<b>Introduction:</b> Almost 7,000 people are diagnosed with ductal carcinoma in situ (DCIS) in the United Kingdom each year, but there remains uncertainty regarding its natural history and optimal management. The aim of this thesis was to evaluate factors contributing to the epidemiology of DCIS and its outcomes. <b>Methods:</b> 1) A cohort study comparing risk factors for DCIS and invasive breast cancer (IBC) using UK Biobank; 2) A cohort study examining the accuracy of preoperative biopsy in DCIS using clinical records from the Netherlands Cancer Institute; 3) A cohort study examining the rate of invasive breast cancer following treatment for screen-detected DCIS in England using the National Health Service Breast Screening Programme (NHSBSP) audit; 4) A methodological study to develop an algorithm to identify invasive breast cancer recurrences, which in the future may used to identify DCIS recurrences, using all relevant routinely collected data stored within Public Health England (PHE). <b>Results:</b> (1) For both DCIS and IBC, postmenopausal BMI was associated with an increased risk of developing disease, and the number of live births was associated with a decreased risk of developing disease. However, the magnitude of the effect differed between DCIS and IBC. The increased risk from postmenopausal BMI &GE;35 kg/m² was larger for DCIS than for IBC (RR 2.35, 95% CI 1.14-4.82), and the trend of reduction in risk with each additional live birth was greater for DCIS than for IBC (p for trend = 0.03). (2) Consideration of mammographic lesion size and the absence of necrosis on biopsy may be helpful in selecting low-risk women for non-operative management of DCIS in the future, as may use of the 9G vacuum-assisted method of biopsy. (3) The cumulative risks of IBC at 5, 10 and 15 years after screen-detected DCIS in England were 3.5%, 7.1%, and 9.4% respectively. Women with clear surgical margins of 1-2 mm had a higher IBC rate than women with clear margins of 5+ mm (RR 1.85, 95% CI 1.20-2.84). Women given breast-conserving surgery (BCS) without radiotherapy had a higher ipsilateral IBC rate than women given BCS with radiotherapy (RR 1.63, 95% CI 1.27-2.10). Women given hormone therapy had a lower rate of any IBC compared with oestrogen receptor (ER) positive women not given hormone therapy (RR 0.76, 95% CI 0.63-0.93). (4) There was good agreement between the number of recurrences indicated by the developed algorithm using routinely collected data sources and the number of recurrences recorded in the test dataset. This finding supports the potential value of compiling recurrence information on a nationwide basis from routinely collected data, for use in future descriptive and epidemiological studies and in follow-up for randomised trials. <b>Conclusions:</b> Using a variety of methods these studies have all succeeded in adding to knowledge about the epidemiology of DCIS. This knowledge can be used to help the future management of women with DCIS. In addition, each of the studies has planned extensions and will continue to contribute further knowledge periodically into the future.

Made available in DSpace on 2014-06-12T15:50:53Z (GMT). No. of bitstreams: 1 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O câncer de mama é a neoplasia mais freqüente e a maior causa de morte de câncer em mulheres no mundo. Dentre as várias neoplasias que acometem esse órgão o carcinoma ductal invasivo (CDI) representa de 65% a 80% de todos os carcinomas, o qual apresenta grande heterogeneidade fenotípica e genotípica. Por causa dessa heterogeneidade a procura por biomarcadores das neoplasias mamárias vem aumento nos últimos anos. Nesse sentido lectinas, (glico)proteínas reconhecedoras de carboidratos, vem sendo utilizadas como tradutoras de glicocódigos e biomarcadores de várias neoplasias. Esse trabalho objetivou analisar o perfil de carboidratos do CDI através da histoquímica com lectinas e correlacionar essa expressão com parâmetros clínicos e histopatológicos (idade, tamanho do tumor, variante histológica e expressão de p53). Oitenta e oito biópsias de CDI e 20 biópsias de mastoplastia redutora e bordas livres de tumor, utilizadas como controles normais foram obtidas no Hospital das Clínicas da UFPE. Para a histoquímica com lectinas, cortes de 4&#956;m foram tratados com tripsina 0,1%, metanol-peróxido de hidrogênio 0,3% e incubadas com as lectinas conjugadas a peroxidase (horseradish peroxidase HRP), Concanavalin A, Con A-HRP, Ulex europeus I, UEA-I-HRP e Peanult Aglutinin, PNAHRP, especificas para glicose/manose, L-fucose e D-galactose, respectivamente. A