Rozprawy doktorskie na temat „Cell state transition”

Several studies have proposed the fallopian tube epithelium as a site of origin of ovarian cancer. The discovery of precursor lesions in the fallopian tube in patients at risk for ovarian cancer supports a probable origin for high-grade serous ovarian carcinoma in this tissue. While the fallopian tube epithelium consists of three distinct cell types, the paired box protein 2 (PAX2) positive cells and potentially the CD44 positive stem-like cells are most relevant to ovarian cancer. Loss of PAX2 expression in the fallopian tube cells is considered to be an early event in epithelial transformation, but the specific role of PAX2 in this transition is unknown. The aim of this study was to define the role of PAX2 in oviductal epithelial cells (OVE) cells and in mouse ovarian surface epithelial cells (MOSE), and to understand its contribution to the formation of serous precursor lesions in the fallopian tubes. Herein, we studied the OVE response to transforming growth factor β (TGFβ, a cytokine found in follicular fluid) and provide evidence of its potential involvement in the regulation of stem cell-like behaviors that may contribute to formation of cancer-initiating cells. Treatment of primary cultures of OVE cells with TGFβ at concentrations found in ovulatory follicular fluid induced an epithelial-mesenchymal transition (EMT) with expected changes in proliferation, cell morphology and expression of SNAIL, Vimentin and E-cadherin. EMT was also associated with decreased expression of PAX2 and an increase in the fraction of cells expressing CD44. Pax2 knockdown in OVE cells and overexpression in ovarian epithelial cells confirmed that PAX2 inhibits CD44 expression and regulates the degree of epithelial differentiation of OVE cells. These results suggest that the loss of PAX2 seen in serous tubal intraepithelial carcinomas (STIC) leads to a shift to a more mesenchymal phenotype associated with stem-like features. Pax2 overexpression in MOSE cells also induced the formation of vascular channels both in vitro and in vivo, which indicate a possible contribution of PAX2 to ovarian cancer progression by increasing the vascular channels to supply nutrients to the tumor cells. Furthermore, since loss of PAX2 in STIC was found associated with P53 and BRCA1 mutations, OVE cells with mutations of the tumor suppressor genes Trp53 and Brca1 were studied. We found that loss of Trp53 with or without loss of Brca1 increased cell proliferation and colony formation in vitro. In addition, loss of Trp53 induced OVE cells to undergo EMT and induced the expression of stem cell–associated genes. We therefore suggest a potential contribution of stem cells in initiating the precursor lesions in the fallopian tubes in combination with tumor suppressor gene mutation.

The system of Nernst-Planck-Poisson equations is modified by including the gradient terms in the chemical potential expression. The gradient terms are important in the regions of significant inhomogeneities, e. g. near the interface boundaries. These modified equations are used for investigating the particle density distribution in the vicinity of interphase boundary of a solid electrolyte. The differential equation of the fourth order for the problem of contact between two solid phases is formulated. Its analytic solution which describes non monotonic distribution of charge in both phases is obtained. It is shown that the gradient component added in the transport equations makes a decisive contribution in the double layer region. The approach is further expanded to the system composed of bulk phases and the intergrain layer between them. The particle density distributions at different conditions are investigated. The quasy-one dimensional lattice model of the fuel cell is considered in the frame of kinetic Monte Carlo simulation. It is shown that the electrostatic interaction between ions makes a significant contribution to the activation energy of migration of the particles. On the other hand, the fluctuations of the energy barriers slightly increase the particle migration activation energy. It is found that at blocked electrodes in the near electrode regions electrical double layers are formed. The thickness of the electrical double layer is around few lattice constants.

Transition metals (Ti, Zr, Hf, Mo, W, V, Nb, Ta, Pd, Pt, Cu, Ag, and Au) are essential building units of many materials and have important industrial applications. Therefore, it is important to understand their thermal and physical behavior when they are subjected to extreme conditions of pressure and temperature. This dissertation presents: An improved experimental technique to use lasers for the measurement of thermal conductivity of materials under conditions of very high pressure (P, up to 50 GPa) and temperature (T up to 2500 K). An experimental study of the phase relationship and physical properties of selected transition metals, which revealed new and unexpected physical effects of thermal conductivity in Zr, and Hf under high P-T. New phase diagrams created for Hf, Ti and Zr from experimental data. P-T dependence of the lattice parameters in α-hafnium. Contrary to prior reports, the α-ω phase transition in hafnium has a negative dT/dP slope. New data on thermodynamic and physical properties of several transition metals and their respective high P-T phase diagrams. First complete thermodynamic database for solid phases of 13 common transition metals was created. This database has: All the thermochemical data on these elements in their standard state (mostly available and compiled). All the equations of state (EoS) formulated from pressure-volume-temperature data (measured as a part of this study and from literature). Complete thermodynamic data for selected elements from standard to extreme conditions. The thermodynamic database provided by this study can be used with available thermodynamic software to calculate all thermophysical properties and phase diagrams at high P-T conditions. For readers who do not have access to this software, tabulated values of all thermodynamic and volume data for the 13 metals at high P-T are included in the APPENDIX. In the APPENDIX, a description of several other high-pressure studies of selected oxide systems is also included. Thermophysical properties (Cp, H, S, G) of the high P-T ω-phase of Ti, Zr and Hf were determined during the optimization of the EoS parameters and are presented in this study for the first time. These results should have important implications in understanding hexagonal-close-packed to simple-hexagonal phase transitions in transition metals and other materials.

