Previamente foi relatado a associação do oleato de etoposídeo à uma microemulsão rica em colesterol (LDE) que é captada por células malignas que superexpressam receptores da Lipoproteína de Baixa Densidade (LDL). A associação do fármaco é estável, sua atividade antiproliferativa é preservada e há uma redução da toxicidade em animais. Dando continuidade, esse trabalho tem como objetivo investigar a cinética plasmática da associação LDE: oleato de etoposídeo e ainda verificar se a associação do fármaco à LDE modifica a propriedade da microemulsão de se concentrar nas células neoplásicas com aumento dos receptores, determinando a captação de ambos os componentes nos tecidos acometidos pelo tumor comparado com o tecido equivalente normal. O [3H]oleato de etoposídeo associado à LDE marcada radioativamente com [14C] oleato de colesterol, foi injetado intravenosamente em 14 pacientes com câncer de ovário (50,6 ± 7,5 anos), 24 horas antes da cirurgia. Amostras de sangue foram coletadas no período de 24 horas para determinar a curva de decaimento plasmático da associação. A radioatividade presente nas alíquotas do plasma foi determinada usando solução cintiladora e a Taxa Fracional de Remoção (TFR) foi calculada através de uma análise compartimental. Amostras de tecido ovariano com tumor e sem tumor foram coletadas durante a cirurgia, onde foi dado início ao procedimento de extração lipídica para determinação da radioatividade. A TFR da LDE e do oleato de etoposídeo foram similares (0,0881 e 0,1722 respectivamente, P= 0,2422). A média da captação tecidual de ambos[14C]-LDE e [3H]-oleato de etoposídeo por tecido maligno de ovário foi quatro vezes maior quando comparado com o tecido contralateral sem a doença (captação da LDE= 448 ± 184 e 143 ± 51 e a captação do oleato de etoposídeo foi de 346 ± 75 e 103 ± 56, respectivamente). O resultado indica que maior quantidade do fármaco fica retido na partícula da microemulsão, sendo removida da circulação e internalizada pelas células. Em adição foi mostrado que a associação LDE: oleato de etoposídeo teve habilidade de se concentrar nos tecidos malignos de ovário. Contudo, a associação pode ser usada para direcionar e concentrar o oleato de etoposídeo nas células malignas de ovário. / Background: Previously we reported the association of etoposídeo oleate to a cholesterol-rich microemultion (LDE) that is taken up by malignant cells that overexpress low-density lipoprotein (LDL) receptors. The association of the drug is stable, preserves the anti-proliferative activity of the drug and reduces the toxicity to animals. In order to investigate the plasma kinetics of the association LDE:etoposídeo oleate and to verify whether the complex has the ability to concentrate in malignant ovarian cancer we performed the following analysis. Methods: [3H]etoposídeo oleate associated to LOE labeled with [14C]-Cholesteryl Oleate (CO) was intravenously injected into 10 patients with cancer of ovary (50,6 ± 7,5 yr.) 24 h before the surgery. Blood samples were collected over the 24 h period to determine the plasma decay curves of the complex labels. Radioactivity present in plasma aliquots was determined in a scintillation solution and the plasma fractional c1earance rate (FCR) was calculated by compartmental analysis. Specimens of tumors and normal ovaries excised during the surgery were collected for lipid extraction, separation by thin layer chromatography and radioactive counting. Results: Fractional clearance rate (FCR) of LDE and of the drug were similar (0,0881 e 0,1722, respectively, P =0.2422). The mean of the uptake of both [14C]-LDE and [3H]-etoposídeo oleate by malignat tissue of ovary was three fold greater when compared with that of the contralateral normal ovaries (LDE uptake = 448 ± 184 and 143 ± 51 and etoposídeo oleate uptake = 346 ± 75 and 103 ± 56, respectively). Conclusions: Our results indicate that most of the drug is retained in the microemulsion particles until its removal from the circulation and internalization by the cells. In addition, we showed that the association LDE:etoposídeo oleate has the hability to concentrate in malignant ovarian tissues. Therefore, the complex can be used to direct and concentrate etoposídeo against malignant ovarian cells.

