Les travaux de thèse ont porté sur le développement de deux plateformes de radiomarquage polyvalentes pour faciliter l’incorporation du fluor-18, un isotope de choix pour l’imagerie TEP (Tomographie par Emission de Positons). La première plateforme comporte une structure sultone conduisant à un [18F]fluorosulfonate par ouverture du cycle avec le [18F]fluorure. Celle-ci a été valorisée par le couplage avec des ligands 2-nitroimidazoliques pour former un agent d’imagerie TEP spécifique de l’hypoxie. Une série de dérivés caractérisés par des propriétés d’hydrophilie différentes a été synthétisée afin de comparer leur efficacité en imagerie. Parmi ces dérivés, le [18F]FLUSONIM a révélé dans différents modèles précliniques tumoraux (rhabdomyosarcome, tumeurs cérébrales et mélanome) des ratios tumeur sur bruit de fond inégalés jusqu’à présent, et ce à des temps très précoces post-injection. La deuxième plateforme est de nature boratrane. Celle-ci est capable de réagir avec le [18F]fluorure en milieu physiologique pour former un [18F]monofluoroborate zwitterionique facile à séparer du précurseur boratrane. / This work focused on the development of versatile platforms for fluorine-18 labelling. The first platform contained a sultone moiety which was converted to [18F]fluorosulfonate by ring opening with [18F]fluoride. The sultone was coupled to 2-nitroimidazolyl ligands to obtain radiotracers for hypoxia PET imaging. A series of compounds were synthesized in order to compare their performance in PET imaging. Among them, [18F]FLUSONIM displayed high tumor/background ratios after a short delay post-injection on different animal models (rabdomyosarcoma, glioblastoma and melanoma). The second platform was based on a boratrane structure, that was able to captur [18F]fluoride in aqueous medium to form zwiterionic [18F]monofluoroborate.

Die folgenden Überlegungen verdanken sich dem Versuch, die Wissenschaftsgeschichte des 18. Jahrhunderts durch die Wissensgeschichte zu unterlaufen, und die akademische Disziplinierung der Erkenntnisweisen durch einen Blick auf die tatsächlich produzierten Enzyklopädien zu durchkreuzen. Der Blick auf die Universität fällt entsprechend kritisch aus.

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La tomographie par émission de positons (TEP) est une modalité d’imagerie nucléaire puissante, permettant des mesures fonctionnelles non-invasive dans les cellules, les animaux et les humains avec une haute sensibilité et résolution. Les exosomes sont des vésicules extracellulaires de 30 à 120 nm qui peuvent transférer leur contenu cytoplasmique entre cellules, mais comprendre leurs cheminements in vivo reste un défi. Les hydrogels thermosensibles à base de chitosane ont été développés et sont sous optimisation pour diverses applications telles que l'embolisation des vaisseaux sanguins, l'administration de médicaments, l’'administration de lymphocytes et la réparation du cartilage et des disques intervertébraux. Il y a un besoin urgent de suivi in vivo à court terme pour évaluer la rétention des hydrogels et des exosomes. Le Hexadécyl-4- [18F]-fluorobenzoate ([18F]HFB) est un radiotraceur lipophile à longue chaîne qui est retenu dans les membranes cellulaires et les biomatériaux. Le but de ce travail était d'automatiser la radiosynthèse de [18F]HFB pour marquer des exosomes et des hydrogels. La radiosynthèse et la purification de [18F]HFB ont été réalisées en utilisant le synthétiseur de chimie commercial IBA Synthera®. [18F]HFB a été préparé via substitution du précurseur d’ammonium quaternaire par [18F]F-. Après une première purification via une cartouche C18, [18F]HFB a été élué avec de l'acétonitrile et purifié par HPLC. [18F]HFB a ensuite été reformulé dans une solution de DMSO (10%) après élimination du