Doctor of Philosophy / Department of Anatomy and Physiology / Deryl L. Troyer / Umbilical cord matrix stem (UCMS) cells are derived from Wharton's jelly and have been shown to express genes characteristic of primitive stem cells. They can be isolated in large numbers in a short time and thus potentially represent an abundant source of cells for therapeutic use. We investigated the migratory nature of human UCMS cells towards MDA 231 human breast carcinoma cells in an in vitro model of cell migration; UCMS cells cultured with or without MDA 231 cells for 24 hours. Next, we evaluated the effect of chemokines, stromal derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) on human UCMS cells by treating with increasing doses of SDF-1 and VEGF. UCMS cells were found to migrate towards MDA 231 cells in a dose dependent manner. Both SDF-1 and VEGF induced migration of UCMS cells in a dose dependent manner. These results suggest that MDA 231 cells might be releasing chemokine factors, such as SDF-1 and VEGF, which promote UCMS cell migration towards the tumor cells in vitro. Stem cells that migrate to tumors may allow targeted delivery of therapeutic agents that otherwise may have severe side effects. To evaluate the selective engraftment and therapeutic efficiency of human UCMS cells that were engineered to express interferon beta (UCMS-IFN-beta) MDA 231 cells (2,000,000) were intravenously injected into severe combined immune deficient (SCID) mice, followed by three weekly intravenous injections of fluorescently labeled UCMS-IFN-beta cells (500,000). To evaluate the synergistic effect of 5-Fluorouracil (5-FU) and IFN-beta, MDA 231 cells were intravenously injected into SCID mice, followed by three weekly intravenous injections of fluorescently labeled UCMS-IFN-beta cells and three weekly intra peritoneal injections of 5-FU. In both of the above experiments, mice were euthanized one week after the last UCMS cell transplant and lung weights were compared to the controls to determine the differences in tumor burden. After transplantation of UCMS-IFN-beta cells into MDA 231 tumor-bearing mice, UCMS cells were found near or within metastatic lung tumors but not in other tissues, and in these animals, the lung weight was significantly less than MDA 231 tumor-bearing animals that received saline injections. Histologically, there was significant reduction in the tumor area in MDA 231 tumor bearing lungs after UCMS-IFN-beta treatment. When 5-FU was given along with UCMS-IFN-beta cells, there was further reduction in tumor area. These results indicate that UCMS cells can potentially be used for targeted delivery of cancer therapeutics.

No description available.

Hedgehog (Hh) est un morphogène secrété qui contrôle la croissance et la différentiation cellulaire chez les métazoaires. La dérégulation de son activité entraine des maladies développementales et de nombreux cancers chez l’adulte. Chez la drosophile, la transduction du signal Hh est initiée par la fixation de Hh sur son récepteur Patched (Ptc), conduisant à la stabilisation de la protéine membranaire Smoothened (Smo) et à l’activation du complexe de transduction composé de 5 protéines : les kinases Fused (Fu), PKA, GprK2, la kinésine Costal 2 (Cos2), et le facteur de transcription Cubitus Interruptus (Ci). Ma thèse a porté sur l’étude de la régulation et des interactions moléculaires entre les composants du complexe de transduction. Par des approches complémentaires, j’ai montré qu’en absence d’Hh, les protéines PKA et Fu interagissent du côté C-terminal de Ci, alors que la présence d’Hh induit leur relocalisation vers le domaine N-terminal de Ci. J’ai pu prouver que l’élément déclencheur de ce remaniement protéique est Smo. En présence d’Hh, Smo s’incorpore dans le complexe de transduction, conduisant à l’activation et au déplacement de Fu vers la région N-terminale de Ci. Ce remaniement entraine la phosphorylation et l’activation de Ci. Ma thèse révèle l’importance des changements de conformation au sein du complexe de transduction de la voie Hh. Le mécanisme de transduction étant conservé entre invertébrés et invertébrés, mon doctorat apporte des éléments de recherche pour mieux comprendre le fonctionnement normal et pathologique des cellules. / Hedgehog (Hh) is a secreted morphogen that controls growth