In this master's thesis I deal with modelling and simulating of multicast routing protocol PIM Sparse Mode in OMNeT++. I also describe basic information about multicast, protocol PIM-SM, its configuration and multicast data streams visualization in computer networks. The thesis is especially focused on design and implementation of PIM-SM in OMNeT++ and extension of ANSAINET library.

Drug Interactions and potentially inappropriate medications at an oncology ward Objectives: this study aimed to quantify the prevalence of clinically significant interactions and potentially inappropriate medication (PIM) use through involving a pharmacist among the cancer patients at an oncology ward and an oncology day- unit. Materials and Methods: Prospective study in patients taking more than 5 drugs who had been admitted to Harzklinikum, Wernigerode, Germany between August 2016 and February 2017. The pharmacist conducts a complete comprehensive medication review including over-the-counter drugs and herbal medications. Besides, she took into consideration the intake of grapefruit juice. This information together with the information in the patient's medical history permits identifying critical drug-drug interactions using the mediQ interaction analysis program as well as PIMs using the Beers, Forta, Priscus and STOPP lists. Results: One hundred and eighty-five cancer patients (mean age ± SD = 70 ± 11 years) were included in the study. The interaction analysis program identified 177 potentially interactions. These interactions were evaluated by the pharmacist and 34 interactions for 31 patients (17 %) were considered clinically significant or critical. After the pharmacist interventions, these interactions were resolved in 51 percent. 123 patients aged over 65 years old were enrolled in the study for PIM. By using the four lists (Beers, Forta, Priscus, STOPP) 52 PIMs at 41 elderly persons (33%) were identifies. 11 recommendations in 10 elderly patients (8 %) were made by the pharmacist and result in 55 % of the cases in a prescription change. Conclusion: the use of an interaction analysis program and the lists of inappropriate medications allowed the pharmacist to identify clinically relevant interactions and PIMs and result in prescription change in agreement with the oncologist.

E-commerce has grown rapidly in the last couple of years and has gotten more demanding customers that want better and more consistent product information. With more products on the market than ever, spreadsheets are not enough. Product Information Management (PIM) systems have been developed to meet those needs. Because these systems contain a lot of different processes and handles a lot of data, they can be complex and contain usability problems. The purpose of the study is to understand and explain the usability of the PIM system process of enriching products. The study answers the research questions: “How do the users experience the usability in the process of enriching products in PIM systems?” and “What are the main usability problems in the enrichment process in an existing PIM system?”. The result shows that the overall usability in the enrichment process is good and the investigated PIM system is easy to use and is flexible. The analysis shows that the main usability problems are the lack of functionality and efficiency. The two problems are connected to each other as the users need to do workarounds because the lack of certain functions. The efficiency would be improved if the missing functions were added. These usability attributes can be difficult to evaluate before the system has been used for a while because it can take time for the users to discover problem regarding them.

