Thesis (doctoral)--Københavns Universitet.

Thesis (doctoral)--Københavns Universitet.

Thesis (M.D.)—Boston University

no / Background Meningiomas are the most common type of intracranial tumor, accounting for between 24 and 30 % of primary intracranial tumors. Thus far, no biomarkers exist to reliably predict the clinical outcome of meningiomas. A previous genome-wide methylation analysis revealed that HOXA9 is one of the most functionally relevant biomarkers. In this study, we have examined whether HOXA9 is a potential therapeutic target in meningiomas, using HXR9, a peptide inhibitor of the interaction between HOXA9 and its cofactor PBX. Methods We determined the expression level of HOXA9 in human meningiomas, meningioma cell lines, and normal brain tissue. Meningioma in culture and in subcutaneous tumors was treated with HXR9. We also examined the disruption of HOXA9/PBX dimers. Results We first confirmed that HOXA9 is highly expressed in meningiomas, but not in normal brain tissue. The HXR9 peptide blocks the binding of HOXA9 to PBX, leading to an alteration of DNA binding, and subsequent regulation of their target genes. HXR9 markedly inhibited the growth of meningioma cells and subcutaneous meningeal tumors. Conclusion There is no effective chemotherapy for meningiomas at present, and targeting the HOXA9/PBX interaction may represent a novel treatment option for this disease.

Made available in DSpace on 2014-06-11T19:23:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-01-29Bitstream added on 2014-06-13T20:50:03Z : No. of bitstreams: 1 lombardi_ias_me_botfm.pdf: 529927 bytes, checksum: 6cb4e1254a86d1683806ac3cb6ca21b7 (MD5) / Meningiomas são os tumores intracranianos primários mais comuns e correlacionam-­‐se com câncer de mama, compatilhando características como incidência maior no sexo feminino, receptores para hormônios sexuais e crescimento a exposição a hormônios sexuais. O gene BRCA1 é amplamente estudado no câncer de mama hereditário e esporádico, entretanto, são poucos os trabalhos que correlacionam BRCA1 e meningiomas. O BRCA1 é gene de supressão tumoral, interagindo com outros oncogenes, atuando no reparo do DNA durante a divisão celular e modulando negativamente receptores de estrógeno e progesterona. Avaliar o padrão de metilação de e expressão de BRCA1 em meningiomas e tecidos controles, e a expressão de receptores de estrógeno e progesterona em meningiomas e controles, correlacionando estes dados com dados epidemiológicos da casuística. Casuística e métodos: pacientes com diagnóstico de meningiomas tiveram amostras tumorais colhidas durante cirurgias de rotina pela disciplina de Neurocirurgia da Faculdade de Medicina de Botucatu (FMB) e do Hospital Mário Gatti, em Campinas. Previamente, o projeto foi aprovado pelo Comitê de Ética em Pesquisa e cada paciente concordou em participar ao assinar o Termo de Consentimento Livre e Esclarecido. Amostras controle de aracnóide foram colhidas de cadáveres no serviço de necropsia da disciplina de Patologia da FMB. As amostras tumorais foram avaliadas para metilação de BRCA1 por PCR específica para metilação e os resultados avaliados por eletroforese. A expressão foi avaliada por PCR em tempo real os resultados dados em relação a amostras comtroles. A expressão de receptores de estrógeno (RE) e progesterona (RP) foram analisadas por imuno-histoquímica, conforme rotina da disciplina de Patologia da FMB. Foram avaliados 50 meningiomas entre... / Meningiomas are the most common primary intracranial tumors and correlate with breast cancer, shearing features like higher incidence in female, sexual hormone receptors and growth to exposure to sexual hormones. The gene is widely studied in hereditary and sporadic breast cancer, however, there are few studies that correlate BRCA1 and meningiomas. The BRCA1 is a tumor suppressor gene and interacts with other oncogenes by DNA repairing during cell division and also negative modulating estrogen and progesterone receptors. To assess the pattern of methylation and expression of BRCA1 in meningiomas and control tissues, and the expression of estrogen and progesterone receptors in meningiomas and control tissues, and to correlate these data with patients epidemiological data. Patients diagnosed with meningioma had collected tumors samples during routine surgeries by the discipline of Neurosurgery in Faculty of Medicine of Botucatu (FMB) and Mario Gatti Hospital in Campinas. Previously, the project was approved by the Research Ethics Committee and each patient agreed to participate by signing the Instrument of Consent. Control arachnoid samples were collected from cadavers during routine of necropsy of Pathology departament in FMB. The tumor samples were analyzed for methylation of BRCA1 by methylation specific PCR and the results were evaluated by electrophoresis. The expression was assessed by real-­‐time PCR results given in relation to samples comtroles. The expression of estrogen receptors (ER) and progesterone (PR) were analyzed by immunohistochemistry, as routine in Pathology departament. There were 50 meningiomas between January 2009 to September 2012, 22 male and 28 female. The methylation of BRCA1 in meningiomas was statistically significant compared to control tissues... (Complete abstract click electronic access below)

