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Cerato, Evelyne. "Repertoire d'anticorps murins diriges contre les gangliosides gd2 et gd3 : production et caracterisation d'un fragment d'anticorps recombinant colorimetrique anti-gd2." Nantes, 1997. http://www.theses.fr/1997NANT02VS.
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Faraj, Sébastien. "Immunochimiothérapie du neuroblastome : nouvelle thérapeutique améliorée ciblant le ganglioside GD2 O-acétylé pour le traitement des neuroblastomes chez l'enfant." Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1037.
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Malgré les récentes avancées dans la prise en charge des neuroblastomes de haut risque, le pronostic des patients qui en sont atteints reste péjoratif. Les modalités thérapeutiques sont agressives et de nombreux enfants souffrent des effets secondaires de celles-ci, dégradant de ce fait leur qualité de vie. L’immunothérapie anti-GD2 offre dans ce contexte une alternative thérapeutique, permettant d’améliorer le pronostic de ces tumeurs, mais leur utilisation est néanmoins limitée par la présence d’une toxicité des molécules existantes. Le GD2 O-acétylé n’étant pas exprimé à la surface des fibres nerveuses périphériques, le choisir comme cible thérapeutique peut s’avérer efficace tout en diminuant la toxicité de l’immunothérapie. Nous avons vérifié l’expression du GD2 O-acétylé à la surface des cellules de 4 lignées cellulaires de neuroblastome (LAN1, LAN5, IMR5, NXS2). Cette expression n’est pas modifiée par les traitements par chimiothérapie utilisés dans les traitements des neuroblastomes de haut grade (cisplatine, doxorubicine et topotecan). Nous montrons que l’anticorps murin 8B6 spécifique du GD2 O-acétylé a une relation synergique in vitro avec les molécules de chimiothérapie testées (cisplatine, doxorubicine et topotecan). Nous montrons par la suite que cet anticorps augmente l’efficacité de la doxorubicine et du topotecan in vivo chez la souris sans diminuer la tolérance globale du traitement multimodal. Nos résultats montrent qu’un traitement combinant chimiothérapie et immunothérapie peut augmenter l’efficacité et la tolérance cliniques des chimiothérapies dans le traitement des neuroblastomes de haut gradeDespite recent advances in high-risk neuroblastoma therapy, the prognosis for patients remains poor. In addition, many patients suffer from complications related to available therapies that are highly detrimental to their quality of life. New treatment modalities are, thus, urgently needed to further improve the efficacy and reduce the toxicity of existing therapies. Since antibodies specific for Oacetyl GD2 ganglioside display pro-apoptotic activity against neuroblastoma cells, we hypothesized that combination of immunotherapy could enhance tumor efficacy of neuroblastoma chemotherapy. We demonstrate here that combination of anti-Oacetyl GD2 monoclonal antibody 8B6 with topotecan synergistically inhibited neuroblastoma cell proliferation, as shown by the combination index values. Mechanistically, we evidence that mAb 8B6 induced plasma cell membrane lesions, consistent with oncosis. Neuroblastoma tumour cells treated with mAb 8B6 indeed showed an increased uptake of topotecan by the tumor cells and a more profound tumor cell death evidenced by increased caspase-3 activation. We also found that the combination with topotecan plus monoclonal antibody 8B6 showed a more potent anti-tumor efficacy in vivo than either agent alone. Importantly, we used low-doses of topotecan with no noticeable side effect. Our data suggest that chemoimmunotherapy combinations may improve the clinical efficacy and safety profile of current chemotherapeutic modalities of neuroblastoma
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Tong, Wenyong. "Chemistry and biology of tumor-associated ganglioside GD2." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107647.
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Effective therapies typically target diseased tissues without significantly affecting healthy tissues. A tumor-related glycosphingolipid (GSL), such as ganglioside GD2, distinguishes neuroectoderm tumors from their healthy counterparts and is a validated tumor target. GD2 is clinically targeted for diagnosis and immunotherapy. GD2 plays an important functional role in tumor progression and in chemoresistance. It also plays an important functional role in pain; however, the mechanisms that make GD2 important in such phenomena remain unknown.Thus, understanding the structure-activity relationship of GD2, a GSL with two sialic acids, would be helpful. However, such studies on glycolipids are challenging. We employed a chemical biology approach to elucidate the structure and function of GD2 and to further direct the rational design of GD2 ligands and vaccines for GD2-related cancer treatment.The combined use of STD NMR spectroscopy, transferred NOE experiments, and molecular modeling furnished details on the molecular recognition of the ganglioside GD2 by the clinically used anti-GD2 monoclonal antibody 3F8 that can induce apoptosis of GD2 expressing tumours. A binding model that provided the basis for a rational development of GD2 ligands and vaccines was then established. Based on the structural information of GD2-3F8 interactions, small molecule monomeric peptide ligands binding to GD2 were developed. ELISA and NMR experiments demonstrated that peptides selectively bound to GD2 via an induced-fit mechanism. Furthermore, peptidic GD2 ligands, including 3F8, mediated similar biological functions in cell-based assays of activation of NMDA receptor via Src family kinase, calcium fluxe and cAMP. These can explain at least some of the mechanisms associated with tumor progression and pain, where GD2 plays a role. However, current GD2 peptide ligands did not demonstrate any treatment effect in vivo. Hence, we turned to the design of GD2 vaccines as a therapeutic approach. The rigid nature of GD2-oligosaccharides, discovered in our structural study, makes it perfectly suited to drive a structurally convergent immune response. A novel and homogenous tetra-GD2 dendrimer was designed to mimic a clustered GD2 lipid raft. Immunization of mice with tetra-GD2 dendrimer elicited a potent anti-GD2 humoral response. The antibodies (sera or mAbs) thus generated can kill GD2-expressing cells in culture, in the absence of a complement. Tumor growth was significantly delayed in vivo in prophylactic and in therapeutic paradigms. Our research strategy may be expanded to other clinically relevant glycolipids.Typiquement, les thérapies efficaces agissent sur les tissus malades sans toutefois nuire considérablement aux tissus en santé. Un glycosphingolipide (GSL) associé à une tumeur, tel que le ganglioside GD2, peut reconnaître selectivement les tumeurs neuroectodermes malignes et est ainsi validé comme une cible tumorale. Sur le plan clinique, on utilise le GD2 à des fins de diagnostic et d'immunothérapie. D'une part, le GD2 joue un rôle fonctionnel important dans la progression tumorale et la chimiorésistance. D'autre part, le GD2 joue un rôle fonctionnel important dans la douleur, mais les mécanismes qui expliqueraient l'importance du GD2 lors de tels phénomènes demeurent encore inconnus. C'est pourquoi il serait utile de mieux comprendre la relation structure-activité du GD2, un GSL constitué de 2 acides sialiques. Toutefois, entreprendre de telles études sur les glycolipides représente un défi de taille. Nous avons alors utilisé une approche basée sur la biologie chimique pour élucider la structure et la fonction des GD2 et pour mieux concevoir rationnellement des ligands GD2 et des vaccins pour le traitement contre le cancer lié au GD2. En combinant l'utilisation de la spectroscopie RMN DTS, des expériences NOE transférées et des modèles moléculaires, il est possible d'obtenir plus de détails sur la reconnaissance moléculaire du ganglioside GD2 au moyen du 3F8, un anticorps monoclonal anti-GD2 utilisé médicalement et qui peut induire l'apoptose de cellues cancereuses exprimant GD2. Comme point de départ pour le développement rationnel des ligands GD2 et des vaccins, nous avons établi un modèle contraignant. En nous appuyant sur l'information structurelle des interactions GD2-3F8, nous avons développé des petits ligands monomériques peptidiques liés au GD2. Des expériences RMN et ELISA ont démontré que les peptides se lient sélectivement au GD2 via un mécanisme d'ajustement induit. Par ailleurs, les ligands peptidiques GD2, dont le 3F8, deviennent médiateurs de fonctions biologiques similaires dans les essais cellulaires de l'activation des récepteurs NMDA via les kinases de la famille Src, les flux de calcium et cAMP. Ces derniers peuvent au moins expliquer certains des mécanismes associés avec la progression tumorale et la douleur, dans lesquels le GD2 jour un rôle prépondérant. Cependant, les ligands peptidiques GD2 actuels n'ont pas démontré les effets désirés au cours des traitements in vivo. C'est pourquoi nous nous sommes tournés vers le développement de nouveaux vaccins GD2 comme une approche thérapeutique. La nature rigide des oligosaccharides GD2, que nous avons découverte par le biais de notre étude structurale, devient une caractéristique parfaitement adaptée pour favoriser une réponse immunitaire structurellement convergente. Un nouveau dendrimère tetra-GD2 homogène a été conçu de manière à reproduire un radeau lipidique GD2 regroupé. L'immunisation des souris par le dendrimère tetra-GD2 a engendré une puissante réponse humorale anti-GD2. En l'absence d'un complément, les anticorps (sera ou mAbs) ainsi générés peuvent tuer les cellules exprimant le GD2 en culture. La croissance tumorale a été considérablement retardée in vivo dans les paradigmes thérapeutiques et prophylactiques. Notre stratégie de recherche pourrait ainsi être élargie pour inclure d'autres glycolipides pertinents sur le plan clinique.