Abstract Malignant tissue growth induces marked biochemical and structural changes in the extracellular matrix of the tumour and its surrounding tissues. In the present study, we evaluated the prognostic value of the serum concentration of the markers of synthesis of type I collagen (PICP, PINP) and type III collagen (PIIINP) as well as the marker of type I collagen degradation (ICTP) and compared them with the conventional indicators of prognosis (clinical stage, grade of differentiation, histological subtype, residual tumour load and the age of the patient). The prognostic value of peritoneal cytological findings at operation was an additional object in our studies. High preoperative serum ICTP (>5.6μg/L) and PIIINP (>3.2μg/L) concentrations and a low PICP:PINP ratio (>2) correlated with poor prognosis in ovarian carcinoma in univariate analysis and in multivariate analysis when each variable was analyzed separately with the conventional factors. However, ICTP concentration was the only prognostic variable in multivariate analysis including PIIINP, PINP, ICTP and CA125. When analyzed with conventional prognostic factors (clinical stage, grade, residual tumour, presence of ascites, histology), clinical stage and ICTP were independent indicators of prognosis. In addition, malignant cells in the peritoneal fluid aspirate at primary operation, grade and the age of the patient predicted poor prognosis in multivariate analysis. Postoperative serum ICTP concentration 9-months after the operation was the strongest prognostic factor as compared to the preoperative ICTP and CA125 values and clinical variables. These results indicate that serum collagen metabolites, especially ICTP, are indicators of prognosis in epithelial ovarian cancer. The present ICTP-test does not detect the degradation products of immature type I collagen, the dominating form in ovarian cancer tissue. Therefore, the excess ICTP in invasive ovarian cancer might originate through the degradation of trivalently matured collagens in non-malignant tissues surrounding the malignancy. ICTP may thus be an indicator of invasive properties of the tumor and its determination opens up new perspective to predict the clinical outcome of ovarian cancer.

Abstract The aim of this population-based cohort study was to evaluate the incidence and relative risk ratios of gynaecological cancers and the mortality of women with at least five children (GM women) compared to the average of Finnish women. We linked together the data of the Population Register (1974–1997), the Finnish Cancer Registry and the national cause-of death files of Statistics Finland (1974–2001) by using a personal identification code. The study population consisted of 86 978 GM women (1974–1997), including 3 752 women with at least 10 children (GGM women). Altogether 7 604 cancer diagnoses and 18 870 deaths were recorded. The incidence (SIR) of breast (0.55, 95% CI 0.52–0.58), endometrial (0.57, 95% CI 0.52–0.63) and ovarian cancer (0.64, 95% CI 0.55–0.73) decreased, and that of cervical cancer (1.13, 95% CI 0.98–1.29) increased in GM women. In multivariate analysis, the increase in parity from five to eight increased the protection against breast and endometrial cancer, but not in ovarian or cervical cancer. A young age at first birth decreased the breast cancer risk, while an older age at first birth decreased the risk for endometrial and cervical cancer. A short premenopausal delivery-free period and a long birth period were risk reducers in women who contracted endometrial cancer after menopause. The mortality (SMR) of breast (0.64, 95% CI 0.59–0.69), endometrial (0.68, 95% CI 0.56–0.80), ovarian cancer (0.68, 95% CI 0.60–0.75) as well as for dementia (0.80, 95% CI 0.72–0.84) decreased. The SMR of kidney (1.38, 95% CI 1.21–1.56) cancer increased in the GM group. The SMR of ischemic heart diseases (1.10, 95% CI 1.08–1.13) and diabetes mellitus (1.42, 95% CI 1.29–1.55) increased. The overall SMR of GM women was 5% less than expected (95% CI 0.94–0.95; deficit 949 deaths), but among GGM women it coincided with the national average (1.01, 95% CI 0.93–1.08). Multiparity affected the spectrum of diseases and causes of death in a specific way: the pregnancy-specific hormonal milieu is responsible for the low SIR and SMR of hormone-dependent cancers, and increased body weight is lightly responsible for the high SMR of cardiovascular and metabolic diseases. These observations advocate for delivering the first child at an age younger than 30 years and to start measures for careful weight control not only during and after pregnancies but even later and permanently.