Quel cadre économique et réglementaire à long terme (2030-50) pour soutenir la transition énergétique des carburants fossiles vers l’hydrogène dans le secteur européen des transports ? Cette recherche combine les approches théoriques et empiriques pour répondre aux trois questions suivantes :1. Comment concevoir des politiques de soutien adaptées pour pallier les imperfections de marché lors du déploiement de technologies de mobilité hydrogène ?2. Comment modéliser les coûts d’abattement en tenant compte des effets d’apprentissage (LBD) ?3. Comment définir la trajectoire optimale de déploiement quand le LBD et la convexité des coûts d’investissement sont présents ?L’article ‘Transition vers un Système de Transport de Passagers à Hydrogène : Analyse Politique Comparée’ passe au crible des politique de soutien destinées à résoudre les imperfections de marché dans le déploiement de la mobilité hydrogène. L’article effectue une comparaison internationale entre les instruments en faveur du déploiement des véhicules. Les indicateurs ex post d’efficacité des politiques sont développés et calculés pour classifier les pays selon leur volontarisme dans la promotion des véhicules à piles à combustible (FCEV). Aujourd’hui le Japon et le Danemark apparaissent comme les meilleurs fournisseurs d’un environnement favorable au déploiement de la mobilité hydrogène. Les autorités locales introduisent de solides instruments prix (tels que des subventions et des exemptions fiscales) pour rendre le FCEV plus attractif par rapport à son analogue à essence et coordonnent le déploiement de l’infrastructure hydrogène sur le territoire.L’article ‘Modélisation des Coûts d’Abattement en Présence d’Effets d’Apprentissage : le Cas du Véhicule à Hydrogène’ présente un modèle de transition du secteur des transports d’un état polluant à un état propre. Un modèle d’équilibre partiel est développé pour un secteur automobile de taille constante. L’optimum social est atteint en minimisant le coût de la transition du parc automobile au cours du temps. Ce coût comprend les coûts privés de production des véhicules décarbonés (sujets aux effets d’apprentissage) ainsi que le coût social des émissions de CO2 qui suit une tendance haussière exogène. L’article caractérise la trajectoire optimale qui est un remplacement progressif des véhicules polluants par les décarbonés. Au cours de la transition, l’égalisation des coûts marginaux tient compte de l’impact des actions présentes sur les coûts futurs via l’effet d’apprentissage. L’article décrit aussi une trajectoire sous-optimale où la trajectoire de déploiement serait une donnée exogène : quelle serait alors la date optimale de début de la transition ? L’article présente une évaluation quantitative de la substitution des FCEV aux véhicules à combustion interne (ICE). L’analyse conclut que le FCEV deviendra une option économiquement viable pour décarboner une partie du parc automobile allemand à l’horizon 2050 dès que le prix du carbone atteindra 50-60€/t.L’article ‘Le rôle des Effets d’Apprentissage dans l’Adoption d’une Technologie Verte : le Cas LBD Linéaire’ étudie les caractéristiques d’une trajectoire optimale de déploiement des véhicules décarbonés dans le cas où les effets d’apprentissage et la convexité sont présents dans la fonction de coût. Le modèle d’équilibre partiel de Creti et. al (2015) est utilisé comme point de départ. Dans le cas LBD linéaire la trajectoire de déploiement optimale est obtenue analytiquement. Un apprentissage fort induit une transition antérieure vers les véhicules verts dans le cas d’une convexité faible et une transition ultérieure dans le cas d’une convexité forte. Ce résultat permet de revisiter le projet H2 Mobility en Allemagne. Un effet d’apprentissage plus fort et une accélération du déploiement aboutissent à une transition moins coûteuse et une période de cash flow négatif plus courte
What economic and policy framework would foster a transition in the European transport sector from fossil fuels to hydrogen in the long term (2030-50)? This research combines empirical and theoretical approaches and aims to answers the following questions:1. How to design appropriate policy instruments to solve inefficiencies in hydrogen mobility deployment?2. How to define abatement cost and an optimal launching date in the presence of learning-by-doing (LBD)?3. How to define an optimal deployment trajectory in presence of LBD and convexity in investment costs?The paper ‘Transition Towards a Hydrogen-Based Passenger Car Transport: Comparative Policy Analysis‘ draws a cross-country comparison between policy instruments that support the deployment of Fuel Cell Electric Vehicle (FCEV). The existing policy framework in favour of FCEV and hydrogen infrastructure deployment is analysed. A set of complementary ex-post policy efficiency indicators is developed and calculated to rank the most active countries, supporters of FCEV. Denmark and Japan emerge as the best providers of favourable conditions for the hydrogen mobility deployment: local authorities put in place price-based incentives (such as subsidies and tax exemptions) making FCEV more financially attractive than its gasoline substitute, and coordinate ramping-up of their hydrogen infrastructure nationally.The paper ’Defining the Abatement Cost in Presence of Learning-by-doing: Application to the Fuel Cell Electric Vehicle’ models the transition of the transport sector from a pollutant state to a clean one. A partial equilibrium model is developed for a car sector of a constant size. In this model the objective of the social planner is to minimize the cost of phasing out a stock of polluting cars from the market over time. The cost includes the private cost of green cars production, which are subject to LBD, and the social cost of carbon, which has an exogenous upward trend. During the transition, the equalization of marginal costs takes into account the fact that the current action has an impact on future costs through LBD. This paper also describes a suboptimal plan: if the deployment trajectory is exogenously given, what is the optimal starting date for the transition? The paper provides a quantitative assessment of the FCEV case for the substitution of the mature Internal Combustion Engine (ICE) vehicles. The analysis concludes that the CO2 price should reach 53€/t for the program to start and for FCEV to be a socially beneficial alternative for decarbonizing part of the projected German car park in the 2050 time frame.The impact of LBD on the timing and costs of emission abatement is, however, ambiguous. On the one hand, LBD supposes delaying abatement activities because of cost reduction of future abatement due to LBD. On the other hand, LBD supposes starting the transition earlier because of cost reduction due to added value to cumulative experience. The paper ‘The Role of Learning-by-Doing in the Adoption of a Green Technology: the Case of Linear LBD’ studies the optimal characteristics of a transition towards green vehicles in the transport sector when both LBD and convexity are present in the cost function. The partial equilibrium model of (Creti et al., 2015) is used as a starting point. For the case of linear LBD the deployment trajectory can be analytically obtained. This allows to conclude that a high learning induces an earlier switch towards green cars in the case of low convexity, and a later switch in the case of high convexity. This insight is used to revisit the hydrogen mobility project in Germany. A high learning lowers the corresponding deployment cost and reduces deepness and duration of the, investment ‘death valley’ (period of negative project’s cash flow). An acceleration of exogenously defined scenario for FCEV deployment, based on the industry forecast, would be beneficial to reduce the associated transition cost