and differentiation in both vertebrates and invertebrates. The dysregulation of its activity leads to severe developmental defects, and the onset of cancer in adults. In Drosophila, the Hh signal transduction is initiated by the binding of Hh to its receptor Patched (Ptc). This induces the stabilization of the transmembrane protein Smoothened (Smo) and the subsenquent activation of a transduction complex consisting of 5 proteins: the kinases Fused (Fu), PKA and Gprk2, the kinesin Costal2 (Cos2), and the transcription factor of the pathway Cubitus Interruptus (Ci). The aim of my thesis was to study the regulation and molecular interactions between the different components of the transduction complex. Thanks to complementary techniques, I have shown that in absence of Hh the proteins Fu and PKA interact in C-terminal part of Ci, whereas on the presence of Hh induces their relocalization toward the N-terminal domain of Ci. I have proved that the trigger element of this moving is Smo. In presence of Hh, Smo goes into transduction complex, allowing the activation and the moving of Fu toward N-terminal domain of Ci. This relocalization is responsible of Ci phosphorylation and activation. My thesis reveals the importance of conformational changes inside the transduction complex of Hh pathway. As the mechanism of transduction is conserved between species, my PhD provides research elements in order to better understand the normal and abnormal functioning of cells.

No description available.

Die Forschung an porösen Hybridmaterialien hat sich rasch entwickelt, und in letzter Zeit ist die Anzahl neuer Strukturen und Zusammensetzungen aufgrund ihrer vielfältigen Anwendungsmöglichkeiten im Bereich des Kristall-Engineering von großem Interesse. Metall-organische Gerüste (metal-organic frameworks, MOFs) sind eine aufstrebende Klasse von Nanomaterialien, deren Eigenschaften durch Variation der Bausteine, die aus Metallionen und organischen Liganden bestehen und sich koordinativ zu einer dreidimensionale Struktur verbinden lassen, leicht angepasst werden können. Eigenschaften wie eine große Oberfläche und eine hohe Porosität verleihen diesen Materialien vielversprechende Eigenschaften, um als Wirtsmaterial verwendet zu werden. Die vorliegende Arbeit konzentriert sich auf die Synthese der Verbindung [Fe3O(H2O)2(OH)(bdc)3]n (bcd = 1,4-Benzoldicarboxylat; MIL-101(Fe), MIL = Materials of Institut Lavoisier), die aus einem carboxylato-verbrückten, oxido-zentriertem, dreikernigen Fe3+-Komplex besteht. Die Struktur besitzt große Poren (Ø: 29 und 34 Å) und eine große Oberfläche mit der Fähigkeit, zahlreiche Moleküle einzuschließen. In der vorliegenden Arbeit wird MIL-101(Fe) als Arzneimittelabgabesystem verwendet. Curcumin, Capecitabin und 5-Fluorouracil (5-FU) wurden als Modellarzneimittel für die Verkapselung in der MIL-101(Fe)-Struktur ausgewählt. Es wurden verschiedene Freisetzungsregime in unterschiedlichen biologischen Medien untersucht. Nach vielversprechenden ersten Ergebnissen bei der Freisetzung dieser Medikamente aus der MIL-101(Fe)-Struktur wurde anschließend die selektive Lasersintertechnik (SLS) verwendet. Die SLS ist ein additives Schichtbauverfahren, das sich in dieser Arbeit als ressourcenschonende Technologie für die schnelle Herstellung erwiesen hat. Die Möglichkeit, die Größe, Form und Geometrie der hergestellten Proben individuell anzupassen, bot die Gelegenheit, die Wirkstofffreisetzung zu modulieren und den Freisetzungszeitraum zu verlängern. / The field of porous hybrid materials has grown rapidly; recently the number of new structures and compositions are of great interest in the crystal-engineering field, due to their various possible applications. Metal-organic frameworks (MOFs) are an emerging class of nanomaterials, whose properties can be easily adjusted by varying the molecular building blocks, obtained from metal ions and organic ligands that can be combined to three-dimensional structures. Properties such as high surface area and high porosity give these materials promising characteristics to be used as host materials. The present work focuses on the synthesis of [Fe3O(H2O)2(OH)(bdc)3]n (bcd = 1,4-benzenedicarboxylate; MIL-101(Fe), MIL = Materials of Institut Lavoisier), composed of carboxylate-bridged, oxido-centered, trinuclear Fe3+ complexes. The