Wachstumsfaktor bedingte Aktivierung des PI3K/Akt/mTOR Signalweg wirkt positiv auf Vermehrung und Überleben. Konstitutive Aktivierung des Signalweges in NHL ist jedoch an Tumorprogression und Therapieresistenz beteiligt. Am Zelllinienmodell wurden zwei mögliche Therapiestrategien der PI3K/Akt/mTOR Inhibition erprobt, PI3K Inhibition mit BKM120 und horizontale Kombination von Zytostatika mit PI3K/Akt/mTOR Inhibitoren Erstens, BKM120 hat Antitumoraktivität in NHL und induziert Zelltod. Auf molekularer Ebene führt BKM120 vermittelte Dephosphorylierung von CDK1 an Y15 zur Aktivierung des M-Phase Komplex CDK1/Zyklin B und Eintritt in die Mitose. Parallel erlaubt die Degradation von Zyklin A und Hochregulation von Zyklin B Progression bis zur Metaphase, hemmt jedoch die Transition in die Anaphase. Anhaltender Metaphasearrest bewirkt programmierten Zelltod über den intrinsischen Signalweg der Apoptose durch Hochregulation der BH3-onlys Puma und Hrk, Aktivierung von Bax/Bak und proteolytische Spaltung von Caspase 9. Verlust von Bax/Bak oder Caspase Inhibition schützt vor BKM120 vermitteltem Zelltod. Bax/Bak defiziente Zellen, welche zusätzlich p53 Mutationen aufweisen, werden polyploid. Die Polyploidie ist ATM-MEK1/2 abhängig und kann mit Caffeine oder U0126blockiert werden. Zur Vermeidung von Polyploidie bedingter Tumorprogression, sollte BKM120 nur in Verbindung mit MAPK/ATM Inhibitoren verwendet werden. Zweitens. Horizontale Kombination PI3K/Akt/mTOR Inhibitoren mit cytotoxischen Substanzen schützt vor Apoptose. Der Schutzeffekt tritt auschließlich bei niedrigen Konzentration auf und ist unabhängig von der Art des Inhibitors bzw. Ebene der Inhibition. Das Onkogen und NFkB Target Pim-2 ist möglicherweise am Schutzmechanismus beteiligt. Durch die PI3K/Akt/mTOR vermittelte Pim-2 Regulation ergibt sich eine neue Rückkopplungsschleife. Im Fazit erschwert die Komplexizität des PI3K/Akt/mTOR Signalweges die Etablierung von Therapien. / Growth factor mediated activation of the PI3K/Akt/mTOR pathway positively regulates proliferation and survival. Constitutive activation in NHL, however, is correlated with tumor progression and therapeutic resistance. Therefore, two possible strategies were tested in a cell line model system, Inhibition of PI3K with BKM120 and PI3K/Akt/mTOR Inhibition in addition to cytostatic drug administration. First, it is demonstrated that the pan PI3K inhibitor BKM120 has antitumor activity in NHL and induces cell death. On molecular level, BKM120 mediated dephosphorylation of CDK1 on Y15 causes activation of the M-phase complex CDK1/Cyclin B and entry into mitosis. In parallel, degradation of Cyclin A and Upregulation of Cyclin B enables progression into metaphase but inhibits transition into anaphase. Prolonged metaphase arrest induces programmed cell death via the intrinsic apoptosis pathway by upregulation of the BH3-onlys Puma and Hrk, activation of Bax/Bak and proteolytic cleavage of caspase-9. Loss of Bax/Bak or caspase inhibition protects from BKM120 induced apoptosis. Bax/Bak deficient cells with additional p53 mutation become polyploid. This polyploidy is ATM-MEK1/2 dependent and can be blocked with Caffeine or U0126. To prevent polyploidy related tumor progression, BKM120 should administered only in combination with ATM or MEK inhibitors. Second, combination of PI3K/Akt/mTOR inhibitors with cytotoxic agents protects from apoptosis. The protective effect is only detectable with low PI3K/Akt/mTOR inhibitor concentrations and independent of inhibitor type or cascade level. The oncogene and NFkB target is possibly involved in apoptosis protection and inhibition of NFkB neutralizes the protective effect. PI3K/Akt/mTOR mediated Pim-2 regulation reveals a new feedback loop within the pathway. In conclusion, the complexity of the PI3K/Akt/mTOR pathway impedes therapeutic targeting.

Made available in DSpace on 2015-04-22T22:10:16Z (GMT). No. of bitstreams: 1 Chul Gu Her.pdf: 4810480 bytes, checksum: cb2ef74020e3c4689e8e51e189818011 (MD5) Previous issue date: 2008-02-13 / A busca de competitividade para a sobrevivência de uma empresa dentro de um mercado apresenta diversos fatores determinantes, com variáveis internas e externas que podem resultar em uma seleção natural das empresas, especialmente daquelas que não estiverem preparadas com flexibilidade no gerenciamento e não tiverem uma política de redução de desperdício atrelado à busca de inovações tecnológicas e campanhas de aperfeiçoamentos da sua força de trabalho. Esta seleção natural pode ocorrer com a indicação da queda dos preços de um produto devido ao avanço de fatores tecnológicos. Uma empresa precisa estar atenta a estes avanços tecnológicos e necessita otimizar o seu gerenciamento a fim de identificar a variabilidade de fatores internos e externos do mercado. Uma empresa que se instale no Pólo Industrial de Manaus - PIM - sofre dificuldades nos dias de hoje devido ao alto custo da energia elétrica e ao decréscimo das vendas motivadas pela competição interna e também externa de outros países, o que a coloca em uma situação de risco, pois, além do alto custo de consumo dos suprimentos (energia elétrica, água, gás, óleo), estes suprimentos sofrem reajustes constantes, sufocando a empresa. O presente trabalho se refere a um estudo de caso no qual se avalia a eficiência de procedimentos na implantação de modelos de tomada de decisão em uma empresa do Pólo Industrial de Manaus. Especificamente analisa os esforços empreendidos por uma empresa do ramo cinescópio, no que se refere ao aumento de eficiência energética. A empresa em estudo conseguiu melhorar a eficiência energética através de várias tomadas de decisões e outras ações que demandaram recursos internos e externos, tendo como principal indicador de resultados o custo com relação direta à quantidade de peças. Este trabalho contribuiu para a diminuição do custo de energia tornando a empresa mais competitiva, conseguindo uma margem de economia com a energia elétrica, água, ar comprimido, ar condicionado e óleo, sem nenhum investimento, conseguindo ainda um aumento de faturamento anual que vem ocorrendo com a demanda de produção

