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Litschka, Michael, Michaela Suske y Roman Brandtweiner. "Decision Criteria in Ethical Dilemma Situations: Empirical Examples from Austrian Managers". Springer, 2011. http://dx.doi.org/10.1007/s10551-011-0922-x.
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This paper is the result of an empirical research project analysing the decision behaviour of
Austrian managers in ethical dilemma situations. While neoclassical economic theory would
suggest a pure economic rational basis for management decisions, the empirical study
conducted by the authors put other concepts to a test, thereby analysing their importance for
managerial decision making: specific notions of fairness, reciprocal altruism, and
commitment. After reviewing some of the theoretical literature dealing with such notions, the
paper shows the results of an online survey working with scenarios depicting ethical dilemma
situations. By judging such scenarios the respondents showed their preference for the named
concepts, though with different degrees of confirmation.
The results (with all limitations of an online survey in mind) support the theoretical work on
the named concepts: Fairness elements (including Rawlsian principles of justice and an
understanding of fairness as conceived by a reference transaction) play a major part in
management decisions in ethical dilemma situations. Also, commitment as a behaviour that
sticks to rules even if personal welfare is negatively touched, and reciprocal altruism as a
cooperative behaviour that expects a reciprocal beneficial action from other persons have
been concepts used by Austrian managers when analysing ethical dilemmas. The article also
tries to put the results into a comparative perspective by taking into account other studies on
ethical decision factors conducted with e.g. medical doctors or journalists, and by discussing
intercultural implications of business ethics.
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Swart, Pieter Jacob. "Bioanalysis and pharmacokinetics of the dopamine D2 agonist N-0923". [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 1992. http://irs.ub.rug.nl/ppn/292732996.
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Schneider, Martin. "Crossmedia-Management". Wiesbaden : Deutscher Universitäts-Verlag, 2007. http://sfx.metabib.ch:9003/sfx_locater?sid=ALEPH:DSV01&genre=book&isbn=978-3-8350-0922-6&id=doi:10.1007/978-3-8350-5484-4.
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Sandu-Dediu, Valentina. "Costin Moisil, Geniu românesc vs. tradiţie bizantină. Imaginea cântării bisericeş, ti în muzicologia românească [Rumänischer Genius versus byzantinische Tradition. Das Image des Kirchengesangs in der rumänischen Musikwissenschaft], Bucureşti: Editura Muzicală 2016, 191 S., rumänisch, ISBN 978-973-42-0922-4. Nicolae Gheorghiţă, Musical Crossroads. Church Chants and Brass Bands at the Gates of the Orient, Bucharest [Bucureşti]: Editura Musicală, 2015, 259 S., englisch, ISBN 978-973-42-0891-3 [Rzension]". Internationale Arbeitsgemeinschaft für die Musikgeschichte in Mittel- und Osteuropa an der Universität Leipzig, 2016. https://ul.qucosa.de/id/qucosa%3A16199.
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Die musikwissenschaftliche Auseinandersetzung mit der psalmodischen Musik, die bis 1990 etwas undifferenziert als ‚Byzantinologie‘ bezeichnet wurde, nahm an Klarheit und Raffinesse zu, so dass man heute von einer regelrechten ‚byzantinischen Musikologie‘ sprechen kann.
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Mappes, Martina. "Polarization vision behavioral studies in tethered flying desert locusts, Schistocerca gregaria = Polarisationssehen /". [S.l.] : [s.n.], 2006. http://archiv.ub.uni-marburg.de/diss/z2006/0902.
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Sarpe-Tudoran, Cristina [Verfasser]. "Adsorption of element 112 on a Au-surface / Cristina Sarpe-Tudoran". Kassel : Kassel Univ. Press, 2004. http://nbn-resolving.de/urn:nbn:de:0002-0920.
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Römer, Dirk. "Grundlagenuntersuchungen zur elektrochemischen Remediation von schwermetallkontaminierten Boden- /Sediment- Wassersystemen am Beispiel von Uran, Chrom, Arsen und Chlorbenzen". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2005. http://nbn-resolving.de/urn:nbn:de:swb:14-1109837957299-09232.
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In den 80-iger Jahren war die DDR hinter den USA und Kanada der drittgrößte Uranproduzent mit einer Jahresproduktion von ca. 200.000 Tonnen. Die Gewinnung erfolgte durch konventionellen Bergbau, durch in- situ- oder offene Haufenlagerung. Die Urangewinnung auf dem Territorium der ehemaligen DDR wurde nach der Wiedervereinigung eingestellt und mit der Sanierung der Altstandorte begonnen. Nach Einstellung des Uranabbaus muss die Wasserhaltung solange betrieben werden, bis eine kontrollierte Flutung der Bergbauschächte erfolgen kann. Die dabei anfallenden Grubenwässer werden je nach Schadstoffkonzentration direkt in den Vorfluter abgeleitet oder in geeigneten Aufbereitungsanlagen meist durch Flockung und Adsorption behandelt. Dieses praktisch oft angewandte Grubenwasserreinigungsverfahren bezüglich Uran und den auftretenden Begleitelementen Chrom und Arsen hat den entscheidenden Nachteil, dass die anfallenden schwermetallhaltigen Fällschlämme auf Deponien verbracht werden müssen. Durch Niederschlagsereignisse oder ansteigendes Grundwasser besteht die Gefahr, dass die Deponien wieder ausgelaugt werden und somit eine erneute Mobilisierung von Schwermetallen in die Umwelt erfolgt. Die Sanierung kontaminierter Gebiete, insbesondere Sedimente, Sondermüll-deponien, Standorte ehemaliger Galvanikbetriebe, Betriebsflächen chemischer Industriestandorte, Rieselfelder oder Orte der Klärschlammaufbereitung erfordern neue Herangehensweisen an das gegenwärtig hochaktuelle Problem der Rehabilitation. Es wurde deshalb u.a. im Rahmen dieser Arbeit ein Konzept auf Grundlage der elektrochemischen Umsetzung im "verdünnten" elektrochemischen Festbettreaktor entwickelt, das es gestattet, die mobilen Schwermetallspezies im Boden bzw. Deponiekörper in immobile Schwermetallverbindungen umzuwandeln. Damit kann die Nachsorge und Sicherung solcher Deponiekörper bezüglich einer Remobilisierung wesentlich kostengünstiger gestaltet werden. Ausgehend von diesem Konzept sollen Möglichkeiten, Einsatzbedingungen und -grenzen der Immobilisierung von Schwermetallen am Beispiel von Uran(VI), Chrom(VI), Arsen(III) und chlorierten Kohlenwasserstoffe aufgezeigt werden. Elektrochemische Verfahren zur Sanierung kontaminierter Böden, Schlämme und Sedimente befinden sich international in einer dynamischen Forschungs- und Entwicklungsphase. Sie sind einzeln und in Verfahrenskombinationen einsetzbar und werden, bei verantwortungsvoller Handhabung, in absehbarer Zeit auch als zertifizierte Verfahren in Deutschland in bestimmten Sanierungsvorhaben ihre Leistungsfähigkeit beweisen. Gegenwärtig befinden sie sich in Deutschland noch im Stadium der Forschung und Entwicklung, während international (z.B. USA, Niederlande) schon kommerzielle Anwendungen angeboten werden. Zur objektiven Beurteilung ihrer Leistungsfähigkeit und Einsatzgrenzen bedarf es spezieller Grundkenntnisse. Elektrochemische Remediationsverfahren können als ergänzende, in Einzelfällen auch als alternative Verfahren zur Sediment- und Bodensanierung angesehen werden. Sie haben dann eine Chance auf Einsatz, wenn vor Ort (in- situ) saniert werden soll. Von ihrem Prinzip her, sind sie preiswerter als Bodenaushub und Verbrennung. Das Sanierungsziel besteht in einer möglichst vollständigen Konzentrierung oder Umsetzung der Wasserschadstoffe an der Feststoffmatrix.
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Mee, Edward. "Manipulation of the immune response to malaria antigens using bacterial-derived lipoproteins". Thesis, University of Oxford, 2004. http://ora.ox.ac.uk/objects/uuid:c98c8f59-092d-482c-b159-6033b9844908.
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Wu, Nicolas. "Generative templates for formal metamodel design". Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:c6b38d2e-0923-4a9b-a4eb-74c6638fd26a.
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Hilton, Catriona. "MicroRNA-196a in human adipose tissue". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:a1a7a7a6-09a2-422f-b900-e133004193da.
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MicroRNAs are small non-coding RNAs that have been shown to play a role in adipose tissue biology. Adipose tissue depots differ in terms of the metabolic risk that they confer. Therefore, I aimed to identify microRNAs which regulate body fat distribution. An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being more highly expressed in gluteal adipose tissue. These expression patterns were retained in primary and immortalised pre-adipocytes from abdominal subcutaneous and gluteal adipose tissue. The precursor of miR-196a contains a single nucleotide polymorphism, rs11614913. Genotyping was performed on 5,823 individuals from the Oxford Biobank and combined with detailed information on body composition by DXA scanning and miR-196a expression determination in fat biopsies. This revealed that the rs11614913 TT genotype was associated with a 32% reduction in miR-196a expression in abdominal subcutaneous adipose tissue (p=0.002), an expansion in waist-to-hip ratio and an increase in mean adipocyte size in abdominal subcutaneous adipose tissue in males. RS11614913 was also found to be associated with bone mineral density, and the relationship between bone mineral density and body fat distribution was explored using the Oxford Biobank. To establish a functional role for miR-196a, the Pt2 abdominal and gluteal cell lines were validated as models for pre-adipocyte proliferation and adipogenesis. MiR-196aKO pre-adipocyte cell lines were generated. MiR-196aKO was found to reduce proliferation in abdominal subcutaneous (p=0.002) and gluteal (p=0.002) pre-adipocytes, with no effect in adipogenesis. In addition, transcriptomic profiling of miR-196aKO pre-adipocytes revealed enrichment for GO term clusters related to extracellular matrix and angiogenesis, suggesting a mechanism by which miR-196a might regulate regional adipose tissue expansion.