Orientador: Adriana Camargo Ferrasi / Coorientador: Maria Inês de Moura Campos Pardini / Coorientador: Marco Antonio Zanini / Banca: Carlos Gilberto Carlotti Junior / Banca: Eny Maria Goloni-Bertollo / Resumo: Meningiomas são os tumores intracranianos primários mais comuns e correlacionam-­‐se com câncer de mama, compatilhando características como incidência maior no sexo feminino, receptores para hormônios sexuais e crescimento a exposição a hormônios sexuais. O gene BRCA1 é amplamente estudado no câncer de mama hereditário e esporádico, entretanto, são poucos os trabalhos que correlacionam BRCA1 e meningiomas. O BRCA1 é gene de supressão tumoral, interagindo com outros oncogenes, atuando no reparo do DNA durante a divisão celular e modulando negativamente receptores de estrógeno e progesterona. Avaliar o padrão de metilação de e expressão de BRCA1 em meningiomas e tecidos controles, e a expressão de receptores de estrógeno e progesterona em meningiomas e controles, correlacionando estes dados com dados epidemiológicos da casuística. Casuística e métodos: pacientes com diagnóstico de meningiomas tiveram amostras tumorais colhidas durante cirurgias de rotina pela disciplina de Neurocirurgia da Faculdade de Medicina de Botucatu (FMB) e do Hospital Mário Gatti, em Campinas. Previamente, o projeto foi aprovado pelo Comitê de Ética em Pesquisa e cada paciente concordou em participar ao assinar o Termo de Consentimento Livre e Esclarecido. Amostras controle de aracnóide foram colhidas de cadáveres no serviço de necropsia da disciplina de Patologia da FMB. As amostras tumorais foram avaliadas para metilação de BRCA1 por PCR específica para metilação e os resultados avaliados por eletroforese. A expressão foi avaliada por PCR em tempo real os resultados dados em relação a amostras comtroles. A expressão de receptores de estrógeno (RE) e progesterona (RP) foram analisadas por imuno-histoquímica, conforme rotina da disciplina de Patologia da FMB. Foram avaliados 50 meningiomas entre... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Meningiomas are the most common primary intracranial tumors and correlate with breast cancer, shearing features like higher incidence in female, sexual hormone receptors and growth to exposure to sexual hormones. The gene is widely studied in hereditary and sporadic breast cancer, however, there are few studies that correlate BRCA1 and meningiomas. The BRCA1 is a tumor suppressor gene and interacts with other oncogenes by DNA repairing during cell division and also negative modulating estrogen and progesterone receptors. To assess the pattern of methylation and expression of BRCA1 in meningiomas and control tissues, and the expression of estrogen and progesterone receptors in meningiomas and control tissues, and to correlate these data with patients epidemiological data. Patients diagnosed with meningioma had collected tumors samples during routine surgeries by the discipline of Neurosurgery in Faculty of Medicine of Botucatu (FMB) and Mario Gatti Hospital in Campinas. Previously, the project was approved by the Research Ethics Committee and each patient agreed to participate by signing the Instrument of Consent. Control arachnoid samples were collected from cadavers during routine of necropsy of Pathology departament in FMB. The tumor samples were analyzed for methylation of BRCA1 by methylation specific PCR and the results were evaluated by electrophoresis. The expression was assessed by real-­‐time PCR results given in relation to samples comtroles. The expression of estrogen receptors (ER) and progesterone (PR) were analyzed by immunohistochemistry, as routine in Pathology departament. There were 50 meningiomas between January 2009 to September 2012, 22 male and 28 female. The methylation of BRCA1 in meningiomas was statistically significant compared to control tissues... (Complete abstract click electronic access below) / Mestre

Malignant brain tumor is one of the most lethal forms of cancers. In the United States alone, approximately 20,500 new cases of primary malignant brain and central nervous system tumors are expected to be diagnosed in 2007 with 12,740 deaths estimated. Treatment of malignant brain tumor remains a major challenge despite recent advance in surgery and other adjuvant therapies, such as chemotherapy. The failure of potential effective chemotherapeutics for brain tumor treatment is usually not due to the lack of potency of the drug, but rather can be attributed to lack of therapeutic strategies capable of overcoming blood brain barrier for effective delivery of drug to the brain tumor. In this thesis, we developed a minimally invasive sustained release system for glioma therapy. The present study was initiated in an effort to incorporated Doxorubicin (DOX) loaded PLGA particle into an agarose gel, which can provide a continuous release of DOX locally to the tumor site. DOX, a toposiomearase II inhibitor, is not currently used clinically for brain tumor treatment because when delivered systemically it does not cross BBB. Our hydrogel particle system can overcome this shortcoming of DOX. The results from this study demonstrate that the DOX/PLGA particle gel system can maintain the bioactivity of DOX and sustained release DOX for at least 15 day in vitro. The result of in vivo study showed the DOX/PLGA particle gel treated group had significantly extend the medium survival of 9L glioma bearing rat from 21 days to 29 days. Therefore, the success experience of this local and sustained delivery device might benefit the development of future glioma therapy strategy.

