Les cellules Natural Killer (NK) sont des effecteurs cytotoxiques impliqués dans la réponse immune contre les infections et les tumeurs. Pendant ma thèse j’ai étudié la fonctionnalité des cellules NK humaines en réponse à des lignées cellulaires de carcinome rénal à cellules claires (RCC) et de mélanome métastatique, deux tumeurs immunogènes. Nos résultats montrent que certaines mutations de VHL augmentent la susceptibilité des lignées RCC à la lyse NK. La perte de fonction de VHL corrèle avec une expression membranaire diminuée des molécules HLA-I par les lignées RCC mutées pour VHL. Chez les patients atteints de mélanome métastatique de stade IV, nous avons décrit un phénotype particulier des NK sanguines (NKp46dim/NKG2Adim) qui leur confère une forte activité antitumorale. Après traitement des patients par chimiothérapie, la fonctionnalité NK était réduite et le phénotype modifié. Pour étudier les cellules NK infiltrant les mélanomes, nous avons mis au point des conditions expérimentales pour caractériser les cellules NK de ganglions métastatiques de patients de stade III. Nos résultats préliminaires montrent que, par rapport aux ganglions sains, les NK des ganglions métastatiques présentent un phénotype altéré et un potentiel fonctionnel diminué. Nos résultats suggèrent que d’une part l’immunogénicité dépendante des oncogènes et d’autre part les altérations NK induites par la tumeur et/ou par la chimiothérapie sont des facteurs importants à considérer dans le choix des protocoles d’immunothérapie basés sur les cellules NK. / Natural Killer cells are cytotoxic lymphocytes involved in the immune response against tumours and infections. We investigated the NK-mediated functions in response to clear-cell renal cell carcinoma (RCC) and metastatic melanoma, two human immunogenic tumours. We showed that certain VHL mutations increased RCC cell susceptibility to NK lysis. VHL loss of function correlated with lower expression levels of membrane HLA-I molecules on VHL-mutated RCC and a decreased triggering of inhibitory NK receptors compared to RCC with a functional VHL. In stage IV melanoma patients, we showed that blood NK cells displayed a unique NKp46dim/NKG2Adim phenotype and high lytic potential towards melanoma cells. Following chemotherapy, NK cell function was reduced and the phenotype modulated. To study melanoma-infiltrating NK cells, we have set up experimental conditions to characterise NK cells in metastatic LNs from stage III melanoma patients. Our preliminary data show that, compared to normal LNs, NK cells from metastatic LNs are altered. Our findings suggest that oncogenic-dependent immunogenicity, tumour-associated NK alterations and chemotherapy are important factors that must be taken into account in the choice of immunotherapeutic protocols based on NK cells.

No description available.

Autonomous systems require a lot of information about the environment in which they operate in order to perform different high-level tasks. The information is made available through various sources, such as remote and on-board sensors, databases, GIS, the Internet, etc. The sensory input especially is incrementally available to the systems and can be represented as streams. High-level tasks often require some sort of reasoning over the input data, however raw streaming input is often not suitable for the higher level representations needed for reasoning. DyKnow is a stream processing framework that provides functionalities to represent knowledge needed for reasoning from streaming inputs. DyKnow has been used within a platform for task planning and execution monitoring for UAVs. The execution monitoring is performed using formula progression with monitor rules specified as temporal logic formulas. In this thesis we present an analysis for providing spatio-temporal functionalities to the formula progressor and we extend the formula progression with spatial reasoning in RCC-8. The result implementation is capable of evaluating spatio-temporal logic formulas using progression over streaming data. In addition, a ROS implementation of the formula progressor is presented as a part of a spatio-temporal stream reasoning architecture in ROS. / Collaborative Unmanned Aircraft Systems (CUAS)

This study examines the baptismal practices of the early Christian community using Tertullian’s ethical text on baptism in relation to his other writings to dialogue with the Roman Catholic understanding of baptism, original sin and grace. Tertullian referring to the sacramental form of baptism that is done with water, held that baptism is indispensable for salvation because it imparts the grace that washes away original sin and makes someone a Christian; and capable of attaining a matured Christian life. At the moment, the Roman Catholic Church does not confer baptism of water on polygamists, and subsequently fails to admit them to her sacramental life because of their polygamous relations. This raises a question regarding the salvation of these polygamous families. How do they receive baptismal grace and become part of the church? This study argues that church and baptism were inseparable right from the beginning of Christianity in the New Testament. People became members of the church by the fact of their baptism. This study does a hermeneutical retrieval of the early church’s teaching on baptism and original sin in the light of Tertullian as the pillar of western theology. The study concludes by invoking pastoral consideration to baptize polygamous families (husband and wives) who married before converting to the faith. They are not to enter into any new marriage after baptism since they have received Christ in their state. “Go and sin no more,” says Christ. / Dissertation (MA Theol)--University of Pretoria, 2014. / gm2014 / Church History and Church Policy / unrestricted