imunohistoquímica para o p53 foi realizada através da técnica da estreptavidina-biotinaperoxidase. Ambas as reações foram reveladas com diaminobenzidina (DAB)-H2O2, contra-coradas com hematoxilina e avaliadas em microscopia óptica. Houve uma associação entre a marcação das lectinas, Con A (p<0,001), PNA (p<0,001) e UEA-I (p<0,001), nos dois grupos de estudo, normal e CDI. A prevalência da positividade foi significativamente maior no grupo com câncer.A proteína p53 mutante foi detectada em 34,1% dos casos. Morfologicamente PNA reconheceu mitoses atípicas e, UEA-I e Con A endotélio vascular e todas as lectinas marcaram as células neoplásicas. Não houve correlação significativa entre a marcação das lectinas e os parâmetros clínicos e histopatológicos (p>0,005). Os resultados indicam que ocorre uma maior disponibilidade de glicose/manose, L-fucose e D-galactose no CDI, sugerindo a utilização das lectinas UEA-I, PNA e ConA como ferramentas histopatológicas na diferenciação dos tecidos normais e portadores dessa malignidade

Washington D.C. is a city of multicultural richness difficult to surpass. The huge diversity of languages, cultures, and people found in the city are the bases of its identity. Countless diplomatic missions, international organizations and agencies are a dramatic proof that Washington D.C. is currently the center of the world, the Rome of modern times. To this extent, each country that holds a diplomatic mission strives to make its representation, its presence to the host country, as good as possible. With this in mind, architecture is provided with a great opportunity to showcase the spirit of each country through the buildings that represent them, their embassies. The desire that sparked the idea of making a thesis about the Embassy of Chile may be traced to the experience of being a foreigner, a Chilean, living in Washington D.C. In the same manner that a person may represent its country, an embassy building gives the opportunity to express and show a lot of what that country is about; it has the potential of becoming a symbol for it. Although this may seem a very straightforward theme, it's actually very broad, and may be regarded in a number of ways. How do we represent Chile? What do we show? What don't we want to show? How do we express it? And even how can we define Chile. These were questions that had to be addressed before even thinking about designing the embassy. In order to this, the concept that had to be adopted had to be capable of handling this selective process. It's a process in which the person doing the representation also takes part in it. In other words, it's a process by which you are presenting yourself. Through research done at this stage of the thesis, the best way to describe the procedure was by making a Self Portrait. By adopting this concept we were given the possibility to create our own image of what Chile was, and to reveal and conceal whatever we thought was appropriate. / Master of Architecture

UHPC (ultra-high performance concrete) is a relatively new type of concrete that exhibits mechanical properties that are far superior to those of conventional concrete and in some cases rival those of steel. The main characteristics that distinguish UHPC from conventional reinforced concrete are the improved compressive strength, the tensile strength, the addition of steel fibers, and the resistance to corrosion and degradation. The mechanical properties of UHPC allow for smaller, thinner, lighter sections to be designed while strength is maintained or improved. The use of UHPC has been limited to a few structural applications due to the high cost of the materials and the lack of established design guidelines. A proposed material model based on material and finite element models has served as the foundation of this research effort. The model was used to minimize the dimension of an optimum section in order to limit the material usage and maximize the performance. In the model, the top flange served as the riding surface and contained no reinforcing steel to resist shear. The lack of steel reinforcement allowed for the possibility of a punching shear failure to occur from the application of a point load such as a wheel tire patch load. The model and optimized section served as the foundation for this research, the characterization of punching shear capacity of thin UHPC plates. A total of 12 UHPC slabs were tested to failure to determine the boundary between a flexural failure and a punching shear failure. The variables considered were the slab thickness and loading plate dimensions. The results of the testing were compared to existing models for punching shears and other failure modes, with varying success. The test results aided in the development of a design equation for the prediction of punching shear in UHPC slabs. After evaluation of the test results, recommendations are made as to which model predicts the punching shear capacity of UHPC slabs and the minimum slab thickness required to prevent a punching shear failure. / Master of Science

