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Zusammenfassung Neueste Daten deuten daraufhin, dass maligne Tumoren der immunologischen Überwachung über eine Herunterregulierung der T-Zell-Aktivierung mittels eines PD-1 (programmed death 1)/ PDL-1/PDL-2 Signals ausweichen. Dies führt offensichtlich zu einer herabgesetzten Immunantwort und kann somit das Tumorwachstum fördern. Das Oberflächenmolekül PD-1, welches auf T- und B-Zellen, myeloischen Zellen und auf vielen menschlichen Karzinomen exprimiert wird, gehört zu der CD28 Familie, und PDL-1 (B7H1) und PDL-2 (B7DC) wurden als Liganden zu PD-1 beschrieben. Der CD28/B7 Signalweg gehört zu der Gruppe kostimulatorischer Signale, die beim zustande kommen einer T-Zell-gerichteten Immunantwort als zweites kostimulatorisches Signal notwendig sind. In dieser Arbeit wurde die molekulare Expression von PD-1, PDL-1 und PDL-2, von Zytokinen und T-Zell-Subpopulationen im Tumorgewebe von 81 Patienten analysiert, die sich einer kurativen oder palliativen Operation (gemäß UICC- Stadien I-IV) eines primären kolorektalen Karzinoms unterzogen hatten. Es zeigte sich auf Protein- als auch auf molekularer Ebene erstmals, dass PDL-1 und PDL-2 im Tumorgewebe fortgeschrittener Tumorstadien (UICC III/IV) signifikant überexprimiert wurden, PD-1 dagegen erniedrigt exprimiert war. PD-1 wurde dagegen deutlich auf infiltrierenden CD4+ Zellen bei Patienten fortgeschrittener Tumorstadien (UICC III/IV) detektiert, wohingegen PDL-1 auf CD4+ Zellen in frühen Stadien gefunden wurde. Im Vergleich zu den frühen Stadien (UICC I/II) wurde eine grössere Anzahl an T-Zellen mit regulatorischem Charakter in den Tumorstadien III/IV beobachtet. Letzteres würde dem Tumor im Bezug auf sein fortschreitendes Wachstum von Vorteil sein, da regulatorische T-Zellen T-Effektorzellen inhibieren können. Im Tumorgewebe fand sich zudem eine verminderte Expression an IFN-gamma, welches unter anderem T-Effektorzellen aktiviert und damit eine Immunantwort verstärkt. Das Zytokin IL-10, welches mit regulatorischen T-Zellen, aber auch mit T-Helfer (Th)2-Zellen und Tumorgewebe assoziiert ist und antiinflammatorische Eigenschaften besitzt, wurde in höheren Stadien verstärkt nachgewiesen. Dadurch verschafft es dem Tumor einen Überlebensvorteil. Die Beobachtungen in dieser Arbeit zeigen, dass PDL-1 und PDL-2 eine Schlüsselrolle während der Tumorprogression zukommen. Regulatorische T-Zellen sind offensichtlich in den Prozeß der Immunantwort gegen den Tumor eingebunden. Die deutliche PDL-1- und PDL-2-Expression auf T-Zellen insbesondere in frühen Tumorstadien lässt darauf schließen, dass die PD-1/PDL-1- bzw. PD-1/PDL-2-Interaktion inhibitorische Signale zwischen Tumorzellen und den T-Zellen vermittelt. In fortgeschrittenen Stadien (UICC III/IV) waren diese kostimulatorischen Signale auf den T-Zellen nur vermindert vorzufinden. Dies hat zur Folge, dass der Tumor sein Wachstum ungehindert fortsetzen kann, da die anti-Tumor-T-Zell-Antwort, die den Tumor normalerweise in seiner Expansion beeinträchtigt, gestört ist. Es wird somit festgestellt, dass eine Blockade der untersuchten Oberflächenmoleküle PDL-1 oder PDL-2 auf Tumorzellen eine wertvolle Option in der Immuntherapie des humanen kolorektalen Karzinoms darstellen könnte. Angesichts der diskutierten Tatsachen im Hinblick auf das Verhalten der regulatorischen T-Zellen in höheren Tumorstadien