Classical midgut carcinoids belong to neuroendocrine tumors of the gastroenteropancreatic tract (GEP-NETs) and are associated with serotonin overproduction. The term midgut is derived from the tumors’ embryological site of origin: enterochromaffin cells in the lower jejunum, ileum, caecum and the ascending colon. Despite their rather benign nature, these tumors can metastasize to mesentery and liver, putting patients at risk for the so-called carcinoid syndrome. This syndrome is characterized by flushes, diarrhoea and valvular heart disease due to the excessive serotonin secretion by tumor cells. Treatment of metastatic disease is currently ineffective and T cell immunotherapy has been suggested as a novel approach. We propose a number of midgut carcinoid-associated proteins as potential antigens for immunotherapy. Chromogranin A (CGA), tryptophan hydroxylase 1 (TPH-1), vesicular monoamine transporter 1 (VMAT-1), caudal type homeobox transcription factor 2 (CDX-2), islet autoantigen 2 (IA-2) and survivin represent interesting candidates based on their fairly restricted neuroendocrine tissue expression. In pursuit of potential antigens we identified a novel splicing variant of VMAT-1, lacking the second last exon. The variant, denoted VMAT1Δ15, encodes a differently translated C-terminal compared to the native form, is localized in the endoplasmic reticulum (ER) instead of large dense core vesicles and is unable to accumulate serotonin. We identify several immunogenic HLA-A*0201-binding peptide epitopes derived from our proposed antigens by analyzing CD8+ T cell responses in blood from midgut carcinoid patients. We demonstrate immune recognition of midgut carcinoid tumors in patients and in vitro generation of activated CD8+ T cells recognizing these peptide epitopes in blood from healthy controls. Patients also exhibit increased frequencies of circulating regulatory T cells (Tregs) with suppressive quality and patient lymphocytes display a decreased proliferative capacity compared to healthy controls. Midgut carcinoid tumors are frequently infiltrated by T cells, however always in the presence of Foxp3-expressing Tregs. Midgut carcinoid-associated antigens recognized by CD8+ T cells are of great interest for cellular therapies such as modified DC vaccines or adoptive T cell transfer. However, the systemic and local suppression of Th1 immunity must be considered and likely corrected in order to obtain clinically effective immunotherapies.

Data Distribution Management (DDM) deals with two basic problems: how to distribute data generated at the application layer among underlying nodes in a distributed system and how to retrieve data back whenever it is necessary. This thesis explores DDM in two different network environments: peer-to-peer (P2P) overlay networks and cluster-based network environments. DDM in P2P overlay networks is considered a more complete concept of building and maintaining a P2P overlay architecture than a simple data fetching scheme, and is closely related to the more commonly known associative searching or queries. DDM in the cluster-based network environment is one of the important services provided by the simulation middle-ware to support real-time distributed interactive simulations. The only common feature shared by DDM in both environments is that they are all built to provide data indexing service. Because of these fundamental differences, we have designed and developed a novel distributed data structure, Hierarchically Distributed Tree (HD Tree), to support range queries in P2P overlay networks. All the relevant problems of a distributed data structure, including the scalability, self-organizing, fault-tolerance, and load balancing have been studied. Both theoretical analysis and experimental results show that the HD Tree is able to give a complete view of system states when processing multi-dimensional range queries at different levels of selectivity and in various error-prone routing environments. On the other hand, a novel DDM scheme, Adaptive Grid-based DDM scheme, is proposed to improve the DDM performance in the cluster-based network environment. This new DDM scheme evaluates the input size of a simulation based on probability models. The optimum DDM performance is best approached by adapting the simulation running in a mode that is most appropriate to the size of the simulation.

B virus (Macacine herpesvirus 1, Cercopithecine herpesvirus 1, herpes B virus) is an Old World monkey simplex virus endemic in macaques. B virus infection in its natural host, macaque, is very similar to HSV-­‐1 infection in humans causing mild or asymptomatic infection. On the other hand, zoonotic infection in humans results in death in the absence of early initiation of antiviral drugs. Viruses evade host immune responses in order to survive and propagate. Most herpes viruses including HSV-­‐1 down-­‐regulate major histocompatibility complex class I (MHC class I) surface expression on infected cells in order to prevent CD8+ T-­‐cell recognition and subsequent cell lysis. MHC class I molecules bind to the inhibitory receptors of NK cells and prevent NK cell activity. Thus, this mechanism protects HSV-­‐1 infected cells from CD8+ T-­‐cell lysis, making them sensitive to natural killer (NK) cell cytotoxicity. To investigate if B virus pathogenicity is a result of novel immune evasion mechanisms employed by B virus, we determined NK cell regulation during B virus infection. To this end, our experiments demonstrate that B virus does not down-­‐ regulate MHC I expression as effectively as HSV-­‐1, leading us to hypothesize that B virus in-­‐ fected cells are resistant to NK cell activity. We examined the expression of MHC I chain related genes (MICA/ MICB), which are activation ligands to NKG2D receptors on NK cells. Our results show that there is no significant difference in MICA and MICB expression between HSV-­‐1 and B virus infected cells. Furthermore, we tested for the up-­‐regulation of cytokines and chemokines responsible for NK cell activation and migration. Our results indicate a significant up-­‐regulation of IFN-­‐α from PBMCs co-­‐cultured with HSV-­‐1 infected cells, which plays an important role in activating NK cells. NK cells within these PBMCs up-­‐regulate perforin release indicative of NK cell activity. PBMCs co-­‐cultured with B virus infected cells do not up-­‐regulate any cytokines or chemokines responsible for NK cell activity. As a result the NK cells within these PBMCs do not significantly up-­‐regulate perforin release. These results demonstrate that B virus employs a novel immune evasion mechanism to subvert NK cell activity.

