The phosphatidylinositol-3-kinase/AKT (Protein Kinase B)/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway, downstream of tyrosine kinase receptors, is upregulated in human cancers including breast and colon cancers. Glycogen synthase kinase 3 (GSK 3) is a serine/threonine protein kinase plays important role in various cellular processes including glycogen synthesis mediated by insulin signalling pathway. Moreover, 5' adenosine monophosphate activated protein kinase (AMPK), a crucial cellular energy sensor, has regulatory role in cell growth and proliferation through mTOR pathway. Phosphatidylcholine (PtdCho) is the major phospholipid in the mammalian cell membranes and is mainly synthesized by the CDP-choline pathway. Malignant transformation has been reported to be associated with altered choline metabolism. Hyperactivation of the PI3K/AKT signalling pathway upregulates the key enzymes of phospholipid metabolism. The first line antidiabetic drug, metformin, modulates glucose and concomitant lipid metabolism through AMPK activation. Studies suggest phosphatidylcholine biosynthesis and breakdown through CDP-choline pathway are modulated by glucose metabolism and de novo fatty acid synthesis. Cancer cell growth inhibitory effect of PI3K/AKT/mTOR/GSK3 pathway inhibitors and metformin were investigated by cytotoxic assay, western blot and cell cycle analysis in breast and colon cancer cells. IC50 values of anticancer drugs and combination indices between drug combinations were determined. 31P-NMR was carried out on cell extracts after drug treatments. [14C (U)] glucose and [3H] choline incorporation into lipids were also determined. All inhibitors targeting PI3K/AKT/mTOR signaling pathway, GSK3 and metformin have cancer cell growth inhibition. By 31P-NMR, PI3K/AKT/mTOR pathway inhibition induced agent-specific changes in PCho intensity. Increased UDP-sugars observed in breast and colon cancer cell extracts treated with LY294002 and AZD8055, an effect abrogated by inclusion of a GSK3 inhibitor. A link between glycolytic intermediates and phosphatidylcholine biosynthesis was investigated by metformin and GSK3 inhibitor in breast and colon cancer cells.

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains x, 152 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 119-149).