iron-based structure features large pore sizes (Ø: 29 and 34 Å) and high surface area with the ability to encapsulate numerous molecules, for use as a drug delivery system in the present work. The curcumin, capecitabine, and 5-fluorouracil (5-FU) were chosen as model drugs for the encapsulation into the MIL-101(Fe) structure. Different delivery regimes were studied in different biological media. After promising initial results with the release of these drugs from the MIL-101(Fe) structure, the selective laser sintering technique (SLS) was introduced subsequently. The SLS is an additive layer manufacturing technique that has emerged in this work as a resourceful technology for rapid manufacturing, the possibility to customize the size, shape, and geometry of the manufactured samples, thus providing the opportunity to modulate the drug release extending it for even longer periods of time.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal. / La thèse se propose d'analyser le développement du fu lyrique sous les Six Dynasties (220-589). Comme le lyrisme est une notion occidentale, il faudra, avant d'aller du côté chinois, expliquer sa signification en Occident et voir ensuite comment elle peut être appliquée à la Chine tout en respectant son intégrité et sa spécificité culturelles. La thèse montrera comment le narratif et le descriptif font partie du lyrisme ainsi que l'expression des sentiments personnels. Des textes critiques tels que L'esprit littéraire et la sculpture de dragons de Liu Xie et les préfaces à certains fu, entre autres, seront utilisés afin de toujours garder à l'esprit la façon chinoise de concevoir le poème lyrique. Le nouvel horizon épistémique des Six Dynasties sera aussi présenté et son impact sur les fu et les shi sera discuté. Le fu est un genre littéraire mi-descriptif, mi-narratif, qui combine prose et rimes et qui a aussi hérité de quelques éléments venant du shi ; c'est pourquoi il en sera question ici. Le Fu sur la résidence dans les faubourgs de Shen Yue (441-513) a été choisi pour illustrer le lyrisme car au-delà de la forme rigoureuse dictée par le genre, Shen Yue y a introduit de nouveaux éléments. Le premier chapitre définira le genre, discutera de ses origines à l'aide de l'opinion des chercheurs qui s'y sont consacrés et en décrira les caractéristiques sous les dynasties Han (-206-+220). Loin de rester stable, il évoluera vers le lyrisme à la fin de ces dynasties. Pour le montrer, des fu de Sima Xiangru, Yang Xiong et Zhang Heng seront présentés. Au deuxième chapitre, il sera question de l'évolution du fu lyrique depuis la fin des Han jusqu'à Tao Qian. Puis il sera question de l'autre genre en développement, le shi. Après une brève récapitulation de ses origines, les Dix-neuf poèmes anciens, des shi de Ruan Ji et de Xie Lingyun seront présentés afin de discerner comment ce genre a évolué. Ceci permettra d'évaluer la contribution de Shen Yue à cet égard en regardant ses fu et ses shi. Cela mène naturellement au troisième chapitre qui se penchera sur le Fu sur la résidence dans les faubourgs, mais en gardant en perspective le Fu sur la résidence en montagne de Xie Lingyun, qui a servi de "modèle" à celui de Shen Yue. Cependant tel n'est pas le cas et ce chapitre s'appliquera à le montrer en examinant le traitement que Shen Yue a fait des narrations et des descriptions, du parallélisme, de la métrique et de la prosodie. Cet examen permettra de voir que le temps et l'espace sont traités de façon particulièrement intéressante par Shen Yue et que son fu n'est nullement une imitation de celui de Xie Lingyun. Il a raccourci les sections descriptives et a introduit des narrations historiques en faisant de fréquents passages de l'une à l'autre. Shen Yue joue beaucoup avec les couleurs et les formes. Sa poésie comporte donc un aspect visuel important, et dans tout ceci, c'est sa vision de la réclusion qu'il apporte. Cette vision est en accord avec l'horizon épistémique des poètes des Six Dynasties. Le fu des Six Dynasties a été peu étudié et cette étude aura permis de dégager son fonctionnement et ses caractéristiques. En appendice, on retrouvera une traduction française annotée de ce fu. Vu qu'il n'existe que deux traductions anglaises, et une partielle, en japonais, de ce fu, j'ai alors décidé de présenter ma propre traduction.