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Ablay, Giray Jan. "Evolution of the Teide-Pico Viejo volcanic complex and magmatic system, Tenerife, Canary Islands". Thesis, University of Bristol, 1997. http://hdl.handle.net/1983/34b7cffc-09b2-4fc7-8f8b-f331abccd9ad.
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Reid, John Nicholas. "Slavery in early Mesopotamia from Late Uruk until the fall of Babylon in the Longue Durée". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:a693cd93-092e-4118-ae02-b9775bc2285e.
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This dissertation looks at slavery in early Mesopotamia (ca. 3200-1595 BC) in the longue durée and establishes theoretical foundations for interpreting the data preserved in the extant sources. Rather than attempting to define slavery, the forms the social institution took from proto-history into the historical era of early Mesopotamia are contextualised, while identifying the broader social changes which might explain the non-linear evolution of the practice. After considering the difficulty of defining the term ‘slave’ in relation to early Mesopotamia in general and numerous attempts to approach the problem, this work moves beyond definition, attempting to historicise slavery. To achieve this, slavery in early Mesopotamia is considered in the high points of the record in relation to key diagnostic features. The acquisition of slaves is studied alongside the release of slaves, demonstrating the numerous ways people in early Mesopotamia could be reduced to some form of bondage or slavery, while there remained relatively few means by which a person could experience upward movement out of slavery, opportunities which were reduced further for foreign and houseborn slaves. The following discussion of the economics of slavery seeks to place the question in an historical context of modern scholarship before assessing the motivations, benefits, and risks of owning slaves in early Mesopotamia. After this chapter which looks at slavery from the perspectives of the elite, the subsequent chapter attempts to move beyond the elite bias of the documentation to understand history from the bottom, by studying flight and the related means of coercion. By considering the ways in which runaways were pursued and the risks members of the lower stratum community were willing to take for a change in status, the discussion presents a way forward to understanding slavery in early Mesopotamia. These diagnostic features of slavery reveal a traceable non-linear evolution of slavery in early Mesopotamia.
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Duran, De Ortiz Emperatriz. "“Fortalecimiento del valor del respeto en la I. E. I. n° 092 de Simbilá para mejorar la convivencia escolar”". Bachelor's thesis, Pontificia Universidad Católica del Perú, 2018. http://tesis.pucp.edu.pe/repositorio/handle/123456789/11119.
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La buena práctica del respeto como valor principal en las relaciones interpersonales entre los actores educativos de la IE 092 del caserío Simbilá, es importante para mejorar sus actitudes de respeto ejecutando diferentes actividades estrategias y proyectos vivenciales donde se involucraron todos los actores educativos medios de comunicación y demás aliados así mismo se desarrolló un proceso de diversificación curricular con un enfoque de cultura de valores con sesiones de aprendizaje para desarrollar fortalecer y vivenciar el valor del respeto implementándose talleres y proyectos vivenciales marchas de sensibilización semblanzas y fotografía viva de paradigmas se construyeron y establecieron entornos motivadores y ordenados tanto dentro como fuera del aula ,murales y afiches banderolas ,el éxito de esta Buena Práctica se debió al buen clima armónico a una comunicación afectuosa abierta respetuosa asertiva y empática con una escucha activa y un trabajo colaborativo y en equipo asumiendo y cumpliendo compromisos tomando en cuenta los sustentos teóricos y líneas temáticas como el Valor del Respeto Convivencia Escolar ,Habilidades Personales Normas de Convivencia Cultura de valores ayudándome a mejorar mi gestión escolar y fortalecer mi liderazgo pedagógico fortaleciendo mis competencias y desempeños para tomar decisiones pertinentes finalmente logramos sensibilizar y concientizar a los padres de familia estudiantes docentes directivos y comunidad que con las buenas prácticas de actitudes donde se fomente y practique el respeto se favorece una buena convivencia escolar en bien de los logros de la mejora de los aprendizajes de los estudiantes y el cumplimientos de los compromisos de gestión escolar en la institución educativa N° 092.Trabajo académico
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Mavroidis, Panayiotis. "Determination and use of radiobiological response parameters in radiation therapy optimization /". Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-7349-092-X/.
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Holmgren, Carl. "Neocortical layer 2/3 microcircuits /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-092-3/.
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Wong, Alfred T. C. "Precipitation behaviour of calcium phosphate : a model for hard tissue mineralisation". Thesis, University of Oxford, 1993. http://ora.ox.ac.uk/objects/uuid:1d2e879d-0972-40ee-a931-664f5f043667.
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Various aspects of the precipitation behaviour of calcium phosphate in aqueous media have been investigated using seeded growth in conjuction with constant-volume and constant-composition techniques under different physical and chemical conditions. In each case, precipitation was allowed to proceed for up to seven days. The solid precipitates thus obtained were characterised by means of scanning electron microscopy, powder X-ray diffractometry and wavelength dispersive spectroscopy. During these precipitation experiments, the formation of the thermodynamically most stable and most supersaturated phase was invariably preceded by the appearance of less supersaturated precursor phase(s). These precursors subsequently underwent step-wise phase transformation into more stable phases. The preferred precursor and the rates of precipitation and phase transformation were dependent on the physical conditions and the chemical composition of the calcifying medium. Under physiological conditions, precipitation experiments were also carried out with the addition of certain non-collagenous bone-specific bio-chemicals. Phosphoserine dramatically accelerated the precipitation of a large quantity of small plate-like crystals, while osteonectin and phosphatidylserine induced the formation of quasi-cubic crystals at a slow rate. Bone protein extract displayed the strongest inhibitory effect on calcification. Bovine serum albumin showed signs of being irreversibly adsorbed to the crystal surface, thereupon inducing a high degree of calcium deficiency in the precipitate stoichiometry. Using a number of phosphorylated amino acids of different molecular masses, it was found that the processes of precipitation and phase transformation were facilitated by organic molecules whose phosphoryl functional groups were sterically accessible and highly electronegative. However, the acceleration brought about by the presence of a phosphorylated amino acid was maximised at an optimum concentration. The existence of such an optimum was very likely to be consequent of the competition for free calcium ions by the ongoing complexation and precipitation reactions. A model has also been developed to describe and predict the precipitation behaviour of calcium phosphate. The model is based on the Avrami-Johnson-Mehl expression for threedimensional nucleation and growth processes. Appropriate modifications to the original equation have been made, in order to adapt to this multi-ionic aqueous system. The resulting model has been found to describe the actual precipitation process accurately. It has also been applied to systems in which organic additives were present, and has again furnished predictions closely resembling the behaviour as observed experimentally.
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Tansey, Oisín. "Democratic regime-building : democratisation in the context of international administration". Thesis, University of Oxford, 2007. http://ora.ox.ac.uk/objects/uuid:2fc9be17-09c2-4b7a-97ad-e6ee79ae3c06.
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This thesis examines democratic transitions that occur in the context of international administration, where international actors not only provide assistance and guidance regarding domestic development, but also hold temporary executive authority over some or all of the functions of government. It argues that the process of regime change in the context of international administration is systematically different from more conventional settings, where such extensive international intervention is absent. The theoretical framework of the thesis suggests that the most significant impact of international administration derives from the fact that external actors assume roles conventionally held by domestic actors, and thus have available to them extensive mechanisms of influence at the domestic level. International agents can favour some local elites over others, structure the political environment through agenda-setting and veto powers, and ultimately bypass local actors if deemed necessary by drafting and imposing laws and institutions. As a result, the presence of international administrators heavily shapes the final mode of transition, and one of the most significant implications of the external influence is that purely non-democratic regime outcomes are unlikely to emerge. However, the influences of international administration are not always positive, and neither are they constant across contexts. The final impact on the transition process itself will depend in large part on the nature of the domestic political landscape, and in particular the balance of power and ideology among the domestic political parties. When domestic elites are favourable to democracy, international administrations can work with local actors to co-author a new democratic regime through a pacted transition. When dominant local parties are opposed to democratic development, however, the international and domestic interaction may contribute to a more conflicrual and contentious mode of transition entailing elements of international imposition. The nature of the transition mode will, in turn, have implications for post-transition regime consolidation. These findings are based on a structured, focused comparison of three cases, those of Bosnia, Kosovo and East Timor. In attempting to isolate the international influence, the case studies utilise the process tracing method to identify the causal mechanisms that connect international actions to democratic political outcomes, and the experiences in each case are compared to facilitate the generation of bounded generalisations about the impact of international administration on the processes of regime change.
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Florence, Margaret Mary. "Migration Stimulating Factor : the search for inhibitors". Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/20738022-0982-4ec5-ade3-3cdf8e5beed3.
