Orientador: Laura Sterian Ward / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T00:19:00Z (GMT). No. of bitstreams: 1 Silva_JoycedoRosarioda_D.pdf: 4211439 bytes, checksum: d230e48c7d6fd16a7f9c75667ad83f9a (MD5) Previous issue date: 2009 / Resumo: A maior expressão de MUC1 tem sido relacionada com o pior prognóstico de diversas malignidades como o câncer de mama e pâncreas. Aproximadamente 20% dos carcinomas diferenciados da tiróide (CDT) evoluem com recidivas locais e a distância. O nosso objetivo foi o de avaliar o gene da MUC1 nos pacientes com CDT e relacionar com aspectos clínicos e anatomo-patológicos. CASUÍSTICA E MÉTODOS: Selecionamos 150 pacientes portadores de carcinoma papilífero (CP), 57 oriundos do Hospital das Clínicas da UNICAMP, acompanhados por 67 (73,29±39,83) meses, de 1995 a 2008 e 93 pacientes do Hospital AC Camargo - Fundação Antônio Prudente em São Paulo acompanhados por 41,37 (32,5±34,30) meses, de 1998 a 2008. Realizamos análise da expressão do gene da MUC 1 por imunoistoquímica e por PCR em Tempo Real e comparamos com dados de evolução clínica e do anatomopatológico. RESULTADOS: Observamos a expressão da proteína MUC1 em 82,19% dos pacientes com CP, no entanto, sem diferenças estatísticas para os dados de evolução clínica e do anatomo-patológico. A análise do RNA-m de MUC1 se correlacionou com a menor expressão nos indivíduos que apresentaram metástases ao diagnóstico (p valor=0,0216). Observamos a pior evolução: no sexo masculino, quando havia metástases ao diagnóstico, na ausência de tiroidite e nos tumores maiores que 4 cm. A presença de invasão tumoral foi mais freqüente nos indivíduos com ausência de tiroidite em 47% dos casos (p=0,0132; OR 2,473 - 95%IC: 1,198-5,104). CONCLUSÃO: Não conseguimos correlacionar a análise do gene MUC1 com aspectos clínicos e anatomo-patológicos de pior prognóstico para o CDT. / Abstract: The over expression of MUC1 has been related with the worst prognosis in malignancies like breast and pancreas cancer. We know that around 20% of the patients with differentiated thyroid cancer (DTC) can develop local and/or distant recurrences and because of that we decide to analyze the MUC1 gene in patients with DTC and tried to relate it with clinical and pathological patterns of the thyroid cancer. PATIENTS AND METHODS: We selected 150 patients with Papillary Thyroid Cancer: 57 from the Clinical Hospital of Campinas State University, followed up for 67 (73,29±39,83) months, since 1995 to 2008 and 93 patients from the A. C. Camargo Hospital - Antonio Prudente Foundation - São Paulo for 41,37 (32,5±34,3) months since 1998 to 2008. We analyzed the MUC1 gene with the immunohistochemistry and the Real Time - PCR techniques and compared the results with clinical and pathological data. RESULTS: The MUC1 expression was positive in 82,19% of the patients with papillary thyroid cancer, however, when we compared with clinical and pathological data, there was not statistical significance. The MUC1 m-RNA analysis was correlated with the less expression of the gene in the individuals who had had metastases at the diagnosis. We could observe the worst outcome in the individuals of the male gender, in the presence of metastases at the diagnosis, in the absence of thyroiditis in the non-neoplasic tissue and in tumors larger than 4 cm. The presence of tumoral invasion was significant in the patients with metastases to the diagnosis and in the ones without thyroiditis in 47% (p=0,0132; OR 2,473 - 95% CI: 1,198-5,104). CONCLUSION: We conclude that MUC1gene analysis was not useful to determine aggressive tumors nor to predict prognosis in papillary thyroid carcinomas. / Doutorado / Clinica Medica / Doutor em Clínica Médica