Data Distribution Management (DDM) deals with two basic problems: how to distribute data generated at the application layer among underlying nodes in a distributed system and how to retrieve data back whenever it is necessary. This thesis explores DDM in two different network environments: peer-to-peer (P2P) overlay networks and cluster-based network environments. DDM in P2P overlay networks is considered a more complete concept of building and maintaining a P2P overlay architecture than a simple data fetching scheme, and is closely related to the more commonly known associative searching or queries. DDM in the cluster-based network environment is one of the important services provided by the simulation middle-ware to support real-time distributed interactive simulations. The only common feature shared by DDM in both environments is that they are all built to provide data indexing service. Because of these fundamental differences, we have designed and developed a novel distributed data structure, Hierarchically Distributed Tree (HD Tree), to support range queries in P2P overlay networks. All the relevant problems of a distributed data structure, including the scalability, self-organizing, fault-tolerance, and load balancing have been studied. Both theoretical analysis and experimental results show that the HD Tree is able to give a complete view of system states when processing multi-dimensional range queries at different levels of selectivity and in various error-prone routing environments. On the other hand, a novel DDM scheme, Adaptive Grid-based DDM scheme, is proposed to improve the DDM performance in the cluster-based network environment. This new DDM scheme evaluates the input size of a simulation based on probability models. The optimum DDM performance is best approached by adapting the simulation running in a mode that is most appropriate to the size of the simulation.

Data Distribution Management (DDM) deals with two basic problems: how to distribute data generated at the application layer among underlying nodes in a distributed system and how to retrieve data back whenever it is necessary. This thesis explores DDM in two different network environments: peer-to-peer (P2P) overlay networks and cluster-based network environments. DDM in P2P overlay networks is considered a more complete concept of building and maintaining a P2P overlay architecture than a simple data fetching scheme, and is closely related to the more commonly known associative searching or queries. DDM in the cluster-based network environment is one of the important services provided by the simulation middle-ware to support real-time distributed interactive simulations. The only common feature shared by DDM in both environments is that they are all built to provide data indexing service. Because of these fundamental differences, we have designed and developed a novel distributed data structure, Hierarchically Distributed Tree (HD Tree), to support range queries in P2P overlay networks. All the relevant problems of a distributed data structure, including the scalability, self-organizing, fault-tolerance, and load balancing have been studied. Both theoretical analysis and experimental results show that the HD Tree is able to give a complete view of system states when processing multi-dimensional range queries at different levels of selectivity and in various error-prone routing environments. On the other hand, a novel DDM scheme, Adaptive Grid-based DDM scheme, is proposed to improve the DDM performance in the cluster-based network environment. This new DDM scheme evaluates the input size of a simulation based on probability models. The optimum DDM performance is best approached by adapting the simulation running in a mode that is most appropriate to the size of the simulation.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thesis (Ph.D. in Epidemiology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 95-109). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 122-140.