Les muscles squelettiques sont présents dans tout le corps et présentent un niveau surprenant d'hétérogénéité, dans leur susceptibilité aux maladies, potentiel de régénération ou capacités métaboliques. Cette diversité est également retrouvée au cours du développement embryonnaire où les cellules myogéniques et non myogéniques établissent le système musculo-squelettique. La tête et le cou sont constitués d'une grande variété de muscles qui remplissent des fonctions essentielles, mais nous en savons peu sur la biologie des muscles craniofaciaux. Ces structures sont associées à l'émergence de cellules de la crête neurale (CCN) qui donnent naissance à la plupart des tissus non myogéniques crâniens et qui sont cruciales à la formation des muscles. Cependant, certains muscles crâniens sont privés de CCN, et nous ignorons comment les cellules myogéniques et non myogéniques contribuent à ces domaines. Cette thèse fournit des preuves démontrant que les progéniteurs en amont du muscle se détournent du programme myogénique pour donner naissance au tissu conjonctif. Nous avons utilisé une approche de single-cell RNAseq non biaisée et restreinte avec différentes lignées transgéniques de souris à des stades embryonnaires distincts, des marquages in situ et de nouvelles méthodes analytiques, et avons montré que les progéniteurs bipotents issus du mésoderme exprimant le gène de détermination musculaire Myf5 donnent naissance au muscle squelettique et au tissu conjonctif anatomiquement associé dans les muscles partiellement privés de CCN. Cette transition est caractérisée par une complémentarité de signalisation de récepteurs tyrosine kinase entre les cellules musculaires et non musculaires, ainsi que par des modules régulateurs distincts. Les muscles crâniens proviennent également de différentes lignées qui impliquent l'activité de cascades de régulation génique spécifiques. Ici, nous avons utilisé une approche non biaisée et large pour découvrir des modules de régulation spécifiques qui sous-tendent différentes populations de cellules myogéniques dans la tête et à travers plusieurs stades de développement. Certaines de ces « tâches de naissance génétiques » uniques sont des facteurs de transcription spécifiques et sont conservées dans les cellules souches musculaires adultes, ce qui indique que leur importance potentielle est de fournir les propriétés uniques qui ont été signalées pour différentes populations de cellules souches musculaires. Enfin, ces études utilisent des méthodes analytiques inédites qui bénéficient des dernières avancées algorithmiques et offrent de nouvelles perspectives pour la découverte de processus biologiques à partir de données à haut débit
Skeletal muscles are found throughout the body and they display a surprising level of heterogeneity in properties and function. For example, some muscles are specifically susceptible to diseases, and some have better regenerative potential or different metabolic capacities. Diversity is also found during embryonic development where myogenic and non-myogenic cells establish the musculoskeletal system. The head and neck are comprised of a wide variety of muscles that perform essential functions such as feeding, breathing and vocalising, yet little is known about craniofacial muscle biology. Novel structures are associated with the emergence of neural crest cells (NCC) which give rise to most craniofacial connective tissue, cartilage and bone and are crucial for muscle morphogenesis. However, some cranial muscles are deprived of NCC, and it is unclear how myogenic and non-myogenic cells contribute to those domains. This thesis provides evidence demonstrating that upstream progenitors redirect from the myogenic program to give rise to the muscle-associated connective tissue that supports the formation of muscular structures. We employed unbiased and lineage-restricted single-cell RNAseq using different mouse transgenic lines at distinct embryonic stages, in situ labelling, and new analytical methods, and show that bipotent progenitors expressing the muscle determination gene Myf5 give rise to skeletal muscle and anatomically associated connective tissue in distinct muscle groups spatiotemporally. Notably, this property was restricted to muscles with only partial contribution from NCCs suggesting that in their absence, the balance of myogenic and connective tissue cells is undertaken by somite-derived or cranial-derived mesoderm. This transition is characterised by a complementarity of tyrosine kinase receptor signalling between muscle and non-muscle cells, as well as distinct regulatory modules. Cranial muscles also originate from different lineages that involve the activity of specific gene regulatory cascades. Here, we used an all-inclusive unbiased approach to uncover specific regulatory modules that underlie different myogenic cell populations in the head and across multiple developmental stages. Some of these unique “genetic birthmarks” are specific transcription factors, and are retained in adult muscle stem cells pointing to their potential importance is delivering the unique properties that have been reported for different muscle stem cell populations. Finally, these studies employ novel computational methods that benefit from the latest algorithmic advancements and they provide prospects for the discovery of new biological processes from high throughput data

Ce travail s’intéresse aux cellules solaires multi-transitions. Deux semiconducteurs à niveaux subbandgap : un highly mismatched alloy, le GaAsPN, et un absorbeur à boites quantiques. Les états subbandgap permettent de modifier l’énergie de gap ou de créer une bande intermédiaire au milieu du gap. En premier lieu, une introduction de la cellule solaire par l’étude de luminescence est présentée. Des liens entre luminescence et propriétés électriques sont établis, et les limites thermodynamiques de l’efficacité des dispositifs multi-transitions sont explicitées. Enfin, une méthode optique de caractérisation des cellules solaires est démontrée. La première partie expérimentale de la thèse est dédiée au développement d’une top cell en GaAsPN en accord de maille avec une bottom cell en Silicium. Des simulations numériques ont mis en évidence les difficultés à surmonter pour ce type de matériau. La dynamique des porteurs a été étudiée par photoluminescence en régime permanent et résolue en temps. Ces mesures ont mis en évidence que les absorbeurs crûs souffraient d’états fortement localisés, majoritairement dus à des clusters d’azote. Ces états nous ont permis en revanche d’étudier les propriétés de bande intermédiaire de cet alliage. Enfin, une méthode optique de caractérisation, adaptée aux IBSCs et à la mise en évidence des deux mécanismes clés de ce concept (two-step two-photon absorption et la préservation de la tension). Cette méthode a été appliquée à deux candidats pour les IBSCs, un absorbeur à multi-puits quantiques et un à boîtes quantiques. Les résultats montrent que l’absorbeur à boîtes quantiques présente un comportement compatible avec les IBSCs
This thesis deals with the multi-transition solar cells by studying two subband gap localised states materials: one highly mismatched alloy, GaAsPN, and one multi-stacked quantum dots heterostructure. These subband gap states give the possibility to tune the band gap energy or create two photon transitions inside a single the absorber. In a first part, a radiance based introduction of the solar cell is presented. Links between radiances and electrical properties are pointed out. From this analysis, the thermodynamic limits of the single and multiple transition solar cells are derived and key mechanisms for multi-transition solar cells are identified. A universal optical characterisation method for probing electrical properties of solar cells is displayed. The first experimental part of this thesis was dedicated to the development of a GaAsPN based pin top cell lattice matched with a Silicon bottom cell. Numerical simulations have been carried out. Carrier dynamics has been studied by steady-state and time-resolved photoluminescence, with the conclusion that the GaAsPN we grew still suffer from multiple strongly localised states below the band gap, mainly due to N-clusters. Finally, we have taken advantages of the strong carrier localisation for a use as an intermediate band solar cell. Eventually, a quantitative optical characterisation method was developed in order to evaluate the potential of an absorber as an IBSC. The two key processes, the two-step two-photon absorption and the voltage preservation, can be widely investigate through it. This method has been applied to two IBSC candidates, a MQW and a MSQD absorbers. The MSQD cell have shown IB compatibility