Two separate experiments were designed to measure urinary cyclic AMP and renal papillary cyclic AMP, respectively, Results suggest that urinary cyclic AMP excretion rate is unchanged and cannot be used as an index of tubular sensitivity to either vasopressin or fluoride. However, renal papillary tissue cyclic AMP increased significantly (p<0.05) at plasma fluoride concentrations which result in polyuric renal failure. Further, it appears that fluoride independently stimulates cyclic AMP in the papilla, demonstrated by the additive effect with vasopressin. It was postulated that the defect in water reabsorption induced by fluoride must be at a step subsequent to the generation of cyclic AMP, because one would expect to see an antidiuresis, not a diuresis with increased tissue cyclic AMP.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers. Despite enhanced understanding of the disease, the 5-year survival rate remains 8% due to the late stage of diagnosis and a lack of effective treatment options. Early detection of precancerous lesions, such as intraductal papillary mucinous neoplasms (IPMNs), is a strategy to prevent pancreas cancer related death. Standard qualitative imaging assessment cannot reliably distinguish between benign and malignant branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). A more consistent risk prediction method is needed to inform clinical decision making such that patients with benign cysts may be spared from unnecessary surgical resection. OBJECTIVE: To assess whether a BD-IPMN malignancy risk prediction model which demonstrated strong potential on preoperative computed tomography (CT) images would show similar results on magnetic resonance imaging (MRI). METHODS: 19 pathologically proven BD-IPMN patients with preoperative contrast-enhanced CT and MRI and were included in the study. Five radiomics features were extracted from the portal-venous phase CT and MR images of the largest cyst. Associations between radiomics features extracted from CT and MR were assessed using Pearson correlations. RESULTS: Of the five radiomics features, average-weighted eccentricity (AWE) was most strongly correlated between imaging modalities in all patients (n=19, r=0.46, 95% CI=0.001-0.75, p=0.05), low-risk patients (r=0.63, 95% CI=0.09-0.88, p=0.028), and patients with a solid component or mural nodule (r=0.66, 95% CI=-0.32-0.96, p=0.15). However, when two outliers within the dataset were removed from analysis, AWE no longer correlated between MR and CT. None of the other radiomics features displayed significant correlations between the modalities. CONCLUSIONS: The CT-based risk prediction model cannot be applied to MR data suggesting that a new model should be created from MRI data alone. / 2021-06-17T00:00:00Z

INTRODUÇÃO: Acredita-se que os fatores de crescimento insulina símile 1 (IGF1) e IGF2 tenham um papel chave na progressão de tumores, resistência à apoptose e terapias. A resistência à insulina tem sido associada ao aumento do volume tireoidiano e aumento do risco de desenvolver nódulos e câncer de tireoide; no entanto, há poucos estudos que avaliaram o papel dos IGFs e seus receptores no carcinoma papilífero de tireoide (CPT) e, até o momento, nenhum estudo foi conclusivo sobre a relação entre a via insulina/IGF e o comportamento do CPT. OBJETIVOS: 1) Estudar a expressão do IGF1, IGF2 e o IGF1R no CPT, incluindo o microcarcinoma papilífero; 2) Correlacionar essa expressão com as características clínicas, variante histopatológica, estadiamento e estratificação de risco. MÉTODOS: Foram selecionados, retrospectivamente, 110 pacientes operados por CPT e atendidos no Ambulatório do Serviço de Endocrinologia do Hospital das Clínicas da FMUSP e separados em dois grupos: 62 microcarcinomas papilíferos (MCP) e 48 CPT > 1,0 cm. A presença e expressão do IGF1, IGF2 e IGF1R foi avaliada, através de exame imunohistoquímico, em 110 tecidos tumorais e 98 tecidos não tumorais (controle). Os casos positivos foram classificados, de acordo com a quantidade de células coradas, em: + (menos de 10% das células); ++ (em 10-50% das células) e +++ (mais de 50% das células). O grau da expressão foi classificada em leve, moderada e forte. A presença e intensidade desses marcadores foram correlacionados com as características clínicas, variante histopatológico, TNM e estratificação de risco. RESULTADOS: O IGF1 e o IGF1R estiveram presentes em 100% e 99% dos CPTs e mostraram-se significativamente hiperexpressos, tanto nos MCPs quanto nos CPTs > 1,0 cm, quando comparados ao tecido adjacente não tumoral (p < 0,001). O IGF2 esteve expresso em 46,7% dos CPTs e mostrou fraca expressão em apenas um tecido não tumoral (p < 0,001). O IGF1 apresentou expressão significativamente maior nos