solvant HPLC sous azote, filtré et dilué dans une solution saline stérile. [18F]HFB a été obtenu en rendement radiochimique allant de 15 à 45% (corrigé pour désintégration), en haute pureté radiochimique et chimique, et dans un temps de synthèse total de 60 minutes. Les exosomes n'ont pas été marqués avec succès. Cependant, les hydrogels de chitosane ont démontré un marquage élevé, avec une stabilité du complexe >90%, même après 8 heures d’incubation en solution saline. La TEP avec [18F]HFB d'exosomes et de biomatériaux présente une approche novatrice pour déterminer leur distribution in vivo. / Positron emission tomography (PET) is a powerful nuclear imaging modality allowing for non-invasive functional measures in cells, animals and humans with high sensitivity. Exosomes are 30-120 nm extracellular vesicles that can transfer their cytoplasmic contents between cells, however, understanding where exosomes traffic in the body remains a challenge. Chitosan-based thermosensitive hydrogels have been developed and are currently under optimization for various applications such as blood vessel embolization, drug delivery, lymphocyte delivery systems, and cartilage and intervertebral disc repair. There is an urgent need for in vivo, short term follow-up of such procedures to assess the retention of hydrogels and exosomes at the site of injection. Hexadecyl-4-[18F]fluorobenzoate ([18F]HFB) is a long chain lipophilic radiotracer that has been reported to be retained within cell membranes or biomaterials. The aim of this work was to automate the radiosynthesis of [18F]HFB for labeling exosomes and chitosan-based hydrogels. The radiosynthesis and purification of [18F]HFB was done using the commercial IBA Synthera® chemistry synthesiser with the R&D IFP-cassette and HPLC module. As previously reported, [18F]HFB was prepared by [18F]F- substitution of the trimethyl ammonium triflate precursor in DMSO. After removal of unreacted [18F]F- and DMSO via a C18 light cartridge, [18F]HFB was eluted with acetonitrile and purified by semi-prep C18 HPLC. [18F]HFB was then reformulated in DMSO (10%) solution after removal of the HPLC solvent from the radioactive product peak under nitrogen, filtered, and diluted in sterile saline. [18F]HFB was obtained in radiochemical yield (isolated after HPLC and evaporation) ranging from 15 – 45% (decay-corrected), high radiochemical and chemical purities, and within a total synthesis time of 60 mins. Exosomes were not successfully labeled. However, high labeling efficiency was observed with the chitosan hydrogels displaying a stability >90%, even after 8 hours incubation in saline. PET imaging with [18F]HFB of exosomes and biomaterials presents a novel approach to determining their in vivo distribution.

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At Tristia 1.117-120, Ovid refers directly to his Metamorphoses, equating his exilic situation with that of characters from his magnum opus, stating that his parvus liber should report to those in Rome that the vultus of his fortune may now be listed among the mutata corpora. This statement, placed in the opening poem of Ovid’s exilic project, is invested with programmatic value and begs the following questions: How has Ovid been changed? Why does he compare himself to characters from the Metamorphoses? What exactly is the payoff – for Ovid and the audience – of such an intertextual move? This dissertation explores these questions, arguing that this line is central to Ovid’s conception of his entire ‘exilic project’. By equating himself with his earlier characters, Ovid makes himself a character who undergoes the same transformations as they did; thus, his exilic transformation should be interpreted as occurring in the same fashion as transformations in the