No / Background Effective and tolerable chemotherapy with gemcitabine and cisplatin for advanced biliary tract cancer (BTC) has been established recently. However, overall prognosis is still poor, and additional therapeutic approaches are needed for patients with locally advanced, irresectable and/or pretreated tumors. Hepatic arterial infusion (HAI) of chemotherapy represents a safe and well-established treatment modality, but data on its use in patients with BTC are still sparse. Methods Patients with irresectable BTC predominant to the liver were included in a prospective, open phase II study investigating HAI provided through interventionally implanted port catheters. Intraarterial chemotherapy consisted of biweekly oxaliplatin (O) 85 mg/m2 and folinic acid (F) 170 mg/m2 with 5-FU (F) 600 mg/m2. Results Between 2004 and 2010, 37 patients were enrolled. A total of 432 cycles of HAI were applied with a median of 9 (range 1–46) cycles. Objective response rate was 16 %, and tumor control was achieved in 24 of 37 (65 %) patients. Median progression-free survival was 6.5 months (range 0.5–26.0; 95 % CI 4.3–8.7), median overall survival was 13.5 (range 0.9–50.7; 95 % CI 11.1–15.9) months. The most frequent adverse event was sensory neuropathy grade 1/2 in 10/14 patients. Conclusions Using a minimal invasive technique, repetitive HAI with OFF is feasible and results in clinically relevant tumor control with low toxicity in patients with liver predominant advanced BTC.

The purpose of this study is to investigate and analyze stops that occur in the painting process of trucks; specifically related to the buffer system after the top coat process. Based on this investigation, improvements are presented in order to eliminate stops and improve overall assembly time. With this scope in mind, the following issues have been raised:   1.     What are the root causes for stops in the buffer system? 2.     How much can corrective maintenance be reduced? 3.     What potential savings are achieved by reducing or eliminating stops in the buffer system? 4.     How would reducing stops increase the availability for the top coat paint shop?   A case study has been performed where historical data has been analyzed and staff from the production, maintenance and IT departments have been interviewed. The analyzed data along with a theoretical framework are the basis for the suggested actions that will improve flows through the top coat production. The result indicates that a great part of the delays related to the buffer system are caused by soft losses. The stops are the results of: Lack of a distinct set of rules for how data and software may be used Lack of communication between the workshops The implications of these delays are: increased costs and reduced efficiency of the production line. The purposed actions presented in the study gives the company opportunity to achieve full capacity, eliminate delays and increase overall efficiency. The study is limited to the top coat paint shop and does not include the primary paint shop or final assembly. The results, analysis and suggestions presented in the study includes the soft losses that causes stop in the buffer system. / Syftet med följande studie är att undersöka och analysera stopp och dess rotorsaker som uppkommer i buffertsystemet på ett täcklacksmåleri. Utifrån denna utredning presenteras sedan åtgärdsförslag i syfte att eliminera undersökta stopp. För att kunna uppfylla syftet med studien har följande frågeställningar formulerats:   Vad finns det för stopp relaterade till buffertsystemet och vad är rotorsakerna till dessa? Hur mycket kan det akuta underhållet reduceras? Hur stora besparingar skulle företaget kunna göra genom reducering eller eliminering av stoppen? På vilket sätt kan en minskning av stoppen öka tillgängligheten för täcklacksmåleriet?   En fallstudie har genomförts där historisk data har analyserats och personal från avdelningar som produktion, underhåll och IT har intervjuats. Den empiri som samlats in tillsammans med det teoretiska ramverket som presenteras i rapporten ligger till grund för resultatet, analysen och åtgärdsförslagen.   Resultatet från studien visar att en stor andel av de stopp som sker i buffertsystemet orsakas av mjuka förluster. Dessa stopp är en konsekvens av bristfällig hantering av data och mjukvara samt bristfällig kommunikation mellan verkstäderna. Konsekvenserna av dessa stopp resulterar i ökade kostnader samt en nedsatt effektivitet för täcklacksmåleriet. Åtgärdsförslagen som presenteras ger företaget goda möjligheter att uppnå sin fulla kapacitet, eliminera stoppen och därmed öka effektiviteten.   Studien är avgränsad till måleriprocessen och omfattas inte av grundmåleriet eller monteringen. De resultat, analyser och åtgärdsförslag som presenteras är avgränsade till de mjuka förlusterna som orsakar stopp i buffertsystemet.