Les cancers du rein métastatiques résistants aux inhibiteurs de tyrosine kinase peuvent faire l’objet de traitements fondés sur le blocage des points de contrôles immunitaires (ICB). Cependant, les ICB induisent des réponses chez une minorité de patients, et des efforts sont en cours pour identifier les mécanismes à l'origine de la résistance. Les ICB compromettent l'intégrité de la barrière intestinale, affectant ainsi la composition du microbiote, favorisant ainsi soit l'accumulation intestinale, soit la translocation de commensaux immunogènes capables de moduler le tonus immunitaire systémique et de reprogrammer le microenvironnement tumoral. Pour déterminer si des profils microbiens distincts du microbiote intestinal pourraient expliquer la résistance aux ICB, ma thèse a montré que dans une cohorte de 249 patients atteints de cancer traités par ICB que la prescription d’antibiotiques (ATB) a significativement diminué la survie sans progression (PFS) et la survie globale (OS) par rapport aux patients sans ATB. Nous avons confirmé ces données en analysant 121 cencers du rein traités par ICB à Gustave Roussy et 239 cancers du poumon traités par ICB au Memorial Sloan Kettering Cancer Center. Nous avons validé que la dysbiose liée à l'ATB diminue l'activité des ICB. Par la suite, nous avons analysé de manière prospective les microbiotes fécaux de 100 patients atteints de tumeurs sensibles à l'anti-PD-1 en utilisant la métagénomique (MG). Nous avons démontré que les bactéries intestinales présentes avant le traitement anti-PD-1 étaient systématiquement différentes entre les patients qui ont répondu (R) au traitement et les patients qui n’ont pas (NR). Entre les R, nous avons observé une surreprésentation d’Akkermansia muciniphila. Au sein d'une large cohorte de patients RCC (n = 85) traités avec un anticorps anti-PD-1, nous avons analysé le microbiote fécal de 69 patients. Des empreintes de MG spécifiques étaient liées aux meilleures réponses et à la survie sans progression. A. muciniphila et Bacteroides spp étaient plus abondants chez les R. Pour valider la pertinence de ces constatations, nous avons mis en évidence deux principaux éléments de preuve. Premièrement, nous avons démontré que chez les patients atteints de NSCLC, la présence de lymphocytes T CD4 + et CD8 + à mémoire spécifiques de l’IFNγ + vis-à-vis de A. muciniphila prédit une PFS plus longue. Deuxièmement, une transplantation de microbiote fécal (FMT) a été réalisée à l'aide de selles de patient pour recoloniser des souris axéniques ou traitées par ATB dans deux modèles murins. Les matières fécales de R entrainaient une réponse immunitaire plus forte contre la tumeur par rapport aux matières fécales de NR. Ensuite, une supplémentation orale d'A. muciniphila post-FMT avec des matières fécales de NR restaurait l'efficacité de l'anti- PD-1. Dans ce contexte, les cellules dendritiques sécrétaient plus d'IL-12, augmentant le recrutement de lymphocytes T CCR9 + CXCR3 + CD4 + à partir des ganglions lymphatiques mésentériques jusque dans les lits tumoraux, ainsi qu'une augmentation du rapport CD4 + /Treg dans le lit tumoral de souris co-traitées avec mAb anti-PD-1 et A. muciniphila. Enfin, nous avons montré qu'une supplémentation orale avec Bacteroides (B. salyersiae mais pas B. xylanisolvens) ou A. muciniphila pourrait restaurer l'efficacité des ICB dans un modèle FMT- défavorable/dysbiotique". La découverte de bactéries immunogènes capables de prédire et d'accroître les avantages cliniques de l'ICB contribuera au développement de nouveaux outils de biomarqueurs et d'un futur concept thérapeutique, grâce auxquels le traitement du cancer peut être amélioré par la modulation du microbiote intestinal. / Metastatic RCC resistant to tyrosine kinase inhibitors are amenable to new therapies based on immune checkpoint blockade (ICB). However, ICB induces responses in a sizeable minority of patients and efforts are ongoing in order to identify mechanisms driving resistance. ICB compromise the integrity of the intestinal barrier, hereby affecting the composition of the intestinal microbiome, thereby promoting either the intestinal accumulation or the translocation of immunogenic commensals capable of modulating the systemic immune tone and reprogramming the tumor microenvironment. To address whether distinct microbial patterns of the intestinal