Made available in DSpace on 2015-06-17T19:33:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-08-27. Added 1 bitstream(s) on 2015-06-18T12:47:47Z : No. of bitstreams: 1 000830951.pdf: 1671352 bytes, checksum: e150ad97472df641fe9aede1e51165a5 (MD5) / INTRODUÇÃO: O valor prognóstico da classificação molecular do carcinoma de mama recentemente proposta tem sido validado por numerosos estudos. Entretanto, a maioria destes trabalhos estudou o tipo histológico mais comum denominado carcinoma ductal invasivo usual (CDI), uma entidade reconhecidamente heterogênea. Poucos estudos concentraram-se especificamente em outros tipos histológicos como o carcinoma lobular invasivo (CLI) que é o tipo especial mais frequente. O CLI apresenta-se com características clínico-patológicas e história natural bastante distintas do CDI sendo claramente entidades biológicas diferentes. Além disso, é uma doença relativamente frequente com aumento de sua incidência no mundo. OBJETIVO: Estudar comparativamente os subtipos moleculares luminais A e B de dois grupos de pacientes com CLI e CDI da mama, bem como determinar o valor prognóstico independente da classificação molecular nestes tumores correlacionando os subtipos moleculares com a sobrevida específica por carcinoma de mama (BCSS) e a sobrevida global (OS). SUJEITOS E MÉTODOS: Estudo do tipo transversal analítico. Foram selecionados blocos de parafina de mulheres com diagnóstico histopatológico de CLI e CDI no Laboratório de Patologia do Hospital Amaral Carvalho (HAC), Jaú, São Paulo, Brasil. Os respectivos prontuários médicos e o Registro Hospital de Câncer (RHC) do HAC foram consultados para a pesquisa das informações clínicas e de seguimento destas mulheres (média de 121,77 e 131,27 meses para o CLI e CDI, respectivamente), totalizando 186 casos. Dos blocos doadores, foram extraídas duas amostras de 2 mm de diâmetro e depositadas nos blocos de parafina receptores usando Tissue Microarray Builder ab1802 (Abcam®, Cambridge, UK). Nestes cortes foi feita a pesquisa dos seguintes marcadores imunoistoquímicos: receptor de estrógeno α (RE), receptor de progesterona (RP), HER2 e Ki67. Os subtipos moleculares (luminal A, luminal ... / INTRODUCTION: The prognostic value of the molecular classification of breast cancer recently proposed has been validated by many studies. However, the great majority of these studies has focused on invasive ductal carcinoma no special type (IDC), a widely recognized heterogeneous entity. Few papers have studied other special types of breast cancer such as invasive lobular carcinoma (ILC) the most common special type. ILC shows clinico-pathological features and natural history quite distinctive from IDC being clearly separate biologic entities. Moreover, ILC is relatively frequent and has been increasing in incidence over the recent years. OBJECTIVE: to study comparatively the luminal molecular subtypes A e B of two groups of patients with ILC and IDC and to determine the prognostic independent value of the molecular classification in ILC patients by correlating the molecular subtypes with clinical outcomes such as breast cancer specific survival (BCSS) and overall survival (OS). MATERIALS AND METHODS: archival paraffin blocks from women diagnosed with ILC and IDC at the Pathology Laboratory of Hospital Amaral Carvalho, Jau, Sao Paulo, Brazil, were retrieved. Patient's charts and the Hospital Amaral Carvalho Cancer Registry were consulted for obtaining the staging and follow-up information (median 121.77 and 131.27 months for ILC and IDC, respectively) and 186 patients were selected. Two samples from each paraffin block were extracted to mount tissue microarray (TMA) blocks by using a Tissue Microarray Builder ab1802 (Abcam®, Cambridge, UK). The following immunohistochemical markers were performed in the TMA blocks: estrogen receptor α, progesterone receptor, HER2 and Ki67 protein. The intrinsic molecular subtypes (luminal A, luminal B, HER2 and triple negative) were determined based on the immunohistochemical profile of each tumor. Prognostic clinico-pathological features were analysed in absolute (n) and relative frequency (%). The ...