microcarcinomas nos estágios III e IVA quando comparados aos estágios I e II (p=0,022). Não houve diferença significativa na quantidade e intensidade de expressão do IGF1 e IGF1R nos MCT quando comparados aos CPTs > 1,0 cm. O IGF2 apresentou expressão significativamente maior nos MCTs e, nesse grupo, apresentou maior expressão nos tumores multicêntricos (p=0,017) e nos estágios III e IVA, quando comparados aos estagios I e II (p=0,041). CONCLUSÕES: No presente estudo, observamos que o IGF1 e IGF2 foram significativamente mais expressos nos microcarcinomas em estágios mais avançados. O IGF2 apresentou maior expressão nos microcarcinomas papilíferos e esta expressão foi significativamente maior nos tumores multicêntricos / INTRODUCTION: Insulin-like growth factor-1 and 2 (IGF-1 and IGF-2) are believed to play a key role in the progression of tumors, resistance to apoptosis and therapies. The insulin resistence has been associated with increased thyroid volume and increased risk in developing thyroid nodules and thyroid cancer. However, few studies have evaluated the role of IGFs and their receptors on papillary thyroid carcinomas (PTC), and there is no conclusive studies about the relationship between IGF axis and PTC behavior. OBJECTIVES: The aim of this study was to investigate the expression of IGF-1, IGF-2, and IGF-1R in PTC, including papillary microcarcinoma (PTMC), and correlate the expression data with clinical, histologic variants, TNM staging, and risk of recurrence. METHODS: We retrospectively selected 110 paraffin-embedded tumoral tissues from patients with PTC who underwent thyroidectomy at Hospital das Clínicas of FMUSP. These patients were divided into two groups: 62 microcarcinomas (PTMC) and 48 PTC > 1.0 cm. The presence and intensity of expression of IGF-1, IGF-2, and IGF-1R were evaluated through immunohistochemical staining in 110 tumoral tissues, and in 98 non-tumoral tissues (control group). Positive cases were classified according to the numbers of staining cells in: + less than 10% of staining cells; ++ in 10-50% of the staining cells, and +++ in more than 50% of staining cells. The degree of expression was classified as mild, moderate and strong. The presence and degree of IGF1, IGF2, and IGF1R staining were correlated with clinical features, histologic type, TNM staging, and risk stratification. RESULTS: IGF-1 and IGF-1R were expressed in 100% and 99% of PTC, and were significantly overexpressed in both PTMC and PTC > 1.0 cm, in comparison with non-tumoral tissues (control group) (p < 0.001). IGF-2 was expressed in 46.7% of PTC and had mild positivity expression in only one non-tumoral tissue (p < 0.001). IGF1 was significantly overexpressed in PTMC on stage III and IVa and was less expressed in stage I and II. There was no significant difference on IGF1 and IGF1R expression between PTMC and PTC >1.0 cm. IGF-2 presented greater expression in multicentric PTMC (p=0.017), specially in stage III and IVa. CONCLUSIONS: In our study, both IGF-1 and IGF2 were significantly overexpressed in PTMC group in advanced stages. IGF-2 was also significantly overexpressed in PTMC multicentric tumors

Este estudo foi desenvolvido com a intenção de propor uma classificação anatômica atualizada para o aparelho subvalvar da valva atrioventricular esquerda de corações humanos. A classificação de Pomerantzeff foi desenvolvida utilizando nomes lógicos e correlatos, baseada na posição anatômica do coração, e tem uma inovação: a identificação de uma nova estrutura anatômica, o músculo papilar basal. Cinqüenta valvas atrioventriculares esquerdas de corações humanos normais foram examinadas através de incisões realizadas na parede do ventrículo esquerdo. Foram analisados o tipo, a quantidade e a extensão das cordas, seus locais de origem e de inserção. Foi identificada a presença de três conjuntos de cordas: aposicional, basal e central. As cordas aposicionais são divididas em três subgrupos: mural, aórtico e comissural. Esses subgrupos se originam respectivamente nas cabeças mural, aórtica e comissural dos músculos papilares clássicos, aqui denominados superior-esquerdo e inferior-direito, e se inserem na região aposicional dos folhetos mural e aórtico da valva mitral e das suas