könnte sich eventuell eine Option damit eröffnen, die regulatorischen T-Zellen mittels eines spezifischen Antikörpers gegen PDL-1 und/oder PDL-2 zu beeinflussen, um somit die hemmenden Auswirkungen gegenüber der anti-Tumor-Immunantwort zu verhindern oder zu revidieren. / Summary Recent data have suggested that malignant tumors are able to escape from the immunological surveillance on a downregulation of the T cells via a PD-1 (programmed death 1) / PDL-1/PDL-2 signal. This obviously leads to a reduced immune response and thus may promote tumor growth. The surface molecule PD-1, which is expressed on T and B cells, myeloid cells and on many human carcinoma, belongs to the CD28 family, and PDL-1 (B7H1) and PDL-2 (B7DC) are ligands to PD-1. The CD28/B7 signal belongs to the group of costimulatory pathways, which is needed for a T-cell-directed immune response as a second costimulatory signal. In this work, the molecular expression of PD-1, PDL-1 and PDL-2, cytokines and T-cell-subpopulations was analyzed in tumor tissue of 81 patients, which have undergone a curative or palliative surgery (according UICC- stages I-IV) of a primary colorectal cancer. For the first time it was shown on the protein and molecular level, that PDL-1 and PDL-2 were significantly overexpressed in tumor tissue of advanced tumor stages (UICC III/IV), the expression of PD-1, on the other hand was decreased. PD-1 was much more detected on infiltrating CD4+ cells in patients of advanced tumor stages (UICC III/IV), while PDL-1 was found on CD4+ cells in the early stages. In comparison to the early stages (UICC I/II), a larger number of T cells with regulatory character in the tumor stage III/IV was observed. The latter would be an advantage for the tumor in relation to its progressive growth, because regulatory T cells are able to inhibit T-effector-cells. In tumor tissue the expression of IFN-gamma was also reduced, which among others activate T-effector-cells and thus reinforced an immune response. The cytokine IL-10, which is associated with regulatory T cells, but also with T-helper(Th)2-cells and tumor tissue, has antiinflammatory properties and was demonstrated enhanced at higher stages. Thus it gives the tumor a survival advantage. The observations in this study show that PDL-1 and PDL-2 plays a key role during tumor progression. Regulatory T cells are obviously involved in the process of immune response against the tumor. The significant PDL-1- and PDL-2-Expression on T-cells, particularly in the early stages of tumor suggests that the PD-1/PDL-1- or PD-1/PDL-2-interaction mediated inhibitory signals between tumor cells and the T-cell. In advanced stages (UICC III/IV) the costimulatory signals on T-cells were decreased. This means that the tumor's growth can continue unhindered, because the anti-tumor-T-cell-response which the tumor usually affected is disrupted in its expansion. It is thus found that a blockade of the investigated surface molecules PDL-1 and PDL-2 in tumor cells could be a valuable option in the immunotherapy of human colorectal cancer. Given the facts discussed in relation to the behavior of regulatory T cells in advanced tumor stages could possibly be an option to influence the regulatory T cells with a specific antibody against PDL-1 and / or PDL-2, thus to prevent or revise the inhibitory effects against the anti-tumor-immunresponse.