Orientador: Rozany Mucha Dufloth / Coorientador: Fernando Carlos de Lander Schmitt / Banca: Mariângela Esther Alencar Marques / Banca: Luis Otávio Zanatta Sarian / Resumo: INTRODUÇÃO: O valor prognóstico da classificação molecular do carcinoma de mama recentemente proposta tem sido validado por numerosos estudos. Entretanto, a maioria destes trabalhos estudou o tipo histológico mais comum denominado carcinoma ductal invasivo usual (CDI), uma entidade reconhecidamente heterogênea. Poucos estudos concentraram-se especificamente em outros tipos histológicos como o carcinoma lobular invasivo (CLI) que é o tipo especial mais frequente. O CLI apresenta-se com características clínico-patológicas e história natural bastante distintas do CDI sendo claramente entidades biológicas diferentes. Além disso, é uma doença relativamente frequente com aumento de sua incidência no mundo. OBJETIVO: Estudar comparativamente os subtipos moleculares luminais A e B de dois grupos de pacientes com CLI e CDI da mama, bem como determinar o valor prognóstico independente da classificação molecular nestes tumores correlacionando os subtipos moleculares com a sobrevida específica por carcinoma de mama (BCSS) e a sobrevida global (OS). SUJEITOS E MÉTODOS: Estudo do tipo transversal analítico. Foram selecionados blocos de parafina de mulheres com diagnóstico histopatológico de CLI e CDI no Laboratório de Patologia do Hospital Amaral Carvalho (HAC), Jaú, São Paulo, Brasil. Os respectivos prontuários médicos e o Registro Hospital de Câncer (RHC) do HAC foram consultados para a pesquisa das informações clínicas e de seguimento destas mulheres (média de 121,77 e 131,27 meses para o CLI e CDI, respectivamente), totalizando 186 casos. Dos blocos doadores, foram extraídas duas amostras de 2 mm de diâmetro e depositadas nos blocos de parafina receptores usando Tissue Microarray Builder ab1802 (Abcam®, Cambridge, UK). Nestes cortes foi feita a pesquisa dos seguintes marcadores imunoistoquímicos: receptor de estrógeno α (RE), receptor de progesterona (RP), HER2 e Ki67. Os subtipos moleculares (luminal A, luminal ... / Abstract: INTRODUCTION: The prognostic value of the molecular classification of breast cancer recently proposed has been validated by many studies. However, the great majority of these studies has focused on invasive ductal carcinoma no special type (IDC), a widely recognized heterogeneous entity. Few papers have studied other special types of breast cancer such as invasive lobular carcinoma (ILC) the most common special type. ILC shows clinico-pathological features and natural history quite distinctive from IDC being clearly separate biologic entities. Moreover, ILC is relatively frequent and has been increasing in incidence over the recent years. OBJECTIVE: to study comparatively the luminal molecular subtypes A e B of two groups of patients with ILC and IDC and to determine the prognostic independent value of the molecular classification in ILC patients by correlating the molecular subtypes with clinical outcomes such as breast cancer specific survival (BCSS) and overall survival (OS). MATERIALS AND METHODS: archival paraffin blocks from women diagnosed with ILC and IDC at the Pathology Laboratory of Hospital Amaral Carvalho, Jau, Sao Paulo, Brazil, were retrieved. Patient's charts and the Hospital Amaral Carvalho Cancer Registry were consulted for obtaining the staging and follow-up information (median 121.77 and 131.27 months for ILC and IDC, respectively) and 186 patients were selected. Two samples from each paraffin block were extracted to mount tissue microarray (TMA) blocks by using a Tissue Microarray Builder ab1802 (Abcam®, Cambridge, UK). The following immunohistochemical markers were performed in the TMA blocks: estrogen receptor α, progesterone receptor, HER2 and Ki67 protein. The intrinsic molecular subtypes (luminal A, luminal B, HER2 and triple negative) were determined based on the immunohistochemical profile of each tumor. Prognostic clinico-pathological features were analysed in absolute (n) and relative frequency (%). The ... / Mestre

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-12-12T13:56:18Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação_Jessica Catarine Frutuoso do Nascimento.pdf: 3226012 bytes, checksum: 795583806a66d8ac66b9fbdb738f7d93 (MD5) / Made available in DSpace on 2016-12-12T13:56:18Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação_Jessica Catarine Frutuoso do Nascimento.pdf: 3226012 bytes, checksum: 795583806a66d8ac66b9fbdb738f7d93 (MD5) Previous issue date: 2015-02-24 / CAPES / FACEPE / CNPQ / O carcinoma ductal invasivo (CDI) é o tumor maligno de mama mais comum e uma das principais causas de morte relacionada ao câncer em mulheres no mundo. A alteração no padrão de glicosilação é uma característica marcante do fenótipo tumoral. Dentre as reações glicosídicas alteradas no câncer está a fucosilação. Os tetrassacarídeos fucosilados sialil Lewis X (sLex) e sialil Lewis A (sLea) são ligantes reconhecidos pelas glicoproteínas transmembrânicas selectinas envolvidos nas interações célula-célula