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Leprieur, Truet Stéphanie Birkle Stéphane. "Production et évaluation chez l'animal d'anticorps thérapeutiques anti-ganglioside GD2." [S.l.] : [s.n.], 2007. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=16881.
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MARQUES, Maria Danielle Rodrigues. "Caracterização estrutural, microestrutural e magnética de amostras tipo Gd2-xHoxRu2O7." Universidade Federal de Pernambuco, 2010. https://repositorio.ufpe.br/handle/123456789/1439.
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Materiais que apresentam estrutura tipo pirocloro tem sido objeto de estudos intensivos nos anos recentes. Estes materiais possuem fórmula geral A2B2O6O, onde A é uma terra rara e B é geralmente um metal de transição. Estudos anteriores mostraram que estes compostos têm muitas propriedades interessantes tais como condução iônica, condução elétrica, fluorescência, supercondutividade e atividade catalítica. O presente trabalho descreve os estudos realizados para a síntese e caracterização dos pirocloros Gd2−xHoxRu2O7, com x = 0,0 , 0,1 , 0,2 , 1,0 e 2,0 . As amostras foram preparadas pelo método de reação de estado sólido, onde quantidades dos óxidos Gd2O3, RuO2 e Ho2O3 foram pesados nas proporções estequiométricas, misturados, homogeneizados em ácido nítrico concentrado e submetidas a tratamento térmico. Em seguida, foram caracterizadas estruturalmente por difração de raios X e morfologicamente por microscopia eletrônica de varredura. Os difratogramas de raios X foram analisados pelo método de Rietveld, que possibilitou a identificação da estrutura e a determinação do parâmetro de rede. O refinamento indicou que as amostras cristalizam em uma rede cúbica de face centrada, onde o parâmetro de rede sofre uma contração com o aumento da dopagem, de acordo com a lei de Vegard. As micrografias obtidas por microscopia eletrônica de varredura revelaram uma morfologia com tamanhos de grãos mais uniformes e homogêneos. Esse resultado foi atribuído ao fato de se ter diluído os grãos em ácido nítrico antes de submetê-los ao tratamento térmico. Um estudo das propriedades magnéticas dos compostos foi realizado mediante medidas de susceptibilidade dc, onde o momento magnético foi obtido. A dependência da susceptibilidade com a temperatura apresentou um comportamento em acordo com a lei de Curie-Weiss no intervalo de 35 K a 300 K, para todas as amostras estudadas, Entretanto, dependendo da quantidade do dopante, foram observados desvios desse comportamento. Os resultados das diferentes caracterizações são discutidos em detalhes
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Cavdarli, Sumeyye. "Deciphering biosynthesis mechanisms of O-acetylated GD2 in breast cancer." Thesis, Lille 1, 2020. http://www.theses.fr/2020LIL1S100.
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Le ganglioside GD2, ré-exprimé dans les cancers d’origine neuro-ectodermique, a été caractérisé comme un antigène oncofetal constituant une cible pour l’immunothérapie. L’anticorps anti-GD2 dinutuximab (Unitixin, TM) a récemment obtenu l’agrément de la Food Drug Administration et de l’Agence Européenne du Médicament pour le traitement des neuroblastomes pédiatriques. Cependant, l’utilisation de cet anticorps se heurte à de forts problèmes de toxicité due à l’expression du GD2 dans les nerfs périphériques sains. La forme O-acétylée du GD2 (OAcGD2) n’est exprimé que dans les tissus cancéreux représentant ainsi une cible thérapeutique moins toxique que le GD2. Les activités de la société OGD2 Pharma, partenaire de ce projet, sont axées sur le développement d’anticorps thérapeutiques dirigés contre le GD2 O-acetylé. L’anticorps développé cible spécifiquement au GD2 O-acetylé sans réaction croisée avec GD2. Dans le cancer du sein, les gangliosides complexes, notamment le GD2 et sa forme O-acetylé sont ré-exprimés. Cette expression est corrélée à un mauvais pronostic chez les patientes atteintes de cancer du sein. L’objectif principale de ma thèse est d’identifier les mécanismes moléculaires régissant l’O-acétylation du GD2 dans le cancer du sein afin de mettre en évidence l’intérêt thérapeutique et diagnostique du ciblage de cet antigèneO-Acetylated GD2 (OAcGD2) ganglioside is neo-expressed in neuroectodermal derived tumors as neuroblastoma and breast cancer. This oncofetal marker is an essential target for immunotherapy. Dinutuximab (Unitixin TM), a therapeutic antibody targeting GD2 has recently obtained Food Drug Administration and European Medicines Agency approval for neuroblastoma treatment. Nevertheless, Dinutuximab causes toxicity due to the expression of GD2 on peripheral nerve fibers. In that way, targeting OAcGD2 seems more beneficial because of absence of this antigen in normal tissues. The activities of OGD2 Pharma Company, partner of this project, are focused on therapeutic antibody development against OAcGD2. OGD2 Pharma developed an antibody specifically targeting OAcGD2 with no cross reaction with GD2. Absent from the normal mammary gland, complex gangliosides especially GD2 and its O-acetylated form have been detected in breast cancer. This expression is correlated with poor patient outcome. The aim of this thesis project was to decipher the molecular mechanisms of OAcGD2 biosynthesis, expression and its role in breast cancer, in order to highlight the therapeutic and diagnostic value of targeting OAcGD2 in breast cancer
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Fleurence, Julien. "Ciblage du GD2-O-acétylé par un anticorps monoclonal dans le glioblastome multiforme." Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1007.
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Le glioblastome multiforme (GBM) est la tumeur cérébrale maligne la plus fréquente et la plus agressive chez l’adulte. Malgré l’utilisation concomitante de la chirurgie avec la radiothérapie et la chimiothérapie (protocole de Stupp), le pronostic des patients reste sombre avec un taux de survie à 5 ans inférieur à 10 %. La présence de cellules souches cancéreuses (CSC) favorise le maintien de la tumeur puis l’échappement tumoral responsable de la rechute des patients. Il est donc nécessaire d’identifier de nouvelles cibles thérapeutiques pour améliorer la prise en charge de ces patients. Dans ce contexte, l’immunothérapie, stratégie utilisant le système immunitaire pour traiter le cancer, représente une voie prometteuse.Nous identifions ici le OAcGD2 comme un nouvel antigène tumoral du GBM et a partir de biopsie tumorale provenant d’une cohorte de 37 patients. L’utilisation de primoculture de GBM nous permet de plus de démontrer que ce marqueur est également exprimé par les cellules souches de GBM. Nous apportons la preuve de concept de l’immunothérapie du GBM à l’aide d’anticorps monoclonaux anti-OAcGD2 in vitro et in vivo. A côté de la cytotoxicté immunologique, nous identifions un nouveau mécanisme de mort programmé, l’oncose, mis en jeu par les AcM anti-OAcGD2 permettant de sensibiliser ces cellules aux agents de chimiothérapie comme le témolozomide. L’utilisation de l’immunothérapie ciblant le marqueur gangliosidique tumoral OAcGD2 pourrait ainsi permettre d’améliorer l’efficacité de la thérapeutique actuelle (protocole de Stupp) du GBMGlioblastoma multiforme (GBM) is the most common and agressive primary brain tumors in adults. Despite the concomitant use of surgery with radiotherapy and chemotherapy, the prognosis of patients remains extremely low. The presence of cancer stem cells (CSC) promotes the maintenance of the tumor and then the tumor escape responsible for the relapse of the patients. Therefore it is necessary to identify new therapeutic targets to improve the management of these patients. In the past few decades, immunotherapy represents an important part of treating certain type of cancer. It uses the immune system to treat cancer. Here, we found that O-acetyl GD2 (OAcGD2) is expressed in surgically resected human glioblastoma tissue. In addition, we demonstrated that 8B6 monoclonal antibody specific for OAcGD2 could effectively inhibit glioblastoma cell proliferation in vitro and in vivo. Mostly, we found that OAcGD2 was expressed on the GBM stem cells. We also observed that mAb 8B6 promoted the elimination of GBM via a oncosis-like mechanism. Moreover, this mechanism of programmed cell death induced by anti-OAcGD2 mAbs, sensitizes GBM cells and CSCs to chemotherapy agents such as temolozomide (TMZ). Taken together, these results indicate that O-acetylated GD2 represents a novel antigen for immunotherapeutic-based treatment of high-grade gliomas, and that anti-OAcGD2 mAbs combined with TMZ could enhance therapeutic response in GBM
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Seidel, Diana. "Mechanism and efficacy of a GD2-specific immunotherapy using NK cells." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2015. http://dx.doi.org/10.18452/17151.