comissuras superior-esquerda e inferiordireita. O conjunto de cordas basal pode ter três locais de origem: nas cabeças murais dos músculos papilares superior-esquerdo e inferior-direito ou em um músculo papilar acessório, nomeado músculo papilar basal. As cordas basais inserem-se próximas da base de implantação do folheto mural no anel valvar mitral. O terceiro conjunto é constituído pelas cordas centrais, que se originam nas cabeças aórticas dos músculos papilares superioresquerdo e inferior-direito e se implantam na porção central do folheto aórtico da valva mitral. Em cada conjunto podem ser encontrados até quatro tipos de cordas: primárias, secundárias, terciárias e quaternárias. As primárias são aquelas que têm sua origem nas pontas dos músculos papilares. As secundárias são ramificações das primárias, as terciárias são ramificações das secundárias e as quaternárias são ramificações das terciárias. Essa classificação, clara e objetiva, permite fácil reconhecimento das estruturas e pode ser utilizada igualmente por anatomistas, cirurgiões cardiovasculares e médicos que realizam exames diagnósticos por imagem / The aim of this study was proposing an anatomic and present classification of the subvalvar apparatus of the left atrioventricular valve in normal human hearts. Pomerantzeffs classification uses logic and correlated names, the anatomic position of the heart, and has an innovation: the identification of a new anatomic structure, the basal papillary muscle. Fifty left atrioventricular valves of normal human hearts were examined via incisions in the left ventricle wall, visualizing the valve from below. The type, quantity and length of the chordae tendineae and their places of origin and insertion were analyzed. Was identified the presence of three groups of chordae tendineae: appositional, basal and central. The appositional group is divided in three subgroups: mural, aortic and comissural, that arise from the respective heads mural, aortic and comissural of the classic papillary muscles here named leftsuperior and right- inferior and has his insertion in the appositional portion of the mural and aortic leaflets of the mitral valve and in the commissures leftsuperior and right-inferior. The basal group of cords can have three places of origin: from the mural heads of the left-superior and right-inferior papillary muscles or from an accessory papillary muscle, named basal papillary muscle, and as his insertion near of the base of implantation of the mural leaflet in the valvar ring. The central group of cords arises from the aortic heads of the classic papillary muscles and has his insertion in the central portion of the aortic leaflet of the mitral valve. In each group described above there are four types of cordae tendineae: primary (arise from the papillary muscles), secondary (ramification of primary), tertiary (ramification of secondary) and quaternary (ramification of tertiary). This classification, clear and objective, allows easy recognition of the subvalvar structures and can be used equally by anatomists, cardiovascular surgeons and physicians who carry out exams with image diagnostic methods

INTRODUÇÃO: Acredita-se que os fatores de crescimento insulina símile 1 (IGF1) e IGF2 tenham um papel chave na progressão de tumores, resistência à apoptose e terapias. A resistência à insulina tem sido associada ao aumento do volume tireoidiano e aumento do risco de desenvolver nódulos e câncer de tireoide; no entanto, há poucos estudos que avaliaram o papel dos IGFs e seus receptores no carcinoma papilífero de tireoide (CPT) e, até o momento, nenhum estudo foi conclusivo sobre a relação entre a via insulina/IGF e o comportamento do CPT. OBJETIVOS: 1) Estudar a expressão do IGF1, IGF2 e o IGF1R no CPT, incluindo o microcarcinoma papilífero; 2) Correlacionar essa expressão com as características clínicas, variante histopatológica, estadiamento e estratificação de risco. MÉTODOS: Foram selecionados, retrospectivamente, 110 pacientes operados por CPT e atendidos no Ambulatório do Serviço de Endocrinologia do Hospital das Clínicas da FMUSP e separados em dois grupos: 62 microcarcinomas papilíferos (MCP) e 48 CPT > 1,0 cm. A presença e expressão do IGF1, IGF2 e IGF1R