necessárias nos processos inflamatórios, hemostase/trombose, cicatrização de feridas e metástase tumoral. A etapa final na síntese do sLex e sLea é realizada pela ação da α1,3/4-fucosiltransferase (FUT3), enzima codificada pelo gene FUT3. A expressão do sLea em carcinoma mamário está relacionada ao estágio tumoral e maiores níveis desse antígeno foram encontrados em tumores metastáticos. Níveis elevados da enzima FUT3 está relacionada ao maior poder metastático em linhagens celulares de câncer de próstata e pâncreas e sua ação é fundamental para o mecanismo de transição epitelial-mesenquimal induzido por TGF-β no câncer colorretal. Apesar da ação pró-tumoral exercida pela enzima FUT3 e seus produtos, estudos vem demonstrando sua importância para a citotoxicidade mediada pelas células NK sobre células tumorais, tanto devido ao reconhecimento do antígeno sLex pelos receptores lectina do tipo C quanto devido a fucosilação dos receptores DR4 e DR5 por essa enzima que é fundamental para o desencadeamento da via de apoptose extrínseca estimulada pelo Apo2L-TRAIL. Visando o maior conhecimento do papel dessa enzima no câncer de mama, o presente trabalho objetivou avaliar os níveis teciduais da FUT3 em tumores mamários malignos (carcinoma ductal invasivo - CDI) de pacientes do Hospital das Clínicas da UFPE (HCUFPE) e do Instituto de Medicina Integral Professor Fernando Figueira (IMIP), investigando se há correlação entre a expressão enzimática com a malignidade tumoral e o risco de metástase. A genotipagem da região promotora do gene FUT3 também foi realizada a fim de identificar possíveis SNPs relacionados à expressão dessa enzima. Para tal biópsias em parafina de carcinoma ductal invasivo (CDI) foram selecionadas no arquivo do Setor de Anatomia Patológica do HC-UFPE e do IMIP. Os níveis teciduais da FUT3 foram avaliados por imuno-histoquímica. O DNA foi extraído por metodologia adaptada de Ramalho et al. (2014), a região promotora amplificada por PCR e posteriormente sequenciada pelo método de Sanger modificado. As sequências obtidas em duplicata foram analisadas através do software CLC Main Workbench. A análise estatística foi realizada através do teste exato de Fisher para os dados de expressão e pelo teste de Qui quadrado para a análise genômica, ambas as análises utilizando o software GraphPad Prism v.5. Nossos resultados demonstraram que a ausência tecidual da enzima FUT3 está relacionada ao CDI em pacientes brasileiros, sendo mais freqüente em tumores maiores e negativos para o receptor do fator de crescimento epidérmico humano 2 (HER2). Análise genômica mostrou que duas variações localizadas na região promotora do gene FUT3 estão associadas ao CDI, embora o efeito direto desses polimorfismos na expressão da FUT3 não pode ser avaliada. O alelo T do SNP rs73920070 (-6933 C> T) está associado a ausência da neoplasia enquanto que o alelo T do SNP rs2306969 (-6951 C> T) está associado a presença do carcinoma ductal invasivo na população brasileira. / Invasive ductal carcinoma (IDC) is the most common breast malignant tumor and the mainly cause of death related to cancer among women in the world. The alteration of glycosylation pattern is a well established feature of tumor phenotype. Fucosylation is one of main glycosidic changes in cancer. The fucosylated tetrasacarides sialil Lewis X (sLex) and sialil Lewis A (sLea) are ligands recognized by the transmembrane glycoproteins selectins involved in cell-cell interactions during the inflammatory process, hemostasis/thrombosis, wound healing and tumor metastasis. The final step in sLex and sLea synthesis is done by the action of α1,3/4-fucosyltransferase (FUT3), enzyme encoded by FUT3 gene. The expression of sLea in mammary carcinoma is related to tumor stage and higher levels of this antigen were found in metastatic tumors. Higher protein expression of FUT3 were related to a bigger metastatic power in prostate and pancreas cancer cell lines and its action is primordial to epithelial-mesenchymal transition induced by TGF-β in colorectal cancer. Despite the protumoral action of FUT3 enzyme and its products, studies have shown their importance to NK cell-mediated citotoxicity against tumor cells, due to the sLex antigen recognition by type C lectin receptors and due to the fucosylation of DR4 and DR5 receptors, fundamental step to the extrinsic pathway of apoptosis stimulated by Apo2L-TRAIL. Aiming to better understand the role of this enzyme in breast cancer, the purpose of this study was evaluate the tissue protein expression of FUT3 in breast malignancies (invasive ductal carcinoma – IDC) in patients from Hospital das Clínicas da UFPE (HC-UFPE) and Instituto de Medicina Integral Professor Fernando Figueira (IMIP). We investigated whether there is correlation between the FUT3 enzymatic expression with malignancy and metastasis risk in this cancer type. The genotyping of the FUT3 promoter region was also realized in order to identify SNPs with potential to interfere on the enzyme expression. IDC formalin-fixed and paraffin-embedded biopsies were selected from pathological anatomy service from