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Das Neuroblastom (NB) ist ein solider, extrakranieller Tumor neuroektodermalen Ursprungs, der sich im Kleinkindalter manifestiert. Ein etabliertes Zielantigen für die passive Immuntherapie beim NB ist das Disialogangliosid GD2. Aufgrund der geringen oder fehlenden Expression von MHC Klasse I Molekülen sowie der Tatsache, dass die Lyse von NB-Zellen durch verschiedene Mechanismen der natürlichen Zytotoxizität von NK-Zellen vermittelt werden kann, stellt eine auf NK-Zellen basierende Therapie einen vielversprechenden Ansatz zur Behandlung dieser Erkrankung dar. Auf dieser Grundlage wurde eine NK-Zelllinie generiert, die einen GD2-spezifischen chimären Antigenrezeptor (CAR) exprimiert (NK-92-scFv(ch14.18)-zeta). Die Hauptbestandteile dieses CARs sind ein Einzelkettenantikörper, welcher die variablen Regionen des GD2-spezifischen Antikörpers ch14.18 enthält, und die CD3ζ-Kette als signaltransduzierende Komponente. Im Rahmen dieser Arbeit konnte gezeigt werden, dass NK-92-scFv(ch14.18)-zeta in der Lage sind, auch Chemotherapie-resistente GD2-positive NB-Zelllinien effektiv abzutöten und dass dabei die Interaktion des CARs mit GD2 den Hauptmechanismus darstellt. Die anti-tumorale Wirkung von NK-92-scFv(ch14.18)-zeta in vivo wurde in einem Chemotherapie-resistenten GD2-positiven Xenograft-Mausmodell gezeigt. Die wiederholte Applikation von NK-92-scFv(ch14.18)-zeta in Kombination mit IL-2 resultierte in einem signifikant verlangsamten Tumorwachstum und einem verbesserten Überleben. Die Ergebnisse dieser Arbeit belegen, dass GD2-spezifische NK-92 das Potential für eine zukünftige klinische Anwendung besitzen. Demnach stellt der Einsatz einer solchen GD2-spezifischen NK-Zelllinie, die unter GMP-Bedingungen expandiert werden kann und zu jeder Zeit in einer standardisierten Qualität verfügbar wäre, eine vielversprechende Alternative zur Behandlung von Hochrisikopatienten dar, deren Erkrankung nicht mehr auf die Standardtherapie anspricht.Neuroblastoma (NB) is a solid extracranial childhood malignancy of neuroectodermal origin. The Disialoganglioside GD2 is an established antigen for passive immunotherapy of NB. Cellular therapy of NB with natural killer (NK) cells is especially appealing because MHC class I expression is absent or low in most NB, rendering this tumor sensitive to NK cell recognition. Additionally, natural cytotoxicity of NK cells, mediated by interaction of activating NK cell receptors and their respective ligands on tumor cells, has been shown to play a role in lysis of NB cells. It is therefore tempting to assume that a combination of passive immunotherapy with GD2-specific antibodies and adoptive transfer of NK effector cells would result in an improved NB therapy. To achieve this goal an NK cell line expressing a GD2-specific chimeric antigen receptor (CAR) was engineered: NK-92-scFv(ch14.18)-zeta. This CAR consists of a GD2-specific scFv-fragment, which was generated from ch14.18, and the CD3ζ-chain as intracellular signal-transducing domain. Within this thesis, GD2-specificity of NK-92-scFv(ch14.18)-zeta as well as efficacy towards GD2-expressing NB cell lines, including relapse cell lines that exhibit partial or multidrug resistance were demonstrated. Blocking the interaction between the CAR and GD2 resulted in almost complete abrogation of NK-92-scFv(ch14.18)-zeta-mediated lysis of GD2-positive NB cell lines in vitro, indicating that this interaction is the main mechanism of activation of NK-92-scFv(ch14.18)-zeta. Importantly, repeated application of NK-92-scFv(ch14.18)-zeta in combination with IL-2 significantly decreased tumor growth and prolonged survival of mice in an aggressively growing drug-resistant xenograft NB mouse model. These findings suggest that GD2-specific NK-92 has potential for a future clinical application as NB-specific effector cells that would be ready on demand in a standardized quality.
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Bahri, Meriem. "Anticorps thérapeutiques du marqueur gangliosidique tumoral GD2 O-acétylé : nouvelles stratégies d'optimisation." Thesis, Nantes, 2020. http://www.theses.fr/2020NANT1009.
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Les anticorps thérapeutiques spécifiques d’antigènes tumoraux permettent d’améliorer le pronostic des patients atteints de cancers. Leur utilisation se heurte toutefois à des mécanismes d’échappement tumoraux variés. L’identification de ces mécanismes permet aujourd’hui d’envisager différentes stratégies d’optimisation basée sur l’utilisation d’association thérapeutique. Ces aspects ont été étudié ici dans le cadre du ciblage immunologique du marqueur gangliosidique tumorale GD2 O-acétylé dans le cadre du neuroblastome chez l’enfant et du glioblastome chez l’adulte. Nous montrons que les propriétés proapoptotiques des anticorps du GD2 O-acétylé permettent de sensibiliser les cellules tumorales aux agents de chimiothérapie et ainsi un meilleur contrôle du développement tumoral. Plus particulièrement, ce mécanisme s’applique également aux cellules souches cancéreuses, population cellulaire particulièrement résistante aux agents cytotoxiques qui est impliquée dans les échecs thérapeutiques et les rechutes. Cette association soulève toutefois des incertitudes atour des bénéfices sur le long terme car nous montrons qu’elle induit la surexpression tumorale du point de contrôle phagocytaire CD47 et inhibe l’activité phagocytaire dépendante des anticorps anti- GD2 O-acétylé. Ces mécanismes d’échappement tumoraux peuvent être contrôlé par l’utilisation combiné d’inhibiteur de point de contrôle immunologique. Ensemble, ces travaux montrent l’intérêt d’associer les anticorps thérapeutiques du GD2 O-acétylé à la chimiothérapie et à des inhibiteurs de point de contrôle immunologique. Cet intérêt pourrait conduire à la réalisation d’un essai clinique de phase I de la prise en charge des neuroblastomesTherapeutic antibodies specific for tumor antigens improve the prognosis of cancer patients. Tumor cells, however, develop various escape mechanisms. The identification of these mechanisms allows different optimization strategies based on therapeutic combinations to achieve long term response in patients with cancer. We studied here some of these aspects in the context neuroblastoma and glioblastoma using O-acetylated GD2- specific monoclonal antibodies. We show that the pro-apoptotic activity of O-acetylated GD2- specific antibodies sensitizes tumor cells to chemotherapeutic agents, allowing thereby a more potent tumor control. Mostly, this mechanism also applies to glioma cancer stem cells, a tumor cell subset particularly resistant to cytotoxic agents which is involved in therapeutic failures and relapses. However, this therapeutic combination might not be able to provide long-term benefits because we show that it further induces the CD47 phagocytic checkpoint in tumor cells. This innate immune checkpoint inhibits the phagocytic activity induced by O-acetylated-specific antibodies against opsonized tumor cells. Yet, this tumor escape mechanism can be controlled by immunological checkpoint inhibitors. Together, we provided the proof of concept of tri-therapy approach to achieve long lasting response in patient with neuroblastoma
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Vogel, Anna [Verfasser]. "Herstellung chimärer Antikörper gegen das Tumorantigen GD2 unter Verwendung einer transgenen Mauslinie / Anna Vogel." Köln : Deutsche Zentralbibliothek für Medizin, 2013. http://d-nb.info/1042336393/34.
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Bleeke, Matthias [Verfasser]. "Aktive Immunisierung mit GD2-Peptidmimotopen und anti-Idiotypen zur Immuntherapie beim Neuroblastom / Matthias Bleeke." Greifswald : Universitätsbibliothek Greifswald, 2013. http://d-nb.info/1044128593/34.
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Michalicka, Matthew. "Combination Immunotherapy with Inhibitor of Apoptosis (IAP) Antagonists to Treat Neuroblastoma." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38739.
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Neuroblastoma is the third most common pediatric cancer. Dinutuximab is a recently approved monoclonal antibody targeting GD2, a ganglioside ubiquitously present on neuroblastoma. Recent studies have shown that αGD2 therapy activates PD1-PDL1 signalling, resulting in the inhibition of its full therapeutic potential. The PD1-PDL1 signalling axis is a cellular checkpoint that inhibits immune responses. The blocking of this interaction has been successful in the treatment of numerous cancers, including in combination with anti-GD2 therapy. The Inhibitor of apoptosis (IAP) proteins are commonly upregulated in cancers and prevent cell death through the inhibition of caspases and through the control of NF-κB activity. Smac mimetic compounds (SMCs) have been designed to target IAP activity, thereby promoting cancer cell death. Here, I used the SMC, LCL161, to improve αGD2 antibody treatment against a GD2+ syngeneic neuroblastoma mouse model. I found that murine cell lines NXS2 and N2a were resistant in vitro to LCL161-mediated apoptosis, despite expressing apoptotic components often silenced in neuroblastoma. In vivo, I observed a slight delay in tumour growth induced by LCL161 and I confirmed an in vivo anti-angiogenic effect of LCL161 through ultrasound imaging and necropsy evaluation. I then combined LCL161 and αGD2 antibody (clone ME361-S2a) treatment and reported a delay in NXS2 subcutaneous tumour growth, which was further potentiated with the addition of an αPD-L1 antibody. With optimization, there is potential for SMCs to be used in combination with αGD2 therapy in GD2+ cancers like neuroblastoma.