Ce travail s’intéresse aux cellules solaires multi-transitions. Deux semiconducteurs à niveaux subbandgap : un highly mismatched alloy, le GaAsPN, et un absorbeur à boites quantiques. Les états subbandgap permettent de modifier l’énergie de gap ou de créer une bande intermédiaire au milieu du gap. En premier lieu, une introduction de la cellule solaire par l’étude de luminescence est présentée. Des liens entre luminescence et propriétés électriques sont établis, et les limites thermodynamiques de l’efficacité des dispositifs multi-transitions sont explicitées. Enfin, une méthode optique de caractérisation des cellules solaires est démontrée. La première partie expérimentale de la thèse est dédiée au développement d’une top cell en GaAsPN en accord de maille avec une bottom cell en Silicium. Des simulations numériques ont mis en évidence les difficultés à surmonter pour ce type de matériau. La dynamique des porteurs a été étudiée par photoluminescence en régime permanent et résolue en temps. Ces mesures ont mis en évidence que les absorbeurs crûs souffraient d’états fortement localisés, majoritairement dus à des clusters d’azote. Ces états nous ont permis en revanche d’étudier les propriétés de bande intermédiaire de cet alliage. Enfin, une méthode optique de caractérisation, adaptée aux IBSCs et à la mise en évidence des deux mécanismes clés de ce concept (two-step two-photon absorption et la préservation de la tension). Cette méthode a été appliquée à deux candidats pour les IBSCs, un absorbeur à multi-puits quantiques et un à boîtes quantiques. Les résultats montrent que l’absorbeur à boîtes quantiques présente un comportement compatible avec les IBSCs
This thesis deals with the multi-transition solar cells by studying two subband gap localised states materials: one highly mismatched alloy, GaAsPN, and one multi-stacked quantum dots heterostructure. These subband gap states give the possibility to tune the band gap energy or create two photon transitions inside a single the absorber. In a first part, a radiance based introduction of the solar cell is presented. Links between radiances and electrical properties are pointed out. From this analysis, the thermodynamic limits of the single and multiple transition solar cells are derived and key mechanisms for multi-transition solar cells are identified. A universal optical characterisation method for probing electrical properties of solar cells is displayed. The first experimental part of this thesis was dedicated to the development of a GaAsPN based pin top cell lattice matched with a Silicon bottom cell. Numerical simulations have been carried out. Carrier dynamics has been studied by steady-state and time-resolved photoluminescence, with the conclusion that the GaAsPN we grew still suffer from multiple strongly localised states below the band gap, mainly due to N-clusters. Finally, we have taken advantages of the strong carrier localisation for a use as an intermediate band solar cell. Eventually, a quantitative optical characterisation method was developed in order to evaluate the potential of an absorber as an IBSC. The two key processes, the two-step two-photon absorption and the voltage preservation, can be widely investigate through it. This method has been applied to two IBSC candidates, a MQW and a MSQD absorbers. The MSQD cell have shown IB compatibility

Many normal and cancerous cell lines exhibit a stable composition of cells in distinct states which can, e.g., be defined on the basis of cell surface markers. There is evidence that such an equilibrium is associated with stochastic transitions between distinct states. Quantifying these transitions has the potential to better understand cell lineage compositions. We introduce CellTrans, an R package to quantify stochastic cell state transitions from cell state proportion data from fluorescence-activated cell sorting and flow cytometry experiments. The R package is based on a mathematical model in which cell state alterations occur due to stochastic transitions between distinct cell states whose rates only depend on the current state of a cell. CellTrans is an automated tool for estimating the underlying transition probabilities from appropriately prepared data. We point out potential analytical challenges in the quantification of these cell transitions and explain how CellTrans handles them. The applicability of CellTrans is demonstrated on publicly available data on the evolution of cell state compositions in cancer cell lines. We show that CellTrans can be used to (1) infer the transition probabilities between different cell states, (2) predict cell line compositions at a certain time, (3) predict equilibrium cell state compositions, and (4) estimate the time needed to reach this equilibrium. We provide an implementation of CellTrans in R, freely available via GitHub (https://github.com/tbuder/CellTrans).

La leucémie myéloïde chronique est une hématopoïèse maligne clonale, caractérisée par l'acquisition de la translocation t (9;22) conduisant au chromosome Ph1 et à son homologue l'oncogène BCR-ABL, dans une cellule souche hématopoïétique très primitive. La LMC est un modèle de thérapies ciblées, car il a été démontré que la preuve de la faisabilité du ciblage de l'activité tyrosine kinase (TK) BCR-ABL à l'aide d'inhibiteurs de TK (TKI) entraîne des réponses et des rémissions majeures. Cependant, les problèmes actuels rencontrés dans ces thérapies sont la résistance des cellules souches leucémiques primitives et leur persistance qui serait liée à l'hétérogénéité des cellules souches au moment du diagnostic, ce qui conduit à la sélection clonale de cellules résistant aux thérapies TKI. J'ai appliqué la technologie de l'analyse du transcriptome des cellule uniques aux cellules de la LMC en utilisant un panel de gènes impliqués dans différentes voies, combinée à l'analyse d'inférence de trajectoire au modèle d'expression des gènes. Les résultats ont montré un état transitoire des cellules souches comprenant des gènes embryonnaires identifiés dans les cellules de la LMC au moment du diagnostic, ce qui pourrait contribuer à la résistance et à la persistance de la LSC. En outre, l'oncoprotéine Bcr-Abl est la tyrosine kinase constitutivement active produite par le gène chimérique BCR-ABL dans la leucémie myéloïde chronique (LMC). Les cibles transcriptionnelles de Bcr-Abl dans les cellules leucémiques n'ont pas été étudiées de manière approfondie. Une expérience de transcriptome utilisant la lignée cellulaire UT7 hématopoïétique exprimant BCR-ABL, a identifié la surexpression du facteur d'élongation eucaryote kinase 2 (eEF2K) qui joue un rôle majeur dans la survie des cellules en cas de privation de nutriments. Dans l'ensemble, les données suggèrent que la surexpression de eEF2K dans la LMC est associée à une sensibilité accrue à la privation de nutriments
Chronic myeloid leukemia is a clonal hematopoietic malignancy, characterized by the acquisition of the t (9;22) translocation leading to Ph1 chromosome and its counterpart BCR-ABL oncogene, in a very primitive hematopoietic stem cell. CML is a model of targeted therapies as the proof of concept of the feasibility of targeting the tyrosine kinase (TK) activity BCR-ABL using TK inhibitors (TKI) has been shown to lead to major responses and remissions. However, the current problems encountered in these therapies are primitive leukemic stem cells resistance and their persistence which is thought to be related to the heterogeneity of the stem cells at diagnosis leading to clonal selection of cells resisting to TKI therapies. I have applied the technology of single cell transcriptome analysis to CML cells using a panel of genes involved in different pathways combined with trajectory inference analysis to the gene expression pattern. The results showed a transitional stem cell states including embryonic genes identified in CML cells at diagnosis which could contribute to LSC resistance and persistence. Furthermore, the oncoprotein Bcr-Abl is the constitutively active tyrosine kinase produced by the chimeric BCR-ABL gene in chronic myeloid leukemia (CML). The transcriptional targets of Bcr-Abl in leukemic cells have not been extensively studied. A transcriptome experiment using the hematopoietic UT7 cell line expressing BCR-ABL, has identified the overexpression of eukaryotic elongation factor kinase 2 (eEF2K) which plays a major role in the survival of cells upon nutrient deprivation. Overall, the data suggest that overexpression of eEF2K in CML is associated with an increased sensitivity to nutrient-deprivation