HC-UFPE and IMIP. FUT3 tissue levels were evaluated by immunohistochemistry. DNA was extracted using the adapted methodology from Ramalho et al. (2014), the promoter region was amplified by PCR and next sequenced by Sanger modified method. The sequences obtained in duplicate were analyzed using the CLC Main Workbench software. Statistical analyzes were realized using Fisher’s exact test for expression data and Qui square test for genomic data. Both analyzes were conducted using GraphPad Prism software v. 5. Our results demonstrate that the lack of FUT3 expression in breast tissues is related to the presence of IDC in Brazilian patients. No expression of FUT3 was more frequent in patients with large neoplastic lesions and tumors that do not express the human epidermal growth factor receptor 2 (HER2). Genomic analyzes showed that two variations localized in FUT3 promoter region are statistically associated to IDC, however the direct effect of these polymorphisms in FUT3 enzyme expression is still to be evaluated. The T allele of rs73920070 (-6933 C> T) SNP is associated to the neoplasia absence while the T allele of rs2306969 (-6951 C> T) SNP is associated to IDC presence in Brazilian northeastern population.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-03-10T13:25:39Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) tese juliana vasconcelos.pdf 2.pdf: 2676689 bytes, checksum: 3be9c8d80ebc1f51f2479aaec4fe30ce (MD5) / Made available in DSpace on 2017-03-10T13:25:39Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) tese juliana vasconcelos.pdf 2.pdf: 2676689 bytes, checksum: 3be9c8d80ebc1f51f2479aaec4fe30ce (MD5) Previous issue date: 2016-02-26 / CNPQ / O câncer de mama é o tipo de tumor que mais acomete as mulheres no mundo. No Brasil estimam-se para 2016/2017, 57.960 novos casos de câncer de mama por ano. O desenvolvimento destes tumores envolve um mecanismo complexo e multifatorial, onde glicosiltransferases e microRNAs (miRNAs) desempenham papeis importantes. O objetivo deste estudo foi avaliar a galactosiltransferase 7 (GALNAC7) e o miRNA 30c no carcinoma ductal invasivo mamário (CDI). Nosso estudo demonstrou, uma baixa expressão do antígeno Tn nos tumores mamários, diante da baixa expressão da GalNAC7 e do seu carboidrato-substrato N-acetil-galactosamina (GalNAc). O estudo evidenciou, também, que o gene GALNT7 não apresenta influência significativa quanto a um prognostico reservado para CDI, diante de sua baixa expressão gênica e proteica, demostrando que o mecanismo de O-glicosilação na formação de mucinas pode ser estimulado, também, por outros genes da família GALNT, porém observamos que o gene GALNT7 pode ser modulado pelo o miRNA 30c frente ao aumento de sua expressão nos tumores estudados, levantando a hipótese de um novo alvo diagnóstico e terapêutico via modulação da expressão de genes da glicosilação. A análise dos dados clínicopatologicos, não demonstrou correlação significativa, com exceção da expressão de GalNAc e tamanho do tumor. Diante da análise do segmento clínico de cada paciente, na curva de sobrevida, não houve resultados significativos quando comparados com os subtipos moleculares, estadiamento clínico, idade e tamanho do tumor. Assim, nossos resultados sugerem que o miRNA 30c pode ser um potencial regulador da expressão do gene GALNT7 e que assim favorece a menor expressão da enzima GALNAC7 levando a uma menor inserção do carboidrato GalNAc nos glicoconjugados de superfície de células de carcinoma ductal invasivo. / Breast cancer is the most common cancer in women in world. In Brazil, it is estimated 57,960 new cases of mammary cancers per year in 2016/2017. The development of these tumors comprises a complex and multifactorial mechanism where glycosyltransferase and microRNAs (miRNAs) play important roles. This study aimed to evaluate the galactosyltransferase 7 (GALNAC7) and the miRNA-30c in mammary invasive ductal carcinoma (IDC). Our results showed a low expression of Tn antigen in mammary tumors resulting from the low expression of GALNAC7 which leads to a low insertion of its saccharidesubstrate N-acetyl-galactosamine (GalNAc) in tumor cell glycoconjugates. The study also evidenced that the gene GALNT7 did not influenced the poor prognostic of IDC, since a low gene expression and, consequently, a low protein expression was observed. Such fact indicates that other genes of the GALNT family may stimulate the O-glycosylation. However, we observed that miRNA-30c might modulate GALNT7 expression and can be a new potential target for diagnosis and therapeutic via modulation of the expression of glycosylation genes. Among the clinocopathologic data, only GalNAc expression and tumor size present a correlation. Patient’s survival curve did not present correlation with tumor molecular subtyping, clinic staging, age and tumor size. Our results suggest that miRNA-30c may be a potential regulator of the GALNT7 gene expression and so favoring a lower expression of the enzyme GALNAC7 leading to a lower insertion of the saccharide GalNAc in glycoconjugates of cell surface in invasive ductal carcinoma.