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Stagno, Matias Julian [Verfasser]. "Evaluation der Tumormarker TKTL1, Apo10 und GD2 in Rhabdomyosarkom- und Neuroblastom-Tumoren / Matias Julian Stagno." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1218073713/34.
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Mezazigh-Hami, Assia. "Caracterisation immuno-chimique et proprietes du disialoganglioside gd2-0-acetyle dans les tumeurs neuro-ectodermiques." Nantes, 1993. http://www.theses.fr/1993NANT11VS.
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Walker, Kristen Elizabeth. "Effects of isolation methods on proliferation and GD2 expression by porcine umbilical cords stem cells." Thesis, Kansas State University, 2011. http://hdl.handle.net/2097/7067.
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Master of ScienceDepartment of Animal Sciences and Industry
Duane L. Davis
Cell isolation method may have effects on the characteristics of the cells isolated from porcine umbilical cords. As stem cells age or approach senescence, it is hypothesized that their properties change. We expect that isolation method and age of cells will have effects on the phenotype of porcine umbilical cord (PUC) cells during in vitro expansion. We investigated the effects of three isolation methods on PUC population doublings, ability to produce colony forming units (CFU), and amount of ganglioside GD2 (GD2) expression over eleven passages. Isolation methods were explant (Exp) in which the Wharton's Jelly was removed from cords, minced and plated, enzyme digest (Dig), and stomacher assisted enzyme digestion (Stom). Cell isolates were analyzed for GD2 expression, CFU, and population doublings at early (3), middle (7), and late (11) passage. The Exp method produced greater (P<0.05) population doublings and more (P<0.05) CFU at passage 7. Explant isolates also were numerically more likely to survive to passage 11 (9/9 isolates vs 5/9 for Dig and 7/9 for Stom). In contrast, the percent cells expressing GD2 was greater (P<0.05) for Stom isolates than Exp isolates at passage 11. There were no trends for increased passage number to decreased population doubling, CFU formation, or percent GD2 positive cells. In summary, our results indicate that the Exp isolation method produced the greatest number of population doublings over 11 passages and there were minimal effects of isolation method on CFU and GD2 expression. Although Exp may be more difficult to scale up to isolate all of the PUCs in a cord, it provided greater in vitro expansion than the enzyme methods in our experiment and may provide the most cells for biotechnological and biomedical applications.
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Wareham, Carol. "Exploring the efficacy of anti-GD2 and anti-4-1BB monoclonal antibody therapy for the treatment of neuroblastoma." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/376894/.
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Terra, Silvia Resende. "Expressão do gangliosídio GD2 nas células tronco mesenquimais de tecido adiposo humano durante a diferenciação para adipócitos ou osteoblastos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2010. http://hdl.handle.net/10183/25903.
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As células tronco mesenquimais de tecido adiposo (MSCs-TA) são células progenitoras que residem entre adipócitos e contribuem para o turnover do tecido adiposo. Gangliosídios são glicoensfigolipídios localizados na membrana das células, envolvidos na regulação do crescimento celular, interação de superfície, sinalização transmembrana e diferenciação celular. O gangliosídio neural GD2 foi relatado como um marcador de superfície de células tronco mesenquimais de medula óssea e cordão umbilical, mas existem poucos dados sobre a expressão do GD2 em MSCs-TA indiferenciadas e nas diferenciadas para adipócito ou osteoblasto. Nosso principal objetivo foi estudar a expressão de gangliosídios nas MSCs-TA, em especial o GD2, durante a diferenciação adipogênica e osteogênica. Para isso, as MSCs-TA foram isoladas de lipoaspirado humano, cultivadas e induzidas para diferenciação adipogênica e osteogênica. As análises foram feitas por HPTLC, microscopia confocal, citometria de fluxo e PCR em tempo real. Por HPTLC, as MSCs-TA indiferenciadas e MSCs-TA diferenciadas para adipócitos e osteoblasto mostraram aumento do perfil de gangliosídios complexos. A microscopia confocal evidenciou os gangliosídios GM3, GM1 e GD2 na superfície das células e, por citometria de fluxo, identificamos uma subpopulação de células GD2 positivas nas MSCs-TA e MSCs-TA diferenciadas para adipócito ou osteoblasto. Entretanto, o percentual de células GD2 positivas decresceu com a diferenciação. A expressão do mRNA da GD2 sintase aumentou na diferenciação adipogênica e diminui na diferenciação osteogênica. O GD2 é um substrato para a biosíntese de gangliosídios complexos e o aumento da expressão da GD2 sintase pode estar relacionado com o aumento de gangliosídios complexos que ocorre durante a diferenciação adipogênica.Mesenchymal Stem Cells from Adipose Tissue (MSCs-TA) are progenitor cells that reside between adipocytes, and contribute to the turnover of adipose tissue. Gangliosides are glycosphingolipids localized in cell membrane, involved in cell growth regulation, surface interaction, transmembrane signaling and differentiation. The neural ganglioside GD2 has been reported as surface marker for MSCs from bone marrow and umbilical cord, but sparse data exist about the expression of GD2 in MSCs-TA and during the differentiation to adipocytes and osteoblast. Our aim was to study the expression of glangliosides, in special of GD2 in MSCs-TA and during the adipogenic and osteogenic differentiation. Thus MSCs-TA were isolated from lipoaspirate, cultured and induced to adipogenic and osteogenic differentiation. Then, we examined the gangliosides expression by HPTLC, confocal microscopy, flow citometry and real-time PCR. By HPTLC, the MSCs-TA and MSCs-TA differentiated into adipocytes and osteoblast demonstrate an increased complex gangliosides profile. The confocal microscopy showed the presence of GM3, GM1, and GD2 on the cell surface. By the flow cytometry, we identified a GD2 positive subpopulation in MSCs-TA and in MSCs-TA differentiated to adipocytes and osteoblast. However, the percentage of GD2 positive cells decreased with the differentiation. The expression of GD2 synthase mRNA increased during the adipogenic differentiation and decreased in osteogenic differentiation. GD2 is a substrate for the complex gangliosides biosynthesis, and the increase in GD2 synthase expression could be related with the increase in complex gangliosides that occurs during the adipogenic differentiation.
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Terme, Mickaël. "Propriétés biologiques des anticorps spécifiques du marqueur gangliosidique GD2 O-acétylé : application au ciblage thérapeutique des tumeurs d'origine neuroectodermique." Nantes, 2014. https://archive.bu.univ-nantes.fr/pollux/show/show?id=314f0ca8-a9c4-47e0-b94d-59d0661b2532.
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Les gangliosides représentent une famille importante des glycosphingolipides porteurs d'acide sialique. Ils sont exprimés majoritairement au niveau de la membrane plasmique et sont impliqués dans les phénomènes d'adhésion et de prolifération. L'expression du disialoganglioside GD2 et de son dérivé O-acétylé (GD2-Oac) est restreinte aux tissus tumoraux et notamment d'origine neuroectodermique. Ils sont de ce fait des cibles intéressantes pour l'immunothérapie des cancers. Le ch14. 18, un anticorps chimérique dirigé contre le GD2, a montré son efficacité thérapeutique lors d'un essai clinique de phase III développé contre le neuroblastome. Cependant, d'important effets secondaires ont été observés et notamment l'apparition de douleurs neuropathiques dues à l'expression du GD2 sur les nerfs périphériques. En revanche, le GD2-Oac n'est pas exprimé sur les fibres nerveuses. Afin de disposer d’un format idoine à l’homme malade, nous avons développé un anticorps chimérique spécifique du GD2-Oac, nommé c. 8B6. Nous montrons que cet anticorps possède la même efficacité anti-tumorale que le ch14. 18 dans un modèle de neuroblastome chez la souris. D'autre part, nous démontrons sur un modèle de mesure de la douleur (allodynie) chez le rat que cet anticorps ne déclenche pas d'effets neurotoxiques. Par ailleurs, nous avons développé une démarche d'ingénierie moléculaire innovante afin d'augmenter les capacités pro-apoptotiques de cet anticorps. Nous montrons que les différents anticorps anti-GD2-Oac ainsi générés sont capables d'inhiber la croissance tumorale indépendamment des effecteurs immunitaires in vitroGangliosides are an important family of glycosphingolipids with sialic acid. They are predominantly expressed at the plasma membrane and are involved in cell adhesion and proliferation. Expression of GD2 disialoganglioside and its O-acetylated derivative (GD2-Oac) is restricted to the tumor tissue and in particular of neuroectodermic tumor. They are therefore of interest for cancer immunotherapy targets. The ch14. 18, an anti-GD2 chimeric antibody showed therapeutic efficacy in a Phase III clinical trial developed against neuroblastoma. However, significant side effects are observed and in particular the appearance of neuropathic pain in the expression of GD2 on peripheral nerves. However, we previously demonstrated that the GD2-Oac is not expressed on nerve fibers. We have developed a chimeric antibody targeting GD2-Oac the c. 8B6. We show that this antibody has the same anti-tumor efficiency as the ch14. 18 in a neuroblastoma mice model. Furthermore, we demonstrate a model for measuring pain (allodynia) in rat that this antibody does not induced neurotoxic effects. Moreover, we have developed an innovative molecular engineering approach to increase the pro-apoptotic activity of this antibody. We show that the antibody anti-GD2-Oac generated are able to inhibited tumor growth cells independently of immune effectors in vitro
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Neumann, Jens [Verfasser], and Gernot [Akademischer Betreuer] Bruchelt. "Granulozyten-ADCC und CDC gegen Neuroblastomzellen unter Verwendung von Anti-GD2-Antikörpern mit und ohne Complementbindungsstelle / Jens Neumann ; Betreuer: Gernot Bruchelt." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1165308274/34.