Mit der vorliegenden Arbeit wird das Wachstum von polykristallinem Silicium auf Glas bei niedrigen Temperaturen aus metallischen Lösungen in einem Zweistufenprozess untersucht. Im ersten Prozessschritt werden nanokristalline Siliziumschichten (nc-Si) hergestellt, entweder durch die direkte Abscheidung auf geheizten Substraten oder durch als ''Amorphous-Liquid-Crystalline''(ALC)-Umwandlung bezeichnete metall-induzierte Kristallisation. Im zweiten Prozessschritt dienen die Saatschichten als Vorlage für das Wachstum von deutlich größeren Kristalliten durch stationäre Lösungszüchtung. Die ALC-Prozessdauer konnte durch umfassende Parameterstudien signifikant reduziert werden. Die Charakterisierung der durch direkte Abscheidung auf geheizten Substraten entstehenden nc-Si Saatschichten offenbarte, dass es sich dabei um individuelle Saatkörner handelt, die in eine quasi-amorphe Matrix eingebettet sind. Die Oxidation der Saatschichten vor dem zweiten Prozessschritt wurde als ein wesentliches Hindernis für das Wachstum identifiziert. Als erfolgreichste Lösung zur Überwindung dieses Problems hat sich ein anfänglicher Rücklöseschritt erwiesen. Da diese Methode jedoch schwierig zu kontrollieren ist, wurde ein UV-Laser-System entwickelt und installiert. Erste Resultate zeigen epitaktisches Wachstum an den Stellen, an denen das Oxid entfernt wurde. Bei der Lösungszüchtung auf ALC-Schichten beginnt das Wachstum an einigen größeren Saatkristallen, von wo aus umliegende Gebiete lateral überwachsen werden. Obwohl Kristallitgrößen bis zu 50 Mikrometern erreicht wurden, war es noch nicht möglich, geschlossene Schichten zu erzielen. Durch Lösungszüchtung auf nc-Si Saatschichten hingegen konnte dieses Ziel erreicht werden. Geschlossene, polykristalline Si-Schichten wurden erzeugt, auf denen alle Si-Kristallite miteinander verbunden sind. Neben den Wachstumsexperimenten wurden 3D-Simulationen durchgeführt, in denen u.a. unterschiedliche Heizerkonfigurationen simuliert wurden.
The subject of this thesis is the investigation of the growth of polycrystalline silicon on glass at low temperatures from metallic solutions in a two-step growth process. In the first process step, nanocrystalline Si (nc-Si) films are formed either by direct deposition on heated substrates, or by a metal-induced crystallization process, referred to as amorphous-liquid-crystalline (ALC) transition. In the second process step, these seed layers serve as templates for the growth of significantly larger Si crystallites by means of steady-state solution growth. Extensive parameter studies for the ALC process helped to bring down the process duration significantly. Characterization of the nc-Si seed layers, formed by direct deposition on heated substrates, showed that the layer is composed of individual seeds, embedded in a quasi-amorphous matrix. The oxidation of the seed layers prior to the second process step was found to be a major obstacle. The most successful solution has been an initial melt-back step. As the process is hard to control, though, a UV laser system has been developed and installed. First promising results show unobstructed epitaxial growth where the oxide has been removed. Steady-state solution growth on ALC seed layers was found to start from a few larger seed crystals, and then cover the surrounding areas by lateral overgrowth. Although crystallites with sizes of up to 50 micrometers were obtained, it was not yet possible to achieve full surface coverage with a continuous layer. By solution growth on nc-Si seed layers, however, it was eventually possible to achieve this goal. Continuous, polycrystalline Si layers were grown, on which all Si crystallites are interlocked. The growth experiments were accompanied by 3D simulations, in which e.g. different heater configurations have been simulated.

O modelo estocástico Raise and Peel é estudado nesta tese. Para isto é utilizado o método de simulação por Monte Carlo junto com os métodos de diagonalização exata e numérica do operador de Liouville. Este modelo estocástico é um modelo de crescimento unidimensional com dois parâmetros livres. Um parâmetro de absorção local e um parâmetro de dessorção não local. Em função destes dois parâmetros se observa um rico diagrama de fase, apresentando regiões massivas, regiões criticamente auto-organizadas, estados quase-estacionários e transições a múltiplos estados absorventes. O principal resultado deste trabalho é ressaltar a existência de células de Jordan no operador de Liouville. Células de Jordan que crescem com o tamanho do sistema e portanto no limite termodinâmico a dinâmica assintótica pode ser mascarada. A nível numérico estas células de Jordan podem levar a errôneas interpretações de fases criticas quando são na realidade fases massivas ou vice-versa. Portanto dependendo da condição inicial observa-se que a presença de células de Jordan pode levar à determinação errônea de expoentes críticos e a observações de tempos de decaimentos excessivamente grandes. Tudo isto ressalta a necessidade de se determinar os expoentes críticos e os tempos de decaimento por diversos métodos, sempre que for possível, além de se controlar o comportamento destas quantidades considerando a evolução do modelo com diferentes condições inicias. Entre outros resultados que obtivemos observamos a existência de estados quase-estacionários com tempos de vida que crescem muito mais rápido que uma lei de potencia do tamanho do sistema. Encontramos o expoente critico dinâmico z=1, no caso da transição a estados multi-absorventes. Este resultado ocorreu tanto nos casos sem absorção como nos casos sem dessorção. O modelo exibe também uma fase rugosa com um expoente de rugosidade próximo de zero quando a taxa de absorção é maior que a taxa dessorção. E finalmente observamos que o modelo estudado em condições periódicas de contorno pode ser enxergado como um modelo KPZ em 1+1 dimensões, sujeito a dois tipos de perturbações. Uma das pertubações sendo relevante e a outra irrelevante.
The stochastic model Raise and Peel is studied in this thesis. we use the Monte Carlo simulation method together with the exact and numerical diagonalization methods of the Liouville operator. This stochastic model is a one-dimensional growth model with two free parameters. A local absorption parameter and a non-local desorption one. As a function of these two parameters, a rich phase diagram is observed, presenting massive regions, critically self-organized regions, quasi-stationary states and transitions to multiple absorbing states. The main result of this work is to emphasize the existence of Jordan cells in the Liouville operator. Jordan cells that grow with the size of the system and therefore in the thermodynamic limit the asymptotic dynamics can be masked. At the numerical level, these Jordan cells can lead to erroneous interpretations of massive phases as being massless critical ones or vice versa. Therefore depending on the initial condition, it is observed that the presence of Jordan cells can lead to the erroneous determination of critical exponents and produce excessively large lifetimes. Due to these effects, it is necessary to determine the critical exponents and the lifetimes by several distinct methods whenever possible, besides controlling the behavior of these quantities, by considering the evolution with different initial conditions. Among other results, we found the existence of quasi-stationary states with lifetimes that grow much faster than a power law of the systems size. We obtained a dynamic critical exponent z = 1 in the transition to multi-absorbent states in both cases without absorption or desorption. The model also shows a rough phase with a roughness exponent close to zero when the absorption rate is higher than the desorption rate. Finally, we observed that the model studied under periodic boundary conditions, can be seen as a KPZ model in 1 + 1 dimensions, under the effect of two perturbations. One of them being relevant and the other one irrelevant.