Made available in DSpace on 2015-04-22T22:10:52Z (GMT). No. of bitstreams: 1 joel.pdf: 1373421 bytes, checksum: 9493a0d93e7c7b57b98f34a2d9660992 (MD5) Previous issue date: 2012-04-13 / Fundação de Amparo à Pesquisa do Estado do Amazonas / The transport infrastructure is essential to the socioeconomic development of a nation. In Brazil, the infrastructure is inefficient and does not meet the potential growth of its different regions. In the state of Amazonas, the situation is critical, because the peculiar characteristics of their climatic and environmental conditions hamper regional mobility. This directly impacts on the productive sector, as the main agent of economic development of the State, the Industrial Pole of Manaus - PIM suffers directly with the conditions of the modal area. The problems related to transport infrastructure are usually from poor management of financial resources and lack of appropriate tools for decision-making in public investments. In this sense, the use of tools that effectively assist the selection of public projects, can provide substantial improvements to society. This study aims to evaluate the applicability of fuzzy AHP model to support decision making in the selection of investment projects to the transportation infrastructure that meet the PIM. The method is based on a complex representation by a hierarchical structure, which consists of defining the main objective and decomposition of the system at different levels, enabling the visualization of the entire system and its components, being used mainly in the treatment the uncertainty and imprecision inherent in decision-making. With the satisfactory outcome of applicability, the AHP fuzzy proved consistently apply the PIM scenario where the uncertainties and inaccurate information are present, besides being a good communication tool between stakeholders. / A infraestrutura de transportes é essencial ao desenvolvimento socioeconômico de uma nação. No Brasil, a infraestrutura é ineficiente e não atende ao potencial crescimento de suas diferentes regiões. No estado do Amazonas, a situação é crítica, pois as características peculiares de suas condições climáticas e ambientais dificultam a mobilidade regional. Isso impacta diretamente no setor produtivo, já que o principal agente do desenvolvimento econômico do Estado, o Polo Industrial de Manaus PIM sofre diretamente com as condições dos modais da região. Os problemas relacionados à infraestrutura de transportes são normalmente oriundos da má gestão de recursos financeiros e à ausência de ferramentas apropriadas à tomada de decisão em investimentos públicos. Nesse sentido, o uso de ferramentas que auxiliem com eficácia a seleção de projetos públicos, pode propiciar melhorias substanciais para a sociedade. Este trabalho tem como objetivo avaliar a aplicabilidade do modelo AHP Fuzzy como suporte a tomada de decisão na seleção de projetos de investimentos para a infraestrutura de transporte que atendam ao PIM. O método tem como base a representação de um problema complexo por meio de uma estrutura hierárquica, que consiste da definição do objetivo principal e decomposição do sistema em vários níveis, possibilitando a visualização do sistema como um todo e seus componentes, sendo utilizado principalmente no tratamento da incerteza e imprecisão inerentes à tomada de decisões. Com o resultado satisfatório da aplicabilidade, o método AHP fuzzy mostrou-se aplicável de forma coerente ao cenário do PIM, onde as incertezas e informações imprecisas estão presentes, além de ser uma boa ferramenta de comunicação entre as partes interessadas.