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Seidel, Diana Verfasser], Holger [Akademischer Betreuer] [Lode, Andreas [Akademischer Betreuer] Radbruch, and Hans-Dieter [Akademischer Betreuer] Volk. "Mechanism and efficacy of a GD2-specific immunotherapy using NK cells / Diana Seidel. Gutachter: Andreas Radbruch ; Holger N. Lode ; Hans-Dieter Volk." Berlin : Lebenswissenschaftliche Fakultät, 2015. http://d-nb.info/1068255447/34.
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Seidel, Diana [Verfasser], Holger [Akademischer Betreuer] Lode, Andreas [Akademischer Betreuer] Radbruch, and Hans-Dieter [Akademischer Betreuer] Volk. "Mechanism and efficacy of a GD2-specific immunotherapy using NK cells / Diana Seidel. Gutachter: Andreas Radbruch ; Holger N. Lode ; Hans-Dieter Volk." Berlin : Lebenswissenschaftliche Fakultät, 2015. http://d-nb.info/1068255447/34.
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MARQUES, Maria Danielle Rodrigues. "Efeito da dopagem nas propriedades físicas das famílias de pirocloros rutenatos Gd2−xMxRu2O7, com M = Ho ou Y e nos novos supercondutores Zr1−xNbxB2." Universidade Federal de Pernambuco, 2014. https://repositorio.ufpe.br/handle/123456789/12273.
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TESE Maria Danielle Marques.pdf: 22782720 bytes, checksum: 356f51640a480d28fe67c9c8fdb4e769 (MD5)
license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5)Made available in DSpace on 2015-03-12T19:05:15Z (GMT). No. of bitstreams: 2 TESE Maria Danielle Marques.pdf: 22782720 bytes, checksum: 356f51640a480d28fe67c9c8fdb4e769 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2014-01-30
CNPq CAPES FACEPE
Esta tese é o resultado da investigação de dois temas: os rutenatos pirocloros Gd2−xMxRu2O7 (0 ≤ x ≤ 2), com M = Ho ou Y; e os novos materiais supercondutores Zr1−xNbxB2 (0,01 ≤ x ≤ 0,05). Para a caracterização estrutural de todas as amostras foi utilizada a técnica de difração de raios X (DRX) com análise por refinamento Rietveld e para o estudo morfológico foi utilizada a microscopia eletrônica de varredura (MEV). Os materiais foram também caracterizados por medidas de calor específico, magnetização e resistividade em função da temperatura. Os padrões de difração de raios X com a análise por refinamento permitiram a identificação de compostos com fase única e verificação da variação do parâmetro de rede com o aumento da concentração do dopante de acordo com a lei de Vegard, independente do dopante, para todas as amostras pirocloros e intermetálicas. Verificou-se que a adição de ácido nítrico, na reação do estado sólido melhora a morfologia das amostras pirocloros proporcionando sistemas mais homogéneos em termos de superfície e o tamanho de grão. Os resultados obtidos a partir da microscopia eletrônica de varredura nas amostras de Zr1−xNbxB2 mostrou uma superfície homogênea, sem segregação de fases secundárias e sem presença de aglomerados dos metais componentes, confirmando a formação de uma fase única, bem distribuída por todo o corpo do material. Os estudos das propriedades magnéticas revelaram que a dopagem com Ho e Y, no sítio do íon Gd provoca um aumento e uma diminuição no momento magnético dos compostos, respectivamente, demonstrando que a resposta magnética destes materiais deve-se predominantemente ao Gd. Concluímos que, a adição de Ho na matriz Gd2Ru2O7 pode-se ajustar o ordenamento magnético da amostra alterando-o de antiferromagnético, na ausência de Ho, para ferromagnético na ausência de Gd, enquanto que, as amostras dopadas com Y preservam a ordem antiferromagnética do composto. Medidas magnéticas, elétricas e térmicas realizadas nas amostras intermetálicas revelam que a supercondutividade pode emergir na matriz não-supercondutora ZrB2 para pequenas concentrações de nióbio, com temperatura crítica supercondutora alcançando o valor máximo de 8,2 K para a composição Zr0;96Nb0;04B2. Foi encontrado um possível comportamento não convencional no diagrama de Hc1 versus a temperatura reduzida (T/Tc), que sugere comportamento de duas bandas.
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Zeng, Yan. "T-cell mediated suppression of neuroblastoma following fractalkine gene therapy is amplified by targeted IL-2." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2006. http://dx.doi.org/10.18452/15401.
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Das Induzieren und Aufrechterhalten einer tumor-protektiven Immunität sind wesentliche Ziele in der Immuntherapie des Neuroblastoms. Eine Erhöhung der Anzahl von tumor-infiltrierenden Leukozyten könnte ein Weg sein, um dieses Ziel zu erreichen. Fractalkine ist ein besonderes TH1 CX3C Chemokin, welches sowohl Adhäsion und Migration von Leukozyten vermittelt. Gerichtetes IL-2 (ch14.18-IL-2) wurde durch eine genetische Fusion von anti-GD2 Antikörper mit IL-2 hergestellt, damit IL-2 spezifisch in das Mikromilieu von Neuroblastomen gebracht werden kann. In dieser Arbeit habe ich die Hypothese getestet, dass Gentherapie mit dem Chemokin Fractalkine (FKN) eine wirksame Antineuroblastom-Immunantwort induziert, welche durch gerichtetes IL-2 amplifiziert wird. Zu diesem Zweck wurden NXS2-Zellen genetisch verändert, damit sie murines FKN produzieren (NXS2-FKN). Transkription und Expression des mFKN Gens konnte in NXS2-FKN Zellen und Tumorgewebe gezeigt werden. Die chemotaktische Eigenschaft von FKN wurde sowohl in vitro als auch in vivo gezeigt. FKN zeigte eine Reduktion des Primärtumorwachstums, welches durch gerichtetes IL-2 mit nicht-kurativen Dosen von ch14.18-IL-2 deutlich verbessert wurde. Ferner wurden experimentelle Lebermetastasen nur in den Mäusen komplett eradiziert, welche die Kombinationstherapie erhalten haben. Die Mechanismen, welche an dieser Antitumorantwort beteiligt sind, schließen eine wirksame T-Zell-Aktivierung (Hochregulation von CD69, CD25, und von TNF-alpha und INF-gamma), sowie eine Erhöhung der tumorspezifischen CTL-Aktivität mitein. Die Depletion von CD4+ und CD8+ T-Zellen in vivo hat diesen therapeutischen Effekt aufgehoben, was die essentielle Rolle von T-Zellen in diesem immuntherapeutischen Ansatz unterstreicht. Zusammenfassend konnte ich zum ersten Mal zeigen, dass Chemokin-Gentherapie mit FKN durch gerichtetes IL-2 amplifiziert wird, was eine Kombination dieser beiden Strategien zur adjuvanten Therapie beim Neuroblastom nahe legt.Induction and maintenance of tumor-protective immunity are the major goals of neuroblastoma immunotherapy. Enhancing the amount of tumor infiltrating leukocytes might be a way to achieve these goals since they may be associated with residual evidence of the ineffective immune response. Fractalkine is a unique TH1 CX3C chemokine known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Targeted IL-2 (ch14.18-IL-2) was constructed by anti-GD2 antibody fused with IL-2 so that IL-2 can be directed into the microenvironment of neuroblastoma tumor. Here, I tested the hypothesis that chemokine gene therapy with fractalkine (FKN) induces an effective anti-neuroblastoma immune response amplified by targeted IL-2. NXS2 cells were engineered to stably produce murine FKN (NXS2-FKN). Transcrip- tion and expression of the mFKN gene in NXS2-FKN cells and tumor tissue were demonstrated. The chemotactic activity of FKN expressed by NXS2 cells was determined both in vitro and in vivo. Importantly, NXS2-FKN exhibited a reduction in primary tumor growth, which was boosted by targeted IL-2 using non-curative doses of ch14.18-IL-2. Furthermore, experimental liver metastases were completely eradicated in mice receiving the combination therapy, demonstrating the induction of a long-lived tumor protective response. The mechanisms involved in antitumor response included effective T cell activation as indicated by the up-regulation of T-cell activation markers (CD69, CD25) and proinflammatory cytokines (TNF-alpha, INF-gamma) as well as the enhancement of tumor specific CTL activity. The depletion of CD4+ and CD8+ T cells in vivo abrogated the therapeutic effect supporting the crucial role of T cells in this immunotherapeutic approach. In summary, I demonstrated for the first time that chemokine gene therapy with FKN is amplified by targeted IL-2 suggesting a combination of both strategies as an adjuvant therapy for neuroblastoma.