foi avaliada, através de exame imunohistoquímico, em 110 tecidos tumorais e 98 tecidos não tumorais (controle). Os casos positivos foram classificados, de acordo com a quantidade de células coradas, em: + (menos de 10% das células); ++ (em 10-50% das células) e +++ (mais de 50% das células). O grau da expressão foi classificada em leve, moderada e forte. A presença e intensidade desses marcadores foram correlacionados com as características clínicas, variante histopatológico, TNM e estratificação de risco. RESULTADOS: O IGF1 e o IGF1R estiveram presentes em 100% e 99% dos CPTs e mostraram-se significativamente hiperexpressos, tanto nos MCPs quanto nos CPTs > 1,0 cm, quando comparados ao tecido adjacente não tumoral (p < 0,001). O IGF2 esteve expresso em 46,7% dos CPTs e mostrou fraca expressão em apenas um tecido não tumoral (p < 0,001). O IGF1 apresentou expressão significativamente maior nos microcarcinomas nos estágios III e IVA quando comparados aos estágios I e II (p=0,022). Não houve diferença significativa na quantidade e intensidade de expressão do IGF1 e IGF1R nos MCT quando comparados aos CPTs > 1,0 cm. O IGF2 apresentou expressão significativamente maior nos MCTs e, nesse grupo, apresentou maior expressão nos tumores multicêntricos (p=0,017) e nos estágios III e IVA, quando comparados aos estagios I e II (p=0,041). CONCLUSÕES: No presente estudo, observamos que o IGF1 e IGF2 foram significativamente mais expressos nos microcarcinomas em estágios mais avançados. O IGF2 apresentou maior expressão nos microcarcinomas papilíferos e esta expressão foi significativamente maior nos tumores multicêntricos / INTRODUCTION: Insulin-like growth factor-1 and 2 (IGF-1 and IGF-2) are believed to play a key role in the progression of tumors, resistance to apoptosis and therapies. The insulin resistence has been associated with increased thyroid volume and increased risk in developing thyroid nodules and thyroid cancer. However, few studies have evaluated the role of IGFs and their receptors on papillary thyroid carcinomas (PTC), and there is no conclusive studies about the relationship between IGF axis and PTC behavior. OBJECTIVES: The aim of this study was to investigate the expression of IGF-1, IGF-2, and IGF-1R in PTC, including papillary microcarcinoma (PTMC), and correlate the expression data with clinical, histologic variants, TNM staging, and risk of recurrence. METHODS: We retrospectively selected 110 paraffin-embedded tumoral tissues from patients with PTC who underwent thyroidectomy at Hospital das Clínicas of FMUSP. These patients were divided into two groups: 62 microcarcinomas (PTMC) and 48 PTC > 1.0 cm. The presence and intensity of expression of IGF-1, IGF-2, and IGF-1R were evaluated through immunohistochemical staining in 110 tumoral tissues, and in 98 non-tumoral tissues (control group). Positive cases were classified according to the numbers of staining cells in: + less than 10% of staining cells; ++ in 10-50% of the staining cells, and +++ in more than 50% of staining cells. The degree of expression was classified as mild, moderate and strong. The presence and degree of IGF1, IGF2, and IGF1R staining were correlated with clinical features, histologic type, TNM staging, and risk stratification. RESULTS: IGF-1 and IGF-1R were expressed in 100% and 99% of PTC, and were significantly overexpressed in both PTMC and PTC > 1.0 cm, in comparison with non-tumoral tissues (control group) (p < 0.001). IGF-2 was expressed in 46.7% of PTC and had mild positivity expression in only one non-tumoral tissue (p < 0.001). IGF1 was significantly overexpressed in PTMC on stage III and IVa and was less expressed in stage I and II. There was no significant difference on IGF1 and IGF1R expression between PTMC and PTC >1.0 cm. IGF-2 presented greater expression in multicentric PTMC (p=0.017), specially in stage III and IVa. CONCLUSIONS: In our study, both IGF-1 and IGF2 were significantly overexpressed in PTMC group in advanced stages. IGF-2 was also significantly overexpressed in PTMC multicentric tumors

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Source: Masters Abstracts International, Volume: 47-06, page: 3373. Adviser: Wenyaw Chan. Includes bibliographical references.