Made available in DSpace on 2015-05-14T13:24:10Z (GMT). No. of bitstreams: 1 parte1.pdf: 2171352 bytes, checksum: 9fe8dbff5679756b66e10550ad40e3bd (MD5) Previous issue date: 2010-06-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The social politics, throughout the years, veem in accordance with if modifying the adopted economic policies, being these politics mechanisms of reproduction of the work force. In this aspect, the intervention of the State goes in accordance with to present of differentiated form the conjuncture and the correlation of forces between the classrooms, form that, the more organized, more fortified they will become. From these relations where the State starts to intervened in the relations of the means of production and accumulation capital it, the third sector appears as half of mediation between the public and the private sector, occupying each time more spaces in such a way in the public sphere as in the private one. With the absence of the State in determined sectors of social order they emerge, in the third sector, the not Governmental Organizations ONGs supplying in many cases the paper of the State in the social relations. Leaving of this perspective, we search to understand this relation in the field of the health, specifically with women, cancer of mastectomizada breast and. Of the social point of view, we perceive that the cancer still is seen as an illness incurable what it unchains a series of negative feelings affecting its recovery. In this context, the civil society has formed nets in support to the health and solidarity the women with breast cancer. Through the action of the ONGs, in the most diverse areas, it is perceived mobilization, the motivation of volunteers next to these organizations, becoming basic in the support and the insertion of segments of the population estigmatizadas by the society. / As políticas sociais, ao longo dos anos, veem se modificando de acordo com as políticas econômicas adotadas, sendo essas políticas mecanismos de reprodução da força de trabalho. Nesse aspecto, a intervenção do Estado vai se apresentar de forma diferenciada de acordo com a conjuntura e a correlação de forças entre as classes, de forma que, quanto mais organizadas, mais fortalecidas elas se tornarão. A partir dessas relações em que o Estado passa a intervir nas relações dos meios de produção e acumulação do capital, surge o terceiro setor como meio de mediação entre o público e o setor privado, ocupando cada vez mais espaços tanto na esfera pública como no privado. Com a ausência do Estado em determinados setores de ordem social emergem, no terceiro setor, as Organizações não Governamentais ONGs suprindo em muitos casos o papel do Estado nas relações sociais. Partindo dessa perspectiva, buscamos entender essa relação no campo da saúde, especificamente com mulheres, com câncer de mama e mastectomizada. Do ponto de vista social, percebemos que o câncer ainda é visto como uma doença incurável o que desencadeia uma série de sentimentos negativos afetando sua recuperação. Nesse contexto, a sociedade civil tem formado redes em apoio à saúde e a solidariedade a mulheres com câncer de mama. Através da ação das ONGs, nas mais diversas áreas, percebe-se a mobilização, a motivação de voluntários junto a essas organizações, tornando-se fundamental no apoio e na inserção de segmentos da população estigmatizadas pela sociedade.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O cÃncer de mama (CM) à um problema de saÃde pÃblica mundial. Uma em cada oito mulheres terà cÃncer de mama, tornando-se assim a neoplasia mais freqÃente entre as mulheres. O cÃncer de mama està ligado à identidade feminina no tocante a sua potÃncia orgÃstica e a sua sensualidade. Elaborar estratÃgicas cirÃrgicas confiÃveis pouco agressivas e menos multilantes tem sido busca de respostas a muitas pesquisas. Objetivo: O presente estudo visou avaliar a concordÃncia do volume tumoral entre a avaliaÃÃo anatomopatolÃgica e os mÃtodos de diagnÃstico por imagem dedicados a mama: Mamografia (MX), Ultra-som (US) e RessonÃncia magnÃtica (RMM), em mulheres com cÃncer de mama localmente avanÃado, submetidas à quimioterapia neoadjuvante. Pacientes e MÃtodos: Foram analisadas 95 mulheres portadoras de neoplasia mamÃria oriundas dos ambulatÃrios da Maternidade Escola Assis Chateaubriant (MEAC), Centro Regional e Integrado de Oncologia (CRIO) e Instituto do CÃncer do Cearà (ICC), no perÃodo de marÃo de 2003 a marÃo de 2005. Estas pacientes foram divididas em dois grupos. Grupo Tratamento (GT) com n=46 e Grupo Controle (GC) com n=49. Realizou-se anÃlise nÃo paramÃtrica correlacionando as variÃveis estudadas com o padrÃo ouro, ou seja, a anatomia patolÃgica. Os resultados mostraram concordÃncia na anÃlise volumÃtrica dos mÃtodos imaginolÃgicos e o padrÃo-ouro no GT nos seguintes percentuais: RMM: 0,70; US: 0,63 e MX: 0,42. Quando comparado ao grupo controle os valores encontrados foram RMM: 0,72; US: 0,70 e MX: 0,41. ConclusÃo: A RMM deteve os maiores valores de concordÃncia volumÃtrica em percentuais semelhantes nos dois grupos (GT e GC) e a MX, mÃtodo de imagem mais difundido, ofereceu os menores Ãndices de concordÃncia imaginolÃgica quando comparado com a avaliaÃÃo anatomopatolÃgica. A US apresentou valores de concordÃncia volumÃtrica satisfatÃria quando, comparada a RMM, devendo ressaltar que se trata de mÃtodo operador dependente. / The cancer of breast (CB) it is a problem of world public health. One in each eight women will have cancer of breast, becoming like this the most frequent neoplasia among the women. CB it is tied up the feminine identity concerning its potency of orgasm and her sensuality. To elaborate surgical strategic reliable not very aggressive and less mutilate has been search of answers to many researches. Objective: The present study was to evaluate the agreement of the volume of tumor to the evaluation anatomopathological and the diagnosis methods for image dedicated to he/she suckles her: Mammography (MX), Ultra-sound (US) and magnetic Resonance (RMM), in women with cancer of breast locally advanced, submitted to the neoadjuvante chemotherapy. Patient and Methods: 95 women carriers of mammary neoplasia originating from of the national health clinics of the Maternity Escola Assis Chateaubriant (MEAC), Center Regional and Integrated of Oncology (CRIO) and Institute of Cancer of Cearà (ICC) were analyzed at the period of 2003 March to 2005 March. These patient ones were divided in two groups. Treatment Group (TG) with n=46 and Control Group (CG) with n=49. Non parametric analysis correlating the variables was compared with the standard gold, the anatomopathological analysis. Results: The data showed agreement in it analyzes at volumÃtrica of the imaginolÃgicos methods and the pattern-gold in TG in the following percentages: RMM: 0.70; US: 0.63 and MX: 0.42, when compared to the control group, where were found values of RMM: 0.72; US: 0.70 and MX: 0.41. Conclusion: RMM stopped the largest values of agreement volumÃtrica in percentile similar in the two groups (GT and GC) and MX, spread image method, offered the smallest indexes of agreement imaginolÃgica when compared with the evaluation anatomopathological. US presented values of agreement satisfactory volumÃtrica when, compared RMM, should stand out that is method dependent operator.

In modern society, cancer has become one of the most terrifying diseases because of its high and increasing death rate. The disease's deep impact demands extensive research to detect and eradicate it in all its forms. Breast cancer is one of the most common forms of cancer, and approximately one in nine women in the Western world will develop it over the course of their lives. Screening programmes have been shown to reduce the mortality rate, but they introduce an enormous amount of information that must be processed by radiologists on a daily basis. Computer Aided Diagnosis (CAD) systems aim to assist clinicians in their decision-making process, by acting as a second opinion and helping improve the detection and classification ratios by spotting very difficult and subtle cases. Although the field of cancer detection is rapidly developing and crosses over imaging modalities, X-ray mammography remains the principal tool to detect the first signs of breast cancer in population screening. The advantages and disadvantages of other imaging modalities for breast cancer detection are discussed along with the improvements and difficulties encountered in screening programmes. Remarkable achievements to date in breast CAD are equally presented. This thesis introduces original results for the detection of features from mammographic image analysis to improve the effectiveness of early cancer screening programmes. The detection of early signs of breast cancer is vital in managing such a fast developing disease with poor survival rates. Some of the earliest signs of cancer in the breast are the clusters of microcalcifications. The proposed method is based on image filtering comprising partial differential equations (PDE) for image enhancement. Subsequently, microcalcifications are segmented using characteristics of the human visual system, based on the superior qualities of the human eye to depict localised changes of intensity and appearance in an image. Parameters are set according to the image characteristics, which makes the method fully automated. The detection of breast masses in temporal mammographic pairs is also investigated as part of the development of a complete breast cancer detection tool. The design of this latter algorithm is based on the detection sequence used by radiologists in clinical routine. To support the classification of masses into benign or malignant, novel tumour features are introduced. Image normalisation is another key concept discussed in this thesis along with its benefits for cancer detection.