microbiome could account for the resistance to ICB in RCC, during my PhD I showed in a cohort of 249 patients with cancers treated with ICB that antibiotic (ATB) prescription in a therapeutic window of -2 months up to +1 month after starting ICB significantly decreased progression-free survival (PFS) and overall survival (OS) compared to patients without ATB. We confirmed this data analyzing 121 RCC treated with ICB at Gustave Roussy and 239 NSCLC treated with ICB at Memorial Sloan Kettering Cancer Center. We validated that ATB-related dysbiosis decreases activity of ICB. More precisely, patients in RCC ATB group treated with ICB had a higher rate of primary progressive disease. Subsequently, we prospectively analyzed the fecal microbiomes of 100 patients with tumours amenable to anti-PD-1 mAb using quantitative metagenomics (MG) by shotgun sequencing. We demonstrated that gut bacteria present before anti-PD-1 therapy was consistently different between patients who responded (R) to treatment and patients who did not (NR). In R we observed an overrepresentation of un- and classified Firmicutes. The commensal most significantly associated with favorable clinical outcome and PFS was Akkermansia muciniphila. Within a large cohort of RCC patients (n = 85) treated in the NIVOREN study with anti-PD-1 Ab at Gustave Roussy, we analyzed the fecal microbiome of 69 patients. Specific MG-fingerprints were related to best responses and PFS. A. muciniphila and Bacteroides spp were more abundant in R (Derosa et al. ASCO Merit Award 2018). To validate the relevance of these findings, we brought up two major lines of evidence. First, we demonstrated that in NSCLC patients, the presence of specific IFNγ+ memory CD4+ and CD8+ T cells toward A. muciniphila predicted a longer PFS. Secondly, fecal microbiota transplantation (FMT) was performed using patient feces to recolonize germ-free or ATB-treated mice in two tumor models (MCA-205 and RENCA, the renal cell carcinoma model). Feces from R conveyed a stronger immune response against the tumor compared to feces from NR. Next, in MCA-205 model oral supplementation with A. muciniphila post-FMT with NR feces restored the efficacy of PD-1 Abs. In this setting, dendritic cells secreted more IL-12, increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes from the mesenteric lymph nodes into tumor beds as well as an increase of CD4+/Treg ratio within the tumor bed of mice co-treated with anti-PD-1 mAb and A. muciniphila. Finally, we showed that oral supplementation with Bacteroides (B. salyersiae but not B. xylanisolvens) or A. muciniphila could restore the efficacy of ICB in "unfavorable/dysbiotic" FMT. The discovery of immunogenic bacteria capable of predicting and increasing clinical benefit of ICB will help for the development of novel biomarker tools and a future therapeutic concept, whereby treatment of cancer can be improved by the modulation of gut microbiome.

This thesis has discussed both properties and geometry of concrete slabs used in bridges. It gave understanding on behavior of concrete in both tension and compression zones and how crack propagates in specimens by presenting both theory of fracture and performing concrete tests like tension splitting, uniaxial compression and uniaxial tension tests. Furthermore, it supported experimental tests with finite elements modelling for each test, and illustrated both boundary conditions and loads. The thesis has used ARAMIS cameras to observe crack propagations in all experimental tests, and its first study at LNU that emphasized on Brazilian test, because of importance of this test to describe both crushing and cracking behavior of concrete under loading. It’s an excellent opportunity to understand how concrete and steel behave individually and in combination with each other, and to understand fracture process zone, and this has been discussed in theory chapter. The geometry change that could affect stresses distributions has also described in literature and modelled to give good idea on how to model slabs in different angles in the methodology chapter. Thus, thesis will use finite elements program (Abaqus) to model both experimental specimens and concrete slabs without reinforcement to emphasize on concrete behavior and skewness effect. This means studying both properties of concrete and geometry of concrete slabs. This thesis has expanded experimental tests and chose bridges as an application.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

A exploração de tecnologias sustentáveis facilitará a adequação dos municípios brasileiros à Política Nacional de Resíduos Sólidos (PNRS) instituída em 2010 e que deve ser aplicada a todos os municípios brasileiros, sejam de grande, médio ou pequeno porte. Entre os diferentes tipos de resíduos gerados no País e no mundo, os resíduos da construção civil, também conhecidos como RCC, ficam no topo da geração de resíduos sólidos, e os mesmos merecem atenção. Os municípios de pequeno porte ainda sofrem algumas dificuldades de elaboração de de diretrizes e implantação da PNRS. O presente estudo propôs subsídios e alternativas para a criação de um plano de gestão e gerenciamento dos resíduos da construção civil para cidades de pequeno porte, e suas vantagens, como forma de minimizar os impactos ambientais gerados por esse resíduo proveniente das diversas atividades da indústria construtiva, e seu efetivo crescimento. Para isto, ainda foi estudado a necessidade e viabilidade da reciclagem dos RCC, pois uma das principais ações incentivadas pela resolução é a reinserção destes resíduos no ciclo produtivo. O trabalho ainda aborda as principais dificuldades e carências que estas municipalidades encontram em seguir e cumprir as leis vigentes para o seu porte. Para isto foi realizado um amplo levantamento bibliográfico que proporcionasse o maior número de alternativas possíveis na criação dos subsídios, e que demonstrasse experiências já enfrentadas por pequenas cidades em se inserir corretamente no que as legislações impõem as mesmas. Foi observado que os municípios de pequeno porte tem dificuldades em elaborar seus planos de gestão no tratamento de resíduos, como falta de recursos para investimentos próprios, e corpo técnico preparado, além de sofrerem uma grande carência de suporte por parte de entidades públicas para se adequarem as leis, e ainda há falta de planejamento adequado das prefeituras em organizarem um plano específico para cuidarem e direcionarem seus RCC, do não conhecimento do assunto por parte da própria população quanto a alternativas de não geração dos mesmos, reuso e disposição correta. / Exploring sustainable technologies will facilitate the adaptation of municipalities to the National Solid Waste Politics (PNRS) established in 2010 and should be applied to all municipalities, whether large, medium or small. Among the different types of waste generated in the country and the world, the construction waste, also known as RCC, are on top of the solid waste generation, and they deserve attention. The small municipalities still suffer some difficulties in the implementation and management of PNRS. This study proposed subsidies and alternatives to the creation of a management plan and management of construction waste to small towns, and its advantages, in order to minimize the environmental impacts generated by this waste from the various activities of the design industry and its actual growth. For this, we have studied the need and feasibility of recycling of RCC, as one of the main actions encouraged by the resolution is the reinsertion of this waste in the production cycle. The work also addresses the main difficulties and shortcomings that these municipalities are to follow and comply with the laws in force for their size. For this we conducted a broad literature that provided the largest number of possible alternatives in the creation of subsidies, and to demonstrate experience already faced by small towns to insert correctly in the laws impose the same. It was observed that the small towns teem difficulties in drawing up their management plans in waste, such as lack of resources for own investments, and prepared staff and suffer a great lack of support by public entities to suit the laws, and there is still a lack of adequate planning of municipalities in organizing a specific plan to care and direct their RCC not a matter of knowledge by the population itself as not generating alternatives thereof, reuse and proper disposal.

Submitted by Cássio da Cruz Nogueira (cassionogueirakk@gmail.com) on 2017-02-13T14:44:27Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_InfluenciaAditivoPolimerico.pdf: 2018043 bytes, checksum: a406f2a853c1d90aabe95e5973eb2e0e (MD5) / Approved for entry into archive by Edisangela Bastos (edisangela@ufpa.br) on 2017-02-15T12:25:45Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_InfluenciaAditivoPolimerico.pdf: 2018043 bytes, checksum: a406f2a853c1d90aabe95e5973eb2e0e (MD5) / Made available in DSpace on 2017-02-15T12:25:45Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_InfluenciaAditivoPolimerico.pdf: 2018043 bytes, checksum: a406f2a853c1d90aabe95e5973eb2e0e (MD5) Previous issue date: 2015-05-12 / As argamassas são consideradas como um sistema particulado em suspensão com agregado miúdo, aglomerante, água e aditivo polimérico constituinte orgânico. Fatores como granulometria, teor de cimento, cinza e aditivo em sua composição influenciam nas propriedades da argamassa tanto no estado fresco quanto no estado endurecido. Foi realizado o estudo reológico e de ensaio mecânico em argamassa elaborada para assentamento e revestimentos pela incorporação do aproveitamento de rejeito da construção civil (RCC) como agregado miúdo e cinza volante resíduo mineral proveniente da combustão das caldeiras da empresa HYDRO ALUNORTE. O presente trabalho visa desenvolver uma argamassa modificada por polimero que possua como aglomerante Cimento Portland CPII E-32RS e cinza volante e como agregado miúdo areia e RCC aditivada por poliacetato de vinila (PVA). Foi realizado o estudo da influência do cimento, da cinza, da granulométrica dos agregados e do uso de aditivo polimérico