Adaptor proteins play a vital role in the propagation of cellular signals. Although they lack endogenous catalytic activity, they contain a variety of protein binding modules, which enable them to promote specific and efficient interactions with their binding partners. They form integrative platforms for a variety of molecules (e.g. lipids, tyrosine kinases, cytoskeletal and signaling proteins), and thereby link and coordinate key functions such as cell growth, motility and shape determination. Our laboratory has recently cloned a novel, 130 kDa adaptor protein, named XB130, as a structural homolog of actin-filament-associated-protein (AFAP-110), a stress fiber-binding Src substrate. However, the molecular interactions and functions of this novel adaptor remained to be elucidated. To characterize the function of XB130 we asked two general questions: (1) Is XB130 involved in the signal transduction pathways of tyrosine kinases? And (2) Is XB130 capable of regulating the cytoskeleton and/or is it regulated by the cytoskeleton? To address these questions first we investigated the tissue distribution of XB130 and discovered that it is abundantly expressed in thyroid. Therefore we asked whether it is a target of the thyroid-specific tyrosine kinase, RET/PTC, a genetically rearranged, constitutively active enzyme that plays a pathogenic role in papillary thyroid cancer. We found that XB130 is a RET/PTC substrate that couples RET/PTC signaling to phosphatidylinositol 3-kinase (PI3K) activation through its phosphorylation dependent interaction with the regulatory subunit p85 of PI3K. XB130 plays an important role in PI3K signaling, as downregulation of XB130 in TPC1 papillary thyroid cancer cells, harboring the RET/PTC1 kinase, strongly reduced Akt activity and concomitantly inhibited cell cycle progression and survival in suspension. In the second part we demonstrate that XB130 is a novel Rac- and cytoskeleton-regulated protein that exhibits high affinity to lamellipodial (branched) F-actin and impacts motility and invasiveness of tumor cells. In conclusion, my work characterized a novel adaptor protein and assigned two well-defined pathophysiological functions to it in the context of thyroid cancer cells.

Adaptor proteins play a vital role in the propagation of cellular signals. Although they lack endogenous catalytic activity, they contain a variety of protein binding modules, which enable them to promote specific and efficient interactions with their binding partners. They form integrative platforms for a variety of molecules (e.g. lipids, tyrosine kinases, cytoskeletal and signaling proteins), and thereby link and coordinate key functions such as cell growth, motility and shape determination. Our laboratory has recently cloned a novel, 130 kDa adaptor protein, named XB130, as a structural homolog of actin-filament-associated-protein (AFAP-110), a stress fiber-binding Src substrate. However, the molecular interactions and functions of this novel adaptor remained to be elucidated. To characterize the function of XB130 we asked two general questions: (1) Is XB130 involved in the signal transduction pathways of tyrosine kinases? And (2) Is XB130 capable of regulating the cytoskeleton and/or is it regulated by the cytoskeleton? To address these questions first we investigated the tissue distribution of XB130 and discovered that it is abundantly expressed in thyroid. Therefore we asked whether it is a target of the thyroid-specific tyrosine kinase, RET/PTC, a genetically rearranged, constitutively active enzyme that plays a pathogenic role in papillary thyroid cancer. We found that XB130 is a RET/PTC substrate that couples RET/PTC signaling to phosphatidylinositol 3-kinase (PI3K) activation through its phosphorylation dependent interaction with the regulatory subunit p85 of PI3K. XB130 plays an important role in PI3K signaling, as downregulation of XB130 in TPC1 papillary thyroid cancer cells, harboring the RET/PTC1 kinase, strongly reduced Akt activity and concomitantly inhibited cell cycle progression and survival in suspension. In the second part we demonstrate that XB130 is a novel Rac- and cytoskeleton-regulated protein that exhibits high affinity to lamellipodial (branched) F-actin and impacts motility and invasiveness of tumor cells. In conclusion, my work characterized a novel adaptor protein and assigned two well-defined pathophysiological functions to it in the context of thyroid cancer cells.