Monoclonal antibodies (mAbs) conjugated to nuclear localization sequences (NLS) and labeled with Auger electron-emitters have great potential for targeted radiotherapy of cancer. This approach may be especially appropriate for the 25-30% of patients with breast cancer whose tumors display overexpression of HER2. Trastuzumab (Herceptin) is a humanized anti-HER2 mAb approved for immunotherapy of HER2-amplified breast cancer. The goal of this research was to radiolabel trastuzumab with [111]In, and to modify it with peptides harboring the NLS (CGYGPKKKRKVGG) of the simian virus 40 large-T antigen for targeted radiotherapy of breast cancer. It was hypothesized that the NLS-peptides would mediate the translocation of covalently linked [111]In-trastuzumab molecules into the nuclei of HER2-overexpressing breast cancer cells where subcellular-range Auger electrons are most damaging to DNA and lethal to cells. Trastuzumab was derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate for reaction with NLS-peptides and labeled with [111]In using diethylenetriaminepentaacetic acid. The dissociation constant for binding of [111]In-NLS-trastuzumab to HER2-overexpressing SK-BR-3 human breast cancer cells was reduced < 3-fold compared to [111]In-trastuzumab, demonstrating relatively preserved receptor-binding affinity. The NLS-peptides did not affect the biodistribution of [111]In-trastuzumab, but promoted its nuclear uptake in HER2-overexpressing MDA-MB-361 xenografts. The cytotoxicity of [111]In-NLS-trastuzumab on breast cancer cells correlated with their HER2 expression. Moreover, [111]In-NLS-trastuzumab was 2-fold and 5-fold more potent at killing MDA-MB-361 and SK-BR-3 cells compared to [111]In-trastuzumab, and nearly 3-fold and 6-fold more effective than unlabeled trastuzumab, respectively. Methotrexate is a known radiosensitizer that can amplify the lethal effects of ionizing radiation on tumor cells. Non-cytotoxic, but radiosensitizing doses of methotrexate were therefore combined with [111]In-NLS-trastuzumab; this enhanced the sensitivity of HER2-overexpressing breast cancer cells to [111]In-NLS-trastuzumab. The blood t1/2 of [111]In-NLS-trastuzumab in non-tumor bearing BALB/c mice was 23-34 h when administered intravenously or intraperitoneally. The maximum tolerated dose was 9.2-18.5 MBq; doses >18.5 MBq caused decreased leukocyte and platelet counts. [111]In-NLS-trastuzumab exhibited strong anti-tumor effects against HER2-overexpressing MDA-MB-361 xenografts, reducing their growth rate 2-fold and 3-fold compared to mice administered [111]In-trastuzumab or unlabeled trastuzumab, respectively. These promising results suggest that [111]In-NLS-trastuzumab may be a useful Auger electron radioimmunotherapeutic agent for HER2-positive breast cancer in humans.

Thesis (M. Sc.)--University of Adelaide, Dept. of Physics, 1985. / Includes bibliographical references (leaves 76-78).

Thesis--University of Oulu, 1987. / Includes bibliographical references (p. 43-46).

Chemnitz, Techn. Univ., Diplomarb., 2002.

Thesis--University of Oulu, 1987. / Includes bibliographical references (p. 43-46).

Techn. University, Diss., 2003--Berlin.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 307-319).

Made available in DSpace on 2014-06-11T19:25:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2003-03Bitstream added on 2014-06-13T19:53:19Z : No. of bitstreams: 1 menezes_m_me_ift.pdf: 1408979 bytes, checksum: c49d46abc2dcaff209c0e561dfd6398a (MD5) / Faz-se aqui o estudo da detecção de neutrinos (v) de altas energias ('E IND.v' > '10 POT.9' GeV) no Observatório Pierre Auger usando os detectores de fluorescência. Introduzimos todo o conhecimento experimental dos raios cósmicos, em conjunto com a fenomenologia das partículas elementares, para que o estudo da detecção possa ser entendido de forma bastante geral. Raios cósmicos de até '10 POT.15' eV vem de fontes em nossa galáxia; já as partículas acima de '10 POT.18' eV não são confinadas no campo magnético da galáxia. Portanto, acredita-se que estas partículas sejam de origem extra-galática. Porém, sua natureza continua completamente desconhecida. Existem vários modelos que resultam em diferentes fluxos de neutrinos de altíssimas energias. Independente do modelo, estes neutrinos vem de distâncias cosmológicas, estando sujeitos à oscilação do seu sabor. A oscilação de neutrinos traz como conseqüência uma igualdade entre os fluxos dos neutrinos de cada família. O método aqui utilizado para detecção de neutrinos consiste em considerar apenas aqueles que se propagam pelo interior terrestre, até chegarem a região de detecção. Estes neutrinos de altíssimas energias podem dar origem a léptons carregados após uma interação de corrente carregada com núcleos atômicos. Estes léptons carregados continuam se propagando na mesma direção do neutrino original, podendo sair da terra. Ao sair da Terra estes léptons carregados poderão ser detectados pelo Observatório Pierre Auger. Destes léptons, apenas o tau dará origem a um chuveiro eletromagnético que deverá ser detectado. Mostramos por fim que um número bastante pequeno de neutrinos atravessando a terra deverá ser observado. Entretando, mesmo a observação de um único evento em vários anos nos indicaria a existência de neutrinos. Além disso, seria o início de uma nova fase na detecção de raios cósmicos. / Abstracts: Here we study the detection of the ultra high energy neutrinos in Pierre Auger Observatory using the fluorescence detectors. We introduce all the experimental knowledge of cosmic rays, together with the elementary particles phenomenology, so that the detection study can be understood in a very genral way. Cosmic rays with energies up to '10 POT.15' eV come from sources in our galaxy. But the particles above '10 POT.18' eV are not confined in the galactic magnetic field. So, it is believed that these particles are of extragalactic origin. But their nature is completely unknown. There are many models that result in different ultrahigh energy neutrino fluxes. Independent of the model, these neutrinos como from cosmological distances, being subject to flavor oscillation. The neutrino oscillation gives as a consequence the equality between the neutrino fluxes of each family. The method used for the neutrino detection is to consider only those that propagate through the earth, until they arrive to the detection area. These ultra high energy neutrinos can create charged leptons after a charged current interaction with atomic nuclei. These charged leptons keep the same direction of the original neutrino and they can exit the Earth. When they exit the Earth, they will be detected by the Pierre Auger Observatory. We show, finally, that very small number of neutrinos crossing the Earth will be detected. However, even the observation of one single event in many years will be an indication of the existence of a neutrino flux. Moreover, it would be the beginning of a new phase in the cosmic ray detection.

Orientador : Carlos K. Suzuki / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Mecanica / Made available in DSpace on 2018-07-28T19:37:54Z (GMT). No. of bitstreams: 1 Gusken_Edmilton_M.pdf: 3792406 bytes, checksum: 1d6fb65581dc8376e41112c0994a21cb (MD5) Previous issue date: 2001 / Resumo: A espectrometria de fluorescência de raios- X (FRX) foi utilizada para o estudo do perfil de concentração do germânio em preformas de sílica-germânia para fibras ópticas, fabricadas pela tecnologia de deposição axial na fase vapor ("V AD - vapor-phase axial deposition"). Atuando em conjunto com o grupo de processamento V AD do Laboratório Ciclo Integrado de Quartzo, FEM/UNICAMP, conseguiu-se estender este estudo ao nível de entendimento da influencia dos parâmetros das diversas etapas de processamento da performa (deposição, desidratação, e consolidação) na concentração do Ge02. m trabalho fundamental da metodologia de análise por FRX envolvendo modernos métodos computacionais (por exemplo, método "Fundamental Parameter") e métodos especiais de preparação de amostras propiciaram resultados de grande confiabilidade e precisão nas medidas realizadas. A técnica de FRX foi também aplicada para estudar o efeito Auger radiativa no espectro característico de fluorescência de raios-X. Esta técnica denominada EXEFS ("Extended X-ray Emission Fine Structure"), mede o espectro K-LL da raia do silício, sendo similar à técnica de EXAFS ("Extended X-ray Absorption Fine Struture"). Assim sendo, utilizou-se neste trabalho a técnica de EXEFS para a análise estrutural da sílica-germânia, obtendo-se informações sobre as distâncias interatômicas do silício com o primeiro vizinho (Si-O), e o segundo (Si-Si ou Si-Ge), e também sobre o numero de coordenação. Os resultados mostram a forte influencia da concentração de Ge02 na estrutura da sílica-germânia fabricadas pelo processo V AD / Abstract: An X-ray fluorescence spectrometry (XRF) characterization was conducted to study the germanium concentration profile in silica-germania optical fiber preform prepared by vapor phase axial deposition (V AD) technique. By working in an interface collaboration with the V AD fabrication group of LIQC - Laboratory of Integrated Quartz Cyc1e, FEMlUNICAMP, it was possible to extend the present research to the leveI of understanding the various processing parameters (soot deposition, dehydration, and consolidation) with the concentration of GeO2. Fundamental steps in terms of XRF methodology of analysis have been developed in order to achieve a high precision and repetitiveness of measurements. Modem computational methods, such as the "Fundamental Parameter", and special sample preparation methods have been conducted. The XRF technique has also been applied to study the radiative Auger effect of the characteristic X-ray fluorescence spectra by using the new technique ofEXEFS (Extended X-ray Emission Fine Structure analysis). In the present study, the EXEFS was measured on the K-LL spectra of silicon to analyse the structure of silica-germania. Atomic leveI informations, such as the distance ofthe first neighbor of silicon (Si-O), and the second n_ighbor (Si-Si or Si-Ge), and also the coordination number were obtained. The result reveals a strong influence of GeO2 concentration in the silica-germania structure prepared by V AD technology / Mestrado / Materiais e Processos de Fabricação / Mestre em Engenharia Mecânica

Orientador: Jose Augusto Chinellato / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-03T16:45:28Z (GMT). No. of bitstreams: 1 Muller_MarcioAparecido_M.pdf: 1532809 bytes, checksum: 6afdf71c3441e371eebb3d6cc7ebbfd8 (MD5) Previous issue date: 2003 / Resumo: Não informado / Abstract: Not informed. / Mestrado / Física / Mestre em Física