O presente relatório teve como base o estágio curricular com duração de quatro meses realizado no Consultório Veterinário Fénix. Encontra-se dividido em três partes: a casuística, a monografia e o caso clínico. Na primeira parte deste documento são relatadas as atividades desenvolvidas durante o estágio curricular, abrangendo a Patologia Médica, Patologia Cirúrgica e profilaxia vacinal praticadas em medicina de animais de companhia. A monografia descreve o carcinoma das células de transição da bexiga do cão desde a sua etiologia ao tratamento. O caso clínico relata o acompanhamento e evolução da afeção em resposta ao tratamento e discussão final; Urinary bladder transitional cell carcinoma in dogs ABSTRACT: This report was based on an internship lasting four months developed at Consultório Veterinário Fénix. It is divided in three parts: a case series description, a monograph and a clinical case. The first part of this document describes the activities performed during the internship, including clinical practice, surgery and medical prophylaxis in small animal medicine. The monograph describes the urinary bladder transitional cell carcinoma in dogs from etiology to treatment. The clinical case reports the monitoring and development of the disease in response to treatment, and a final discussion.

Non-stoichiometric strontium iron oxide is described by an abbreviated formula SrFeOx (2.5 ≤ x ≤ 3.0) exhibits a variety of interesting physical and chemical properties over a broad range of temperatures and in different gaseous environments. The oxide contains a mixture of iron in the trivalent and the rare tetravalent state. The material at elevated temperature is a mixed oxygen conductor and it, or its derivatives,can have practical applications in oxygen conducting devices such as pressure driven oxygen generators, partial oxidation reactors in electrodes for solid oxide fuel cells (SOFC). ¶ This thesis examines the behaviour of the material at ambient and elevated temperatures using a broad spectrum of solid state experimental techniques such as: x-ray and neutron powder diffraction,thermogravimetric and calorimetric methods,scanning electron microscopy and Mossbauer spectroscopy. Changes in the oxide were induced using conventional thermal treatment in various atmospheres as well as mechanical energy (ball milling). The first experimental chapter examines the formation of the ferrite from a mixture of reactants.It describes the chemical reactions and phase transitions that lead to the formation of the oxide. Ball milling of the reactants prior to annealing was found to eliminate transient phases from the reaction route and to increase the kinetics of the reaction at lower temperatures. Examination of the thermodynamics of iron oxide (hematite) used for the reactions led to a new route of synthesis of the ferrite frommagnetite and strontium carbonate.This chapter also explores the possibility of synthesis of the material at room temperature using ball milling. ¶ The ferrite strongly interacts with the gas phase so its behaviour was studied under different pressures of oxygen and in carbon dioxide.The changes in ferrite composition have an equilibrium character and depend on temperature and oxygen concentration in the atmosphere. Variations of the oxygen content x were described as a function of temperature and oxygen partial pressure, the results were used to plot an equilibrium composition diagram. The heat of oxidation was also measured as a function of temperature and oxygen partial pressure. ¶ Interaction of the ferrite with carbon dioxide below a critical temperature causes decomposition of the material to strontium carbonate and SrFe12O19 . The critical temperature depends on the partial pressure of CO2 and above the critical temperature the carbonate and SrFe12O19 are converted back into the ferrite.The resulting SrFe12O19 is very resistant towards carbonation and the thermal carbonation reaction does not lead to a complete decomposition of SrFeOx to hematite and strontium carbonate. ¶ The thermally induced oxidation and carbonation reactions cease at room temperature due to sluggish kinetics however,they can be carried out at ambient temperature using ball milling.The reaction routes for these processes are different from the thermal routes.The mechanical oxidation induces two or more concurrent reactions which lead to samples containing two or more phases. The mechanical carbonation on the other hand produces an unknown metastable iron carbonate and leads a complete decomposition of the ferrite to strontiumcarbonate and hematite. ¶ Thermally and mechanically oxidized samples were studied using Mossbauer spectroscopy. The author proposes a new interpretation of the Sr4Fe4O11 (x=2.75) and Sr8Fe8O23 (x=2.875)spectra.The interpretation is based on the chemistry of the compounds and provides a simpler explanation of the observed absorption lines.The Mossbauer results froma range of compositions revealed the roomtemperature phase behaviour of the ferrite also examined using x-ray diffraction. ¶ The high-temperature crystal structure of the ferrite was examined using neutron powder diffraction.The measurements were done at temperatures up to 1273K in argon and air atmospheres.The former atmosphere protects Sr2Fe2O5 (x=2.5) against oxidation and the measurements in air allowed variation of the composition of the oxide in the range 2.56 ≤ x ≤ 2.81. Sr2Fe2O5 is an antiferromagnet and undergoes phase transitions to the paramagnetic state at 692K and from the orthorhombic to the cubic structure around 1140K.The oxidized formof the ferrite also undergoes a transition to the high-temperature cubic form.The author proposes a new structural model for the cubic phase based on a unit cell with the Fm3c symmetry. The new model allows a description of the high-temperature cubic form of the ferrite as a solid solution of the composition end members.The results were used to draw a phase diagramfor the SrFeOx system. ¶ The last chapter summarizes the findings and suggests directions for further research.

碩士
國立彰化師範大學
光電科技研究所
98
We investigate the transformation processes of the optically compensated bend （OCB）cell. The observed results reveal that the transformation time of the cell from the Ha state to the bend state is well below that of the cell from the Hs state to the bend state. The transformation time of the cell from the splay state to the bend state is shorter in the cell with the higher pretilt angle. The obtained results also reveal that the lifetime of the Hs state increases with increasing voltage. The lifetime of the Hs state can be modified by generating polymer networks in the cell.