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The oncofetal protein Migration Stimulating Factor (MSF) is a truncated isoform of human fibronectin which exhibits numerous bioactivities that are pertinent to cancer progression. The MSF protein (70kDa) has potent motogenic activity, with only femtomolar concentrations required to produce half-maximal. The proteolytic degradation of MSF generates the functionally equivalent 43kDa Gel-BD domain and 21kDa IGD peptide. The screening of conditioned medium (CM) for bioactivity revealed two sources of MSF-inhibitory (MSF-I) activity; the spontaneously immortalised human keratinocyte cell line (HaCaT) and endothelial cells (ENDO 742) specifically when exhibiting a cobblestone phenotype. The CM from the HaCaT keratinocyte line was fractionated by both molecular weight and ionic charge, followed by sequence analysis which identified the inhibitor as Neutrophil Gelatinase Associated Lipocalin (NGAL). Both recombinant and cell-produced NGAL neutralise the motogenic activity of MSF. This novel bioactivity for NGAL is not dependent on its iron transportation capability or direct binding to MSF. HaCaT cells also secrete MSF; the bioactivity of which is masked by the co-expression of NGAL. The relative expression levels of the pro- and anti-motogenic factors, MSF and NGAL, were assessed using an in vitro model for human skin carcinogenesis, the HaCaT –ras clones. The shift in tumorigenic potential from benign to metastatic was characterised by a decrease in NGAL and an increase in MSF expression, indicating their potential role in tumour progression. The protein responsible for the MSF inhibitory activity is cell- type specific; NGAL is not expressed by endothelial cells in vitro. MSF stimulates the generation of sprouting endothelial cells from a cobblestone monolayer and acts a survival factor for spontaneously sprouting cells within a 3D matrix. NGAL does not selectively the target sprouting phenotype of endothelial cells, but induces apoptosis in all endothelial cells. Fractionation of endothelial CM revealed that both sprouting and cobblestone cells express bioactive MSF and a MSF-I. Endothelial MSF-I was located in fractions of MW 70kDa, 40kDa and =25kDa; further investigation is required to identify the protein responsible.
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Ostendorff, Daniel A. "Militancy, moderation, & Mau Mau". Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:0cf867ef-09c2-41bf-8b9a-36d2e1e0c26c.
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This thesis examines the lives of Senior Chief Koinange wa Mbiyu and his eldest son, Peter Mbiyu Koinange. It joins with the growing rise of biographical work within African Studies. It challenges the historical understanding of late colonial rule in Kenya and the role of official myth in pre- and post-independence historical narratives. Koinange wa Mbiyu was the patriarch of one of the most respected, wealthy, and politically influential Kikuyu families of Kenya's colonial and post-colonial period. His eldest son, Peter Mbiyu, received a prestigious education abroad and returned to Kenya where he became a prominent leader for African independent education African political action. Koinange and Peter bear frequent mention in academic discussions of collaboration, discontent, nationalism, and militancy in Kenya's colonial era. This thesis challenges the widely held narrative that Koinange and Peter embraced militant politics opposing colonial rule during the 1940s. While fitting larger understandings of decolonisation, it is not an honest depiction of the Koinange's political actions. As a result, this thesis is intentionally a work of revisionist history that looks to the profound changes in the culture and nature of colinal rule during the 1940s, rather than a political shift in the Koinanges. In addition to challenging the prevalent understanding of Koinange and Peter's political action, this thesis raises a number of areas - gender, wealth, elite and family dynamics, to name a few - where the Koinange family history would further illuminate the historical understanding of the colonial era. This thesis is a dual biography, crafted as a work of narrative history. It challenges a breadth of current scholarship, utilizing the largest collection of pre-Mau Mau archival records to date. This thesis engages with a number of historiographical challenges related to biography, the individual, the family, and the challenges of oral history shaped in the crucible of cultural crisis.
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Ollivry, Florence. "Louis Massignon et la mystique musulmane : analyse historiographique, méthodologique et réflexive d’une contribution à l’islamologie". Thesis, Paris Sciences et Lettres (ComUE), 2019. http://www.theses.fr/2019PSLEP051.
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Née d’un questionnement épistémologique sur la manière dont les concepts véhiculés par la recherche découpent le réel et sur la place de la subjectivité en sciences des religions, cette thèse analyse la vision de la mystique musulmane selon Louis Massignon (1883-1962). Elle met en lumière la posture herméneutique de ce chercheur qui, après avoir démontré l’origine qur’anique du soufisme, fait de la figure d’al-Mansûr b. Hallâj (m. 309/922), le paradigme de la sainteté en islâm. L’analyse montre que sa vision de la réalité étudiée est tributaire de sa propre spiritualité : il perçoit la mystique authentique comme une voie d’ascèse, de purification par la souffrance. Au cœur de l’union mystique, le mystique devient le témoin de Dieu. A cette voie, il oppose celle d’Ibn 'Arabî (m. 638/1240) et perçoit l’influence du néoplatonisme comme une altération de la pureté ascétique primitive. La voie la plus pure est une mystique de l’annihilation (fanâ') au sein de laquelle l’être humain serait indigne d’endosser les attributs divins et de connaître l’état de subsistance (baqâ'). Sa quête, mue par des questionnements existentiels, illustre la difficile conciliation entre la quête du vrai et la quête de la Vérité. Cette étude montre combien la subjectivité du ou de la chercheur.e sert la recherche et l’entrave à la fois. Elle suggère, afin de construire les conditions du comprendre qu’il importe de prendre conscience de la particularité de sa posture herméneutique, d’énoncer son intention, d’interroger ses catégories conceptuelles, de maintenir une distance critique à son sujet, de réfléchir sur sa pratique, afin que la subjectivité ne déforme pas le réel, mais l’éclaire et le révèleBorn from epistemological questions about the way in which the concepts conveyed by research cut out the real and about the place of subjectivity in the academic study of religion, this thesis analyzes Louis Massignon’s (1883-1962) vision of Muslim mysticism. It highlights in particular the hermeneutic posture of this researcher who, after having demonstrated the Qur’anic origin of Sufism, makes the figure of al-Mansûr b. Hallâj (d. 309/922) the paradigm of holiness in Islâm. The analysis shows that his vision of the studied reality depends on his own spirituality: he perceives authentic mysticism as a path of asceticism, of purification through suffering. At the heart of the mystical union, the mystic becomes the witness of God. To this path, he opposes that of Ibn 'Arabî (d.638/1240), in which he perceives the influence of Neoplatonism as an alteration of primitive ascetic purity. The purest mysticism is, in his eyes, a mysticism of annihilation (fanâ') in which the inconsistency of the human being renders them unworthy to endorse the divine attributes and to know the state of subsistence (baqâ'). His quest, driven by existential questioning, illustrates the difficult reconciliation between the quest for “truth” and the quest for “Truth”. This study shows the extent to which the researcher’s subjectivity supports research and hinders it at the same time. It suggests, in order to construct the conditions of understanding, that it is important to become aware of the peculiarity of one’s hermeneutical situation, to state one’s intention, to question one’s conceptual categories, to maintain a critical distance from one’s work, and to wonder about one’s practice in a reflexive way, so that subjectivity no longer deforms reality, but illuminates and reveals it
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Pinto, Rosemeire Rocha. "O profissional da informacao em Ciencias da Saude: subsidios para o desenvolvimento de cursos de capacitacao no Brasil". Sao Paulo : [s.n.], 2005. http://lildbi.bireme.br/lildbi/docsonline/lilacs/092-TeseMestRose2005.pdf.
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Wong, Karrie. "CD200: A Novel Therapeutic Target for Chronic Lymphocytic Leukemia". Thesis, 2012. http://hdl.handle.net/1807/34969.
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The ability of cancer cells to escape anti-tumor immune responses is acknowledged as one of the hallmarks of cancer. Overexpression of immunoregulatory molecules is one mechanism responsible for the immunsuppressive network that is characteristic of the tumor microenvironment.
In this thesis, we investigated the role of CD200, a potent immunoregulatory molecule, in Chronic Lymphocytic Leukemia. We showed that functional blockade of CD200 on lymphoma cells or primary CLL cells, both of which express CD200 at high levels, augmented cytotoxic killing of these cells by effector CD8+ T cells in vitro. We also identified and characterized a previously unrecognized soluble form of CD200, sCD200, present in elevated levels in CLL plasma when compared to plasma from controls.
The data reported show that patients with high sCD200 levels have more aggressive disease, inferring that sCD200 may be a novel prognostic marker for CLL. The in vivo function of sCD200 was investigated for its ability to support engraftment of CLL splenocytes in NOD.SCID mice. Infusion of sCD200hi CLL plasma, but not sCD200lo normal plasma, enhanced engraftment of CLL-splenocytes in vivo, an effect which was abrogated by depletion of sCD200 from CLL plasma. The prolonged engraftment of CLL cells seen in this model (>6 months) suggests these mice represent a useful pre-clinical model for drug screening. The effect of CD200 blockade was tested in this model, and was found to be as effective in eliminating engrafted CLL cells as rituximab. Investigation of the mechanisms leading to the release of sCD200 from CLL cells showed that sCD200 was produced following ectodomain shedding by ADAM proteases and MMPs.
Results from studies reported in this thesis support the hypothesis that CD200 plays a major role in CLL biology, and suggests it may represent a novel therapeutic target for CLL.
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Perova, Tatiana. "Characterization of Signal Transduction Abnormalities Revealed Spleen Tyrosine Kinase as a Therapeutic Target in High-risk Precursor B Cell Acute Lymphoblastic Leukemia". Thesis, 2013. http://hdl.handle.net/1807/65500.
Texto completoResumen
Currently, the intensive chemotherapy remains the first line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although these regimens have significantly improved patient outcomes, their use is associated with debilitating morbidities and fatal relapses, highlighting the great need in new agents that target essential survival signals in leukemia. Thus, the overall goal of my project was to gain insights into the signaling abnormalities that regulate aberrant proliferation and survival of B-ALL cells in an effort to identify novel targets in this malignancy.