Made available in DSpace on 2018-08-01T23:58:53Z (GMT). No. of bitstreams: 1 tese_11421_Max Correia.pdf: 502543 bytes, checksum: 6da80bebbea69ca2c85187d546caf14e (MD5) Previous issue date: 2017-06-23 / Criado com intuito de ser um equipamento simples e versátil, devido à velocidade de execução e à possibilidade de ser facilmente transportado, o Penetrômetro Dinâmico Leve (PDL) é um ensaio geotécnico de campo utilizado no exterior há vários anos e que vem timidamente ganhando espaço no cenário nacional brasileiro. No entanto, apesar de alguns trabalhos publicados, esse método de investigação carece de mais pesquisas, principalmente correlacionando-o a ensaios clássicos, em que se pretenda, além de consolidar seus conceitos, buscar maior confiabilidade na sua utilização. Assim, neste trabalho, com a contribuição de algumas empresas da Região Metropolitana da Grande Vitória, no Espírito Santo, foram realizados ensaios de laboratório e de campo com objetivo de confrontar o PDL com outros ensaios. Em laboratório, com amostras de solos moldadas em cilindros metálicos, foram realizados os ensaios PDL, Cone Penetration Test Adaptado (CPTAD), Califórnia Bearing Ratio (CBR) e cisalhamento direto em dois materiais com caraterísticas distintas, para que a resistência de ponta do ensaio PDL pudesse ser confrontada e correlacionada com a resistência de ponta do CPTAD, Índice de suporte Califórnia e ângulo de atrito. As análises desses resultados consideraram diferentes condições de umidade e densidade dos solos. Para o levantamento em campo, realizaram-se campanhas de ensaios em áreas experimentais com características de solo selecionadas, onde foram executados os ensaios PDL e Standard Penetration Test (SPT), com locação dos furos devidamente aproximados. Os resultados foram correlacionados por meio de equações obtidas de regressões estatísticas. Em laboratório, a resistência de ponta do PDL apresentou resultados similares ao ensaio CPTAD e uma correlação muito boa com o CBR. Quanto ao cisalhamento direto, a pesquisa limitou-se pelo pequeno número de amostras, porém, apresentou compatibilidade razoável entre o PDL e o ângulo de atrito. Já os resultados de campo do PDL e SPT apresentaram boa concordância em alguns casos e nem tão boa em outros. Palavras-chave: Ensaios penetrométricos, Penetrômetro, PDL, CPT, SPT, CBR.

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Novel theoretical formulations and efficient simulation methods for polarization-mode dispersion (PMD) and polarization-dependent loss (PDL) that are directly applicable to optical network design are developed. In particular, a formalism based upon the Magnus expansion is advanced for the determination of the frequency evolution of the Mueller matrix in terms of increasing orders of PMD and PDL. Several previous models of polarization evolution are shown to be specializations of this more general formalism. A least-squares algorithm that extracts PMD and PDL coefficients from repeated measurements of the output Stokes vector of an optical system for a random set of input polarization states is introduced and subsequently applied to the rapid experimental determination of the probability density of the differential group delay of a fiber-squeezer based PMD emulator. The applicability of Clifford algebra and Pade-approximant techniques to the efficient simulation of the wavelength dependence of PMD and PDL is also discussed.

Novel theoretical formulations and efficient simulation methods for polarization-mode dispersion (PMD) and polarization-dependent loss (PDL) that are directly applicable to optical network design are developed. In particular, a formalism based upon the Magnus expansion is advanced for the determination of the frequency evolution of the Mueller matrix in terms of increasing orders of PMD and PDL. Several previous models of polarization evolution are shown to be specializations of this more general formalism. A least-squares algorithm that extracts PMD and PDL coefficients from repeated measurements of the output Stokes vector of an optical system for a random set of input polarization states is introduced and subsequently applied to the rapid experimental determination of the probability density of the differential group delay of a fiber-squeezer based PMD emulator. The applicability of Clifford algebra and Pade-approximant techniques to the efficient simulation of the wavelength dependence of PMD and PDL is also discussed.