The ovarian surface epithelium, a very small portion of the total mass of the ovary, is generally thought to be the site of origin of over 85% of ovarian cancers. Such cancers are classified with the "Common Epithelial Tumours" of the ovary. In most industrialized countries, malignancies of the ovary rank fourth in cancer deaths in women; over 70% of these neoplasms have spread beyond the ovary when first diagnosed. Experimental approaches to the study of carcinogenesis in this tissue have been limited by the lack of pure populations of ovarian surface epithelial cells. Studies done on rodents in vivo suggest that both chemicals and C-type RNA viruses can induce ovarian cancers similar to those which are said to arise from the surface epithelium. However, the cell of origin cannot be proven in such studies. The purpose of this project was to develop a model for ovarian cancers of surface epithelial origin based on-carcinogenesis in vitro. To this end a method was devised to culture the rat ovarian surface epithelium in pure form. These cultured cells, whose identity has been confirmed by morphological, histochemical and ultrastructural means, are polygonal with clear cytoplasm, have well-defined borders, and grow in confluent monolayers. Their morphology is quite distinct from those of other ovarian cells in vitro. Cultured rat ovarian surface epithelial cells are histochemically positive for 17β-hydroxysteroid dehydrogenase, and negative for Δ5-3β-hydroxysteroid dehydrogenase, the same as in frozen sections of whole rat ovary. Ultrastructurally, cultured surface epithelial cells have basal laminae, microvilli, apical intercellular junctions, large nuclei, abundant rough endoplasmic reticulum, Golgi complexes, perinuclear bundles of microfilaments, and numerous vesicles. Although the ovarian suface epithelium is suspected of being an estrogen target tissue, there is no previous report of estrogen receptors in these cells. In this study cultured rat ovarian surface epithelial cells have been shown by autoradiographic means to exhibit estrogen receptor-like activity. Translocation of tritiated estradiol from cytoplasm to nucleus, and estrogen-specific binding have been demonstrated. Estradiol was shown to be mitogenic for cultured ovarian surface epithelial cells. From these results, the surface epithelial .cells of the ovary should be considered an estrogen target tissue. Kirsten murine sarcoma virus was used to produce three transformed cell lines from pure, first passage cultures of these cells. These three lines retained 170-hydroxysteroid dehydrogenase activity and showed slight Δ5-3β-hydroxysteroid dehydrogenase activity. Tumours resulting when these cells were injected into immunosuppressed female rats were highly malignant and resembled histologically human endometrioid stromal sarcomas of the ovary. This neoplasm is classed with the "Common Epithelial Tumours" of the ovary, but is generally not considered a derivative of the surface epithelium. In light of this study, perhaps this tumour should: be considered, to be of surface epithelial origin. A continuous cell line arising from pure cultures of rat ovarian surface epithelial cells produced structures in vitro resembling those found in ovarian serous papillary cystadenomas of borderline malignancy. This tumour is classed as a common epithelial ovarian tumour. Hence, in this study the rat ovarian surface epithelium has been cultured in pure form, has been characterized for a number of properties by several investigative techniques, and has been shown to be susceptible to transformation by an oncogenic virus; This work supports the theory that the "Common Epithelial Tumours" of the ovary are, in fact, derived from the surface epithelium. The availability of cultured ovarian surface epithelial cells should allow investigation into factors which make this tissue so susceptible to malignant transformation. From such cultures could come markers suitable for use in tests to detect ovarian cancers at an early stage. The culture of pure rat ovarian surface epithelium, as described herein, could readily be used to study chemical, physical and viral carcinogenesis in this tissue to produce experimental models of cancers arising in the ovarian surface epithelium. / Science, Faculty of / Zoology, Department of / Graduate