Orientador: Gabriela Castellano / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin. / Made available in DSpace on 2018-08-12T12:39:12Z (GMT). No. of bitstreams: 1 CuellarBaena_SandraPatricia_M.pdf: 2971806 bytes, checksum: 993051b37ed11a93fc4c48a83e24003d (MD5) Previous issue date: 2008 / Resumo: Este trabalho visou o estudo e validação de técnicas de pre-processamento e quantificação de dados provenientes da técnica de Espectroscopia por Ressonância Magnética (MRS, do inglês Magnetic Resonance Spectroscopy), obtidos do cérebro humano in vivo, para a extração de informação que fosse clinicamente relevante para o estudo e diagnostico de tumores cerebrais. Para isso, foi feito o estudo da técnica com base na literatura, incluindo a revisão dos aspectos físicos envolvidos, estudando os métodos computacionais utilizados para o pre-processamento e quantificação dos dados, e os aspectos bioquímicos dos metabólicos de interesse presentes no cérebro humano, passiveis de serem quantificados através da técnica. Especificamente, foi estudado um método de quantificação de dados de MRS, o método. AMARES (Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS data), aplicado na quantificação de dados de MRS adquiridos de sujeitos controles e pacientes portadores de tumores cerebrais, provenientes de uma base de dados do Laboratório de Neuroimagem (LNI - Hospital das Clinicas - UNICAMP). Isso foi feito utilizando o software de domínio público jMRUI (http://sermn02.uab.es/mrui/)[1], que possui o método AMARES já implementado. Estes resultados foram comparados com resultados provenientes de uma quantificação manual desses mesmos dados, realizada previamente como parte do projeto de doutorado da Dra. Andréia Vasconcellos (atual docente do Depto. de Radiologia da FCM/UNICAMP)[2]. Foi verificada a concordância entre os dois métodos de quantificação, e também a viabilidade de usar os resultados da quantificação com o método automático para alem de diferenciar entre os grupos de pacientes e controles, realizar a separação dos Pacientes com tumores em diferentes grupos. Obteve-se que os resultados obtidos com o método automático foram mais precisos e consistentes que os obtidos com o método manual, e permitiram uma melhor classificação dos tipos de tumores. Adicionalmente, foram incluídos neste trabalho os resultados do estudo de perfis metabólicos ex vivo em tumores cerebrais pediátricos através da técnica HR-MAS (do inglês High Resolution Magic Angle Spinning). Este estudo adicional foi realizado no Laboratório de Imagem Molecular da Faculdade de Medicina da Universidade de Valencia (Espanha) através do Programa Santander de Mobilidade Internacional e financiado através de uma bolsa do Banco Santander-Banespa. / Abstract: The aim of this work was to study and validate techniques for pre-processing and quantificating Magnetic Resonance Spectroscopy data, obtained in vivo from the human brain, in order to get information clinically useful for the study and diagnosis of brain tumors. Therefore, a literature-based study of the technique was made, including a review of the Physics concepts involved, the data acquisition process in the scanner and the computational methods used to pre-process and quantificate the spectral data, as well as the biochemical aspects of the metabolites of interest in the human brain that can be detected by this technique. Special attention was given to the AMARES (Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS data) method for MRS data quantification, which was studied and applied to the quantification of data from control subjects and patients with brain tumors. The data came from a database of the Neuroimaging Laboratory (LNI - Hospital das Clinicas - UNICAMP). The quantification with AMARES was made through the jMRUI software (http://sermn02.uab.es/mrui/) [1], a public domain software for processing and quantification of MRS data. These results were compared to the results obtained with a manual quantification of the same data, previously done as part of the PhD thesis work of Dr. Andreia Vasconcellos (lecturer from the Radiology Department of the School of Medicine, UNICAMP) [2]. The agreement between the results from both quantification methods was verified, as well as the feasibility of using the automatic quantification results to differentiate among tumor types, besides differentiating between patients and controls. Results obtained by the automatic method were more accurate and consistent than those obtained by the manual method allowing a better classification. Additionally, in this work were included the results of the study of ex vivo and in vivo metabolic profiling in pediatric brain tumors using the HR-MAS (High Resolution Magic Angle Spinning) technique. This study was carried out in the Molecular Imaging Laboratory, School of Medicine at the University of Val¿encia (Spain), within the Santander-Banespa Bank International Exchange Program. / Mestrado / Física / Mestre em Física