Orientador: Erick da Cruz Castelli / Resumo: O Complexo Principal de Histocompatibilidade (MHC) é um complexo gênico que está intimamente envolvido com a regulação do sistema imune. Esse complexo comporta o sistema de Antígenos Leucocitários Humano (HLA), cuja principal importância está relacionada com o reconhecimento do que é próprio ou não do organismo. HLA-C é o gene polimórfico menos variável dos genes HLA clássicos e o que tem menor expressão nos tecidos, exceto na interface materno-fetal, em que é o único gene clássico expresso. A molécula codificada por esse gene possui significante função na apresentação antigênica e regulação da atividade de células NK, o que permite uma íntima associação com situações fisiológicas, como gestação, e patológicas, como doenças infecciosas, autoimunes, inflamatórias, neoplasias e rejeições a enxertos transplantados. Sua porção gênica mais estudada é a que codifica a fenda de ligação a peptídeos antigênicos, devido sua destacada importância na apresentação de antígenos a células T citotóxicas. No entanto, outras regiões do gene, que são negligenciadas nos estudos de variabilidade, também merecem destaque por influenciarem na sinalização e modulação da citotoxicidade de células efetoras, na ancoragem e estabilidade da molécula na membrana plasmática e na internalização e reciclagem da molécula HLA-C. Desta maneira, nós exploramos a variabilidade dos segmentos que codificam α3 (éxon 4), transmembrana (éxon 5) and cauda citoplasmática (éxon 6 and éxon 7) da molécula HLA-C em uma popu... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The Major Histocompatibility Complex (MHC) is a gene complex closely involved in the regulation of the immune system. This complex includes the Human Leukocyte Antigen (HLA) system, whose main role is related to the recognition of self/non-self structures of humans. HLA-C is the least variable polymorphic gene of classical HLA genes and has the lowest expression in tissues, except at the maternal-fetal interface, where it is the only classical HLA class I expressed gene. The molecule encoded by this gene has a significant role in the antigen presentation and regulation of NK cells activities, which allows an intimate association with physiological conditions, such as pregnancy, and pathological conditions like infectious, autoimmune, and inflammatory diseases, cancer, and transplantation rejection. The most studied HLA-C portion is that encoding the peptide-binding groove, due to its outstanding importance in presentation of antigens to cytotoxic T cells. However, other regions of the gene, which are neglected in the variability studies, are also important in influencing the signaling and modulation of effector cell cytotoxicity, in the anchorage and stability of the molecule on the cell surface, and in the internalization and recycling of the HLA-C molecule. Here, we explore the variability of the segments encoding the α3 (exon 4), transmembrane (exon 5) and cytoplasmic tail (exon 6 and exon 7) domains of the HLA-C molecule in an admixed population sample from Southeastern B... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2016-06-02T19:05:40Z (GMT). No. of bitstreams: 1 2682.pdf: 1041726 bytes, checksum: e49637dd5b33d0f2161039b6aea0e32e (MD5) Previous issue date: 2007-12-20 / Financiadora de Estudos e Projetos / Distributed and parallel simulations can be used to create virtual collaborative environments that involve human beings in applications of training, entertainment, etc. The High Level Architecture - HLA, developed by the Defense Modeling and Simulation Office (DMSO) of the North American Department of Defense - DoD and adopted by IEEE for modeling and simulation of high level, is a framework of simulation standardization that basically aims at the reuse and interoperability of/among simulations. The HLA comprises the following services: Federation Management, Declaration Management, Object Management, Ownership Management, Time Management and Distribution of Data Management (DDM). RTI (Run-Time Infrastructure) is the implementation of the interface specification of HLA, whose main objective is to separate the communication from the simulation. A version of the RTI (RTI kit version 1.3 from Georgia Institute of Technology - Georgia Tech) was installed in the cluster of the Computer Department of the Federal University of São Carlos. This version consists of a set of support libraries for real-time distributed simulation. The problem with this version of the RTI is that it has many limitations, such as lack of support for human interaction. In order to overcome these limitations, an architecture was developed and evaluated, as part of this work, that uses the JXTA platform to initiate federates (simulations) and federations (set of federates) at runtime web services. This architecture aims to manage the distribution of data among federates, one of the most important services for distributed simulations. / Simulações paralelas e distribuídas podem ser utilizadas para criar ambientes virtuais colaborativos que envolvem seres humanos em aplicações de treinamento, entretenimento, etc. A Arquitetura de Alto Nível (High Level Architecture - HLA) desenvolvida pelo Escritório de Modelagem e Simulação de Defesa (DMSO) do Departamento de Defesa Norte-Americano DoD e adotada pelo IEEE para modelagem e simulação de alto nível é um framework de padronização de simulações que visa, basicamente, o reuso e a interoperabilidade de/entre simulações. A HLA compreende os seguintes serviços: Gerenciamento de Federação (conjunto de federados), Gerenciamento de Declaração, Gerenciamento de Objetos, Gerenciamento de Posse, Gerenciamento de Tempo e Gerenciamento de Distribuição de Dados (DDM). A RTI (Run-Time Infrastructure) é a implementação da especificação de interface da HLA, cujo objetivo principal é separar a comunicação da simulação. Uma versão da RTI (kit RTI versão 1.3 do Instituto de Tecnologia da Georgia - Georgia Tech) foi instalada no cluster do DC da UFSCar. Esta versão consiste de um conjunto de bibliotecas de suporte a simulações de tempo-real distribuídas. O problema com esta versão da RTI é que ela possui várias limitações, dentre elas, a falta de suporte à interação. De modo a superar essas limitações uma arquitetura foi desenvolvida e avaliada, como parte deste trabalho, que utiliza a plataforma JXTA para iniciar federados (simulações) e federações (conjunto de federados) em tempo de execução por meio de serviços web. Esta arquitetura visa gerenciar a distribuição de dados entre os federados, um dos serviços mais importantes de simulações distribuídas.