This study demonstrated that pre-B cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) activity was required for the survival and proliferation of a p53-/-PrkdcSCID/SCID mouse model of B-ALL. I extended this discovery to human disease, demonstrating that SYK was activated in primary B-ALL, independent of the pre-BCR expression. The small molecule SYK inhibitor fostamatinib (fosta) significantly attenuated proliferation of 79 primary diagnostic B-ALL samples at clinically achievable concentrations. Importantly, fosta treatment reduced dissemination of engrafting B-ALL cells into the spleen, liver, kidney and central nervous system (CNS) in a NOD.Prkdcscid/scidIl2rgtm1Wjl/SzJ xenotransplant model of B-ALL. Analysis of signaling abnormalities using a high-throughput phospho-flow cytometry platform demonstrated that pediatric and adult B-ALL samples exhibit variable basal activation of BCR,
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PI3K/AKT/mTOR, MAPK and JAK/STAT pathways. Importantly, we identified that fosta-mediated inhibition of SYK, PLC2, CRKL and EIF4E phosphorylation in B-ALL was predictive of its anti-leukemic activity, and was distinct from the cellular actions of other small molecule inhibitors of key nodal signaling pathways. Examination of molecular mechanism of fosta action by gene expression profiling revealed transcriptional effects of fosta treatment that included, most notably, potent inhibition of pathways involved in lymphocyte activation and inflammation. In conclusion, this study demonstrates that SYK signaling is crucial for B-ALL survival and provides detailed characterization of cellular and molecular mechanisms of fosta action in B-ALL. These data argue in favor of testing small molecule SYK inhibitors in pediatric and adult B-ALL.
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Daniella, Perri. "The Role of Intravenous Immunoglobulin Anti-A and Anti-B in Complement Activation and Red Blood Cell Phagocytosis". Thesis, 2009. http://hdl.handle.net/1807/18976.
Texto completoResumen
Intravenous immunoglobulin is a human blood derived product that is used to treat immunodeficiencies and autoimmune disorders. An adverse side effect of IVIg therapy is hemolysis. Patients who experience hemolysis are mainly blood group A or AB. Clinical laboratory studies have demonstrated that IVIg contains ABO blood group antibodies, which can bind complement proteins. This study hypothesizes that anti-A/B in IVIg will bind to A/B antigens and activate complement in a dose dependant manner, which may lead to enhanced RBC phagocytosis. This study observed that the quantity of ABO antigens does not affect the in vitro binding of IVIg to RBCs. IVIg induced C3b deposition at high doses; however, the amount of complement deposition was insufficient to enhance phagocytosis of IVIg-sensitized RBCs by monocytic THP-1 cells in vitro. These studies emphasize that hemolytic reactions involve many factors in conjunction with antibodies and complement proteins.
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Loh, Christina. "Identification of Genetic Loci that Contribute to the Immunopathogenesis of Systemic Lupus Erythematosus using Congenic Mouse Strains". Thesis, 2011. http://hdl.handle.net/1807/29797.
Texto completoResumen
Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by the production of antibodies directed against self-antigens, such as nuclear components. Genetic analyses of lupus patients have consistently demonstrated a complex genetic basis for disease susceptibility that involves multiple genes. Identifying genes and pathways that promote disease genesis has been aided by murine studies. In particular, congenic mouse studies that examine the role of chromosomal intervals from inbred lupus-prone mouse strains on a non-autoimmune background have been useful in dissecting the genetic contribution of novel susceptibility loci in
lupus pathogenesis. In this thesis, the role of New Zealand Black (NZB) chromosomes 4 and 13 are examined in non-lupus prone C57BL/6 (B6) congenic mouse strains, denoted B6.NZBc4 and B6.NZBc13, respectively. Although repeatedly mapped to contain disease augmenting alleles,NZBc4 alone was not sufficient to initiate disease, despite an expansion of NKT and B1a cells���both with controversial pathogenic roles in lupus. Instead, by crossing the B6.NZBc4 mouse
with another congenic mouse strain that develops fatal lupus autoimmunity, NZBc4 was
unexpectedly found to contain a suppressor locus; disease suppression was mediated by a shift away from pathogenic immunoglobulin isotypes and associated with changes in the NKT and B1a cell compartments. In contrast to the NZBc4 locus, the NZBc13 locus is sufficient to initiate polyclonal B cell activation, ANA production and mild GN, similar to NZB mice. A B cell intrinsic defect was found to be responsible for initiating the abnormal cellular phenotype in
B6.NZBc13 mice. Functional analyses of the B cell subset in B6.NZBc13 mice revealed normal
BCR-signaling responses and tolerance mechanisms; however, they were hyper-responsive to TLR3 stimulation, resulting in increased survival and proliferation. Thus, the study of these NZB congenic mouse strains has been instrumental in confirming the presence of loci on NZB chromosomes 4 and 13 that modulate the development of disease and highlights that disease onset is mediated by a balance of both susceptibility and suppressor alleles. Collectively, these
findings contribute to the current field of lupus immunogenetics and confirm the power of
congenic mouse models in understanding the genetic basis of SLE.
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Lang, Philipp. "Innate immune functions during chronic infections". Thesis, 2011. http://hdl.handle.net/1807/29711.
Texto completoResumen
About 10% of the world population suffers from chronic virus infections such as infections with hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Chronic virus infection is associated with the loss of functional cytotoxic T cells. Recent studies uncovered several mechanisms that play a central role in T cell exhaustion and thus development of chronic infections. The role of the innate immune system in the development of chronic virus infections remains unclear. Here we show that type I interferons trigger not only inhibition of virus replication but also immunoregulatory functions. The antiviral effects of type I interferons in the liver were dependent on the presence of macrophages. Macrophage depletion led to excessive virus replication and the development of chronic infection. Moreover, specific deletion of the type I interferon receptor on macrophages led to a decreased innate immune response. The regulatory functions of type I interferons were carried out by natural killer cells. Activated natural killer cells inhibited the virus specific cytotoxic T cell response and therefore delayed virus control. Depletion of natural killer cells prevented development of chronic infections and immunopathology. Moreover, type I interferons acted directly on the cytotoxic T cell response. Treatment with interferon 3 lead to increased T cell function. This resulted in induction of autoimmune diabetes in transgenic mice.
In conclusion, the nature of the innate immune response triggers the development of chronic virus infection. These results uncover new mechanisms that might provide the foundation for new therapeutic approaches for patients with chronic infections.
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Mossoba, Miriam Esmat. "Development of Immunotherapy Against Prostate Cancer Using Lentivirally-transduced Dendritic Cells Expressing Murine erbB2 as a Model Tumor-associated Antigen". Thesis, 2008. http://hdl.handle.net/1807/16783.
Texto completoResumen
Prostate cancer is a leading cause of cancer deaths in North American men. Current treatments are often not curative, particularly in cases of advanced metastatic disease. Immunotherapy is a promising approach to treating cancer as it harnesses the immune system’s ability to mount potent responses against tumor-associated antigens (TAAs). Dendritic cells (DCs) play a central role in mediating antigen-specific immunity and have been recently used with some success in clinical trials. The difficulties associated with obtaining sufficient quantities of DCs from cancer patients provided the rationale for developing low-dose DC-based immunotherapy approaches in my thesis project. DCs were genetically engineered using a lentiviral vector (LV) to express erbB2tr, a kinase-deficient version of erbB2. The human form of erbB2, HER2/neu, is overexpressed in 20% of primary prostate tumors and 80% of their metastases, making this TAA an attractive target. Using this LV system, efficient transgene delivery into DCs was achieved without compromising DC function or phenotype. Administering low prime and boost doses (2x10^5 or 2x10^3) of LV-transduced DCs to mice yielded potent and long-term anti-tumor responses against murine prostate tumors engineered to overexpress erbB2tr. The 2x10^5 DC dose yielded complete tumor protection and was associated with humoral and cellular responses. The 2x10^3 dose also offered complete protection in some mice, suggesting that we had reached a lower threshold DC dose. This novel finding prompted us to determine if co-transducing DCs with an additional LV carrying the cDNA for an immunomodulatory factor could augment the efficacy of our low-dose strategy. We chose to test both the DC survival-enhancing RANKL protein and DC function-enhancing IL-12 in combination with erbB2tr. Although DCs co-transduced with the LV/RANKL and LV/erbB2tr did not appear to offer enhanced anti-tumor benefits in a prophylactic setting, co-transduction with LV/IL-12 and LV/erbB2tr did. The incorporation of IL-12 into the low-dose immunization strategy led to robust long-term tumor protection and relatively high levels of Th1 immunity. This is the first demonstration of the efficacy of low-dose DC-mediated immunotherapy using lentiviral vectors as gene transfer tools. These studies establish a platform for DC-mediated therapies that can be realistically translated to the clinic.
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Chege, Duncan Mwithiga. "Evaluating the Interaction of HIV and the Immune System in Mucosal Tissues". Thesis, 2013. http://hdl.handle.net/1807/35172.