This dissertation includes three issues, however, they are all adopted the view of firm¡¦s foreign exchange rate exposure to do the research. The main results of three topics as follows: In the first topic, this study uses the example of a Taiwanese firm investing in China and develops an exchange rate exposure model which depends on only four endogenous variables: the percentage of the firm¡¦s revenues denoted in the currency of trade country, the percentage of the firm¡¦s expenses denoted in the currency of trade country and third country, and its profit rate. The main issue in this research attempts to detect whether producing goods in the third country will affect a multinational firm on the exchange rate exposure and whether the currency manipulation will affect the decision of producing goods in the third country. This study finds that if a multinational firm can effectively adjust operational strategy and match foreign currency income with its cost, most of the exposure can be reduced. Besides this reducible effect of operational strategy, it is worth to note that diversified strategy just works under some conditions. For example, whether producing goods in the third country or not, the firm¡¦s exposure will not make changes as long as the currency is equal to its true value. However, under the case of currency manipulation, the firm producing goods in the third country can reduce exchange rate risk further. In the second topic, this paper studies the sensitivity of the cash flows generated by Chinese and Taiwanese firms to the movements in a trade-weighted exchange rate index, as well as to the currencies of their major trading partners. To overcome the deficiencies in previous researches using variations of the market-based model, this paper adopts the polynomial distributed lag (PDL) model to investigate the relative importance of transaction exposure versus economic exposure by decomposing exchange risk into short-term and long-term components. In contrast to the market-based model, we find that PDL model is better in detecting exposures with evidence confirmed both in China and Taiwan markets. Furthermore, our empirical results also verify past findings in Taiwan market that firms with higher foreign involvement have larger exchange rate exposure, firms with larger size have less exchange rate exposure, firms with larger exporting business are less exposed to the currency of primary exporting country, and firms with larger importing business are less exposed to the currency of primary importing country. However, these results are seldom agreed in China market. These findings imply that the exchange rate under the pegging regime and the floating system significantly affects firms in managing their exchange risk. In the third topic, it is generally argued that the choice of an appropriate exchange rate regime depends on which regime minimizes fluctuations in output, consumption, domestic price level, or some other macroeconomic variables. However, our study provides alternative analytic evidences on the firm-specific behavior. Using the real performance of operating income, this paper attempts to investigate the impact of fluctuating currencies on the values of U.S., Chinese, and Taiwanese companies. We find that the Chinese companies have more short-term exposures under the pegged regime, and the U.S. companies have more long-term exposures under the floating regime. Under the managed floating system, optimal lag length for Taiwanese companies is close to that of U.S. companies. However, the magnitude of exposure for Taiwanese companies is close to that of Chinese companies. These findings imply that the exchange rate under different exchange rate regimes significantly affects firms in managing their exchange risk.

Magíster en Ciencias, Mención Computación / Ingeniero Civil Matemático / Las bases de datos de grafos son un modelo que ha ganado terreno en los últimos años, dada la necesidad de modelar situaciones complejas en donde el modelo relacional no es suficiente. En este trabajo introducimos el tema haciendo una revisión del estado del arte de las bases de datos de grafos, explicando algunas de sus aplicaciones reales, definiendo algunos de los diferentes modelos teóricos y analizando las implementaciones más importantes que existen en la realidad. De nuestro análisis concluimos que la gran falencia en el tema es la ausencia de un lenguaje de consulta formal, con una sintaxis y semántica clara, y que tenga un buen equilibrio entre expresividad y complejidad. Nuestra propuesta para solucionar este problema es utilizar Converse-PDL como lenguaje de consulta de bases de datos de grafos, definiéndolo formalmente, y demostrando que su complejidad teórica es óptima. Además, mostramos que la expresividad de este lenguaje es suficiente para una gran cantidad de aplicaciones. Una vez definido nuestro lenguaje, procedemos a diseñar una implementación eficiente, definiendo los algoritmos y las estructuras de datos necesarias, cuidando de cumplir todas las restricciones que están presentes en nuestro modelo computacional. Luego, procedemos a realizar la implementación en sí, describiendo en detalle las representaciones internas de los distintos elementos, respaldando con resultados experimentales las decisiones tomadas. Además, explicamos las distintas mejoras y optimizaciones que realizamos, con el fin de obtener la mayor eficiencia posible. Una vez terminada la implementación, procedemos a explicar todos los archivos programados y la interfaz de usuario implementada, con el fin de facilitar los futuros desarrollos. Con el fin de validar nuestra implementación, procedemos a diseñar un experimento para evaluar cuantitativamente el desempeño de nuestra implementación. El experimento diseñado se ejecuta en nuestra implementación, así como en otras tres implementaciones existentes, escogiendo los proyectos más competitivos, para así realizar una comparación objetiva. Finalizamos nuestro trabajo con las conclusiones obtenidas a partir de los experimentos, destacando los aspectos más importantes de nuestra implementación, y exponiendo algunas ideas a desarrollar en el futuro.

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