Myc transcriptionally regulates genes involved in processes such as cell proliferation, metabolism, differentiation, and angiogenesis.  MYC expression is deregulated in many types of human cancer; therefore discovering the mechanisms behind MYCs role in tumorigenesis is essential.  In this dissertation, I have focused on several Myc target genes, Spermidine synthase (Srm); Lactate dehydrogenase (Ldh); 3-phosphoglycerate dehydrogenase (Phgdh); Serine hydroxymethyltransferase (SHMT) 1 and 2; and Pim-3 (a member of the Pim family of serine/threonine kinases).  These enzymes play a role in various functions: Spermidine synthase (polyamine synthesis); Lactate dehydrogenase (glycolysis); Phgdh and Shmt (serine metabolism); and Pim-3 (cell signaling).  In order to elucidate the impact Myc over-expression has on metabolism in tumorigenesis, we use human cell lines, and transgenic mice as well as cell lines and tissues derived from these mice.  The impact of inhibition of these target genes on Myc-driven tumorigenesis was done by genetically inhibiting the target gene (using RNAi or mouse models) or inhibiting the protein with a chemical inhibitor.  Investigating these Myc target genes will help determine if inhibition of Myc target genes is a viable approach for chemotherapeutics, and under what conditions this inhibition may be the most valuable.  In paper I, we examine SRM; a highly expressed enzyme in the polyamine synthesis pathway that converts putrescine to spermidine, and is important for actively growing cells.  Genetic inhibition via RNAi against Srm, or chemical inhibition of Srm, resulted in decreased proliferation of B-cell tumor lines from transgenic mice in vitro.  In vivo treatment of λ-Myc transgenic mice with a chemical SRM inhibitor exhibited a significant chemopreventative effect on tumor formation. These results support previous findings that inhibition of polyamine synthesis pathway enzymes has a place in cancer therapy.  Many Myc target genes have been suggested as attractive targets in battling Myc-driven tumorigenesis.  Surprisingly in paper II, when we analyzed the inhibition of other Myc target genes, such as Ldh, Shmt, and Phgdh, we found that inhibition of these genes did not inhibit Myc-driven tumorigenesis to any significant degree. However, inhibition of Ldh, Phgdh and Shmt2 had a notable effect on in vitro Ras-driven transformation.  These findings suggest that chemotherapeutic inhibition of metabolic genes such as Ldh, Phgdh and Shmt2 may be effective in genetically defined settings, keeping in mind the oncogenic lesion behind the tumor.  The Pim kinase family consists of three serine/threonine kinases, Pim1-3.  In paper III, we found that Pim-3 is a direct Myc target gene and that Pim-3 expression is high in Burkitt Lymphoma samples taken from human patients, as well as spontaneously arising lymphomas from Myc transgenic mice. We also found that inhibition of Pim-3 using a pan-Pim kinase inhibitor, Pimi, in these spontaneously arising Myc lymphomas resulted in caspase independent cell death.  These results indicate that Pim kinase inhibition may be a potential chemotherapeutic strategy in human lymphomas that rely on Pim-3 kinase expression.