With this essay I aim to illustrate the simultaneous tension between and entanglement of narratives of mire and modernity in Sara Lidman’s novel Hjortronlandet. Both mire and modernity are understood wide concepts; as temporal as well as spatial markers relating to nature. Through the theoretical frame of Kate Soper’s What is Nature?, Yi-Fu Tuan’s Space and Place and Doreen Massey’s Space, Place and Gender I explore how concepts of nature, time and place are conceptualized, discussed and rewritten in the novel. The analysis shows that nature, time and place are simultaneously understood through narratives and through the intimate experience of material surroundings. Narratives are thus discussed and rewritten when applied to new material surroundings, and the natural surroundings are experienced through already established narratives. Hjortronlandet explores the lives of poor settlers in northern Sweden during the first half of the 20th century in their attempt to convert their allotted wetland to farmland. Throughout the novel the propaganda narratives of the Swedish state clash with the settlers’ intimate experience of place and natural surroundings. All the while, the settler project is undertaken on behalf of the state and plays a part in the creation of a unified modern state. I argue that though an exploration of the perceived dichotomy of mire and modernity presented by the state the entanglement of the two concepts is made visible in the novel. By examining ostensibly contrasting positions I conclude that the novel exposes the untenable approach of the modern state to material surroundings.

Denna studie syftar på att undersöka hur Sveriges myndigheter arbetar med krishantering med fokus på oljeutsläpp till havs. Tidigare forskning visar att Sverige har ett fungerande nätverk när det kommer till krishantering (Pålsson m.fl. 2018), men i det tvärsektionella arbetet brister Sverige i sin hantering. En definierad och strukturerad ledningskultur behövs för att spara tid, för att undvika okunskap och felinformation vid krishantering som exempelvis vid oljeutsläpp. Genom innehållsanalyser av utvärderingar från två tidigare oljepåslag, Fu Shan Hai i Ystad, 2003 och Golden Trader i Tjörn, 2011 samt semistrukturerade intervjuer med berörda aktörer vid händelsen av Marco Polo’s grundstötningar i Sölvesborg, 2023 har processerna analyserats och jämförts. Med berörda aktörer syftar denna studie på myndigheter, kommuner och organisationer som verkar och samarbetar runt händelser som exempelvis oljeutsläpp. Genom en sammanvägd analys kom det fram att samverkan i händelsen med Marco Polo har förbättrats, dock förekommer brister inom kommunikation och statlig satsning för krishantering till havs, och behöver utvecklas vidare. / This study aims to examine how Swedish authorities work with crisis management, with a focus on oil spills at sea. Previous research indicates that Sweden has an effective network for crisis management (Pålsson et al., 2018), but shortcomings exist in its cross-sectional work. A defined and structured leadership culture is needed to save time, and to avoid ignorance and misinformation during crisis management, such as in the event of oil spills. By conducting content analyses of evaluations from two previous oil spills, Fu Shan Hai in Ystad, 2003, and Golden Trader in Tjörn, 2011, as well as semi-structured interviews with relevant stakeholders involved in the Marco Polo grounding in Sölvesborg, 2023, the processes were analyzed and compared. By relevant stakeholders, this study refers to authorities, municipalities, and organizations that operate and collaborate around events such as oil spills. The comprehensive analysis revealed that cooperation during the Marco Polo incident has improved; however, deficiencies in communication and state investment in maritime crisis management persist and need further development.