Metamorphoses. Those transformations, it is argued, were conceived of in terms of speech, community, and memory: whenever a character is transformed, that character suffers speech loss, is exiled from community, and is forgotten. In his exilic project, Ovid portrays himself as passing through these same steps. Furthermore, Ovid depicts his transformation in this way with an eye towards memory: reformulating how his exile would be perceived by his audience and how he, as a poet, would be remembered by posterity. In Chapter One, I begin by 1) setting the study within current scholarly trends and 2) examining what it meant to be ‘speechless’ in Ovid’s Rome. In Chapter Two, I set out the model for speech loss and community for the characters of the Metamorphoses. In Chapter Three, I turn to how Ovid applies this model to himself in his exilic project. In Chapter Four, I connect this model to memory, arguing that Ovid focuses on this model of speech and community because he, as an exile, is attempting to place himself back within the social frameworks of his community not only to be remembered, but to be remembered as he wants to be remembered. / text

Le suivi continu des substituts tissulaires en développement est crucial afin de comprendre leur évolution au fil du temps. Par contre, la tâche représente tout un défi quand vient le temps d'évaluer des échantillons de grande taille avec les techniques de microscopie. De plus, les méthodes de caractérisation les plus courantes sont fastidieuses et entraînent le sacrifice des cultures. Le développement d'approches de suivi in situ en temps réel, non invasives et non destructives, adaptées aux échantillons non transparents et de grandes tailles, est essentiel dans le domaine du génie tissulaire. Les techniques d'imagerie médicale peuvent répondre à ces besoins sans perturber ni interrompre les cultures en cours. L'hypoThèse de travail de cette Thèse était de démontrer la possibilité d'établir des méthodes d'imagerie in situ, non invasives, non destructives et en temps réel pour le suivi de la viabilité et du métabolisme de cultures tridimensionnelles (3D) de cellules endothéliales dans un gel de fibrine perfusé. Afin d'y arriver, une chambre de culture à perfusion munie de fibres creuses pour la croissance de cellules endothéliales à l'intérieur d'un gel de fibrine a d'abord été conçue. Ensuite, un bioréacteur pulsatif à perfusion apte à assurer la survie et la croissance de cultures 3D in vitro pour le génie tissulaire a été développé et validé. Dans un second temps, les protocoles d'imagerie par tomographie d'émission par positrons (TEP) n'étant pas adaptés aux systèmes de bioréacteurs, il a fallu en développer et valider un en utilisant un radiotraceur bien connu : le [indice supérieur 18]F-fluorodésoxyglucose ([indice supérieur 18]FDG) qui est un marqueur capable de détecter le métabolisme cellulaire. L'imagerie au [indice supérieur 18]FDG d'un bioréacteur permet d'évaluer la perfusion de la culture, de contrôler sa viabilité ainsi que d'estimer la densité cellulaire et le positionnement des structures tissulaires émergentes. Ainsi, les conditions optimales favorisant sa capture par les cellules ont été déterminées au préalable sur des monocouches afin d'optimiser le signal TEP correspondant. Enfin, les paramètres actifs identifiés précédemment ont été mis en application pour le suivi de cultures 3D où les densités cellulaires ont pu être estimées après seulement 12 heures de culture et des structures émergentes décelées dans les gels de fibrine au bout d'une à deux semaines. L'imagerie TEP au FDG est une approche très prometteuse pour effectuer le suivi non destructif de cultures tridimensionnelles en génie tissulaire et pour comprendre l'évolution des tissus en croissance in vitro.