Texto completoResumen
90% of Human Immunodeficiency Virus (HIV) infections are acquired across the genital or gastrointestinal mucosa, and infection leads to profound depletion of CD4+ lymphocytes. Antiretroviral therapy can restore blood CD4+ T cells. However, immune dysfunction and defects in mucosal antimicrobial defence persist. Some CD4+ T-subsets, particularly antimicrobial Th17 cells, show enhanced susceptibility to HIV infection and are also preferentially depleted in the course of HIV infection; the latter may allow microbial translocation into the bloodstream. Genital infections have been shown to have direct mucosal immune effects and to increase susceptibility to HIV; however, the effect of systemic infections, such as Malaria (which is holo-endemic in some HIV prevalent regions) is unknown. Understanding the relationship between HIV, highly susceptible immune cells, immune activation and malaria infection on mucosal tissues has been the main focus of my thesis.
In HIV-infected individuals, I explored whether HIV antiretroviral therapy restores gut Th17 populations and improves gut antimicrobial defences. Therapy restored gut Th17 populations in some, but not all individuals, but antimicrobial defence remained impaired. I then piloted a novel mucosal-optimized PCR assay to measure cervical immune gene responses, as standard mucosal assays are inadequate. I succeeded in measuring mitogen-induced, but not HIV-specific, cervical immune responses in HIV-infected individuals. Next, using this PCR platform I examined mitogen-induced cervical immune responses in individuals demonstrating reduced susceptibility to HIV, and found that they had reduced production of both Th17-associated and pro-inflammatory cytokines from cervical cells. Finally, in a murine model I found that malaria caused genital and gastrointestinal mucosal immune activation, and increased both the expression of mucosal HIV susceptibility immune markers, and mucosal T cell immune activation.
In summary, insufficient gastrointestinal Th17 cells restoration does not underlie persistent mucosal immune activation and microbial translocation in HIV-infected people on therapy. A reduced frequency of highly susceptible Th17 cells in the cervix of HIV-exposed but uninfected individuals was identified as a correlate of reduced HIV susceptibility. Malaria, a common systemic infection in HIV-endemic countries, may enhance susceptibility to HIV through increasing putative immune markers of HIV susceptibility and immune activation in potential mucosal sites of HIV exposure.
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Baker, Jillian M. "Influence of Length of Time to Diagnosis and Treatment on the Survival of Children with Acute Lymphoblastic Leukemia and Hodgkin Disease: A Population-based Study". Thesis, 2010. http://hdl.handle.net/1807/24535.
Texto completoResumen
Introduction: Objectives were to describe time intervals between presentation to a tertiary care center, diagnosis and treatment in pediatric acute lymphoblastic leukemia (ALL) and Hodgkin disease (HD), and measure their impact on overall survival (OS) and event-free survival (EFS).
Methods: Children in POGONIS (Pediatric Oncology group of Ontario Networked Information System) with ALL or HD from 1997-2007 were eligible. Time intervals were dichotomized at clinically defined cut-points. OS and EFS were examined with univariate and multivariable Cox proportional hazards (CPH) models.
Results: In ALL, in multivariable analysis, those with treatment > 3 days after diagnosis had inferior OS (adjHR=2.49; 95%CI 1.4-4.43;p=0.002), and inferior EFS (adjHR=1.73; 95%CI 1.01-2.96;p=0.047). In HD, in multivariable analysis, those with treatment > 7 days after diagnosis had superior EFS (adjHR=0.37; 95%CI 0.18-0.77;p=0.008).
Conclusions: Time to treatment is associated with survival in ALL and HD. Future research will further delineate the relationship between time to treatment and outcome.
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Wong, Dennis Kachun. "Assessing the Combined Effect of Targeting ILK Signaling and Chemotherapy in Rhabdomyosarcoma". Thesis, 2011. http://hdl.handle.net/1807/31640.
Texto completoResumen
The pediatric sarcoma alveolar rhabdomyosarcoma (ARMS) is highly aggressive with a poor prognosis for diagnosed patients. Here, we demonstrate that targeting the unique oncogene integrin-linked kinase (ILK) in ARMS cells in conjunction with the common chemotherapy agent vincristine, a synergistic effect is found in the reduction of cell viability in vitro. This result was achieved by both RNAi-mediated depletion of ILK and using a small molecule kinase inhibitor specific for ILK. Both techniques were found to disrupt important protein interactions at the site of the centrosome. Combination ILK disruption and vincristine treatment of cells induced the expression of apoptotic markers and arrested cells in the G2/M stage of the cell cycle. Interestingly, protein levels of JNK and its target c-Jun were regulated with combined treatment. Altogether, these findings indicate that the use of molecular targets like ILK may further improve the clinical treatment of ARMS.
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Gregory, Allison. "Structural and Functional Characteristics of a Soluble Form of Endoglin in the Context of Preeclampsia". Thesis, 2011. http://hdl.handle.net/1807/30615.
Texto completoResumen
Endoglin is an auxiliary receptor for ligands of TGF-β receptor superfamily, present in endothelial cells and the placental syncytiotrophoblast. The expression of placental membrane endoglin (mEng) is further increased during preeclampsia, a pregnancy-specific hypertensive syndrome. We hypothesize that the soluble form of endoglin (sEng) released from the placenta leads to endothelial dysfunction and hypertension by disrupting normal BMP-9 signaling. We show that cell surface mEng inhibits TGF-β1, BMP-2, and BMP-7 induced Smad1,5,8 phosphorylation while potentiating BMP-9 induced signaling. sEng has been shown to be elevated in the sera of preeclamptic women and is postulated to interfere with endothelial cell function. We show that sEng binds to BMP-9 with a 2 nM affinity and can compete for its binding to endothelial cells, inhibiting downstream Smad1,5,8 phosphorylation. Our results suggest that sEng is contributing to endothelial dysfunction by dysregulating BMP-9 signaling.
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Gillis, Lisa. "Gads is a Regulator of Normal and Leukemic Hematopoiesis". Thesis, 2012. http://hdl.handle.net/1807/35716.
Texto completoResumen
Hematopoiesis describes the formation and development of blood cells. All blood cells originate from a pluripotent hematopoietic stem cell (HSC) which has the capacity for long and short term self-renewal as well as differentiation into myeloid or lymphoid lineages. The balance between HSC differentiation and proliferation is tightly controlled by both extrinsic and intrinsic factors. During leukemogenesis, this regulation is disrupted as transformation events lead to changes in proliferation, differentiation, and survival. Two distinct experimental strategies were utilized to examine the role of the hematopoietic adaptor protein GADS (GRB2-related adaptor downstream of SHC) in both leukemogenesis and in normal hematopoiesis. Philadelphia chromosome positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and B cell acute lymphoblastic leukemia (B-ALL), are mediated by the oncogenic BCR-ABL fusion protein. Animal modeling experiments utilizing retroviral transduction and subsequent bone marrow transplantation have demonstrated that BCR-ABL generates both myeloid and lymphoid disease in mice when whole bone marrow is used as donor material. Strikingly, we observe that the lymphoid disease is absent in experiments completed with Gads-deficient bone marrow expressing BCR-ABL. Gads-deficient mice were generated previously and display a decrease in mature T cells, indicating that GADS is critical to T cell differentiation. Through immunophenotyping analysis we observed that Gads-deficient mice have increased numbers of lymphoid progenitors and HSCs. The increased number of HSCs in Gads-deficient mice did not induce enhanced HSC function as Gads-deficient bone marrow cells have impaired repopulation potential. Our data suggests that the T cell defect previously observed in Gads-deficient mice may be due to an early block in differentiation and functional defect in the HSC. Taken together, our studies demonstrate that GADS is a critical mediator in the hematopoietic system for both normal and leukemic differentiation and proliferation.
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Jia, Danlin. "Influenza Virus H5N1 Non-structural Protein 1 Alters Interferon-alpha/beta Signaling". Thesis, 2009. http://hdl.handle.net/1807/18772.
Texto completoResumen
Type I interferons (IFNs) function as the first line of defense against viral
infections by modulating numerous biological processes to establish an antiviral state and influencing the activation of various immune cells. During influenza A infection, the NS1 encoded by the virus genome disrupts many cellular processes to block type I IFN responses. We show that expression of H5N1 NS1 in HeLa cells reduces IFN-inducible activation of STAT proteins and its subsequent binding to DNA complexes. Subsequent analysis suggests NS1 blocks IFN signaling by inhibiting expression of type I IFN receptor subunit, IFNAR1, as well as up-regulating SOCS1 expression. Finally, we demonstrate that pretreatment of primary human lung tissue with IFN alfacon-1 inhibits H5N1 viral replication by up-regulating a number of interferon-stimulated genes. The data suggest that NS1 can directly interfere with Type I IFN signaling, and that pretreatment with IFN can inhibit H5N1 infection in primary human lung tissue.
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Mikhailova, Anastassia. "Characterization of a Novel Dendritic Cell Population". Thesis, 2012. http://hdl.handle.net/1807/33452.
Texto completoResumen
Conventional DC (cDC) arise from circulating immediate precursors (pre-cDC), and are currently thought to be terminally differentiated. Here we show that cDC are capable of generating progeny that lost all characteristic features of cDC and aquired regulatory properties. Sorted bone marrow pre-cDCs were cultured on a stromal monolayer in the presence or absence of granulocyte-macrophage colony stimulating factor (GM-CSF). In the absence of GM-CSF, pre-cDC derived DCs gave rise to a homogeneous population of CD11clow MHClow cells (DC-regs) on day 8-10 of culture. DC-regs failed to up-regulate major histocompatibility complex class II (MHCII) and co-stimulatory molecules in response to DC maturation stimuli, were poor stimulators in T cell proliferation assays and suppressed T cell proliferation in cultures containing immuno-stimulatory DC. Co-transfer of DC-regs with DCs in vivo did not inhibit proliferation of T cells. These findings reveal the potential of DCs to generate a regulatory DC population with immunosuppressive properties.