Orientadores: Gustavo Antonio de Souza, Sophie Françoise Mauricette Derchain / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-18T16:26:27Z (GMT). No. of bitstreams: 1 Dragosavac_Sanja_M.pdf: 1871037 bytes, checksum: 792409d11e54caa65d34f4ecbee851f0 (MD5) Previous issue date: 2011 / Resumo: O exame PET/CT com FDG-18F é um método de diagnóstico por imagem, útil em oncologia. O câncer de ovário é o câncer ginecológico de maior letalidade, sendo a terceira neoplasia mais freqüente do trato genital feminino no Brasil. O objetivo deste estudo foi avaliar o PET/CT com FDG-18F em pacientes com suspeita de recidiva de carcinoma de ovário e descrever a distribuição das lesões encontradas. Sujeitos e Métodos: Foram incluídas neste estudo retrospectivo 45 mulheres com suspeita de recidiva de câncer de ovário. As pacientes foram encaminhadas para clínica PET/CT Campinas de novembro 2006 até novembro de 2010, por aumento do CA-125, sintomas clínicos e/ou alterações na ultrassonografia (US), tomografia (TC) ou ressonância (RM). Para a confirmação da recidiva, 15 pacientes foram submetidas à cirurgia e 30 foram acompanhadas por um período mínimo de seis meses. Resultados: Quarenta e duas pacientes foram diagnosticadas com recidiva e três não apresentaram evidência de doença durante o período de acompanhamento. O CA-125 estava aumentado em 34 pacientes, 14 apresentavam sintomas clínicos e 23 tinham alterações em US, TC ou RM. Trinta e oito pacientes apresentaram o exame PET/CT positivo, todas com recidiva confirmada. Três pacientes apresentaram achados inconclusivos na PET/CT, todas com doença. Quatro exames de PET/CT eram negativos, sendo que uma paciente teve recidiva confirmada e as demais permaneceram sem evidências de doença durante o acompanhamento. Onze pacientes com CA-125 elevado apresentavam resultados de US, TC ou RM normais. Todas tiveram doença confirmada, sendo que a PET/CT detectou recidiva em nove e foi inconclusiva em duas. Entre as onze pacientes com CA- 125 normal, foram detectadas metástases na PET/CT em oito. As metástases mais freqüentes foram diagnosticadas em linfonodos, sendo localizados na região pélvica e abdominal em 30 pacientes, na região torácica em 16 e em sete pacientes, na região cervical. Implantes pélvicos e abdominais foram detectados em 27 pacientes. Outros locais de metástases foram fígado (n=7), baço (n=2), pleura (n=2), pulmão (n=2) e osso (n=2). O exame PET/CT detectou lesões não suspeitas em 20 das 45 pacientes (44,4%). A PET/CT detectou um novo tumor primário de tireoide numa paciente sem recidiva de carcinoma de ovário. Conclusão: O exame PET/CT foi útil para avaliação da extensão da recidiva de carcinoma de ovário. A recidiva acometeu mais freqüentemente os linfonodos, sendo a maioria localizada na região pélvica e abdominal. Metástases em linfonodos torácicos foram um achado freqüente nesta população estudada / Abstract: 18F-FDG PET/CT is a diagnostic method useful in oncology. Ovarian cancer is the third most frequent cancer of the female genital tract in Brazil, however, it has the highest mortality of all gynecological cancers. The aim of this study was to evaluate the use of 18F-FDG PET/CT in patients with suspected ovarian cancer recurrence and describe the distribution of metastasis. Methods: Fortyfive female patients with suspicion of ovarian cancer recurrence were included in this retrospective study. They were referred to PET/CT Campinas clinic from November 2006 to November 2010, because of elevated CA-125, clinical suspicion of ovarian cancer recurrence, or alterations detected on ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI). PET/CT results were compared with histologic findings (n=15) or clinical followup for at least six months (n=30). Results: Forty-two patients were confirmed with ovarian cancer recurrence. Three patients remained free of disease during clinical follow-up. CA-125 was elevated in a total of 34 patients, 14 patients had clinical symptoms of disease and 23 presented with alterations on US, CT and MRI. Thirty eight patients had positive PET/CT scan, all with confirmed disease. Three patients had equivocal PET/CT findings and in all three, recurrence was confirmed. Four patients had negative PET/CT scan: one with confirmed recurrence and three free from disease during follow-up. Nine out of 11 patients with elevated CA-125 and normal conventional imaging had positive PET/CT scan and two had equivocal findings. There were eleven patients with normal