Introdução: Câncer gástrico é uma doença multifatorial influenciada por fatores externos e hereditários. Embora a síndrome do câncer gástrico difuso hereditário causada por mutações germinativas no gene CDHl seja uma condição rara, sua influência sobre a incidência de câncer gástrico no Brasil, que é considerado um país de alta incidência desta neoplasia, é desconhecida. Objetivos: Avaliar a frequência de variantes germinativas em CDHl e os hábitos de dieta/estilo de vida em pacientes diagnosticados câncer gástrico com idade precoce «55 anos) no Brasil. Metodologia: De outubro de 2013 a agosto 2015, foram recrutados 88 pacientes consecutivos e não aparentados diagnosticados com câncer gástrico em idade precoce em um hospital público brasileiro. Todos os éxons e regiões intrônicas flanqueadoras do CDHl foram sequenciados. Os hábitos de dieta/estilo de vida dos pacientes com câncer gástrico em idade precoce foram comparados com informações sobre os hábitos da população armazenados em bancos de dados populacionais brasileiros. Resultados: Dos 88 pacientes, 51,1% eram do sexo feminino e a média de idade no momento do diagnóstico do câncer era de 39 anos (variação, 20-55); 23% relataram história familiar de câncer gástrico em parentes de primeiro ou de segundo. A maioria dos tumores era do tipo difuso (74%), pouco diferenciado (74%) e localizava-se no terço médio ou distal do estômago (67%). No total, 24 variantes germinativas foram detectadas: 3 (12.5%) benignas, 17 (70.8%) provavelmente benignas e 4 (16.7%) variantes de significado clínico incerto (VSI). Todas as VSI são mutações missense e nunca foram relatadas previamente na literatura: c.313T> A, c.387G> T, c.1676G> A e c.1806C> A. Os pacientes com câncer gástrico diagnosticados em idade precoce apresentaram maior consumo de carne vermelha (OR: 2.591, IC 95%: 1.371-4.894) e carne processada (OR: 3.093, IC 95%: 1.591- 6.009) em comparação com os hábitos alimentares da população brasileira. Conclusão: De acordo com o nosso conhecimento, esta é a maior série investigando a contribuição de mutações germinativas de CDHl em pacientes diagnosticados com câncer gástrico em idade precoce na América Latina. Para um país considerado de alta incidência, a frequência encontrada de variantes germinativas em CDHl foi maior do que o esperado; 4 novas mutações missense foram identificadas e mais estudos são necessários para confirmar a patogenicidade dessas variantes. Fatores de risco modificáveis, como o consumo de carne vermelha e/ou de carne processada podem ter contribuído para o desenvolvimento de câncer gástrico em idade precoce na população estudada / Introduction: Gastric cancer is a multifactorial disease influenced by inherited and noninherited factors. Although hereditary diffuse gastric cancer syndrome caused by germline mutation in CDHl is arare condition its contribution to gastric cancer burden in Brazil, which is considered a high-incidence country for this neoplasia, is unknown. Objectives: To evaluate the frequency of CDHl germline variants and the dietjlifestyle habits in early-onset gastric cancer (EOGC, < 55 years old) patients in Brazil. Methodology: From October 2013 to August 2015, a total of 88 unrelated and consecutive patients attending a Brazilian public hospital with EOGC were enrolled. Ali CDHl exons and intronic boundaries were sequenced. The dietjlifestyle habits of EOGC patients have been compared to Brazilian population data bases. Results: Of 88 patients, 51.1% were female and the mean age at gastric cancer diagnosis was 39 years (range 20-55); 23% reported family history of gastric cancer in first- or second-degree rei atives. The majority of the tumors were diffuse (74%), poorly differentiated (74%), and located in the middle and distal-third of the stomach (67%). In total, 24 germline variants were detected: 3 (12.5%) benign, 17 (70.8%) likely benign, and 4 (16.7%) variants of unknown significance (VUS). Ali VUS were missense novel mutations: c.313T > A, c.387G > T, c.1676G > A, and c. 1806C > A. EOGC patients had ahigher red (OR: 2.591, 95% CI: 1.371-4.894) and processed (OR: 3.093, 95% CI: 1.591-6.009) meat intake compared to eating habits of the Brazilian population. Conclusion: To our knowledge, this is the largest series investigating the contribution of CDHl germline mutations in EOGC cancer in Latin America. For a high-incidence country, the incidence of CDHl germline variants was higher than expected; 4 novel CDHl missense mutations were identified and further studies are warranted to confirm their pathogenicity. Modifiable risk factors, such as the consumption of red and/or processed meat may have contributed to early- onset gastric cancer development in our studied population

Yiu Wai Han. / "June 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 146-156) / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Thesis (Ph.D.)--University of Toledo, 2007. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: James Willey. Includes abstract. Title from title page of PDF document. Bibliography: pages 47-51, 73-76, 120-174.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 106-143).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 4 uppsatser.