Submitted by Erika Demachki (erikademachki@gmail.com) on 2015-12-04T17:19:49Z No. of bitstreams: 2 Dissertação - Nayara Alves de Freitas Lemos - 2015.pdf: 1558373 bytes, checksum: f3d20ea70bfd08864a3c3eaae4b69cad (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Erika Demachki (erikademachki@gmail.com) on 2015-12-04T17:21:49Z (GMT) No. of bitstreams: 2 Dissertação - Nayara Alves de Freitas Lemos - 2015.pdf: 1558373 bytes, checksum: f3d20ea70bfd08864a3c3eaae4b69cad (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-12-04T17:21:49Z (GMT). No. of bitstreams: 2 Dissertação - Nayara Alves de Freitas Lemos - 2015.pdf: 1558373 bytes, checksum: f3d20ea70bfd08864a3c3eaae4b69cad (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-07-17 / Objective: To analyze the temporal evolution of DCIS in residents of Goiânia during the period 1994-2010. Methods: It used the database of the Population Based Cancer Registries of Goiania (RCBPGo), cases coded as carcinoma in situ of the breast in females, at (ONCOSIS) program in Goiânia, between 1994 and 2010. It was later made individual search of histopathological reports of DCIS. We sought to identify the temporal evolution of standardized and crude incidence of DCIS. The incidence rates, crude, as standard, set by the global population Doll, were calculated by age groups to 10 years from 30 years, and was estimated to MPMA using Poisson Regression to these age groups. They calculated the disease-free survival and overall survival at 60 and 120 months, using the Kaplan-Meier method. The data on DCIS deaths were obtained from the Mortality Data System (SIM), the medical record information and the electoral higher court (TSE). Results: In the initial database were recorded 376 cases of DCIS. In reviewing the reports, 114 cases were excluded because it is not dealt with DCIS. Of the 282 cases of DCIS in the period studied, there were four cases in 1994 and 21 in 2010. The crude rate of annual incidence of DCIS was 1.33/100,000 in 1994, and of 4.21/100,000 in 2010. The adjusted incidence for the world population Doll was 0.58/100,000 in 1994, and of 1.85/100,000 in 2010. The average annual percentual change (AAPC) of the crude incidence rate for the period was 11.93% per year (95 9-15% CI; P <0.01) and standardized incidence rate of 11.94% per year (95% CI 9-15; p <0.01). There were 17 cases of local recurrence, 16 invasive ductal carcinomas and only one case of in situ recurrence. Three cases evolved with distant metastases. The cumulative rate of local recurrence was 3,9% at 60 months and 10% to 120 months. Overall survival was 96,5% and 91,9% at 60 and 120 months, respectively. The cancer-specific survival was 99,5% at 60 months and 98,4% at 120 months. Abstract xvii Conclusions: The study showed that there are a large number of cases that need to be recoded by changing the initial bank. Thus, we suggest that the highest injury potential aggressiveness is described first, standardized reports and the training of collectors, so there are no unknown information to transcribe the DCIS for RCBP the chips. There was an increasting incidence of DCIS rate in Goiânia, possibly related to mammographic screening. Despite the small number of local recurrences when appeared they arose mostly with invasion. Still, it was confirmed in the studied group high overall survival rate after 10 years of treatment. / Objetivo: Analisar a evolução temporal do carcinoma ductal in situ em moradores de Goiânia durante o período de 1994 a 2010. Métodos: Trata-se de um estudo descritivo retrospectivo de série temporal dos casos de carcinoma ductal in situ, no sexo feminino, em Goiânia, registrados no banco de dados do Registro de Câncer de Base Populacional dessa cidade no período entre 1994 a 2010. Posteriormente, realizou-se busca individual dos laudos histopatológicos de carcinoma ductal in situ para identificar a evolução temporal do carcinoma ductal in situ. As taxas de incidências, tanto bruta, quanto padronizada, ajustada pela população padrão, foram calculadas por grupos etários a cada 10 anos, a partir de 30 anos, e calculou-se a mudança percentual da média anual utilizando-se a regressão de Poisson. Para a análise de sobrevida global foi realizada busca ativa das pacientes no Sistema de Informações em Mortalidade, nas informações do prontuário médico e no Tribunal Superior Eleitoral. Foram calculadas a sobrevida livre de doença e a sobrevida global em 60 e 120 meses, pelo método de Kaplan-Meier. Resultados: No banco de dados inicial foram registrados 376 casos de CDIS. Na revisão dos laudos, foram excluídos 114 casos, pois não faziam parte dos critérios de inclusão. Dos 262 casos em Goiânia no período estudado, houve quatro casos em 1994 e 21 em 2010. A taxa bruta de incidência anual de CDIS foi 1,33/100.000 em 1994, e de 4,21/100.000 em 2010. Já a incidência ajustada para a população padrão foi de 0,58/100.000 