La formation de cancers est liée à des dérèglements de la progression du cycle cellulaire ou de l’apoptose. L’identification des acteurs cellulaires mis en jeu dans la maladie et l’élucidation des mécanismes responsables de ces dysfonctionnements sont à la base de nouveaux traitements anticancéreux. Ainsi, en vue du développement de thérapies ciblées, les kinases Pim et les protéines anti-apoptotiques de la famille des Bcl-2, surexprimées dans de nombreux types de cancers et associées à des phénomènes de chimiorésistance, constituent des cibles pertinentes. Les kinases Pim (Pim-1,-2 et -3) sont une famille de sérine / thréonine kinases qui jouent un rôle fondamental dans les processus de survie, de prolifération ou de différenciation cellulaire. Bien qu’elles possèdent un substrat commun avec les autres protéines kinases, l’ATP, des différences structurales permettent de les différencier et de les inhiber sélectivement. En tenant compte de ces spécificités, nous nous sommes intéressés à la synthèse de nouveaux inhibiteurs sélectifs des kinases Pim, compétitifs de l’ATP. Parmi les autres agents impliqués dans la formation de tumeurs, les protéines de la famille des Bcl-2, responsables du phénomène d’apoptose ou mort cellulaire programmée, font l’objet d’un domaine d’étude récent. Elles se classent en deux familles selon leur fonction : les protéines pro-apoptotiques et les protéines anti-apoptotiques dont la surexpression est observée dans de nombreux cancers. Nous avons poursuivi l’étude de relations structure-activité initiée au laboratoire à partir de trimères d’alkoxyquinoléines, inhibiteurs micromolaires des protéines anti-apoptotiques Bcl-2 et Bcl-xL, en préparant de nouveaux analogues. / Cancer development is associated with dysfunctions in cell cycle progression or apoptosis. The identification of cellular agents involved in this disease, and the elucidation of mechanisms responsible for these dysfunctions provide the basis for the development of novel anti-cancer drugs.Thus, Pim kinases and Bcl-2 anti-apoptotic proteins which are overexpressed in many malignancies and contribute significantly to chemoresistance are of great interest for the development of targeted cancer therapy. Pim kinases (Pim-1,-2 and -3) belong to a family of serine / threonine kinases which play a key role in cell survival, proliferation and differenciation. Although all protein kinases share ATP as a common substrate, the structure of the ATP-binding pocket of Pim kinases is unique and offers an opportunity for a selective inhibition. Taking account of these specificities, we were interested in the synthesis of novel selective ATP competitive Pim kinase inhibitors. Among the other agents involved in tumorigenesis, Bcl-2 family proteins, which govern apoptosis (or programmed cell death), are subject of a recent interest. These proteins are divided in two classes depending on their function : pro-apoptotic and anti-apoptotic members that are overexpressed in a variety of cancers. In a preliminary work in the laboratory, alkoxyquinoline trimers have demonstrated micromolar inhibition against antiapoptotic proteins Bcl-2 and Bcl-xL. Therefore, we carried on this structure-activity relationship study with the synthesis of novel analogues.

L’inhibition de protéines kinases constitue une voie pleine de promesses pour la découverte de nouvelles thérapies ciblées contre le cancer. En 2003, le criblage de la chimiothèque de l’Institut Curie/CNRS a permis de mettre en évidence une famille de composés actifs sur deux de ces enzymes : CK2 et Pim-1. L’objectif de cette thèse était de synthétiser des analogues des « hits » de la chimiothèque possédant le squelette 5-azaindole afin d’en améliorer les propriétés biologiques. La préparation de tels composés étant peu décrite dans la littérature, trois voies de synthèse flexibles et efficaces ont été développées. L’élaboration de 5-azaindoles diarylés symétriques a tout d’abord été mise au point par hétéroannélation pallado-catalysée à partir de dérivés de la 4-aminopyridine. Les composés monosubstitués en position 2 ont ensuite été obtenus par réaction domino sila-Sonogashira/cyclisation 5-endo. Enfin, un procédé one-pot couplage de Sonogashira/aminopalladation/élimination réductrice a permis d’accéder aux molécules diarylées non symétriques avec une régiosélectivité contrôlée. L’application de ces méthodologies a conduit à la préparation de 70 composés fonctionnalisés dont la cytotoxicité et l’activité inhibitrice sur CK2 ont été évaluées. Une étude structure-activité a été réalisée et les fragments d’intérêt que doit posséder une molécule de type 5-azaindole pour inhiber efficacement la kinase ont ainsi été identifiés. / Protein kinases represent promising targets for anti-cancer drug design. In 2003, inhibitors of two of these enzymes, CK2 and Pim-1, were identified by the screening of the Curie Institute/CNRS small-molecule library. The aim of this thesis was to synthesize derivatives of these hits with a 5-azaindole scaffold in order to optimize their biological activity. As the synthesis of such molecules was not reported in the literature, efficient and flexible procedures were developed to access to these structures. Diarylated symmetrical 5-azaindoles were thus prepared by palladium-catalyzed heteroannulation from 4-aminopyridines derivatives. The methodology was subsequently extended to silylalkynes and led to monoarylated products through domino sila-Sonogashira/5-endo cyclization. Finally, a one-pot Sonogashira coupling/aminopalladation/reductive elimination afforded unsymmetrical compounds with a total control of the regioselectivity. Using these methodologies, 70 functionalized molecules were easily prepared. Their cytotoxicity and biological activity as CK2 inhibitors were then evaluated. A structure-activity relationship study was performed, which led to the identification of two key structural elements for the CK2 inhibitory potency of 5-azaindoles.

The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type protein's ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases.