Vinyl acetate (VA) is an important monomer used in the production of paints, surface coatings and adhesives. Synthesis of VA is usually carried out over supported Pd alloy catalysts with a selectivity as high as 96% and described as C2H4 + CH3COOH + ½ O2 -> C2H3OOCCH3 + H2O Although the VA synthesis reaction has been industrially carried out for many years, the nature of the active sites and the reaction mechanism is still unclear. The goal of this study was to acquire a fundamental understanding of the VA reaction mechanism by carrying out detailed kinetic and spectroscopic investigations on single crystals and supported Pd catalysts, and to detail the role of alloying in optimizing the selectivity of this important industrial reaction. A combination of surface science techniques and kinetic measurements has been used to address the mechanism. Supported catalysts, 1 wt% Pd/SiO2 and 5 wt% Pd/SiO2, and 1 wt% Pd-0.5 wt% Au/SiO2, were prepared by an incipient wet-impregnation method and characterized using XRD and TEM. On Pd-only catalysts the reaction rates were found to be: Pd(100) < 5 wt% Pd/SiO2 (dpd = 4.2 nm) < 1 wt% Pd/SiO2 (dpd = 2.5 nm). Particle size-dependence of the reaction rates is evident for the Pd-only catalysts, which suggests a degree of structure sensitivity of the reaction. There is an increased availability of uncoordinated, edge atoms on small particles. With a Pd single crystal, fewer less-coordinated surface sites are present compared to a comparable area on a small Pd particle on a supported Pd catalyst. The formation of Pd carbide (PdCx) during the synthesis of VA was investigated over Pd/SiO2 catalysts with two different Pd particle sizes, as well as over a Pd-Au/SiO2 mixed-metal catalyst. XRD data indicate that smaller Pd particles show greater resistance to the formation of PdCx. The alloying of Au with Pd is apparently very effective in preventing PdCx formation in Pd-based catalysts for VA synthesis. Addition of Au to Pd/SiO2 catalysts significantly enhances the VA formation rate and selectivity. Infrared reflection absorption spectroscopy (IRAS) of CO on Pd/Au(100) and Pd/Au(111) confirms the presence of Pd as isolated monomers on a Au-rich surface. A pair of Pd monomers is the most favorable active site for the formation of VA. The spacing between the two active isolated Pd atoms is critical and is demonstrated by the relative rates of VA formation on Pd/Au model catalysts, i.e. Pd/Au(111) < Pd/Au(100). The role of Au is to isolate the surface Pd atoms and thus suppress the formation of by products, CO and CO2. A pair of Pd monomers required for VA synthesis is further confirmed by the results from model studies of Sn-Pd.

Existing research shows the importance of teacher professional development and that decisions regarding professional development in schools lie with administrators. However, while studies have been conducted on the need for administrators fostering professional development in schools in the USA, there appears to be limited research on administrator views of professional development in international school environments. The purpose of this study was to consider views of administrators in international schools regarding professional development activities. Using a mixed methods sequential explanatory design, a questionnaire followed by in-depth interviews, data was collected from a convenience and purposive sample of administrators from international schools in Europe, Asia, Africa, Latin America and the Middle East so as to explore and provide answers to the main research question: “What are the views of administrators on how professional development is planned, implemented, evaluated and resourced in international schools?” Findings from quantitative data indicated strong agreement that administrators should work collaboratively with teachers to determine the professional development needs of the school and that teachers should be involved in assessing professional development effectiveness. Analysis of qualitative data indicated the following themes: teachers are sent to conferences/workshops for professional development or content experts are brought to the school; decisions about professional development should align with school goals; professional development needs should be determined by teachers and administrators collaboratively; there are no significant professional development evaluation processes in place; 2% of the budget is standard allocation in schools for professional development and school boards approve the budget while administrators decide on allocation. By addressing the study’s purpose, this research seeks to contribute to the larger conversation on how administrator views on professional development in international schools can add knowledge to the limited research on effective avenues to professional development in the international school context.

Size-selected Pd nanoparticles were synthesized by the reverse-micelle encapsulation method and deposited on a ZrO2 support for the catalytic NO reduction by H2. All of our samples were found to be highly selective, but a significant size effect was not seen for Pd nanoparticles of between 1.2 nm and 5.5 nm. Ultra-small Pd clusters of less than 1 nm were found to be much less active, and are assumed to be affected by an encapsulation effect of the support. Catalyst activity was comparable to that of literature, and is applicable to H2-SCR research.

Melanoma is a highly malignant neoplasia with high rates of metastasis in humans and dogs. Regardless of being considered a highly immunogenic neoplasm, the function of the immune system is hampered by the expression of immune checkpoint molecules by the cancer cells. In contrast, soft tissue sarcomas are poorly immunogenic, as Tumor infiltrating Lymphocytes are lacking, or when present they are usually at the periphery of the tumor. Still, soft tissue sarcomas are considered immunosuppressed. Checkpoint molecules from the PD-axis are overexpressed in numerous human malignant neoplasia and have recently gained attention with a few reports in canine tumors. Immunotherapies against these checkpoint molecules have shown great efficacy in humans, but in order to determine translational approaches into canine patients, more research is needed. Here we determined the gene expression of Programed Death receptor-1, and its ligands PD-L1 and PD-L2 in canine tumors with two distinct immune profiles. Our results show that regardless of their immune profiles, melanoma versus soft tissue sarcoma, checkpoint molecules expression was higher in malignant tumors with a higher grade. Additionally, we evaluated the expression of these molecules in a set of patients that received histotripsy, which is a non-invasive and non-thermal ultrasound focused therapy that induces mechanical stress to the cells, leading to liquefactive necrosis. Here we reported a focal decrease of the expression of these checkpoint molecules in tissue sections obtain at the treatment interface, compared to those taken from untreated areas of the tumor. In addition, a positive relationship was noticed between the infiltration of CD3+ T lymphocytes and the expression of these checkpoint molecules in both canine melanoma, and soft tissue sarcoma. Our findings demonstrate that immunotherapies targeting these checkpoint molecules have a great potential for efficacy in canine neoplasia, along or combined with tumor ablation therapies that increased immune cell infiltration in poorly immunogenic neoplasia. / Doctor of Philosophy / Melanoma is a highly malignant tumor and very resistant to therapy for humans and dogs. At the same time, this neoplasia is usually highly infiltrated by cells from the immune system. However, this immune infiltration is often inhibited by molecules expressed by the melanoma cells. In contrast, soft tissue sarcoma is considered poorly immunogenic, as they often contain low levels of immune cell infiltrates but are still considered immune suppressed. In this study, we determined the expression of molecules that inhibit the effect of T lymphocytes, specifically Programed cell death receptor-1, PD-Ligand 1, and PD-Ligand 2 for these neoplasms with distinct immune profiles. We encounter that despite their immune profiles, the expression of these molecules is higher in malignant tumors. Additionally, we evaluated the expression of these molecules in a set of patients that received histotripsy, which is a non-invasive and non-thermal focused ultrasound therapy that induces mechanical stress to the cancerigenous cells, leading to its death (necrosis). Here we reported a focal decrease of the expression of these checkpoint molecules in tissue sections obtain at the treatment interface, compared to those taken from untreated areas of the tumor. In addition, a positive relationship was noticed between the infiltration of T lymphocytes and the expression of these checkpoint molecules in both canine melanoma, and soft tissue sarcoma. Our findings demonstrate that immunotherapies targeting these checkpoint molecules have a great potential for efficacy in canine neoplasms, along or combined with tumor ablation therapies that increased immune cell infiltration in poorly immunogenic neoplasia.

Thesis Abstract. The purpose of this thesis is to examine Old English and Old Icelandic literary examples of monstrosity from a modern theoretical perspective. I examine the processes of monstrous change by which humans can become identified as monsters, focusing on the role played by social and religious pressures. In the first chapter, I outline the aspects of monster theory and medieval thought relevant to the role of society in shaping identity, and the ways in which anti-societal behaviour is identified with monsters and with monstrous change. Chapter two deals more specifically with Old English and Old Icelandic social and religious beliefs as they relate to human and monstrous identity. I also consider the application of generic monster terms in Old English and Old Icelandic. Chapters three to six offer readings of humans and monsters in Old English and Old Icelandic literary texts in cases where a transformation from human to monster occurs or is blocked. Chapter three focuses on Grendel and Heremod in Beowulf and the ways in which extreme forms of anti-societal behaviour are associated with monsters. In chapter four I discuss the influence of religious beliefs and secular behaviour in the context of the transformation of humans into the undead in the Íslendingasögur. In chapter five I consider outlaws and the extent to which criminality can result in monstrous change. I demonstrate that only in the most extreme instances is any question of an outlaw’s humanity raised. Even then, the degree of sympathy or admiration evoked by such legendary outlaws as Grettir, Gísli and Hörðr means that though they are ambiguous in life, they may be redeemed in death. The final chapter explores the threats to human identity represented by the wilderness, with specific references to Guthlac A, Andreas and Bárðar saga and the impact of Christianity on the identity of humans and monsters. I demonstrate that analysis of the social and religious issues in Old English and Old Icelandic literary sources permits nuanced readings of monsters and monstrosity which in turn enriches understanding of the texts in their entirety.

The administration of soluble antigenic peptides is known to be effective at inducing tolerance in naïve antigen-reactive CD4+ T cells. This observation forms the basis of antigen-based therapy, which offers the potential to specifically target the auto-reactive CD4+ T cells involved in driving autoimmune disease pathogenesis, whilst leaving the rest of the immune system intact. The prophylactic administration of soluble autoantigen-derived peptides has proven to be effective at inhibiting disease induction in various experimental models of autoimmune disease. However, the clinical requirement is to switch off the activated antigen-experienced CD4+ T cells that are present during an ongoing immune response. The effect of soluble peptide administration of antigenexperienced CD4+ T cells is poorly understood, and several clinical trials using peptides in multiple sclerosis patients had to be halted due to the exacerbation of disease. This thesis characterises the effect of soluble peptide administration on pathogenic antigen-experienced CD4+ T cells, using experimental autoimmune encephalomyelitis (EAE) as a model of autoimmune disease of the central nervous system. Using traceable myelin-reactive T cells from Tg4 mice, it was determined that soluble peptide administration induces substantial expansion of antigen-experienced CD4+ T cells. Despite the increase in number, these cells were no longer able to induce EAE. Production of effector cytokine was significantly decreased in peptide treated antigen-reactive CD4+ T cells, and this correlated with high level expression of the co-inhibitory molecule PD-1. The induction of tolerance in both naïve and antigen-experienced CD4+ T cells was found to be dependent upon PD-1 expression, whereby peptide treatment of naïve and antigen-experienced CD4+ T cells that were deficient in PD-1, did not inhibit disease induction. This thesis identifies a novel mechanism of peptide-induced tolerance in CD4+ T cells, and demonstrates that soluble peptide administration can induce tolerance in antigen-experienced T cells.

No description available.

La chirurgie est la pierre angulaire du traitement curatif des sarcomes, lorsqu’elle est possible. En revanche, en cas de maladie avancée ou métastatique, les traitements systémiques ont une efficacité assez limitée avec un réel besoin de nouvelles options thérapeutiques. Le récent succès de l’immunothérapie dans les tumeurs épithéliales soulève donc la question de la possibilité d’une telle approche dans les sarcomes, et surtout pour quels sous-types histologiques. L’objectif de ce travail de thèse était d’obtenir des données précliniques en caractérisant le microenvironnement immunitaire au sein de trois types de sarcomes potentiellement candidats à l’immunothérapie, prérequis indispensable avant d’envisager une application clinique : 1) Dans le chondrosarcome, l’expression de PD-L1 a été retrouvée exclusivement dans près de 50% des chondrosarcomes dédifférenciés, et s’associait à une infiltration lymphocytaire T et l’expression des molécules HLA de classe I. Ces données incitent donc à inclure les patients avec ce sous type de chondrosarcome dans des essais cliniques évaluant un traitement anti PD-1/PD-L1. 2) Dans l’ostéosarcome, un infiltrat lymphocytaire T était observé de façon bien plus importante dans les lésions métastatiques que dans lésions primitives ou rechutes locales. De plus, l’expression de PD-L1 était retrouvée dans presque 50% des métastases mais pas ou peu dans la tumeur primitive correspondante, traduisant ici une dynamique d’échappement au système immunitaire lors de la progression de la maladie. Une stratégie ciblée sur les lymphocytes T visant à amplifier et potentialiser cette réponse immune préexistante dans les lésions métastatiques pourrait donc offrir un bénéfice clinique. 3) Dans le léiomyosarcome, les molécules HLA de classe I étaient fortement exprimées et l’expression de PD-L1 retrouvée dans 30% des tumeurs de haut grade, également très infiltrées par des macrophages immunosuppresseurs CD163+. Une importante infiltration de macrophages CD163+ était un marqueur indépendant de mauvais pronostic pour la survie, indiquant l’intérêt de d’une approche ciblée visant les macrophages dans ce type de sarcome, éventuellement en association avec un traitement anti PD-1/PD-L1. / Local control with adequate surgery is the cornerstone of sarcoma treatment. However, most sarcoma lack effective systemic therapies in case of advanced disease, emphasizing an unmet medical need for new therapeutic targets. The recent success of immunotherapy in epithelial malignancies raises the question whether such therapies, and which ones, would be applicable in sarcomas. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in three sarcoma subtypes potentially candidate to immunotherapy: 1) In chondrosarcoma, PD-L1 expression was exclusively found in nearly 50% of the dedifferentiated subtype, in association with immune-infiltrating cells and HLA class I expression. These data provide rationale for including such patients in clinical trials with PD-1/PD-L1-targeted therapies. 2) In osteosarcoma, we observed a high density of tumor-infiltrating T cells in metastatic lesions compared to primary tumors and local relapses. Furthermore, PD-L1 positivity in almost half of metastases while mainly negative in the associated primary tumors, emphasises the dynamics of an adaptive mechanism of immune escape. Enhancing the preexisting immune response in metastatic lesions using T-cell-based immunotherapy may offer clinical benefit. 3) In leiomyosarcoma, HLA class I molecules were strongly upregulated and PD-L1 expression found in 30% of high-grade tumors, which were also highly infiltrated with CD163+ immunosuppressive macrophages. CD163+ was found to be an independent poor prognostic factor for overall survival, indicating the need for assessing a macrophage-targeted approach in this tumor type, as single agent or in combination with anti PD-1/PD-L1agents.

One of the key elements to the success of Pd-Ag membrane based reactor for the H2 production is the synthesis of thin and highly selective membranes using the electroless plating method. This work describes the effect of electroless plating conditions on the obtained Pd and Ag deposits properties (morphology, compactness, phase structure, compositional homogeneity and adhesion) important from synthesis of thin and H2 selective membrane viewpoint. Both sequential and co-deposition deposition methods were investigated. The conventional Pd and Ag plating conditions (NH3+EDTA based bath) produced dendritic and non-uniform sequential (multi layer) deposits, not suitable for synthesizing the thin and H2 selective Pd-Ag membranes. Ag under the conventional plating conditions deposited at high overpotential resulting in the dendritic and non-uniform sequential deposits. The modified Ag plating conditions eliminated Ag deposition at high overpotential and the sequential deposits obtained were non-dendritic and uniform. Thin (< 10 µm thick) and H2 selective Pd-Ag membranes were successfully synthesized using the modified Ag plating conditions. The membranes were then successfully annealed at 550 oC. After the annealing step, the membranes showed activation energy for the H2 permeation (4.3-11.5 kJ/mole) lower than that of the pure Pd membrane (12-16.4 kJ/mole) meaning that the Pd-Ag membranes were more effective for the H2 separation at lower temperatures than the pure Pd membrane. A Pd-Ag (20 wt%) membrane showed H2 permeance higher by a factor of 2.47 at 250 oC than the pure Pd foil. The Pd-Ag membranes also showed decline in the H2/He selectivity on exposure to the annealing and H2 permeation (300-500 oC) study conditions. The Pd-Ag co-deposits obtained (using NH3+EDTA bath) were dendritic, inhomogeneous with poor substrate adhesion, therefore not suitable for the membrane synthesis. The co-deposits were bi-metallic and required the annealing step to form the Pd-Ag alloy. There existed a large difference in the deposition potentials (600 to 650 mV) of Pd and Ag. The Ag deposition was severely controlled by its mass transfer in the solution resulting in the dendritic and inhomogeneous deposits. Among the different complexing agents investigated, KCl showed the least difference between the Pd and Ag deposition potentials. The co-deposits obtained using the KCl bath were non-dendritic, homogeneous and were Pd-Ag alloy therefore required no annealing step. Finally, the multi step plating, annealing and polishing approach was used to avoid the decline in the selectivity of the sequentially prepared Pd-Ag membranes. The membranes prepared by the plating, annealing and polishing approach showed very high selectivity (H2/He) and no decline in the selectivity was observed between 300-450 oC for the total exposure time > 550 h (> 200 h at 450 oC).

Cancer is the second most common cause of death in the United States behind heart disease. While current treatments such as surgery, chemotherapy, and radiation therapy are effective and widely used, medicine is moving towards more targeted and personalized therapies. Immunotherapy is one such treatment that utilizes the patient’s own immune system to target and eliminate tumor cells. It allows for the patient’s adaptive immune system to bypass the self-tolerance mechanisms used by the cancerous cells and be activated against the cancer. Two such self-tolerant mechanisms that are co-opted by tumor cells are the interactions between CTLA-4 and T lymphocytes and the interactions between PD-1 and PD-L1. Blocking these interactions allows for the recruitment of CTLs to the site of the tumor and subsequent attack. CTLA-4 and PD-1 are inhibitory costimulators that play a role in the suppression of the adaptive immune system. The interaction of these receptors with their respective ligands leads to self-tolerance, and is a common mechanism used as a protective measure against autoimmune reactions. Monoclonal antibodies against these two receptors and ligand have been tested in clinical trials and have shown efficacy against ovarian cancers, non-small cell lung carcinomas, colon cancers, and melanomas. By targeting the inhibitory signals, these monoclonal antibodies expose cancer cells as being “non-self” thus prompting the immune system to attack. Now, studies are focusing on combination therapies, which combine chemotherapeutics or other monoclonal antibodies with PD-1 and CTLA-4 inhibitors to enhance the effectiveness of the drug. However, drawbacks and side effects to the therapy range from fatigue and nausea to development of autoimmune diseases. It brings forward that future studies will need a panel of predictive biomarkers to identify the best candidates for the immunotherapy. While there are many obstacles, such as a lower than expected efficacy of the immunotherapy, the progress made has important implications in the development of personalized medicine.