Purpose: In vivo screening of phage-displayed random peptide libraries (RPLs) has been used to identify peptide ligands to targets found on endothelial cells of blood vessels supplying specific tissues such as brain, kidney, and tumor tissue. Peptides that bind specifically to blood vessels supplying tumor tissue have been conjugated to cytotoxic agents and used to successfully eradicate tumors in a mouse model. With the ultimate goal of developing similar methods for treating human cancer, we describe an in vivo RPL screening process that, unlike previous in vivo experiments, does not harm the animal being screened. Methods: RPLs were administered to FVB, BalbC, and tumor-bearing MRL/MpJ-fasLPR mice in a variety of dosing formats. Tumor nodules were excised 10 min following infusion and phage were amplified from the specimens. Phage were reinjected into the same animal within 48 h. This process was repeated twice for a total of three in vivo screens of mouse tumor tissue within the same animal. Mice were observed for systemic side effects, histopathologic damage, and presence of phage in organs. Peptide sequences were determined from several third-pan phage clones. Results: Overall there was minimal toxicity from administration of single or repeat doses of RPLs. Amino acid consensus sequences were identified and some of the sequences were similar to those of peptide ligands that bind matrix metalloproteinases. Conclusions: Serial administration of an RPL is well tolerated and serial panning in individual mice leading to consensus sequence motifs is possible. Based on these preclinical data the Food and Drug Administration has approved the implementation of human clinical trials with this technique.

nÃo hà / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Procedemos, a partir dos pressupostos da LingÃÃstica da EnunciaÃÃo, à problematizaÃÃo do quadro das heterogeneidades do tipo mostrada (marcada vs. nÃo-marcada), proposto por Authier-Revuz (1982). Nossa proposta consiste em sugerir que o escopo das ocorrÃncias dos fatos de heterogeneidade marcada seja flexibilizado, de modo a abarcar fenÃmenos de natureza (mais) cognitiva que evidenciam a presenÃa do alheio na materialidade lingÃÃstica num ponto especÃfico da cadeia do dizer, promovendo, destarte, uma articulaÃÃo entre heterogeneidade mostrada/marcada e referenciaÃÃo. Submetemos a um reexame, acrescentando o que nos pareceu pertinente, um conjunto de marcas que nÃo apenas as consagradas (como, por exemplo, negrito, mudanÃa de fonte, aspas, discurso direto) na tentativa de lhes conferir um estatuto de marcadores da presenÃa consciente do outro no fio discursivo, considerando a noÃÃo de leitor-modelo sugerida por Eco (1979). Para tanto, elegemos como categorias principais de anÃlise os processos referenciais anafÃricos e dÃiticos, o discurso indireto livre e a intertextualidade por alusÃo. Nossos resultados legitimaram nossa proposta e confirmaram o potencial marcativo de tais categorias. Palavras-chave: Heterogeneidade enunciativa; heterogeneidade mostrada/marcada; referenciaÃÃo; processos referenciais. / We proceed to the problematization of the frame of heterogeneities of the displayed type (marked versus not marked) as proposed by Authier-Revuz (1982) from the assumptions of the Linguistics of Enunciation. Our proposal consists in suggesting that the scope of the occurrences of facts of marked heterogeneity be widened in order that it includes phenomena of a (more) cognitive nature that make evident the presence of the other in the linguistic materialization in a specific point of the chain of the saying and, besides, articulate the displayed marked heterogeneity and the referentiation. We reexamine, appending whatever seems to us pertinent, a set of marks, besides those already established (e.g., bold face, font changing, inverted commas, direct speech) in an attempt to confer them the statute of markers of the conscious presence of the other in the discursive thread, considering the notion of model reader suggested by Eco (1979). To achieve this goal, we choose for main categories of analysis the deictic and anaphoric referential processes, the free indirect speech and the intertextuality by allusion. Our results legitimize our proposal and confirms the marking potential of such categories. Keywords: Enunciative heterogeneity, displayed/marked heterogeneity; referentiation; referential processes.

Cette thèse traite de l'estimation du mouvement à partir d'une séquence d'images par des méthodes d'assimilation de données. Les travaux ont porté sur la prise en compte des objets dans les processus d'estimation, afin de corréler en espace les résultats obtenus. Les deux composantes méthodologiques que sont approche variationnelle et approche séquentielle sont traitées. L'algorithme variationnel repose sur une équation d'évolution, une équation d'ébauche et une équation d'observation. L'estimation s'obtient comme le minimum d'une fonction de coût. Dans une première étape, l'objet est décrit par sa courbe frontière. Le modèle dynamique caractérise l'évolution des images et déplace les objets afin que leurs positions correspondent à celles observées dans les acquisitions image. Cette approche impacte fortement les temps de calculs, mais permet une amélioration de l'estimation du mouvement. Deuxièmement, les valeurs de la matrice de covariance des erreurs d'ébauche sont modifiées afin de corréler, à moindre coût, les pixels de l'image. L'algorithme séquentiel présenté repose sur la création d'un ensemble de vecteurs d'état ainsi que sur des approches de localisation. Pour modéliser les objets, un nouveau critère de localisation portant sur l'intensité de niveau de gris des pixels a été défini. Cependant, la localisation, si elle est appliquée directement sur la matrice de covariance d'erreur, rend la méthode inutilisable pour de grandes images. Une approche consistant à découper le domaine global en sous-domaines indépendants, avant d'estimer le mouvement, a été mise au point. La prise en compte des objets intervient lors du découpage du domaine d'analyse global. / This thesis describes approaches estimating motion from image sequences with data assimilation methods. A particular attention is given to include representations of the displayed objects in the estimation process. Variational and sequential implementations are discussed in the document.The variational methods rely on an evolution equation, a background equation and an observation equation, which characterize the studied system and the observations. The motion estimation is obtained as the minimum of a cost function. In a first approach, the structures are modeled by their boundaries. The image model describes both the evolution of the gray level function and the displacement of the structures. The resulting motion field should allow the position of the structures in the model to match their observed position. The use of structures betters the result. A second approach, less expensive regarding the computational costs, is designed, where the structures are modeled by the values of the background error covariance matrix.The sequential approach, described in the thesis, relies on the creation of an ensemble of state vectors and on the use of localization methods. In order to model the structures, a new localization criteria based on the gray level values is defined. However, the localization method, if directly applied on the background error covariance matrix, renders the approach inoperable on large images. Therefore, another localization method is designed, which consists to decompose the image domain into independent subdomains before the estimation. Here, the structures representation intervenes while decomposing the global domain.

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