Fuel cells offer the best solution to the imminent energy and environmental crisis staring at our face, urging the scientific community to overcome all the challenges faced by its effective commercialization. These harness the power of hydrogen, which requires efficient methods to store hydrogen reversibly. Fuel cells have been known to function the best while employing Pt as the catalyst. An acute setback to the coherent working of a fuel cell is the degradation of expensive and scarce Pt catalyst by CO. Converting this CO to CO2 through fast reaction kinetics promises an answer to this vital issue. However, CO2 production will further increase its concentration in the atmosphere undesirably adding to the steady emissions from consumption of fast depleting fossil fuels. Consequently, global warming will accelerate, which threatens the sustainability and prosperity of the society. Converting CO2 to value-added products should solve both fossil-fuel shortage and anomalous climate change. Storing energy in chemical bonds, as fuels such as CH4, and finding an electrochemical catalyst to reduce CO2 to such hydrocarbon fuels would provide an ideal solution for discontinuous renewable energy sources. This thesis effectively addresses these major issues faced by a successful global implementation of fuel cells and sustainable energy. The reported results and findings provide a better understanding of materials properties, which can be generalized to other systems as well. The thesis has been organized as follows: Chapter 1 introduces fuel cells and heterogeneous catalysis, challenges associated with their large-scale commercialization, and pathways to achieve optimized catalytic and hydrogen storage performance. An overview of importance of nanoparticles in heterogeneous catalysis is given along with traditional methods followed to parametrize and evaluate hydrogen storage and catalytic efficiencies. The motivation of the research work has been highlighted in this chapter. Chapter 2 describes the theoretical methodology employed for the work. It gives an understanding of first principles-based Density Functional Theory (DFT) and various exchange and correlation energy functional used to obtain electronic and structural information. Theory underlying the methods employed for computationally calculating reaction energy pathways, barriers, rates, and turnover frequency are also described briefly. Chapter 3 proposes a strategy to enhance the hydrogen storage properties of transition metal clusters. Doping of small Ti clusters by B, enhances their reversible hydrogen storage capacity. Among all Tin−1B (n = 3, 4, 5, 6, and 7) clusters, Ti3B stores the maximum number of 12 H2 molecules (three dissociated and nine Kubas type). The best capacity of Ti3B originates from the combined effect of a large charge transfer from Ti to B and a high localization of Ti empty d states at a large distance above the Fermi-level. For Ti3 anchored to B of BC3, the number of Kubas-bound hydrogen remains the same as that of the free-standing Ti3B, while the unusable chemisorbed hydrogen are absent. Gibbs energy of adsorption as a function of H2 partial pressure shows that Ti3@BC3 adsorbs and desorbs nine Kubas-bound hydrogen at ambient pressures and room temperature. Chapter 4 investigates the problem of O2 interference in hydrogen storage on metal decorated carbonaceous systems, which remains one of the major stumbling blocks in the successful realization of the theoretically promised high storage of Kubas bound H2. The interference is a consequence of preferred O2 binding at the metal site, thereby blocking it for H2 adsorption. Arene capping of a Sc-metallocarbene (MCB) efficiently reverses the preferential adsorption of O2 over H2. The capped Sc-MCB completely repels O2 off the Sc-site allowing solely Kubas binding of H2, consequent of the down-shift of the d-band center of Sc from 1.29 eV in the uncapped to 5.67 eV in the capped MCB, below the Fermi-level, respectively. This optimized d-band center position enables the empty Sc antibonding states to only be available for hydrogen adsorption via Kubas interaction, thereby, to completely avoid oxygen binding. Chapter 5 shows for the first time that on supported Pt3Co/MgO(100), the preferred CO adsorption site inverts to Co from Pt. This inversion results from the better availability of empty anti-bonding d-states of Co atom in Pt3Co than those of the Pt atoms. The d-band center has a one-to-one correlation with CO adsorption energy and its relative position determines the adsorption site. Furthermore, for Mars van Krevelan (MvK) mechanism of CO oxidation on Pt3Co /Li-doped MgO(100), low reaction barrier of 0.11 eV predicts excellent reaction kinetics. A novel design strategy of d-band center inversion for CO oxidation catalysts with no Pt poisoning and excellent reaction kinetics is proposed. Chapter 6 extends the search for bimetallic Pt clusters, which possess the CO adsorption site inversion properties inherently. Among all 3d transition metals (M) in Pt3M, only V d- band center is closer to the Fermi level than that of Pt. This leads to a larger affinity of V towards CO, making it more reactive than Pt. The relative position of d-band center from Fermi-level describes the favorable adsorption site in a system. The d- band center position of only the V atom (among all M = Sc, Ti, V, Mn, Fe, Co, Ni, Cu, and Zn) is closer to the Fermi level than that of the Pt atoms, increasing its preference towards CO. Furthermore, anchoring Pt3V on Li-doped MgO(100) activates a spontaneous oxygen vacancy, oxidizing CO via small reaction barrier of 0.13 eV, exhibiting better reaction kinetics than the free-standing cluster. Chapter 7 elucidates the prospect of tuning catalytic processes as a function of cluster size, which has been a long-sought goal in heterogeneous catalysis. Ptn(V/Co)m, for (n m = 4, 2; 9, 3; 15, 5; 41, 14; and 59, 20) are studied as CO oxidation catalysts. The site inversion is preserved for the CO adsorption on V for all PtnVm. This inversion to Co from Pt is introduced beyond 12-atom cluster for PtnCom. A subsequent peroxo-like O2 adsorption after CO, on the adjacent Pt sites leads to the efficient oxidation of CO to CO2 with low Langmuir-Hinshelwood (L-H) mechanism barriers. The maximized catalytic activity is observed for the 55-atom cluster of Pt41(V/Co)14 pertaining to the optimal CO binding and best reaction kinetics. Finally, MvK mechanism of CO oxidation on Pt41V14/Li-doped MgO(100) proceeds via low reaction barrier of 0.14 eV, promising efficient CO oxidation catalytic activity. Chapter 8 exhibits insights into low and ambient temperature CO oxidation catalytic activities of Pt plates supported on reconstructed Si 7×7 (111) surface. The catalytic activity of CO oxidation over Pt/Si 7 × 7 (111) reconstructed surface with restricted platinum loading is analysed. We report, tuning of CO oxidation catalytic activity with size of single-layered platinum clusters Ptn/Si-RS (n = 10, 20, 30, and 45). The catalytic performance varies for Ptn plates, which is a consequence of the different interactions between Pt and Si-RS with changing n. The distance of d-band centers of Ptn/Si-RS from π orbitals of CO and O2 correlates with the strength of adsorption energy as n changes. The reaction kinetics analysis reveals that more than 10 CO2 molecules can be produced via CO oxidation on Ptn/Si-RS. This turn over frequency of CO2 exceeds that of the conventional CO oxidation catalysts. The results of this work will lead to the effective use of platinum and Si 7×7 (111) components at ambient atmospheres to design CO tolerant catalysts and ensure its fast oxidation. Chapter 9 presents a facile solution to the enormous problem of efficient CO2 mitigation, utilizing the knowledge of increasing catalytic efficiency by employing trimetallic nanoparticles. DFT calculations in combination with the computational hydrogen electrode (CHE) model develop a detailed description of the free-energy landscape and limiting potential for NiTM@Cu (TM = 3d transition metals) alloy core shell nanoparticles. An overview of the thermodynamics of CO2 conversion to CH4 as a function of limiting potential establishes that these alloy core shell catalysts promise excellent CO2 reduction at overpotentials as low as 0.17 V with respect to the equilibrium potential or standard potential value (SPV). This efficiency stems from the fact that the rate limiting step of CO protonation to CHO has small exothermicity, especially for the early transition metals (Sc, Ti, and V). Furthermore, the better stabilization of CHO than CO on the NiTM@Cu core-shell catalysts makes the vastly reported rate limiting step of CO protonation exergonic at very small overpotentials. The chapter also establishes that the limiting potential can be tuned by varying the core composition in Ni13−xMx@Cu, in turn affecting the catalytic activity. The complete reaction profile of CO2 electro-reduction in the presence of water affects the binding energies. Moreover, the intrinsic solvation effect does not relatively change the reaction pathways and overpotential values. Chapter 10 summarizes and concludes the work presented in this thesis in addition to a brief description of future projects.