Dans une première partie consacrée à l’étude textuelle de ces chapitres, nous offrons d’abord une traduction en français (avec notes lexicales) du texte antiochien (LXX-L) de 4 Règnes/2 Rois 18 à 25, puis, à partir d’une comparaison avec le Vaticanus (édition de Cambridge) et le texte massorétique (TM, édition BHS), nous proposons une étude des caractéristiques de LXX-L (cité à partir de l’édition de Fernández-Marcos et Busto Saïz) classées en interventions littéraires, différences textuelles et modifications théologiques. Dans une deuxième partie exégétique, nous identifions les enjeux théologiques de ces chapitres, montrant que le TM et LXX-L, malgré des accentuations différentes, ont la même visée : montrer l’effacement progressif des « institutions » (maison du Seigneur, sacerdoce et prophétie) au profit du roi Josias (mis en contraste avec Ezékias et Manassé) qui lui-même cède la place à une nouvelle autorité : celle du livre de l’alliance, le rouleau découvert dans le Temple, authentifié par Houlda la prophétesse. Cette émergence de la suprématie du livre se déploie sur la trame narrative de l’échec de la royauté, puis le jugement de l’Exil et l’espoir d’une alliance nouvelle. La thèse montre que malgré la diversité réelle de ces états textuels que sont LXX-L et le TM, il existe une unité dans leurs lignes de force. / In the first part of the dissertation, we deal with the textual analysis of 4 Kingdoms (2 Kings) 18-25 ; we first translate the Antiochian text (LXX-L) into French for these chapters. Then, through a comparison with the codex Vaticanus (Cambridge edition) and with the Masoretic text (MT, BHS edition), we present a detailed study of the characteristics of LXX-L (as edited by Fernández-Marcos and Busto Saïz), classifying them into three categories: literary changes, textual differences and theological modifications.In the second part, mainly exegetical, we identify the theological issues of these chapters, showing that MT and the Antiochian text, although differing in their emphasis, both have the same purpose : to describe the progressive phasing out of the main “institutions” (house of the Lord, priesthood, and prophecy) for the benefit of king Josias (who is contrasted with Ezekias and Manasseh). Josias himself gives precedence to a new authority : the book of the alliance, the scroll discovered in the Temple, authentified by Houlda, the prophetess. This emergence of the book’s supremacy unfolds as the monarchy is failing, the judgement of the Exile is taking place and a hope for a new covenant is dawning.The dissertation shows that despite the evident diversity of the textual types of MT and LXX-L, there is a strong unity in their key themes.

As complicações hepáticas secundárias à infecção crônica pelo vírus da hepatite C (HCV) são uma importante causa de morte em portadores da infecção pelo vírus da imunodeficiência humana (HIV). Pacientes com coinfecção HIV/HCV apresentam progressão acelerada da fibrose hepática, na qual há participação da resposta inflamatória do sistema imunológico, e requerem maior atenção no tratamento da hepatite C e de suas reações adversas. Assim, os objetivos principais do estudo foram tipificar e comparar os polimorfismos -607 e -137 da interleucina-18 (IL-18), +874 do interferon gama (IFN-?? e -308 e -238 do fator de necrose tumoral alfa (TNF- ?? em quatro grupos (coinfecção HIV/HCV, monoinfecção pelo HIV, monoinfecção pelo HCV e controles saudáveis); investigar a associação dos alelos e genótipos desses polimorfismos com a resposta ao tratamento da hepatite C (respondedor e não respondedor), graus de atividade necroinflamatória (METAVIR A0A1 vs. A2A3) e de fibrose hepática (METAVIR F0-F2 vs. F3F4) em portadores do HCV e identificar os sinais e sintomas relacionados às reações adversas do tratamento da hepatite C. Os dados foram coletados nos prontuários médicos e no sistema informatizado do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto e os polimorfismos tipificados pela técnica de reação em cadeia da polimerase com iniciadores de sequência específica. Participaram do estudo 400 indivíduos, distribuídos em quatro grupos de 100, predominantemente constituídos por homens com idade média entre 33 e 50 anos. Na avaliação geral, os genótipos -238 G/G (TNF-?? e +874 A/A (IFN-?? foram mais frequentes no grupo coinfecção HIV/HCV em relação ao monoinfecção pelo HCV. O genótipo -308 G/A e o alelo -308 A (TNF-?? foram associados com a susceptibilidade à coinfecção HIV/HCV e o genótipo -308 G/G e o alelo -308 G (TNF-?), com proteção. No grupo coinfecção HIV/HCV, a frequência do genótipo - 137 G/C (IL-18) foi maior nos sujeitos com atividade necroinflamatória A0A1 que nos com A2A3. Nos pacientes com fibrose F3F4, o genótipo -238 G/G (TNF-?? foi mais frequente no grupo coinfecção HIV/HCV que no monoinfecção pelo HCV e naqueles com F0-F2, o genótipo +874 A/A (IFN-?? também foi mais frequente no grupo coinfecção HIV/HCV. A frequência do genótipo +874 T/T (IFN-??, dentre os pacientes do grupo coinfecção HIV/HCV, foi maior naqueles com fibrose F3F4 que nos com F0-F2. Não foram encontradas associações estatisticamente significantes entre as frequências alélicas e genotípicas e os tipos de resposta ao tratamento da hepatite C nos pacientes do grupo coinfecção HIV/HCV; nos do monoinfecção pelo HCV, houve diferenças nas frequências alélicas e genotípicas (posição -238 do TNF-?) entre pacientes respondedores e não respondedores. Os principais sinais e sintomas relacionados às reações adversas do tratamento da hepatite C foram mialgia, febre, fraqueza, cefaleia e hiporexia. Anemia, hiporexia e vômito foram mais frequentes no grupo coinfecção HIV/HCV. Conclui-se que há relação dos alelos e genótipos de citocinas com a gravidade da doença hepática e resposta ao tratamento da hepatite C. Adicionalmente, algumas reações adversas ao tratamento foram mais pronunciadas em coinfectados HIV/HCV / Hepatic complications secondary to chronic infection by hepatitis C virus (HCV) are a major cause of death in people infected by the human immunodeficiency virus (HIV). Patients with HIV/HCV coinfection present rapid progression of liver fibrosis, with involvement of the immune system\'s inflammatory response, and require more attention in hepatitis C treatment and its adverse reactions. The main goals of this study were to typify and compare the polymorphisms -607 and -137 of the interleukin-18 (IL-18), +874 of the interferon gamma (IFN-?? and -308 and -238 of the tumor necrosis factor-alpha (TNF-?? in four groups (HIV/HCV coinfection, HIV monoinfection, HCV monoinfection and healthy controls), to investigate the association of the alleles and genotypes of these polymorphisms with response to hepatitis C treatment (responder and non-responder), degrees of necroinflammatory activity (METAVIR A0A1 vs. A2A3) and of liver fibrosis (METAVIR F0-F2 vs. F3F4) in HCV patients and to identify the signs and symptoms related to adverse reactions of hepatitis C treatment. Data were collected on medical records and on the computerized system of the Hospital das Clínicas of the University of São Paulo Ribeirão Preto Medical School and the polymorphisms were typified using the polymerase chain reaction technique with sequence specific primers. The study included 400 individuals, distributed in four groups of 100, predominantly consisting of men with an average age between 33 and 50 years. In the overall evaluation, genotypes -238 G/G (TNF-?? and +874 A/A (IFN-?? were more frequent in the HIV/HCV coinfection group compared to HCV monoinfection. The genotype -308 G/A and allele -308 A (TNF-?? were associated with susceptibility to HIV/HCV coinfection and the genotype -308 G/G and allele -308 G (TNF-?), with protection. In the HIV/HCV coinfection group, the frequency of genotype -137 G/C (IL-18) was greater in subjects with necroinflammatory activity A0A1 than in the ones with A2A3. In patients with fibrosis F3F4, genotype -238 G/G (TNF-?? was more frequent in the HIV/HCV coinfection than in the HCV monoinfection group and in those with fibrosis F0-F2, genotype +874 A/A (IFN-?? was also more frequent in the HIV/HCV coinfection group. The frequency of genotype +874 T/T (IFN-??, among patients of the HIV/HCV coinfection group, was higher in those with fibrosis F3F4 compared to the ones with F0-F2. No statistically significant associations were found between the allele and genotype frequencies and the types of answer to hepatitis C treatment in patients of the HIV/HCV coinfection group. On the ones of the HCV monoinfection group, there were differences on the allele and genotype frequencies (position -238 of TNF-?? among responder and non-responder patients. The main signs and symptoms related to adverse reactions to hepatitis C treatment were myalgia, fever, weakness, headache and loss of appetite. Anemia, loss of appetite and vomiting were more frequent in the HIV/HCV coinfection group. It is concluded that there is relationship of the alleles and genotypes of cytokines with the severity of liver disease and response to hepatitis C treatment. Additionally, some adverse reactions to treatment were more frequent in HIV/HCV coinfected patients