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Sharmeen, Sumaiya. "Activation of Chloride Channels with the Anti-parasitic Agent Ivermectin Induces Membrane Hyperpolarization and Cell Death in Leukemia Cells". Thesis, 2010. http://hdl.handle.net/1807/24641.
Texto completoResumen
FDA-approved drugs with previously unrecognized anti-cancer activity could be rapidly repurposed for this new indication. We compiled a library of such off-patent drugs to screen four leukemia cell lines and identified the anti-parasitic agent ivermectin that induced cell death at low micromolar concentrations. In cell death and clonogenic growth assays, low micromolar concentration of ivermectin significantly reduced viability of leukemia cell lines and patient samples compared to normal peripheral blood stem cells. In xenograft mouse models of leukemia, ivermectin decreased tumor volume and weight by up to 72% when compared to control without observable toxicity at pharmacologically achievable dosage. In this study, we further demonstrate that ivermectin activates chloride channels in leukemia cells leading to membrane hyperpolarization and increased reactive oxygen species generation. In addition, it demonstrated synergistic interaction when used in combination with Daunorubicin and Cytarabine. Therefore, this study highlights a potential new therapeutic strategy in repurposing ivermectin for the treatment of AML.
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Albert-Vartanian, Alenoush. "Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma". Thesis, 2013. http://hdl.handle.net/1807/42661.
Texto completoResumen
Glioblastoma (GBM), similar to many other cancers, exhibits enhanced aerobic glycolysis with concomitant lactate production, a phenomenon known as the Warburg effect. We have demonstrated that preferential expression of Hexokinase 2 (HK2) is a critical mediator of metabolic reprograming in GBMs and its inhibition is a potential therapeutic strategy for sensitization of GBM tumors to radiation (RAD) and/or temozolomide (TMZ). Our results
indicate that conditional HK2 inhibition disrupts energy homeostasis and sensitizes GBMs to radiochemotherapy under hypoxia. In GBM xenografts, conditional HK2 loss sensitizes GBM tumors to concomitant RAD/TMZ and results in a significant survival benefit in the mice. Moreover, loss of HK2 resulted in GBM remodeling with HK2 knockdowns showing increased necrosis, hypoxia, inflammatory infiltration and reduced vascularization. We anticipate that targeting a key metabolic enzyme involved in the Warburg effect might improve the efficacy of current therapeutic regimen and provide a unique paradigm for the management of GBMs.
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Shyu, Wendy Huei-Ping. "Induction of Tolerance: Mechanisms and Implications for Clinical Transplantation". Thesis, 2013. http://hdl.handle.net/1807/42931.
Texto completoResumen
Therapies that promote tolerance will improve outcomes in solid organ transplantation by eliminating the need for long-term immunosuppression. This thesis investigates two possible tolerance induction mechanisms: rapamycin induced expression of regulatory T cells and re-education of the immune system using syngeneic hematopoietic stem cell transplantation. Fibrinogen-like protein 2, a effector molecule of regulatory T cells, was also determined as a key mediator in the tolerance induction pathway as depletion of fibrinogen-like protein 2 lead to allograft rejection. The feasibility of using syngeneic hematopoietic stem cells for inducing allograft tolerance was studied by setting up a murine heart and bone marrow transplant model. Syngeneic T-depleted bone marrow transplantation resulted in a slight prolongation of the graft survival time compared to the animals reconstituted with total bone marrow cells. We provide compelling evidence to suggest that fibrinogen-like protein 2 and syngeneic hematopoietic stem cells can possibly be used to induce transplantation tolerance.
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Pau, Evelyn Yin-Wah. "Insights into the Iimmune Mechanisms Leading to Lupus-like Autoimmunity in New Zealand Black Mice". Thesis, 2013. http://hdl.handle.net/1807/43707.
Texto completoResumen
Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease characterized by the production of antibodies against self nuclear antigens. Genetics play a dominant role in disease pathogenesis and functional examination of spontaneously-arising lupus-prone animal models has provided key insights into understanding the genetic complexity of the disease. The overarching goal of the work presented here is to identify the underlying immunologic abnormalities, together with lupus susceptibility loci that produce them, that promote the development of autoimmunity in the lupus-prone New Zealand Black (NZB) background. Chapter 2 identifies the critical role of CD40-CD40L interactions in the pathogenesis of disease in NZB mice. We showed that this interaction is required for the production of class-switched IgG autoantibodies and development of hemolytic anemia and kidney disease. Polyclonal B cell activation, expansion of plasmacytoid dendritic cells (pDC), and elevated gene expression of baff were maintained in CD40L-deficient NZB mice, despite the lack of IgG immune complexes. Chapter 3 utilizes bicongenic mice carrying both NZB chromosomes 1 and 13 to investigate the genetic complexity in disease pathogenesis. In addition to identifying new phenotypes, examination of bicongenic mice showed that chronic stimulation of pDC due to the persistence of nuclear antigens leads to a refractory state with a failure to produce more IFN-α upon subsequent stimulation. Chapter 4 identifies a novel lupus susceptibility locus on NZB chromosome 13 associated with impaired clearance of apoptotic debris, a key initiating step in the development of autoimmunity. Using subcongenic mice, this locus was localized and examined its impact on immune function. Work from this thesis will contribute to understanding the complex immunogenetic mechanisms that lead to development of SLE.
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Becker, Henry. "The Role of Alpha-1 Beta-1 Integrin in Extravascular Leuckoyte Migration as Revealed by Novel In-situ Pulse Labeling Technology". Thesis, 2013. http://hdl.handle.net/1807/43486.
Texto completoResumen
Leukocyte exit from peripheral tissues is fundamental to host defense, yet little is known about the role of adhesive molecules in this process. In my thesis I ask the question “can an integrin regulate leukocyte exit from inflamed peripheral tissues” and specifically investigate the leukocyte integrin α1β1. This is an important question because leukocyte exit, or persistence, at an inflammatory lesion can have a profound effect on the immune response. In addition, I present special in situ staining techniques which had to be developed in order to assay endogenous leukocyte migration in a murine model. The introductory sections review functional differences between myeloid and lymphoid leukocyte subsets, the leukocyte adhesion cascade, integrins, chemokine receptors and the essential concepts of signaling and the relationship between chemokines and integrin activation. I also discuss the pro-migratory paradigm of leukocyte integrins, in other words that integrin adhesion is equated with leukocyte migration. The current literature regarding what is known about integrin function in peripheral tissues and leukocyte migration is also discussed. Chapter 2 characterizes my inflammatory model and implicates α1β1integrin and macrophages as important molecular and cellular entities respectively, involved in sustaining the inflammatory response. Chapter 3 develops endogenous in-situ labeling in the blood compartment, establishing the fundamentals of my in-situ approach. Chapter 4 extends this and establishes in-situ pulse labeling (ISPL) to label endogenous leukocytes in peripheral tissues. Chapter 4 then goes on to combine the technological advances and conceptual framework established in the previous chapters to elucidate a role for α1β1integrin in the exit of macrophages from inflamed peripheral tissues. Finally, in Chapter 5 I discuss the implications of my results in the context of the host defense, how it might impact the immune response and future directions for this research.
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Papp, Eniko. "Functions of Novel Ligand-independent Flt3 Alleles and RANKL in Promoting Dissemination of Murine B-Cell Leukemias to the Central Nervous System". Thesis, 2013. http://hdl.handle.net/1807/65499.
Texto completoResumen
Survival rates for pediatric B-cell acute lymphoblastic leukemia (B-ALL) have improved dramatically, but outcomes for the 15% who relapse and for adults with B-ALL remain poor. Up to 40% of pediatric B-ALL patients require central nervous system (CNS) prophylaxis that causes significant treatment-related morbidities. p53-/- Rag-2-/- Prkdcscid;scid triple mutant (TM) mice spontaneously develop B-ALL that disseminates to the CNS. We used this model to investigate molecular mechanisms that drive CNS dissemination of leukemic B-cells. We show that CNS-disseminating B-ALLs had recurrent genomic rearrangements that replaced N-terminal Fms-like tyrosine kinase 3 (Flt3) exons with endogenous retrovirus (ERV) transcriptional control elements. ERV-Flt3 fusion genes encoded truncated FLT3 (trFLT3) proteins that induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, trFLT3 promoted de novo development of CNS-disseminating B-ALL from hematopoietic progenitors. Thus, a novel mutational mechanism involving ERV-mediated FLT3 activation can drive the development of B-ALL characterized by high degree of CNS-invasion. Ectopic expression of trFlt3 suggested that TM B-ALLs initiate prior to B-cell commitment, since Flt3 is normally repressed by PAX5 upon B-cell commitment, co-incident with Cd19 expression. In support of this idea, we report evidence of Flt3 amplification in a rare subset of CD19- progenitors, and we show that CD19- FLT3+ cells from leukemic TM mice contain leukemia-initiating cells. Finally, we compared gene expression profiles of trFl3+ and trFl3- B-ALLs to identify potential Flt3 effectors important for CNS dissemination. TM B-ALLs uniquely expressed RANKL, a key regulator of osteoclast differentiation and normal B-cell development. FLT3 inhibition decreased RANKL expression, suggesting at least partial dependence on trFLT3 signaling. RANKL-expressing TM B-ALLs decreased trabecular bone density after adoptive transfer to normal mice, demonstrating a role for RANKL in leukemia-associated bone pathology. Importantly, a RANKL biologic antagonist inhibited CNS dissemination of TM B-ALLs in adoptive transfer experiments. Thus, my studies identified novel ligand-independent Flt3 mutations that arise prior to B-cell commitment and promote development of CNS-disseminating B-ALLs. Furthermore, I identified RANKL as a potential therapeutic target that may limit leukemia CNS dissemination and leukemia-associated bone pathology.