CA-125 levels, eight presented with positive PET/CT scan. Lymph nodes were the most frequent site of relapse of disease, most being in the pelvic/abdominal region (n=30) and others in thoracic (n=16) or cervical region (n=7). Peritoneal implants were found in 27 patients. Distant sites of metastasis included liver (n=6), spleen (n=2), pleura (n=2), lung (n=2) and bone (n=2). PET/CT detected unsuspected lesions in 20/45 patients (44.4%). One patient with PET/CT negative for ovarian cancer recurrence was diagnosed with primary papillary carcinoma of the thyroid. Conclusion: 18F-FDG PET/CT was a useful tool for evaluation of the extension of ovarian cancer recurrence. In the current series, lymph nodes were the most frequent site of relapse of disease, with supradiaphragmatic lymph node metastasis in large number of cases / Mestrado / Oncologia Ginecológica e Mamária / Mestre em Ciências da Saúde

Orientadores: Liliana Aparecida Lucci De Angelo Andrade, Sophie Francoise Mauricette Derchain / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T12:06:20Z (GMT). No. of bitstreams: 1 Pinto_PaolaBertolottiCardoso_D.pdf: 22982855 bytes, checksum: ca4a4e679f0037c1494bf2866a333968 (MD5) Previous issue date: 2013 / Resumo: Os carcinomas mucinosos do ovário são raros e representam apenas 3% dos carcinomas. Frente a este diagnóstico, é preciso descartar a possibilidade de metástase para o ovário, principalmente de neoplasia primária do trato gastrointestinal. Apesar da avaliação morfológica, macro e microscópica, e das reações imunoistoquímicas contribuírem para o diagnóstico diferencial, existem casos de difícil diferenciação. Um algoritmo para separar os carcinomas mucinosos primários dos metastáticos no ovário foi proposto na literatura e determina que são metastáticos os tumores bilaterais ou unilaterais menores que 13cm, classificando as neoplasias com uma acurácia de quase 90%. Objetivos: comparar os aspectos macro e microscópicos aliados à avaliação imunoistoquímica para a diferenciação entre tumores mucinosos primários e metastáticos no ovário, avaliando a acurácia do algoritmo nos casos, os dados clínicos e sua evolução. Métodos: Todos os tumores mucinosos envolvendo o ovário, dos arquivos do Laboratório de Anatomia Patológica da UNICAMP no período de 1994 a 2009 foram levantados. Feita revisão dos prontuários com descrição dos dados clínicos, evolução das pacientes, revisão de lâminas para avaliação de dados histopatológicos e seleção dos blocos de parafina para a construção de micro-arranjo de tecidos, onde foram realizadas as reações imunoistoquímicas para: CK7, CK20, ?-catenina, WT-1, CDX-2, Dpc-4, CA125, RE e RP. Resultados: Dos 76 casos selecionados, 35 eram carcinomas mucinosos primários do ovário, 33 eram metastáticos e em 8 casos o primário não foi definido, sendo excluídos da análise estatística. A sobrevida média foi maior nos primários (65X35 meses; p<0.0001). A acurácia do algoritmo foi de 82,1%. A maioria dos metastáticos originou-se do cólon ou reto (54%). Dos primários, 85% eram unilaterais >13 cm e dos metastáticos, 61% eram bilaterais e 18% unilaterais <13cm. Entre as características histológicas, êmbolos carcinomatosos e a ausência de gradiente morfológico foram mais observados nos metastáticos. Na análise bivariada dos marcadores apenas CK7, CK20 e CDX2 mostraram diferenças significantes entre os grupos, entretanto houve muita sobreposição de resultados. Após análise multivariada foram selecionados: gradiente histológico e CK7 para formação de um novo algoritmo que definiu, com acurácia de 91%, que um tumor é metastático quando apresenta qualquer um dos aspectos: bilateral; unilateral e <13 cm; ausência de gradiente histológico; ou gradiente histológico presente com falta de expressão do CK7. Conclusão: tanto o algoritmo, como as reações imunoistoquímicas e os aspectos morfológicos são úteis no diagnóstico diferencial entre primário e metastático, porém não há nenhum dado discriminatório e, em alguns casos, somente a análise com equipe multidisciplinar pode definir o primário, reconhecendo as peculiaridades deste diagnóstico desafiador / Abstract: Primary ovarian mucinous carcinomas are uncommon and the most important differential is metastatic adenocarcinoma, mainly from gastrointestinal origin. Besides immunohistochemical profile, an algorithm determines, with a high accuracy, that unilateral and >13cm tumors are primary carcinomas and all the others, metastasis. Objective: to describe clinical and histopathological aspects of mucinous carcinomas, assessing the algorithm accuracy and immunohistochemical markers contributory to diagnosis. Methods: 76 mucinous carcinomas from our files (1994-2009) were revised; immunohistochemical reactions for CK7, CK20, Ca125, hormonal receptors (ER, PR), WT1, SMAD4, ?