em 1994, e de 1,85/100.000 em 2010. A mudança percentual da média anual da taxa de incidência bruta para o período foi de 11,93% ao ano (95% IC 9-15; p<0,01) e da taxa de incidência padronizada de 11,94% ao ano (95% IC 9 - 15; p<0,01). Houve 1 7 casos de recidiva local, sendo 1 6 carcinomas ductal invasores e apenas um caso de recidiva in situ. Três casos evoluíram com metástases à distância. A taxa cumulativa de recidiva local foi de 3,9% aos 60 meses e de 10% aos 120 meses. A sobrevida global Resumo xv foi de 96,5% e de 91,9% aos 60 e 120 meses, respectivamente. A sobrevida câncer-específica foi de 99,5% aos 60 meses e de 98,4% aos 120 meses. Conclusões: o trabalho mostrou um grande número de casos que precisam ser recodificados, alterando o banco inicial. A sugestão é que os laudos histopatológicos descrevam primeiramente a lesão de mais alto potencial de agressividade. É necessária uma padronização dos laudos, e a partir daí, o treinamento dos coletadores, para que não haja informações desconhecidas ao transcrever o CDIS para as fichas do RCBPGo. Foi constatado o aumento da taxa de incidência do CDIS na cidade de Goiânia, possivelmente relacionado à melhora do rastreamento mamográfico. E apesar do pequeno número de recidivas locais, quando apareciam, surgiam na sua grande maioria com invasão. Ainda assim, confirmou-se no grupo estudado alta taxa de sobrevida global após 10 anos do tratamento.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Metastatic, treatment‐resistant pancreatic ductal adenocarcinoma (PDAC) is a rapidly fatal disease that typically carries a bleak prognosis. Contrast‐enhanced CT is the current standard of care tool for imaging evaluation, and repeat imaging is routinely performed in clinical trials. The availability of these imaging data render them exploitable for further analysis. CT texural analysis (CTTA), a quantitative tool for examining a region of interest on CT and generating statistical parameters based on gray‐level pixel data, is powerful technique that has been studied in other cancers and shown to correlate with features such as tumor grade, stage, and prognosis. However, the application of CTTA to PDAC has not been studied. Given the paucity of diagnostic tests to guide therapy, validated CTTA biomarkers could be immensely useful. Identifying PDAC variants that have a relative deficit in DNA repair might allow these cancers to be treated with targeted cytotoxic regimens sooner. Additionally, identifying prognostic CTTA parameters would be useful in gauging the severity of disease. We sought to perform quantitative textural analysis on CT imaging from a clinical trial cohort of patients with metastatic, treatment‐resistant PDAC. We aimed to correlate CTTA features to molecular profiling results (copy number variations obtained by array CGH) and clinical features (overall survival). Metastatic tumor sites from patients with treatment‐resistant PDAC were biopsied and molecularly profiled. Intrachromosal copy number were assessed by CGH in tumor specimens, and patients were treated based on these individual molecular profiling results. Pre‐biopsy portal‐venous phase and non‐contrast CT scans were obtained for retrospective analysis (n=15). CTTA was performed by drawing regions of interest around the primary pancreas adenocarcinoma and the normal pancreas tissue. CTTA parameters including mean positive pixels, entropy, kurtosis, and skewness were derived using the TexRAD platform at texture filtering densities of 0, 2, 3, 4, 5, and 6 pixels. CTTA values were then compared to intrachromosomal copy number variation (CNV) per tumor and overall survival (OS) post treatment using a Spearman’s rank correlation coefficient. Additional linear regression analysis was performed for positive correlations, and a Kaplan‐Meier statistic was generated for OS using median CTTA entropy. Multivariate analyses for CNV and OS were also performed. CNV were negatively correlated with the kurtosis value of the primary tumor mass using medium texture filtering (p=0.034, n=15). Linear regression revealed a significant negative correlation between kurtosis and CNV (p=0.038). Secondary analysis of the normal pancreas using coarse texture filtering revealed that increasing entropy was associated with decreased OS (p=0.0014, n=12). Using median entropy as a cutoff value (median: 4.165), median OS was greater in the entropy < 4.165 group versus the entropy > 4.165 group (179 days v 43 days; 95% CI 73.137 – 166.87; p=0.004, n=12). This exploratory study with admittedly limited sample size raises interesting questions about the use of CTTA parameters as diagnostic tools and/or biopsy adjuncts in assessing PDAC susceptibility to commercially available cytotoxics. Secondarily, entropy, a potential marker of heterogeneity and inflammation in the normal pancreas, represents an intriguing possibility for gauging prognosis.