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Guerra, Fiona. "The Role of Homeodomain-interacting Protein Kinase (HIPK)-1 in B Lymphocytes". Thesis, 2011. http://hdl.handle.net/1807/29736.
Texto completoResumen
The homeodomain-interacting protein kinase (HIPK) family is comprised of four evolutionarily conserved and highly related serine/threonine kinases originally identified as co-repressors for homeodomain-containing transcription factors. While the HIPKs are most noted for regulation of apoptosis, proliferation and differentiation, I report a pleiotropic function of HIPK1 within the B cell lineage. Although lymphocyte development was normal within the thymus and bone marrow of HIPK1-deficient (HIPK1-/-) mice, the spleen exhibited a reduced number of transitional and follicular (FO) B cells, but with an increase in the marginal zone (MZ) B cell population. HIPK1-/- B cells exhibited impaired proliferation in response to B cell receptor (BCR) cross-linking in vitro; and immunization of HIPK1-/- mice with T-independent type 2 (TI-2) antigen resulted in a significantly impaired humoral response despite the expanded MZ B cell population. Immunization with T-dependent (TD) antigen resulted in a kinetically delayed response, with impaired affinity maturation. Identification of a kinase-substrate interaction between HIPK1 and the B cell adaptor 3BP2 suggests a potential context for HIPK1 function in BCR signaling. HIPK1-/- B cells were uniquely resistant to reactive oxygen species (ROS)-induced apoptosis, but equally susceptible to UV- and γ-irradiation compared to controls. In vitro class-switch recombination (CSR) assays revealed that HIPK1 is required for the negative regulation of CSR. HIPK1-/- B cell cultures harbored more viable cells, more switched cells, and elevated AID mRNA levels. The findings presented in this thesis demonstrate that HIPK1 is required for splenic B cell homeostasis and optimal BCR-responsiveness. In contrast, HIPK1 is also required for the negative regulation of CSR, possibly by mediating CSR-induced apoptosis.
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Chan, Yin. "Analysis of Adipose CD4+ TCR alpha/beta T cells in Obesity-associated Insulin Resistance". Thesis, 2009. http://hdl.handle.net/1807/19180.
Texto completoResumen
Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Valpha/betarepertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNgamma-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAGnull mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with anti-CD3 antibody or its F(ab’)2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. CD4+ T cells impact the progression of obesity-associated metabolic abnormalities and can be manipulated by immunotherapy.
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Lee, Daniel Yen-Hong. "Role of Microornas in Tumroigenesis and their Modulation by Versican 3' Untranslated Region". Thesis, 2010. http://hdl.handle.net/1807/29971.
Texto completoResumen
MicroRNA is a single-stranded RNA molecule of about 22 nucleotides in length and is expressed endogenously. It functions as a gene regulator by pairing imperfectly with 3’ untranslated region (3’UTR) of target mRNAs, leading to translational inhibition. MicroRNA is implicated in many regulatory pathways and hence affects various cellular activities. In the development of cancer, genetic alterations occurred at miRNA locus and its expression level is dysregulated in various cancers versus normal tissue counterparts. It is thus important to find the targets of dysregulated microRNAs contributing to progression of cancer. To facilitate long term functional studies, a microRNA expression construct with unique futures was generated. Stable expression of miR-378 enhanced cell survival, reduced caspase-3 activity, and promoted tumor growth and angiogenesis. By algorithmic predictions and proteomic analysis, two tumor suppressors, SuFu and Fus-1, were found to be translationally regulated by miR-378. Target validation was confirmed by co-transfection experiments and luciferase activity assays, reassuring its oncogenic role by regulating two tumor suppressor genes simultaneously. Conversely, microRNA can also function as a tumor suppressor by modulating expression of Versican, an extracellular matrix protein known to facilitate tumorigenesis and angiogenesis. By a novel PCR method, more than one microRNA were found to bind to Versican 3’UTR.
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Among these microRNAs, targeting of Versican and Fibronectin by miR199a-3p was validated. Expression of a fragment of Versican 3’UTR was expected to antagonize the function of miR-199a-3p. Stable expression of Versican 3’UTR resulted change in cell morphology and increased cell-cell adhesion. Analysis of primary tissues from transgenic mice expressing versican 3’UTR showed an increase expression of Versican and Fibronectin, and organ adhesion was found between liver and its surrounding tissues. In addition, 3’UTR also modulated the level of miR-199a-3p and miR-136, alleviating translation of negative cell cycle regulators, PTEN and Rb1. This resulted in reduced cell proliferation and hence diminished tumor growth. These findings suggest a role of microRNA in tumor growth, providing a valuable target for therapeutic intervention.
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Fung, Andrea. "The Effect of Molecular Targeted Agents used in Combination with Chemotherapy to Inhibit the Repopulation of Tumour Cells and Xenografts". Thesis, 2010. http://hdl.handle.net/1807/26174.
Texto completoResumen
Chemotherapy is often administered once every three weeks to allow repopulation of essential normal tissues such as the bone marrow. Repopulation of surviving tumour cells can also occur between courses of chemotherapy and can decrease the efficacy of anticancer treatment. This thesis aims to characterize repopulation, to study the effect of targeted cytostatic agents to inhibit repopulation, and to determine the optimal scheduling of chemotherapy and molecular targeted treatment.
The distribution of proliferating and apoptotic cells in human squamous cell carcinoma (A431) xenografts was studied following chemotherapy using fluorescence immunohistochemistry. There was an initial decrease in cell proliferation and in the total functional blood vessels, and an increase in apoptosis observed following treatment with paclitaxel chemotherapy. A rebound in cell proliferation occurred approximately 12 days following treatment, which corresponded with a rebound in vascular perfusion.
The effect of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, to inhibit repopulation between courses of chemotherapy was determined using EGFR-overexpressing A431 cells and xenografts. Furthermore, concurrent and sequential schedules of combined chemotherapy and molecular targeted treatment were compared. Gefitinib inhibited the repopulation of A431 cells in culture when administered sequentially between chemotherapy; sequential treatment was more efficacious than concurrent treatment probably because concomitant scheduling rendered quiescent cells less responsive to chemotherapy. However, in vivo studies using chemotherapy in combination with gefitinib or temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, showed that concurrent scheduling of combined treatment was more effective at delaying regrowth of xenografts than sequential treatment; this was likely due to dominant effects on the tumour microenvironment.
The work completed in this thesis has shown that repopulation occurs in A431 xenografts following paclitaxel treatment, and these changes are associated with changes in the tumour vasculature. Repopulation of A431 cells was inhibited by gefitinib administered sequentially with paclitaxel. However, studies in mice showed better inhibitory effects when chemotherapy was given concomitantly with cytostatic agents such as gefitinib or temsirolimus. Our in vivo data highlight the importance of characterizing changes in the tumour microenvironment when determining optimal scheduling of chemotherapy and molecular targeted treatment.
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Mesci, Aruz. "The Role of NKR-P1B:Clr-b Recognition in NK Cell Mediated Immunity To Cytomegalovirus Infection". Thesis, 2011. http://hdl.handle.net/1807/32079.
Texto completoResumen
NK cells are innate lymphocytes that are crucial for host immunity during infections. Discrimination between healthy and infected cells is facilitated through a sum of inhibitory and stimulatory signals. Host cells can modulate the expression of NK ligands in response to infection, transformation, and stress, while viruses can exploit these mechanisms to prevent the killing of the infected cells. This thesis focuses on the interaction between the NK receptor, NKR-P1B, and its ligand, Clr-b. First, we used a reporter cell-based protocol to establish hybridomas producing monoclonal antibodies against a putative viral immunoevasin, RCTL. We express CD3ζ-fusion proteins on the reporter cells, which we then use to immunize and screen hybridoma specificities. Our results demonstrate a rapid, efficient, and high-throughput method of monoclonal antibody screening, and provide the framework for our work on cytomegalovirus evasion of the NKR-P1B:Clr-b system.
Next, we show that RCMV infection results in a notable downregulation of rClr-b at the protein and transcript levels. Conversely, RCTL is upregulated during infection, and binds to the same NK-inhibitory receptor as Clr-b, NKR-P1B. In the absence of RCTL, RCMV-mediated Clr-b loss leads to increased NK-killing of infected targets and an NK-dependent reduction of viral titers in vivo. Notably, NKR-P1B is highly polymorphic, and certain rat NKR-P1B alleles have lost binding to the viral RCTL but not to the host Clr-b molecule, suggesting co-evolution between the host and the virus.
In the next chapter, we address some of the mechanisms responsible for CMV-mediated Clr-b downregulation, and show that Clr-b downregulation also occurs to mice in response to MCMV infection. Moreover, early gene expression (host or viral) appears to be required for Clr-b downregulation. Interestingly, engagement of any one conventional pattern recognition receptor is insufficient to mimic MCMV-mediated Clr-b downregulation. Similarly, fibroblasts lacking various intermediates for the interferon or inflammasome pathways still downregulate mClr-b, with the exception of the DNA sensor, Zbp-1. Lastly, a recently identified autocatalytic motif conserved in the rat and mouse Clr-b transcripts, the hammerhead ribozyme, appears to be involved in Clr-b regulation.
Taken together, our results explore a novel and important role for NKR-P1B:Clr-b interactions in viral immunity.