A new approach to the discovery of high absorbing semiconductors for solar cells was taken by working under a set of design principles and taking a systemic methodology. Three transition metal chalcogenides at varying states of development were evaluated within this framework. Iron pyrite (FeS���) is well known to demonstrate excellent absorption, but the coexistence with metallic iron sulfides was found to disrupt its semiconducting properties. Manganese diselenide (MnSe���), a material heavily researched for its magnetic properties, is proposed as a high absorbing alternative to iron pyrite that lacks destructive impurity phases. For the first time, a MnSe��� thin film was synthesized and the optical properties were characterized. Finally, CuTaS���, a known but never characterized material, is also proposed as a high absorbing semiconductor based on the design principles and experimental results.
Graduation date: 2013

The area of systems biology evolved in an attempt to introduce mathematical systems theory principles in biology. Although we believe that all biological processes are essentially chemical reactions, describing those using precise mathematical rules is not easy, primarily due to the complexity and enormity of biological systems. Here we introduce a formal approach for modeling biological dynamical relationships and diseases such as cancer. The immediate motivation behind this research is the urgency to find a practicable cure of cancer, the emperor of all maladies. Unlike other deadly endemic diseases such as plague, dengue and AIDS, cancer is characteristically heterogenic and hence requires a closer look into the genesis of the disease. The actual cause of cancer lies within our physiology. The process of cell division holds the clue to unravel the mysteries surrounding this disease. In normal scenario, all control mechanisms work in tandem and cell divides only when the division is required, for instance, to heal a wound platelet derived growth factor triggers cell division. The control mechanism is tightly regulated by several biochemical interactions commonly known as signal transduction pathways. However, from mathematical point of view, these pathways are marginal in nature and unable to cope with the multi-variability of a heterogenic disease like cancer. The present research is possibly one first attempt towards unraveling the mysteries surrounding the dynamics of a proliferating cell. A novel yet simple methodology is developed to bring all the marginal knowledge of the signaling pathways together to form the simplest mathematical abstract known as the Boolean Network. The malfunctioning in the cell by genetic mutations is formally modeled as stuck-at faults in the underlying Network. Finally a mathematical methodology is discovered to optimally find out the possible best combination drug therapy which can drive the cell from an undesirable condition of proliferation to a desirable condition of quiescence or apoptosis. Although, the complete biological validation was beyond the scope of the current research, the process of in-vitro validation has been already initiated by our collaborators. Once validated, this research will lead to a bright future in the field on personalized cancer therapy.

碩士
國立嘉義大學
管院碩士在職專班
99
This study used the universal insurance claims data to investigate the risk of urothelial transitional cell carcinoma (TCC) for patients with hemodialysis (HD). This study followed 2,689 new patients with end-stage renal disease (ESRD) undergoing maintenance HD and 21,449 patients without HD identified from claims data of National Health Insurance in 2000-2002 to the end of 2007. Incidence densities of TCC in upper urinary tract (UUT) and bladder only were estimated for these two cohorts. Hazard ratios (HRs) of TCC were measured in association with HD, covariates and comorbidities. Incidences of urothelial carcinoma were significantly higher in patients of HD cohort than that of the reference cohort for both UUT with or without concomitant bladder TCC (21.8 versus 0.65 per 10,000 person-years) and bladder TCC only (17.7 versus 3.55 per 10,000 person-years). The multivariate Cox proportional hazard regression analysis showed that the HRs of TCC in HD cohort was 33.3 for UUT (95% CI = 15.9 - 69.5) and 5.14 for bladder (95% CI = 3.24 - 8.15). Comorbidities of hematuria, urinary tract infection and hydronephrosis interact with HD for the hazards of TCC. In summary, ESRD patients undergoing HD therapy are at high risk of developing TCC, the risk is much greater for the carcinoma of UUT than that of urinary bladder while bladder TCC is the most common urothelial cancer among general population.

博士
國立陽明大學
臨床醫學研究所
105
Tumors growth is influenced by a microenvironment rich in inflammatory cytokines, growth factors and chemokines. Interleukin-6 (IL-6) has also been reported to be associated with tumor progression and chemoresistance in different types of cancers. In our study, we demonstrate that IL-6 enriches the properties of lung CSCs by enhancing cell proliferation through downregulation of p53 and p21. IL-6 also increases DNA methylation and the expression of DNA methyltransferase 1 (DNMT1) in lung CSCs. Knockdown of DNMT1 eliminated IL-6-mediated hypermethylation of cell cycle regulators p53 and p21. Upon blockage of the IL-6/JAK2/STAT3 pathway and inhibition of DNMT1, the proliferation of lung CSCs is reduced and their formation of spheres and ability to initiate tumor growth are decreased. These data suggest that targeting of the IL-6/JAK2/STAT3 signaling pathway and DNMT1 may become important strategies for treating lung cancer. Tumour-initiating cells (TICs) have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen XVII (Col XVII) gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin-5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-Col XVII pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with Col XVII expression in colon tumour samples, and correlate inversely with survival. This signaling axis also enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis. Epithelial-to-mesenchymal transition (EMT) is associated with metastasis and tumorigenesis in cancer stem-like cells (CSCs) but the underlying mechanism is not clear. We used microarray analysis to identify that Col XVII is one of candidate genes responsible for EMT in lung cancer cells cultured in spheroid and monolayer system. We show that Col XVII is required for maintenance of EMT phenotypes and metastasis ability in lung CSCs. We also show that Col XVII stabilizes laminin-5 to activate the FAK/AKT/GSK3β pathway, thereby suppressing Snail ubiquitination-degradation. The function of Col XVII is mainly dependent on shedding by ADAM9 and ADAM10. Patients who underwent surgical resection for lung cancer, and displayed overexpression of both Col XVII and laminin-5, had the worst prognosis of all expression types. Moreover, blockage of the Col XVII/laminin-5 pathway reduces the EMT phenotypes of lung CSCs in vitro and decreases the potential of lung metastasis in vivo. Our findings suggest that targeting Col XVII and laminin-5 could be novel therapeutic strategies for treating lung cancer patients, and warrant further investigation.

Non-stoichiometric strontium iron oxide is described by an abbreviated formula SrFeOx (2.5 ≤ x ≤ 3.0) exhibits a variety of interesting physical and chemical properties over a broad range of temperatures and in different gaseous environments. The oxide contains a mixture of iron in the trivalent and the rare tetravalent state. The material at elevated temperature is a mixed oxygen conductor and it, or its derivatives,can have practical applications in oxygen conducting devices such as pressure driven oxygen generators, partial oxidation reactors in electrodes for solid oxide fuel cells (SOFC). ¶ This thesis examines the behaviour of the material at ambient and elevated temperatures using a broad spectrum of solid state experimental techniques such as: x-ray and neutron powder diffraction,thermogravimetric and calorimetric methods,scanning electron microscopy and Mossbauer spectroscopy. Changes in the oxide were induced using conventional thermal treatment in various atmospheres as well as mechanical energy (ball milling). ¶ ...