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Jorg, Tobias [Verfasser], and Marion [Akademischer Betreuer] Subklewe. "Immuntherapeutische Strategien für Patienten mit Weichteilsarkomen : Augmentation der Zytotoxizität Natürlicher Killerzellen mittels ex vivo-Expansion und Verwendung eines Anti-GD2 Antikörpers / Tobias Jorg ; Betreuer: Marion Subklewe." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1175878162/34.
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Jorg, Tobias Justus [Verfasser], and Marion [Akademischer Betreuer] Subklewe. "Immuntherapeutische Strategien für Patienten mit Weichteilsarkomen : Augmentation der Zytotoxizität Natürlicher Killerzellen mittels ex vivo-Expansion und Verwendung eines Anti-GD2 Antikörpers / Tobias Jorg ; Betreuer: Marion Subklewe." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1175878162/34.
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Endres, Stefanie [Verfasser], Holger [Akademischer Betreuer] Lode, Holger [Gutachter] Lode, and Patrick [Gutachter] Hundsdörfer. "Pharmakokinetik und -dynamik einer Langzeitinfusion mit dem anti-GD2 Antikörper ch14.18/CHO bei Patienten mit einem Hochrisiko-Neuroblastom / Stefanie Endres ; Gutachter: Holger Lode, Patrick Hundsdörfer ; Betreuer: Holger Lode." Greifswald : Universität Greifswald, 2021. http://d-nb.info/1231434694/34.
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Troschke-Meurer, Sascha [Verfasser], Holger [Akademischer Betreuer] Lode, Holger [Gutachter] Lode, and Peter [Gutachter] Lode. "Immunmodulatorische und genetische Parameter als prognostische Marker für das Ansprechen einer GD2-gerichteten Immuntherapie in Kombination mit Interleukin-2 bei Patienten mit Hochrisikoneuroblastom / Sascha Troschke-Meurer ; Gutachter: Holger Lode, Peter Lode ; Betreuer: Holger Lode." Greifswald : Universität Greifswald, 2020. http://d-nb.info/1221271040/34.
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Jonsson, Sara. "Gender Inequality, GDP per capita and Economic Growth." Thesis, Internationella Handelshögskolan, Högskolan i Jönköping, IHH, Nationalekonomi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-15339.
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The purpose of this thesis is to investigate the effects of gender inequality on GDP and GDP per capita. A cross sectional analysis of 177 countries over the time period 1998 to 2008 is undertaken with the use of linear regressions. There are several different factors that contribute to the gender inequality within a country and several ways to measure that disparity. The most well known measurement is the Gender-related Development Index and the components within this composite index have been studied thoroughly, although the index as a whole has not. This thesis then contributes with an overall view of how the gender inequality is important for the GDP and GDP per capita. The findings illustrate how significant equality between the genders is for the economy, irrespective of the human development level within the countries. The implication of this is that gender equality is important for the GDP and GDP per capita, which is in accordance with the theories. One large issue is that there is no way of confirming the way of causality between gender equality and GDP or GDP per capita.
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Nguyen, Anh-Minh. "Safer-by-design emerging nanomaterials : the case of bimetallic gadolinium-cerium oxysulfides." Electronic Thesis or Diss., Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2019SORUS279.pdf.
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Les nanomatériaux possèdent des propriétés fascinantes, mais sont considérés comme potentiellement dangereux. Cette image négative limite les possibilités d’innovation dans la recherche ainsi que dans l’industrie. Afin d’utiliser au mieux le potentiel des nanomatériaux émergents et d’assurer la sureté tout au long de leur cycle de vie, l’approche « safer-by-design » peut être appliquée dès les premières étapes de la recherche. Il s’agit d’étudier simultanément leurs propriétés, leur fonctionnalité et leur toxicité. Avec les informations acquises à chaque étape, la performance et la sureté de ces matériaux pourraient être améliorées.Les oxysulfures bimétalliques de gadolinium et de cérium de compositions Gd2(1-x)Ce2xO2S sont des nanomatériaux émergents, prometteurs pour la photocatalyse et l’imagerie biomédicale. Des nanoplaquettes de dimension 2 × 20 nm ont été préparées par synthèse colloïdale en milieu organique. Une caractérisation approfondie des produits a été fournie. Ensuite, l’approche « safer-by-design » a été discutée en relation avec la conception des nanoplaquettes d’oxysulfure pour la photocatalyse (absorption de lumière, photodégradation de colorants, production de radical) et l’imagerie biomédicale (revêtement, photoluminescence, propriétés magnétiques). Leur toxicité a été étudiée par une combinaison de modèles in vitro ainsi que in vivo. Pour les deux applications, le taux de cérium et les propriétés de surface des nanoplaquettes semblaient être les paramètres clés qui influent à la fois sur leur fonctionnalité et leur toxicité. Globalement, ce travail présente la première tentative de développement de nanoparticules d’oxysulfure métallique par l’approche « safer-by-design »Nanomaterials possess fascinating properties but are regarded as potentially harmful. This negative image limits the potential for innovation in both research and industry. To maximize the potential of emerging nanomaterials and ensure safety during their life cycle, “safer-by-design” may be employed in the early stage of nanomaterial research. It consists in investigating their properties, functionality and toxicity at the same time. With feedback between each step of the studies, the performance as well as the safety of the materials may be improved.Bimetallic gadolinium-cerium oxysulfides of compositions Gd2(1-x)Ce2xO2S are emerging nanomaterials that show potentials in photocatalysis and biomedical imaging. Nanoplatelets of dimension 2 × 20 nm were prepared by colloidal synthesis in organic solvent. In-depth characterization of the products was provided. Then, safer-by-design approach was discussed in relation with oxysulfide nanoplatelets design for photocatalysis (light absorption, photodegradation of dyes, radical production) and biomedical imaging (coating, photoluminescence, magnetic properties). Their potential toxicity was assessed using a combination of in vitro and in vivo models. For both applications, the cerium content and the surface properties of the nanoplatelets appeared to be key parameters that impact their functionality and toxicity. Overall, this work presents the first attempt to develop safer-by-design metal oxysulfide nanoparticles
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Lindmark, Magnus. "Webbaserat Tidrapporteringssystem." Thesis, Blekinge Tekniska Högskola, Sektionen för teknokultur, humaniora och samhällsbyggnad, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-1706.
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Systemet som förenklar hantering och information av tidrapportering, projekt, kunder, lager och anställda. Syftet är att företaget skall få en mera överblick över deras verksamhet, då all information samlas på samma ställe. De anställda kan via webben snabbt och enkelt rapportera in deras arbetstider under den gångna veckan. Systemet innefattar: SMS-tjänst, automatiskt utskick, hanteringen för lager, projekt, kunder och semester, kontinuerlig statistik med grafiska diagram samt utskriftsfunktioner. Allt är utvecklat i PHP och MySQL.The system simplifies the management and information, about time reports, projects, customers, storage and employees. The main purpose for this system is that the company shall have a more structured overview about their company, and where all the information is gathered, at the same spot. The employees are able to report in their working progress during the week, in a simple easy way trough the internet. The system contains a SMS service, automatically circular messages, management of storage, projects, clients and employees vacations. The system also contains continuous dynamic statistics, with graphical layout and also print functionality. Everything is developed in PHP with MySQL as database.
Detta är en reflektionsdel till en digital medieproduktion. mange@mdw.se www.mdw.se
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Austin, Dominic. "GDP and post-GDP - A Spurious Divorce." Thesis, Malmö universitet, Fakulteten för kultur och samhälle (KS), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-21130.
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Where post-GDP, a socio-ecological substitute of GDP, has become increasingly salient within international relations, its practice at an institutional economic level remains largely marginalised. At a discursive level, however, both GDP and post-GDP appear to be both supplementary and antithetical to one another. This thesis investigates this relationship between GDP and post-GDP discourse, as well as the dependency of economic institutions to exercise such a discourse. Constructivist institutionalism initially frames these economic ideas as both constitutive and antagonistic towards institutional stability. This thesis, however, draws primarily upon institutional poststructuralism, articulating GDP/post-GDP discourse, not the agent, as a mechanism that produces economic knowledge and, by association, the institutions that are shaped by it. A two-part analysis takes place, consisting of an historical genealogy of GDP/post-GDP and a discourse logics analysis between the IMF development committee and the economic departments of India and surrounding countries. The findings show that the formative discourse of GDP and post-GDP had become divorced during the 20th century and that while GDP logics often struggle to reconcile requisite development outcomes, economic institutions exercise the two as a unitary discourse; albeit one that maintains a GDP centre.
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Mattos, Pedro Montero. "Nowcasting Brazilian GDP." reponame:Repositório Institucional do FGV, 2017. http://hdl.handle.net/10438/18775.
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Based on recent surveys on nowcasting methods, we apply the one-step estimation of dynamic factor models to the Brazilian case. Such methodology copes well with the problems of mixed-frequency series, ragged edges, timeliness and high dimensionality of data sets. We use the daily expectation published by the Brazilian Central Bank as a benchmark for our model and we do not find enough evidence to reject that both models have equal predictive accuracy, under non-distressed circumstances.