-catenin, CDX2 were performed by TMA. Results: 35 were ovarian primary tumors (group 1), 33 were metastasis (group 2). In eight cases the primary was not identified and these were excluded from statistic analysis. Most of the metastasis were from colorectal cancer (54%). Mean survival differed between the groups (65X35 months; p<0.0001). Agreement with the algorithm was 82.1%. In group 1, 85% were unilateral >13cm; in group 2, 61% were bilateral and 18% unilateral tumors <13cm. Different from group 1, common features in group 2 were vascular invasion and tumors without histological gradient. Bivariate analysis pointed out CK7, CK20 and CDX2 as main markers to distinguish both groups, but overlapping of the results was observed. After multivariate analysis, 2 aspects were selected: histological gradient and CK7; a new algorithm was designed and established with an accuracy of 91%, that a mucinous carcinoma is metastatic to the ovary when it shows one of the aspects: bilateral, or unilateral and <13cm, or without histological gradient, or presence of histological gradient but CK7 is negative. Conclusion: Algorithm and immunohistochemistry are useful, but there is no gold-standard marker. In some cases, only multidisciplinary evaluation can achieve reliable anatomo-clinical diagnosis, in this challenging situation / Doutorado / Anatomia Patologica / Doutora em Ciências Médicas

In the studies about ovarian cancer cells, basal iNOS expression in the chemosensitive OV2008 cells was significantly higher than in the chemoresistant C13* cells. Cisplatin further increased iNOS expression in OV2008 cells, but had no effect in C13* cells. Furthermore, cisplatin dramatically reduced the expression levels of eNOS and nNOS, but again only in OV2008 cells. The data suggest that failure of cisplatin to upregulate iNOS and downregulate eNOS and nNOS in C13* cells could be an etiological factor in chemoresistance. Addition of exogenous NO at high levels, using SNAP, significantly increased p53 protein levels and caused apoptosis in both cell types. Specific iNOS inhibitor (1400W) partially blocked the pro-apoptotic effects of cisplatin in OV2008 cells, suggesting involvement of iNOS in cisplatin-induced apoptosis. However, blocking of all three isoforms of NOS with NG-amino-L-arginine in C13* cells dramatically changed these cells from chemoresistant to chemosensitive, greatly potentiating the pro-apoptotic effects of cisplatin. / Inhibition of Src-kinase activity reduces DNA synthesis in ovarian cancer cells. In an in vitro experiment, Src phosphorylated PKG on a tyrosine residue and PKG, presumable via serine-phosphorylation of Src, enhanced Src auto(tyrosine)phosphorylation. In ovarian cancer cells, inhibition of basal PKG activity with DT-2 decreased both basal and EGF-stimulated Src kinase activation and DNA synthesis. The data suggest that PKG at basal activity, is necessary for both basal and growth factor-stimulated Src kinase activation and enhanced DNA synthesis in human ovarian cancer cells. / The novel role of sGC/cGMP/PKG pathway on stimulating cell proliferation, potentially via interaction with the Src kinase pathway in human ovarian cancer cells, was demonstrated. ODQ dramatically reduced DNA synthesis rates, suggesting that basal sGC activity and basal cGMP levels are needed for ovarian cancer cell proliferation. DT-2 also reduced cell proliferation, suggesting the direct involvement of PKG. ANP and BNP had no effect on cell proliferation, suggesting that further activation of cGMP/PKG pathway above basal levels does not further enhance cell proliferation. / The present study also demonstrated that elevating cGMP slightly above the basal levels further protects pancreatic islet cells against spontaneous onset of apoptosis. The results showed that natriuretic peptides (both ANP and BNP) and low-level NO (i.e. physiological levels) as supply by NO donor, S-nitroso-N-acetylpenicilamine (SNAP) further prevented spontaneous apoptosis in pancreatic islets after isolation, whereas