Η ερευνητική προσπάθεια ανάπτυξης νέων αντινεοπλασματικών φαρμάκων, περιλαμβάνει μεταξύ άλλων και την τροποποίηση γνωστών χημειοθεραπευτικών ενώσεων, με σκοπό την ελάττωση των τοξικών τους παρανεργειών και τη βελτίωση της δραστικότητας των παραγώγων τους. Τέτοιες ενώσεις αποτελούν οι στεροειδικοί αλκυλιωτικοί παράγοντες, οι οποίοι αποτελούν και το αντικείμενο της παρούσας μελέτης. Ειδικότερα, μελετήθηκαν το προφίλ και η βιολογική δραστικότητα των χημικών αυτών ενώσεων έναντι της λευχαιμίας Ρ388, με απώτερο στόχο την προσπάθεια εξαγωγής Ποσοτικών Σχέσεων Δομής-Δράσης (QSAR). Αρχικά δημιουργήθηκε μια διαδραστική βάση δεδομένων-χημική βιβλιοθήκη, στην οποία περιελήφθησαν όλες οι πληροφορίες που αφορούν φυσικοχημικά χαρακτηριστικά και δεδομένα βιολογικής δραστικότητας των υπό μελέτη ενώσεων. Στη συνέχεια από τα δεδομένα της βάσης αυτής, συγκρίθηκαν μεταξύ τους και αναλύθηκαν διάφοροι συσχετισμοί μεταξύ των ενώσεων αυτών. Από την πρωταρχική μελέτη των ενώσεων που συμπεριλήφθηκαν στην βάση δεδομένων και εμφανίζουν αντινεοπλασματική δράση καθίσταται προφανές ότι άσχετα με το δοσολογικό σχήμα δραστικές έναντι της λευχαιμίας Ρ388 εμφανίστηκαν οι ίδιες (στην συντριπτική τους πλειοψηφία 43 έναντι 44 ανά κατηγορία δοσολογικού σχήματος) ενώσεις. Για τιμές λιποφιλικότητας LogP < 4, δεν καταγράφονται ενώσεις και αναγνωρίζεται μεγάλη ποικιλία συντεταγμένων, διότι είναι αρκετά δύσκολο να προκύψουν ενώσεις τόσο μικρής λιποφιλικότητας από το συνδυασμό στεροειδικού σκελετού και αλκυλιωτικού παράγοντα, εκτός αν προστεθούν στο στεροειδικό σκελετό και άλλες υδρόφιλες ομάδες. Από την παρούσα μελέτη προκύπτει ότι ο κατάλληλος συνδυασμός αλκυλιωτικού παράγοντα και στεροειδικού σκελετού οδηγεί σε ενώσεις υψηλής εκλεκτικότητας, ενώ η εισαγωγή στον Β δακτύλιο του στεροειδικού σκελετού του συζυγιακού συστήματος, οδηγεί κατά κανόνα σε μόρια υψηλής αντινεοπλασματικής ικανότητας και χαμηλής τοξικότητας. / -

The Cbl family of E3 ubiquitin ligases are important negative regulators of multiple receptor and cytoplasmic tyrosine kinases, and participate in a wide variety of cellular processes. Uncoupling of Cbl-mediated negative regulation allows activated receptor tyrosine kinases such as the Met receptor to escape degradation, enhancing their oncogenic potential in vitro and in vivo. Despite the consequences of loss of Cbl-mediated negative regulation for human disease, little is known about the mechanisms regulating Cbl protein levels themselves. / In this thesis work, I demonstrate a differential regulation of c-Cbl and Cbl-b downstream of the Met receptor tyrosine kinase. Cbl-b protein levels decrease in response to Met kinase activity, whereas c-Cbl levels remain stable. Cbl-b is partially degraded in a proteasome-dependant manner. This requires Cbl-b ubiquitin ligase activity and a carboxy terminal domain region located between the RING and UBA domains. I conclude that the regulation of c-Cbl and Cbl-b differs downstream of Met, and propose that negative regulation of Cbl-b by a dysregulated Met receptor may contribute to tumourigenesis.

Vitamin D3 must be metabolically activated by the liver to 25-hydroxyvitamin D3 (25OHD3) and then by the kidney 1alphahydroxylase (1alphaOHase) to become 1,25dihydroxyvitamin D 3 (1,25(OH)2D3). 1,25(OH)2 D3 is a potent inhibitor of tumor growth in vitro and in vivo. Recent studies indicate that metabolic activation of 1,25(OH) 2D3 also occurs in cancer cells such as breast cancer. Consequently, the major objective of this project was to determine if tumoral 25OHD 3-1alphahydroxylase modulates any or all of the stages of breast tumor progression without inducing the hypercalcemic side effects of 1,25(OH) 2D3. For this purpose we used the PyVMT breast cancer mouse model in which the oncoprotein, polyomamiddle T antigen (PyMT) is under the control of mouse mammary tumor virus LTR (MMTV LTR). Mice exhibited tumors restricted to the mammary epithelium progressing to the various stages of breast cancer. Animals were treated with either vehicle, 25OHD3 (2000 pM/24h) or 1,25(OH)2D3 (12pM/24h). Mice treated with the vitamin D precursor, 25OHD3, exhibited a marked reduction in tumor onset and growth comparable to the 1,25(OH)2D3 treated group. Furthermore, biomarkers of tumor progression were markedly reduced in 25OHD3 and 1,25(OH)2D3 animals as compared to vehicle-treated animals. However, mean circulating calcium concentrations remained unchanged in 25OHD3 treated animals but increased significantly in 1,25(OH)2D3 treated animals as compared to controls. Tumoral levels of 1,25(OH)2D3 in mice treated with 25OHD3 were increased 79% in comparison to vehicle control mice. Additionally, 25OHD3 and 1,25(OH)2D 3 treated animals had a significant decrease in the mean number of lung metastases per animal as compared to vehicle treated control animals. This study therefore suggests an important autocrine role of 1alphaOHase expression in breast tumor cells. Furthermore, accumulation of intra-tumoral 1,25(OH) 2D3 in response to 25OHD3 administration strongly suggests that locally produced 1,25(OH)2D3 plays a significant role in restraining tumor growth without inducing the hypercalcemic side effects associated with 1,25(OH)2D3.

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