927e2736fd180ae8 (MD5) / Made available in DSpace on 2017-03-30T11:21:22Z (GMT). No. of bitstreams: 1 joselucaspereirajunior.pdf: 1221730 bytes, checksum: 46c988cc882709d3927e2736fd180ae8 (MD5) Previous issue date: 2009-08-28 / Marcadores biológicos têm sido estudados com objetivo de identificar fatores que possam predizer a evolução dos pacientes com câncer colorretal e ajudar a selecionar os grupos com alto risco de recidiva; porém estudos existentes são insuficientes para serem recomendados para emprego clínico. O objetivo deste trabalho foi verificar a correlação da resposta inflamatória em pacientes com câncer colorretal como potenciais marcadores de atividade tumoral. Foi realizado um estudo observacional do tipo descritivo para avaliação de marcadores de atividade tumoral em pacientes portadores de adenocarcinoma colorretal. Foram coletadas amostras de sangue no pós-operatório para a dosagem do nível da proteína C-reativa (PCR) e análise da interleucina-10 (IL-10). Os níveis séricos dos pacientes foram analisados de acordo com dois grupos de pacientes: ressecção curativa e não curativa. A correlação dos níveis da PCR e do antígeno carcinoembrionário (CEA) no grupo de ressecção curativa foi significativamente menor em relação ao grupo de ressecção não curativa (p<0,05). Em relação aos níveis de IL-10, não foi observada uma diferença significativa entre os grupos (p >0,05). O estudo sugere que a PCR reflete atividade tumoral quando seus níveis estão elevados. Não houve uma correlação dos níveis de IL-10 com atividade tumoral. / Biological markers have been studied in order to identify factors that would be able to predict evolution of patients with colorectal cancer that could help to select high risk relapse groups. However, none of them has been recommended for clinical use. The objective of this work was to verify the correlation between the inflammatory response and tumor activity in patients with colorectal carcinoma. An observational and descriptive study was performed. Blood samples from 28 patients were collected postoperatively for determination of C-reactive protein (CRP) and Interleukin-10 (IL-10). The analysis was performed comparatively according to curative and non curative resection. The correlation levels of CPR and carcinoembryonic antigen (CEA) in the curative resection group was lower compared with non curative resection group (p< 0.05). No difference between the groups was observed in the levels of IL-10. This study suggests that high levels of CRP, but not IL-10 reflect tumor activity.

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Das essentielle Spurenelement Selen (Se) wird als einziges Spurenelement über den genetischen Code als Bestandteil der 21. proteinogene Aminosäure Selenocystein (SeCys) in eine kleine Gruppe von Proteinen eingebaut. Als Bestandteil des aktiven Zentrums dieser Selenoproteine ist Se bzw. SeCys essentiell für deren Funktion. Die Biosynthese der Selenoproteine ist durch eine Reihe von Besonderheiten gekennzeichnet, so z.B. durch eine hierarchisch abgestimmte Versorgung der unterschiedlichen Organe mit dem limitierenden Spurenelement bzw. durch eine hierarchische Versorgung der einzelnen Selenoproteine während ihrer Biosynthese. Für die biologische Verwertung und Verteilung ist das Selenoprotein SePP von zentraler Bedeutung. Transkriptomanalysen haben aufgezeigt, dass gerade in Tumoren die Expression von SePP stark erniedrigt ist. In dieser Arbeit wurde untersucht, inwieweit der Verlust von SePP einen kausalen Einfluss auf die Tumorigenese nimmt. Hierzu wurden zwei transgene Mausmodelle verkreuzt: zum einen Mäuse mit einem partiellen bzw. kompletten genetischen Verlust der SePP-Expression und zum anderen Mäuse mit einer Mutation im APC-Tumorsuppressorgen, welche multiple intestinale Neoplasien (Min) auslöst und als Paradigma in der experimentellen Darmkrebsforschung dient. Der komplette Verlust des SePP-Gens bewirkte eine stark erhöhte Tumorrate im Dünndarm der APCmin-Mäuse. Hierdurch konnte SePP als neuer wichtiger Modulator der APC-abhängigen Tumorigenese etabliert werden. Interessanterweise genügte bereits der Verlust eines einzelnen SePP-Allels, um mehr, größere und weniger differenzierte Adenome im Dünndarm entstehen zu lassen. Diese Beobachtung deutet auf einen entscheidenden Gen-Dosis-Effekt von SePP für die intestinale Tumorigenese hin und könnte damit als weiteres sinnvolles Kriterium zur Feindiagnostik von Darmkrebs dienen. Die molekularbiologischen Untersuchungen der Tumore lassen eine Aktivierung von Zellzyklus-, Angiogenese- und Akutphaseprozessen vermuten. Hierdurch und über die erhöhte Produktion von Wachstumsfaktoren kann die vermehrte Tumorigenese bei SePP-Mangel erklärt werden. Weitergehend konnte auch der Darm, ungeachtet seiner primären Rolle bei der Selenaufnahme, als abhängig von einer regulären SePP-Expression erkannt werden. Somit stellt sich SePP als zentraler Vermittler des Selenmetabolismus dar, und könnte auf lange Sicht als funktioneller Biomarker des Selenstatus für die individuelle Risikoabschätzung etabliert werden. / Selenium (Se) is the only trace element which is encoded in the genome as the 21st proteinogenic amino acid selenocystein (Sec). Se is essential for the catalytic activity of the small group of Sec-containing selenoproteins. The biosynthesis of this group of extraordinary proteins is characterized by several specialities, e.g. the distribution of Se differs between the organs giving rise to a hierarchical biosynthesis of the selenoproteins and there is an intracellular hierarchy of selenoprotein biosynthesis in times of Se depletion. One particular selenoprotein is of central importance for the organification and trafficking of Se within the organism, i.e., Selenoprotein P (SePP). From transcriptome analyses it was deduced that this Se transport protein is markedly reduced in tumours of several origins. The aim of this thesis was to elucidate whether SePP has a causal impact on the tumourigenesis within the intestinal tract. For this purpose, the SePP-KO mouse model with a genetically impaired SePP expression was crossed with the well-established APCmin intestinal tumour model. A stop mutation in the APC tumour suppressor gene causes multiple intestinal neoplasias (Min) in these mice. The combined deletion of SePP caused a sharp increase in tumour incidence in the small intestines of APCmin mice. Interestingly, even the inactivation of only one SePP allele was sufficient to induce more and less well differentiated adenomas in the small intestine. These results indicate that SePP acts as an important modulator of APC dependent tumorigenesis in a gene dose dependent manner. In the long run, SePP might turn out as another valuable biomarker to estimate the individual cancer risk. From a mechanistic point of view, the transcriptome analyses indicate that an impaired SePP expression favors cell cycle progression, angiogenesis and acute phase response. In addition, an elevated production of growth factors in response to SePP deficiency might contribute to the phenotype of bigger and more undifferentiated tumours. Additional analyses of the intestines revealed that the intestinal tract is dependent on a regular SePP expression in order to synthesise its regular set of selenoproteins even so it represents the prime organ of Se absorption. Therefore, SePP represents a central Se transport and storage protein also within the intestinal tract, highlighting its essential role to preserve health and regular Se metabolism.