NO at high concentrations (i.e. pathological levels) promoted apoptosis in pancreatic islet cells. The commonly-used PKG inhibitor KT5823 and the newly-developed specific PKG inhibitor DT-2 completely prevented anti-apoptosic effect of ANP, suggesting the direct involvement of PKG in protection against spontaneous apoptosis. / The present study demonstrated that basal activity of sGC/cGMP/PKG signaling pathway is essential for partially limiting spontaneous apoptosis in pancreatic islet cells. The sGC inhibitor ODQ caused induction of apoptosis, which was completely blocked by co-treatment with ANP or BNP, agents that elevate cGMP via pGC, bypassing the ODQ block. Co-treatment with 8-Br-cGMP, a direct activator of PKG also completely prevented ODQ-induced apoptosis in islets. / Leung Lai-han. / "July 2006." / Adviser: Ronald Ray Fiscus. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1483. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 175-191). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Orientadores: Luis Otávio Zanatta Sarian, Sophie Françoise Mauricette Derchain / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-11-07T13:36:45Z (GMT). No. of bitstreams: 1 Toledo_MariaCarolinaSzymanski_M.pdf: 838964 bytes, checksum: 3c546db1a656989db9f433b93287b2d2 (MD5) Previous issue date: 2012 / Resumo: Introdução: o câncer de ovário é comumente diagnosticado em estágios avançados, sendo atualmente a neoplasia ginecológica de maior letalidade. As pesquisas têm direcionado esforços na tentativa de descobrir novos fatores prognósticos e métodos terapêuticos. Muitos trabalhos estudam a expressão dos receptores de esteróides (dentre eles, estrógeno (RE), progesterona (RP) e andrógeno (RA)) e HER2 (receptor estimulador de crescimento epitelial - subtipo 2) como fatores prognósticos e associados à resposta terapêutica, apresentando; entretanto, resultados conflitantes. Até onde conhecemos, não há estudos desta natureza no Brasil. Objetivo: Correlacionar à expressão dos RE, RP, RA e HER2 aos fatores clínico patológicos, ao intervalo livre de doença e à sobrevida nos cânceres epiteliais de ovário. Material e métodos: Este é um estudo observacional de coorte retrospectiva. Foram incluídas 152 mulheres com tumores epiteliais malignos, selecionados através dos prontuários no período de 1993 a 2008, no Centro de Atenção Integral à Saúde da Mulher (CAISM) da Universidade Estadual de Campinas - UNICAMP, São Paulo, Brasil. A avaliação da expressão dos RE [subtipos alfa (RE?) e beta (RE?)], RP, RA e HER2 foram realizadas por imunoistoquímica através da construção de microarranjos de tecidos (TMA). Inicialmente, foi realizada análise uni variada da expressão dos receptores acima quanto à idade, estado menopausal, índice de massa corpórea (IMC), tipo histológico, grau histológico, estadiamento inicial de acordo com a classificação proposta pela FIGO e presença de doença residual pós-tratamento cirúrgico. Em seguida, as pacientes foram divididas em dois grupos: ausência da expressão de RE?, RP e HER2 (triplo negativo) e positividade para pelo menos um desses receptores (não triplo negativo); e, avaliadas em relação aos critérios clínicos e epidemiológicos acima. Foram, então, realizadas análises multivariadas dos padrões de expressão de RE ? e ?, RP, RA, HER2 e triplo negativo em relação a estes mesmos critérios. Por fim, análise de sobrevida multivariada foi realizada utilizando-se todos os padrões de expressão e os fatores clínicos epidemiológicos estudados. Resultados: Nas análises multivariadas, mostraram-se significativas as seguintes associações: do receptor de estrógeno alfa (ER?) com tumores de grau histológico menos diferenciado (p=0.01); do receptor de progesterona (RP) à obesidade (p= 0.01); do receptor de andrógeno (RA) com tumores do subtipo seroso (p= 0.01); do receptor de HER2 com tumores dos graus histológicos II-III (p=0.02); do subgrupo triplo negativo com tumores de grau histológico menos diferenciado (II-III) (p<0.01). Não houve associação do RE? com nenhum dos fatores estudados. Quanto à análise multivariada de sobrevida livre de doença e sobrevida global; dentre os padrões de expressão de receptores, apenas o RE? esteve associado com melhor sobrevida livre de doença (RR=0.39; 95%CI 0.17 -0.90). Conclusões: A expressão do RE? esteve mais significativamente associada a fatores clínicos de pior prognóstico. O RP esteve associado