Baseado em recentes pesquisas em métodos de Nowcasting, foi aplicada a estimação de modelos de fatores dinâmicos em um passo ao caso brasileiro. Esta metodologia lida com os problemas de frequências mistas, amostras recortadas, horizonte temporal e alta dimensão da amostra. Foram utilizadas as expectativas diárias do PIB publicadas pelo Banco Central como um benchmark do modelo. Não foram encontradas evidências que rejeitam a hipótese de igual poder preditivo, para circunstâncias econômicas não estressadas.
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Pallanca, Jane Emma. "The chemo-enzymic synthesis of GDP-mannose and GDP-mannose analogues." Thesis, University of Exeter, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294003.
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JAZIRI, NOUREDDINE. "Analogues de gdp-mannose : inhibiteurs potentiels de la gdp-mannose deshydrogenase." Paris 6, 1992. http://www.theses.fr/1992PA066661.
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Cette these est consacree a la synthese de molecules analogues du gdp-mannose, substrat d'une enzyme specifique de la biosynthese des alginates chez les souches mucoides de pseudomonas aeruginosa: la gdp-mannose deshydrogenase. Dans la premiere partie de ce travail, nous avons choisi une strategie qui consiste en une protection convenable de la guanosine en vue de brancher en position 5 une chaine qui reliera le nucleoside a un derive du mannose. La seconde partie est relative a l'etude de la chimie du ribose au moyen de reactions classiques de protection en positions 1, 2 et 3 et le branchement de differentes chaines en position3 15. Dans la troisieme partie, ont ete mises au point differentes methodes d'activation de la position anomere du mannose ainsi que les conditions de condensation avec les differentes chaines en 5 du ribose. Les methodes de couplage de vorbruggen ont ete utilisees pour la condensation de la guanine et d'autres bases pyrimidiques en position 1 du ribose. La quatrieme partie relate l'ensemble des proprietes biologiques des produits obtenus
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Marczynski, Elaine Sirlei. "Avaliação de membranas hidrocarbônicas não fluoradas para uso como eletrólito em célula a combustível tipo DEFC." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/103831.
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Membranas hidrocarbônicas não fluoradas têm sido desenvolvidas para uso em substituição as membranas fluoradas (Nafion®) em células a combustível de eletrólito polimérico (PEMFC), ou em temperaturas superiores a 80 °C, ou em células com adição direta de álcool. Este trabalho teve como objetivo avaliar o desempenho de membranas hidrocarbônicas catiônicas, desenvolvidas para uso em célula a combustível alimentada com etanol (DEFC), e de camadas de difusão gasosa (GDL – Gas Difusion Layer) e eletrodos (GDE – Gas Difusion electrode) preparados para uso com as mesmas. Duas membranas hidrocarbônicas (E-750 e P-730) da empresa FuMATech®/GR foram avaliadas quanto à capacidade de troca iônica e grau de inchamento em água/etanol, quanto a composição química, morfologia, comportamento térmico e visoelástico e condutividade por impedância. As GDLs foram preparadas a partir de uma emulsão aquosa de Teflon® e pó de carbono Vulcan XC-72R®, com e sem agente emulsificante (resina sulfonada), dispersa em ambas as faces do tecido de carbono pelo método de aspersão. Os GDEs foram preparados pela deposição de emulsão catalítica de diferentes eletrocatalisadores sobre as respectivas GDLs do ânodo e catodo. Os GDEs anódico e catódico foram preparados com 1 mg.cm-2 do eletrocatalisador de PtSn/C 20% (75:15) e de Pt/C (20:80), respectivamente, e caracterizados por MEV-EDS. As características fisico-químicas das membranas hidrocarbônicas foram similares às apresentadas pela membrana Nafion®. O desempenho do protótipo de célula unitária DEFC com as membranas FuMATech® foi inferior ao obtido com a membrana Nafion® usando-se GDE comercial. Por outro lado, ensaios com a membrana Nafion® utilizando-se os eletrodos preparados neste trabalho e eletrodos comerciais apresentaram valores de potencial similares.Non-fluorinated hydrocarbon cationic membranes have been developed for use instead of Nafion® in Polymer Electrolyte Membrane Fuel Cells (PEMFCs), or at higher temperatures than 80 ºC, or in fuel cells fed with alcohol. The aim of this work was to evaluate the performance of commercial non-fluorinated hydrocarbon cationic membranes with potential use in direct ethanol fuel cell (DEFC), and also evaluate the Gas Difusion Layer (GDL) and Gas Difusion electrode (GDE) prepared for use with them. Two hydrocarbon membranes (E-750 and P-730) produced by FuMATech®/GR were analyzed according to their ion exchange capacity, water uptake in water/alcohol solution, morphology, chemical composition, thermal and viscoelastic behaviour, and conductivity by impedance. The GDLs were prepared by spraying an aqueous emulsion of Vulcan carbon/Teflon®, with and without emulsifier agent (sulfonated hydrocarbon resin), in both sides of a carbon fabric. The electrodes were prepared by the respective deposition of the electrocatalysts emulsions on the cathode and anode GDLs. The anodic and cathodic GDEs were prepared with 1 mg.cm-2 of the electrocatalyst of PtSn/C 20% (75:15) and of Pt/C (20:80), respectively, which were characterized by SEM-EDS. The physicochemical properties of the hydrocarbon membranes were similar to the Nafion® membrane ones. The potential values obtained in a DEFC prototype unit cell with FuMATech® membranes were lower than those with Nafion-117 membrane. On the other hand, the performance of the DEFC prototype with Nafion-117 membrane was the same if used GDEs commercial or here prepared.
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Mäki, Minna. "Conversion of GDP-mannose into various GDP-deoxyhexoses in Gram-negative bacteria." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/maki/.
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Nevelsteen, Kim J. L. "GDD as Development Methodology." Thesis, Uppsala University, Department of Information Technology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98283.
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The Game Design Document is a well defined set of requirements for a game design and a methodology for game development. The most pertinent aspects of the GDD are described and the relative research collected, in order to better the reader's understanding of the concept. This is a work in two parts, theoretical and practical. Research was an ongoing effort while attempting toproduce a game design according to the content prescribed for the GDD. The resultant design was for a fictitious game dubbed Arcane Dominion.
Knowledge gained about the GDD is used to make a comparison and attempt to identify a possible evolution towards existing software engineeringmethodologies. Some differences are brought to light between the GDD and a popular contemporary methodology, Agile Development.
To compliment the research, one aspect of the designed game was implemented in a prototype and thereafter analyzed in order to obtain neededfeedback and be confronted with the complexities of game balancing pertaining to one chosen game strategy.
No knights or soldiers were hurt in the making of this thesis.
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Heep, Maria. "Periodenrelationen für GL2(F)." Bonn : [s.n.], 1989. http://catalog.hathitrust.org/api/volumes/oclc/20437035.html.
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Brennan, Benjamin. "Essays on Nominal GDP Targeting." Thesis, University of Oregon, 2018. http://hdl.handle.net/1794/23784.
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The subject of this dissertation is nominal GDP (NGDP) targeting. In the wake of the Great Recession, some economists have proposed using some form of NGDP target to replace current monetary policy. We evaluate the desirability of NGDP targets based upon their ability to deliver unique and \learnable" equilibria and their welfare gains in the presence of nancial frictions.
In the second chapter, we assess the determinacy and E-stability conditions for simple interest rate rules which respond to NGDP's deviation from target in a simple three-equation New Keynesian model. The rules under consideration target either NGDP level or growth, and can either be contemporaneous, one period ahead, or two periods ahead. We also allow for dierent types of information sets for the agents.
In the third chapter, we compare welfare loss in consumption equivalent terms for NGDP targets with more conventional monetary policy in a New Keynesian model which features nancial frictions.
Finally, in the fourth chapter we continue our analysis from chapter one but now allow for strictly positive trend inflation. We present
findings for the relationship between trend inflation and the determinacy and E-stability of the equilibrium when using interest rate rules that target NGPD.
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(GDV), Gesamtverband der Deutschen Versicherungswirtschaft e. V. "Forschungsberichte / Unfallforschung der Versicherer, GDV." Gesamtverband der Deutschen Versicherungswirtschaft e. V. (GDV), 2021. https://publish.fid-move.qucosa.de/id/qucosa%3A74629.
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Al-Qahtani, Ahmed. "Development and clinical applications of monoclonal antibodies to human AMH, GDF-9 and GDF-9B." Thesis, Oxford Brookes University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444326.
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Naser, Hanan. "An econometric investigation of forecasting GDP, oil prices, and relationships among GDP and energy sources." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/7041/.