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Corfe, Steven A. "Regulation of B Lymphopoiesis: The Role of IL-7, SOCS-1, Heparan Sulfate and CD19 in Mediating B Cell Development". Thesis, 2012. http://hdl.handle.net/1807/32690.
Texto completoResumen
B lymphopoiesis is regulated by cytokines, chemokines and cell surface proteins that initiate signal transduction pathways necessary for maturation to proceed. Many of these factors are expressed by cells in the surrounding bone marrow (BM) microenvironment, which also form the niches that support development. Interleukin-7 (IL-7) is an essential cytokine for progenitor B cells and is important in providing survival, proliferation and maturation signals. By growing BM B cells for extended periods of time in vitro with IL-7 it is possible to select for cells that possess the ability to grow indefinitely, and these cultures can be used to generate cell lines. Data presented herein describe the generation and characterization of IL-7-dependent B cell lines as well as their utility in investigating aspects of B cell development. As B cells mature they lose responsiveness to IL-7, yet retain IL-7 receptor expression. I demonstrate that a B cell’s ability to respond to IL-7 is controlled by the expression of suppressor of cytokine signaling (SOCS) proteins, which are regulated by a variety of signaling pathways including those initiated by IL-7. Development of progenitor B cells to mature immunoglobulin secreting B cells is mediated in part by surface proteins present on stromal cells as well as on B cells themselves. Heparan sulfate and CD19 play important roles in regulating this transition and I provide data that demonstrates how their ability to regulate Erk activation downstream of the pre-B cell receptor (pre-BCR) alters the proliferation and maturation of developing B cells.
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De, Souza Raquel S. M. G. "Impact of Chemotherapy Dosing Schedule on Ovarian Cancer Tumor Responsiveness". Thesis, 2012. http://hdl.handle.net/1807/32698.
Texto completoResumen
In Canada, ovarian cancer kills about 67% of diagnosed patients, largely due to difficulties in early diagnosis. Current treatment consists of debulking surgery and intermittent chemotherapy every three weeks. This approach leads to insufficient drug concentrations at disease sites, and long treatment-free intervals cause accelerated tumor proliferation and drug resistance, resulting in a 5-year survival rate of only 25-35%. Drug resistance development is the ultimate cause of the majority of patient deaths. Improvements yielding more effective treatment are fundamental for successful management of this disease. This thesis investigated a continuous chemotherapy strategy devoid of treatment-free intervals for ovarian cancer treatment. A biocompatible, biodegradable polymer-lipid injectable formulation PoLigel, was used for continuous DTX delivery. The formulation was well tolerated; no alterations in body weight, behaviour, histology of peritoneal tissues, or interleukin-6 levels were seen in CD-1 mice treated with the PoLigel. Continuous DTX therapy via the PoLigel was considerably more efficacious than intermittent therapy, resulting in significantly less tumor burden and ascites fluid in models of human and murine ovarian cancer. Continuous therapy resulted in less tumor cell proliferation and angiogenesis, and more tumor cell death than intermittent DTX. The presence and length of treatment-free intervals was shown to contribute to the development of drug resistance. Eliminating these intervals by continuous dosing resulted in superior antitumor efficacy in both chemosensitive and chemoresistant xenograft models of human ovarian cancer, and prevented drug resistance increase after a 21-day treatment period. Survival studies revealed that intermittent dosing led to a mild survival prolongation of 36% and 10% in chemosensitive and chemoresistant models, respectively, whereas continuous DTX prolonged survival by a striking 114% and 95%. Although long-term continuous chemotherapy substantially improved survival, increased drug resistance mechanisms were found at the endpoint. Overall, results presented here encourage the clinical implementation of continuous chemotherapy due to greater achievable therapeutic advantages.
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Miliotis, Helen. "The Role of the PTPN22 (Lyp/Pep) Phosphatase and its Disease-associated Variant in T-cell Signalling". Thesis, 2012. http://hdl.handle.net/1807/34810.
Texto completoResumen
The PTPN22 gene encoding the Lyp/Pep protein tyrosine phosphatase has recently been described as a negative regulator of T-cell receptor signalling. Little biological information is available on this protein, but a variant allele in this gene conferring a R620W change has been associated with rheumatoid arthritis and other autoimmune disease states. To gain further understanding into the roles of Lyp, this work is aimed at identifying and characterizing Lyp interactions, and elucidating the effect of the variant Lyp in immunological disease. Specifically, the interaction of Lyp with the ubiquitin ligase Cbl was further examined and characterized to uncover its role in T-cells. Furthermore, the biochemical and functional differences of the variant Lyp were examined by utilizing a murine model of the variant, Pep R619W. This work led to novel findings on the stability of the protein and its resulting dysfunction, leading to cell hyperresponsiveness. Finally, a new role for Lyp in controlling cell migration was uncovered through its interaction with GRK2. The inhibitory properties of Lyp on cell migration are disrupted in the presence of the Lyp R620W variant, leading to dysregulation of GRK2 function and altered migratory properties of cells, particularly in the collagen-antibody induced arthritis model. Understanding the normal function of Lyp, as well as dysfunction of the variant, will provide new insights into normal T-cell signalling and aid in the understanding of the processes of autoimmunity.
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Lee, Benjamin. "Interaction between Macrophages and Epithelial Cells in Innate Immune Responses against Adenoviral Vectors". Thesis, 2012. http://hdl.handle.net/1807/34780.
Texto completoResumen
Although induction of innate immune responses during viral infection is essential, it can cause acute inflammation and lead to devastating results. The deleterious effect of innate immune responses has been demonstrated in gene therapy where administration of a replication deficient adenoviral vector (Ad) caused fatality during a clinical trial. Despite recent advances in our understanding of the innate immunity, there is a lack of understanding on how different cell types interact to mount inflammatory responses, which may play an important role in regulating immune responses in vivo.
In this study, we investigated the interaction between macrophages and epithelial cells, the two major cell types capable of sensing and responding to viral infection in the airway, in induction of inflammatory responses against replication deficient Ads. We show in Chapter 2 that Ad infection of the macrophage-epithelial cell co-culture resulted in synergistic induction of inflammatory responses. Ad infection of the co-culture compared to macrophages alone resulted in higher cytotoxicity and induction of significantly higher levels of inflammatory mediators including pro-inflammatory cytokines, chemokines, nitric oxide, and reactive oxygen species. We found that these synergistic responses require macrophages and epithelial cells to be in close proximity suggesting that a novel mechanism regulates the inflammatory responses.
In Chapter 3, we studied whether ATP plays a role in regulating inflammatory responses during acute Ad infection. Using the co-culture system, we found that ATP signaling through P2X7 receptor (P2X7R) is critical as inhibition or deficiency of P2X7R resulted in reduced inflammatory responses. We demonstrate that ATP-P2X7R signaling regulates inflammasome activation and IL-1β secretion. Furthermore, intranasal administration of Ad resulted in high mortality in mice but inhibition of ATP-P2X7R signaling enhanced survival and reduced inflammatory responses. These results suggest that ATP released by the infected cells plays an important role in regulating inflammatory responses during acute viral infection.
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Ho, Louisa. "Modulators of Hedgehog Signaling in Neoplasia". Thesis, 2012. http://hdl.handle.net/1807/34055.
Texto completoResumen
The Hedgehog (Hh) signaling pathway plays a critical role in modulating various developmental processes that requires fine tuning of the Hh signal, such that dysregulation can lead to cellular
events involved in cancer. To elucidate the factors responsible for aberrant Hh activation and subsequent tumorigenesis, I investigated three distinct modulators of Hh signaling: (1) p53 tumour suppressor (2) primary cilia (3) PTHLH.
During chondrocyte development, abnormal Hh signalling can result in benign cartilage
tumours, called Enchondroma. As precursor lesions, enchondroma may progress to malignant neoplasia, collectively known as chondrosarcoma. Although the molecular events involved in this progression are poorly understood, inactivation of the p53 tumour suppressor has been identified in approximately one-third of chondrosarcoma. Using an enchondroma mouse model, I showed that p53 deficiency can cause chondrosarcoma to develop. The combined inhibitory effects of Hh and p53 pathways on the pro-apoptotic factor, IGFBP-3, suppressed apoptosis and
was demonstrated to play a critical role in the progression to chondrosarcoma.
The primary cilium is an organelle that serves as a signaling centre for the Hh pathway to allow for greater control of the signal output. Loss of primary cilia results in abnormal Hh signaling that is associated with cancer and various developmental defects. I observed a depletion of
primary cilia in both human Chondrosarcoma and Enchondroma tumours compared to normal
cartilage. Analysis of cilia-deficient mice revealed that defective ciliogenesis alone could lead to the formation of benign cartilage tumours. Furthermore, loss of primary cilia potentiated the effect of Hh signaling activation, revealing a novel role in cartilage tumorigenesis.
Parathyroid-like hormone (PTHLH) is an essential inhibitor of the Hh pathway during
chondrocyte development, however its function as a regulator of Hh in other tissue types are largely unknown. Through activation of PKA, PTHLH suppresses the activation of Gli transcription factors; downstream effectors of the Hh pathway. Using irradiated Ptch+/- mice that exhibit a high incidence of skin and brain tumours, I demonstrated that treatment with PTHLH agonist, PTH (1-34), results in inhibition of the Hh pathway, increased survival and a
reduction in tumour incidence and size. Thus, PTH (1-34) may have therapeutic potential for Hhrelated cancers, especially given its known clinical safety in treating osteoporosis.