à obesidade. O RA esteve significativamente mais presente nos tumores serosos. A expressão do HER2 e a presença de tumores triplo negativo foram maiores em tumores menos diferenciados. Paradoxalmente; o RE? foi o único receptor a apresentar associação com maior sobrevida livre de doença apesar de sua relação significativa com fatores reconhecidos de pior evolução clínica. Não houve diferença estatística significativa na análise multivariada de sobrevida total e sobrevida livre de doença quanto ao grupo de tumores triplo negativo / Abstract: Introduction: Ovarian cancer is commonly diagnosed in advanced stages and currently is the most lethal gynecological malignancy. Surveys have focused efforts in an attempt to discover new prognostic and therapeutic methods. A plenty of studies investigates the expression of steroid receptors (among them, estrogen (ER), progesterone (PR) and androgen AR)) and HER2 (epidermal growth receptor stimulator - subtype 2) as prognostic factors and associated to therapeutic response, presenting, however, conflicting results. As far as we know, there are no studies of this nature in Brazil. Objective: The aim of this study was to correlate the expression of ER (subtypes ? (ER ?) and ? (ER ?), PR, AR and HER2 to clinical pathological factors, the disease-free survival and overall survival of epithelial ovarian cancers. Methods: This is a retrospective observational cohort study. The study included 152 women with malignant epithelial tumors, selected through the records from 1993 to 2008, in the Centro de Atenção Integral à Saúde da Mulher (CAISM) at the State University of Campinas - UNICAMP, São Paulo, Brazil. The expression of ER (? and ?), PR, AR and HER2 was evaluated by immuno histochemistry through tissue microarray (TMA) technique. Initially, univariate analyses were performed, evaluating the expression of each receptor mentioned above to age, menopausal status, body mass index (BMI), histological type, histological grade, initial staging as preconized by FIGO staging of ovarian tumors and presence of residual disease after surgical treatment. Then, the patients were divided into two groups: absence of the expression of ER?, PR and HER2 (triple negative) and positive for at least one of these receptors (not triple negative), and evaluated in relation to the clinical and epidemiological criteria mentioned above. Multivariate analyzes were performed with ER ?, ER?, PR, AR, HER2 and triple negative towards these same criteria. At last, multivariate survival analyses were conducted using all the patterns of receptors' expression, epidemiological and clinical factors studied. Results: In multivariate analyzes, there were the following significant associations: of the estrogen receptor alpha (ER?) with less differentiated histological grade tumors (p = 0.01); of the progesterone receptor (PR) to obesity (p = 0.01); of the androgen receptor (AR) with the serous tumors (p = 0.01); of the HER2 receptor with tumors of histological grades II-III ( p = 0.02); of the triple negative subgroup with less differentiated histological grade tumors (II-III) (p <0.01). There was no association of the ER? with any of the factors studied. In the multivariate analysis of disease-free survival and overall survival; considering the patterns of receptors' expression, only the ER? expression was associated with better disease-free survival (RR= 0.39, 95% CI 0.17 to 0.90). Conclusions: The expression of ER? was more significantly associated with clinical factors of poor prognosis. The PR was associated with obesity. The AR was significantly more prevalent in serous tumors. The HER2 expression and the presence of triple negative epithelial ovarian cancer tumors were higher in less differentiated tumors. Paradoxically, the ER? was the only receptor which showed association with better disease-free survival despite its significant relationship with recognized factors of worse clinical outcome. There was no statistically significant difference in multivariate analysis of overall survival and disease-free survival regarding to the triple negative group / Mestrado / Oncologia Ginecológica e Mamária / Mestra em Ciências da Saúde

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 154 pages. Includes vita. Includes bibliographical references.

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references (leaves 123-154). Also available online.