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In order for a policy to be effective, the links between the policy tools and the sub- sequent targets must be known, understandable, stable, and predictable. In this respect, this thesis is composed of three separate yet related empirical studies, that target important macroeconomic variables, which play a central role in the conduct of macroeconomic policies. First, simple regression estimates and a factor-based model are utilized to produce forecasts for Bahrain quarterly GDP growth using quarterly data-set that cover the period from 1995: Q1 to 2008: Q3. To do so, we run a simple regression model using a small data-set including six explanatory variables carefully selected based on in-sample correlation with the target variable. Alternatively, a factor model based on 65 indicators is employed to forecast Bahrain GDP growth. Using simulated out- of-sample experiments we assess and compare the performance of both approaches. The main finding from our forecasting experiment is that the best forecasting performance can be reached using simple regression estimates with a carefully selected small set of variables. In particular, by looking at point and density nowcasts, we find that a simple regression model that use industrial production as an indicator are more accurate than a static factor approach that uses over 65 variables. The official flash estimates of Bahrain quarterly GDP are published with a delay of 90 days after the end of the reference quarter. Our flash estimates, based on simple regression model, reduce the lag to 54 days. Second, we aim to forecast West Texas Intermediate (WTI) crude oil prices using a large monthly data-set that cover the period from March 1983 to December 2011. To achieve this aim, forecasting with factor models offer a usual approach that utilizes large data-sets, however; a forecasting model which simply includes all factors in state space equation and do not allow for time varying may be not suitable with a highly volatile market such as oil market. To overcome these limitations, we employ an approach that accounts both for parameter and model uncertainty. In particular, we implement the the Dynamic Model Averaging (DMA) approach suggested by Koop and Korobilis (2012). The key element of the DMA approach is that it allows both for model and parameter to vary at each point of time. By doing so, the DMA is robust to structural breaks. Empirical findings show that DMA approach outperforms any other alternative model used in the forecasting literature. We show that there is model but not parameter variation. Finally, we find that the DMA approach provides a better proxy of expected spot prices than future prices. Third, the Johansen cointegration technique is used to examine the long-run relationship between oil consumption, nuclear energy consumption, oil price and economic growth for eight countries over the period from 1965 - 2010. The countries investigated are divided into two groups. The first group includes four industrialized countries: USA, Canada, Japan and France, while the second group includes four emerging economies: Russia, China, South Korea and India. Results suggest that there is a long-run relationship between the four variables. Exclusion tests show that at least one energy source enter the cointegration space significantly, which im- plies that energy a long-run impact on economic growth. The emerging economies found to be heavily dependent on both oil and nuclear energy consumption. We also examine the causal linkage between the variables through exogeneity test. There is evidence of a unidirectional causality between energy consumption (oil or nuclear) and economic growth in all investigated countries. Our findings have important pol- icy implications that should be taken into account in designing appropriate energy policies. Energy conservation policies might have drawbacks or damaging repercus- sions on economic growth for this group of countries.
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Pedak, Martin. "The Effect of Tourism on GDP." Thesis, Internationella Handelshögskolan, Högskolan i Jönköping, IHH, Nationalekonomi, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-41334.
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International tourism plays a huge role for many countries in the world. The significance of tourism differs between countries, however increase in tourism tends to lead to gross domestic product growth. The purpose of this paper is to measure those general effects of tourism on gross domestic product per capita. The theory part is focused on determinants of economic growth and GDP and the literature review examines general effects of tourism as well as the effect of tourism on specific countries and regions. The data is cross sectional and was gathered from 111 countries provided by World Bank. The results of this thesis show that international tourism seems to have positive relation with the level of gross domestic product per capita. However, the study also found that tourism specialisation tends to have negative relation on level of gross domestic product per capita and that countries that are most specialised in tourism are quite small states, usually located in the Caribbean Sea.
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Tomlinson, Dennis Churchill. "Nature and technology in GDR literature." Thesis, University of Bath, 1993. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332289.
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(GDV), Gesamtverband der Deutschen Versicherungswirtschaft e. V. "Unfallforschung kompakt / Unfallforschung der Versicherer, GDV." Gesamtverband der Deutschen Versicherungswirtschaft e. V. (GDV), 2021. https://publish.fid-move.qucosa.de/id/qucosa%3A74497.
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(GDV), Gesamtverband der Deutschen Versicherungswirtschaft e. V. "Unfallforschung kommunal / Unfallforschung der Versicherer, GDV." Gesamtverband der Deutschen Versicherungswirtschaft e. V. (GDV), 2021. https://publish.fid-move.qucosa.de/id/qucosa%3A74743.
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Björnfot, Fredrik. "GDP Growth Rate Nowcasting and Forecasting." Thesis, Umeå universitet, Institutionen för fysik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-132951.
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The main purpose of this project was to help Swedbank get a better understandingof how gross domestic product growth rate develops in the future froma data set of macroeconomic variables. Since GDP values are released long aftera quarter has ended Swedbank would like to have a model that could predictupcoming GDP from these data sets. This was solved by a combination ofgrowth rate predictions from a dynamic factor model, a vector autoregressivemodel and two machine learning models. The predictions were combined usinga weighting method called system averaging model where the model predictionwith least historical error receives the largest weight in the nal future prediction.In previous work a simple moving average model has been implementedto achieve this eect however there are several aws in a simple moving averagemodel. Most of these defects could in theory be avoided by using an exponentialweighting scheme instead. This resulted in the use of an exponentialweighting method that is used to calculate weights for future predictions. Themain conclusions from this project were that some predictions could get betterwhen removing bad performing models which had too large of a weight. Puttingtoo high weight on a single well performing model is also not optimal since thepredictions could get very unstable because of varying model performance. Theexponential weighting scheme worked well for some predictions however whenthe parameter , that controls how the weight is distributed between recent andhistorical errors, got too small a problem arose. Too few values were used toform the nal weights for the prediction and the estimate got unsteady results.
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Costa, Filipa Barbosa da. "Modelo de planeamento – GDH de ambulatório." Master's thesis, FCT - UNL, 2009. http://hdl.handle.net/10362/3384.
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Dissertação apresentada na Faculdade de
Ciências e Tecnologia da Universidade Nova de
Lisboa para obtenção do grau de Mestre em
Engenharia BiomédicaA Administração Central do Sistema de Saúde (ACSS), é uma entidade do Sistema Nacional de Saúde que tem como principal missão a gestão dos recursos humanos e financeiros bem como promover a qualidade organizacional das entidades prestadoras de saúde. O Modelo de Planeamento criado pela Siemens SA surge como o sistema de informação que vem colmatar a falta de informação necessária para a ACSS fazer um ajuste adequado dos recursos à procura por parte da população. No entanto, o mercado onde o Modelo se insere caracteriza-se por estar em constante alteração/actualização exigindo ao Modelo a necessidade de se adaptar para continuar a responder adequadamente. No seguimento desta necessidade surge este trabalho com o principal objectivo de adequar o Modelo à recente criação do conceito de Grupo de Diagnóstico Homogéneo (GDH) para Ambulatório. O conceito de GDH surgiu no mercado da saúde como um sistema de classificação de episódios agudos, associados a Internamento, sendo ainda utilizado para definir operacionalmente a produção de um Hospital. A adaptação deste conceito ao Ambulatório surge na consequência da evolução tecnológica permitir, no presente,tratar doentes num período inferior a 24 horas. Pela análise do impacto do conceito no Modelo, realizado no projecto, foi possível confirmar que o problema está no facto de ser a base de dados dos GDHs que alimenta o Internamento no Modelo, levando a que GDHs de Ambulatório fossem introduzidos erradamente nesta linha de produção. Para corrigir esta situação foi crucial estabelecer regras que impedissem a entrada desses episódios em Internamento. Desta forma, a partir da ferramenta Oracle Warehouse Builder, responsável pela manipulação da informação no Modelo, aplicaram-se as regras necessárias para transferir estes dados, considerando o tempo de internamento e o próprio GDH. Para além da actualização do Modelo ao conceito de GDH Ambulatório foi possível trabalhar a outros níveis promovendo um sistema de informação de qualidade, actual e de alta contribuição para quem é responsável pela distribuição e afectação de recursos no sistema de saúde.
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Gregson, Julie. "Engendering the GDR : DEFA cinema 1956-1966." Thesis, University of Nottingham, 2002. http://eprints.nottingham.ac.uk/14353/.
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This thesis examines four films made during two key phases in East German film history in the mid-1950s and the mid-1960s which have earned critical acclaim for their challenge to cultural-political orthodoxy and which I read as national narratives offering political, social, cultural and historical constructions of GDR identity. I argue that narrative representations of gender and sexuality serve in the films as a means towards negotiating between affirmation and critique. My analyses are informed by a wide range of other DEFA films. Chapter One sketches broader political and film-historical contexts. Chapter Two examines the role that gender discourse plays in differentiating East from West in the depiction of the frontier city of Berlin in Gerhard Klein's Berlin-Ecke Schonhauser. Chapter Three focuses on Konrad Wolf’s adaptation of Christa Wolfs novel Der geteilte Himmel. It shows how the film articulates competing views of the GDR, but instrumentalizes the female character ultimately to endorse socialist society in a divided Germany, and expresses her attachment to this new society in terms of a family-type relationship. Chapter Four examines how Frank Vogel's Denk bloss nicht, ich heule seeks to mediate between the 'national' past and present, using a triangular family plot. In Chapter Five, the analysis of Frank Beyer's Spur der Steine centres upon the role of a lone female in the film's reforming exploration of the overwhelmingly male collective, but shows how it leaves the status of sexuality - whether for pleasure or for reproductive ends - unresolved. There has been little in-depth study of the way gender representation relates to constructions of the GDR in films of this period. This study remedies this omission, showing how the film-makers frequently rely upon conservative gender paradigms to manage the contradictions implicit in their project and how the endings of the films increasingly come under strain.
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Chen, Helen Yee-Fang. "Characterization of ganglioside GD3 9-O-Acetylation /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112855.
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