PVA nas propriedades da argamassa. Os materiais foram submetidos à caracterização física e química através de análise granulométrica, fluorescência de raio-x e FTIR. Na elaboração dos corpos de provas foi realizado o estudo de 6 traços com 5% em massa de cimento e 3 traços com 10% em massa de cimento, ambos com diferentes teores de cinza, areia, RCC e mantendo quantidade de cimento portland constante. Ainda foi avaliado a comparação das propriedades mecânicas e reológicas dos traços com e sem PVA. Os traços no estado fresco foram submetidos a ensaio reológico. Após 28 dias de cura os corpos de prova dos traços já no estado endurecido foram submetidos a ensaios de resistência mecânica a compressão, massa especifica, absorção aparente e porosidade aparente. A pesquisa demonstrou que o emprego de aditivo polimérico a base de PVA melhorou as propriedades mecânicas da argamassa elaborada com rejeitos industriais além de garantir comportamento reológico satisfatório para possível aplicação da mesma na construção civil. / Mortars are considered to be particulate systems in suspension with fine aggregate, binder, water and organic polymeric additive. Factors such as granulometry, cement, ash and additive contents in their composition influence mortar properties in both the fresh and hardened states. A rheological study and mechanical test were performed on mortar prepared for floors and coatings through incorporating civil construction wastes (RCC) such as fine aggregate and fly ash, a mineral waste derived from combustion in boilers at the HYDRO ALUNORTECompany. This study seeks to develop a polymeric mortar that uses CPII E-32RS Portland cement andflyashas binders and fine sand and RCC with polyvinyl acetate (PVA) as aggregates. A study was performed on the influence of cement, ash, granulometry of aggregates and use of PVA based-polymeric additives on mortar properties.The materials were submitted to physical and chemical characterization using granulometric analysis, X-ray fluorescence and FTIR. In preparing the specimens, 6 formulas with 5% cement and 3 formulas with 10% cement were used, both with different levels of ash, sand and RCC andmaintaining a constant level of Portland cement content. A comparison of the mechanical and rheological properties of formulas with and without PVA was also made.Formulas in a fresh state were submitted to rheological tests. After 28 days of curing specimens of these formulas, by then in a hardened state, were submitted to tests for mechanical resistance to compression, specific mass, apparent absorption and apparent porosity. The research demonstrated that employing a PVA-based polymeric additive improved the mechanical properties of the mortar prepared with industrial wastes, as well as guaranteeing satisfactory rheological behavior for possible applications of such mortars in civil construction.

Renal Cell Carcinoma (RCC) has low 5 year survival rate and is resistant to radiation and chemotherapy. Phenethyl Isothiocyanate (PEITC) is a naturally occurring phytochemical that has a variety of anti-cancer properties. Here we explore two anti-cancer properties of PEITC: induction of apoptosis and induction of cell cycle arrest in RCC cells and the underlying mechanisms. We used two human RCC cell lines Caki-1 and Caki-2. Survival and cell proliferation was assayed using Calcein AM. Annexin V staining was used to measure apoptosis. Caspase-3/7 induction was measured using a fluorescent substrate. Cell cycle was studied using Propidium Iodide staining. DNA damage was determined using phospho [gamma]-H2AX antibody. Protein expression and phosphorylation was determined using immunoblotting. PEITC significantly reduced survival of Caki-1 and Caki-2 cells and inhibited their proliferation as determined by Calcein AM. 15 and 20 [mu]M PEITC induced apoptosis in both cell lines and induced caspase-3/7 activity. Western blot analysis revealed caspase-8, caspase-9 and Bid cleavage as well as upregulation of the death receptors Fas and DR5. Lower doses (up to 10 [mu]M) arrested Caki-1 cells in G2/M phase, and this was associated with increased p38 and MK2 (Thr334) phosphorylation. The p38 inhibitor SB203850 inhibited this G2 arrest induced by PEITC. 15 and 20 [mu]M PEITC treatment resulted in increased [gamma]-H2AX phosphorylation suggesting DNA damage, but this was completely blocked by caspase inhibitor. In summary, our study shows that PEITC induces apoptosis in Caki-1 and Caki-2 cells by upregulating Fas and DR5 and activating the downstream apoptosis cascade. PEITC does not cause direct DNA damage to the cells; the observed DNA damage is a result of the apoptotic process and is blocked by caspase inhibitor. PEITC induces G2/M arrest in Caki-1 cells and the mechanism involves p38 phosphorylation which activates MK2. Inducing cell cycle arrest and apoptosis may play an important role in the anti-cancer properties of PEITC. Fully understanding the mechanism by which PEITC induces apoptosis and cell cycle arrest in RCC cells may lead to development of novel chemotherapeutic drugs against RCC. / text