Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the Philadelphia chromosome (Ph) that arises from a reciprocal translocation between chromosomes 9 and 22, thereby resulting in the formation of the chimeric BCR-ABL oncogene encoding a constitutively activated tyrosine kinase. BCR-ABL tyrosine kinase inhibitors (TKIs) induce a complete hematologic and cytogenetic response in the majority of chronic phrase CML patients. However, TKIs cannot efficiently eradicate leukemia stem cells (LSCs) because of the insensitivity of LSCs to TKIs. Therefore, developing new strategies to target LSCs is necessary and critical for curing CML, and success of this approach depends on further understanding the molecular mechanisms by which LSCs survive and are maintained. In Chapter I, I briefly introduce CML disease, BCR-ABL oncoprotein, and TKIs. I also describe the identification and features of LSCs. Several key pathways in LSCs including Wnt/ß-catenin, hedgehog, FoxO, Bcl6 and HIF1, are discussed. I also propose our strategy to identify unique molecular pathways that are important for LSCs but not their normal stem cell counterparts. In Chapter II, I describe our finding about the function of the positive regulator, HIF1α, in CML development and LSC survival. I show that loss of HIF1α impairs the maintenance of CML through impairing cell cycle progression and inducing apoptosis of LSCs, and I also report that p16Ink4a and p19Arf mediate the effect of HIF1α on LSCs, as knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1α-/- LSCs. As detailed in Chapter III and IV, through comparing the global gene expression profiles of LSCs and HSCs, I find two novel regulators, Blk and Scd1, which act as tumor suppressors in CML development. In Chapter III, I show that Blk is markedly down-regulated by BCR-ABL in LSCs, and that c-Myc and Pax5 mediate this down-regulation. Deletion of Blk accelerates CML development; conversely, Blk overexpression significantly delays the development of CML and impairs the function of LSCs. I also demonstrate that p27, as a downstream effector, is involved in the function of Blk in LSCs. Blk also functions as a tumor suppressor in human CML stem cells, and inhibits the colony-forming ability of human CML cells. In Chapter IV, I investigate the function of another negative regulator, Scd1, in CML LSCs, and find that expression of Scd1 is down-regulated in mouse LSCs and human CML cells. We report that Scd1 acts as a tumor suppressor in CML, as loss of Scd1 causes acceleration of CML development and overexpression of Scd1 delays CML development. Using a colony-forming assay, I demonstrate that Scd1 impairs the maintenance of LSCs due to the change of expression of Pten, p53 and Bcl2. Importantly, I find that both Blk and Scd1 do not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Taken together, our findings demonstrate that HIF1α is required for the maintenance of CML LSCs, and conversely that Blk and Scd1 suppress the function of LSCs, suggesting that combining TKI treatment with specific targeting of LSCs will be necessary for curing CML.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-10-26T10:38:27Z No. of bitstreams: 2 Tese - Adriana do Prado Barbosa - 2015.pdf: 900945 bytes, checksum: c7a5ed7dcaeb54e2967829169a9de269 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-26T13:18:13Z (GMT) No. of bitstreams: 2 Tese - Adriana do Prado Barbosa - 2015.pdf: 900945 bytes, checksum: c7a5ed7dcaeb54e2967829169a9de269 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-10-26T13:18:13Z (GMT). No. of bitstreams: 2 Tese - Adriana do Prado Barbosa - 2015.pdf: 900945 bytes, checksum: c7a5ed7dcaeb54e2967829169a9de269 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-04-10 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / The treatment of chronic myeloid leukemia (CML) has changed dramatically with the advent of imatinib mesylate (IM). Besides the convenience of oral use, other benefits were achieved with the new drug, with faster therapeutic responses and increased survival, giving the CML similar characteristics as chronic diseases. In this scenario, there was another challenge, drug compliance, since a significant proportion of patients fail to ingest all the prescribed doses of imatinib. The concern was to optimize the adherence of CML patients, the hematology ambulatory at the Clinical Hospital of the Federal University of Goias (HC-UFG), led the authoress to create a film cartoon, as a pro-adhesion educational intervention model. To investigate the effectiveness of this new educational material, we used in 65 patients three adherence measures, two indirect (Morisky Test and Molecular Response [MR]) and direct (plasma dosage of IM), before and after the screening of film. In univariate analysis, from the Morisky Test, the film was striking, with increased adherent patients, which increased from 15 (23.1%) to 43 (66.1%). The results of MR showed an improvement trend after the movie, because the positive molecular response (major MR or complete MR) increased from 81.5% to 86.1%. Regarding the serum levels of IM, with daily doses of 400-800 mg IM, the premovie samples showed higher average than the post-movie (2473.16 ± 1049.55 ng/ml versus 1414.72 ± 715 73 ng/ml), with a variation coefficients interpatients of 43.4% and 50.6%, respectively. This high dispersion index found has been reported by other authors. By multivariate analysis, patients were divided into three groups. The first brought together compliant patients before and after the film with a good therapeutic response (major MR) after the intervention. It was: patients over 53 years old, females, with associated diseases before and after the treatment of CML that use more than two drugs in addition to imatinib. The second group was marked by the change of not adherence pre to adherence post-film. Its features were younger than or equal to 53, the absence of other disease before the CML, the use of less than two drugs and complete molecular response after the film. In the third group, we observed patients without molecular response before and after the educational intervention and no medication adherence after the film. They had in common their age (less than or equal to 53 years), and drug discontinuation due to adverse reactions. The last represents the set of patients resistant to the educational film, drawing attention to the fact that only one pro-adhesion method may be insufficient for all individuals. It is concluded that medication adherence was higher among patients older than 53 years, the educational film is an effective proadhesion assistance and continuing education, if combined with another method, it could help maintain or enhance the benefits achieved in this work. / O tratamento da leucemia mielóide crônica (LMC) mudou radicalmente com o advento do mesilato de imatinibe (MI). Além da comodidade do uso oral, outros benefícios foram alcançados com o novo fármaco, como respostas terapêuticas mais rápidas e aumento da sobrevida, dando `a LMC características semelhantes `as de doenças crônicas. Neste cenário, surgiu outro desafio, a adesão medicamentosa, pois uma proporção significativa de pacientes deixa de ingerir a dose prescrita de imatinibe. A preocupação em otimizar a adesão dos pacientes com LMC, do Ambulatório de Hematologia do Hospital das Clínicas da Universidade Federal de Goiás (HC-UFG), motivou a autora a criar um filme em desenho animado, como modelo de intervenção educativa pró-adesão. Para investigar a eficácia deste novo material educativo, empregou-se, em 65 pacientes, três medidas de adesão, duas indiretas (Teste de Morisky e Resposta Molecular [RM]) e uma direta (dosagem plasmática do MI), antes e depois da exibição do filme. Em análise univariada, pelo teste de Morisky, o filme foi impactante, com aumento dos pacientes aderentes, que passaram de 15 (23,1%) para 43 (66,1%). Os resultados da RM indicaram uma tendência de melhora após o filme, pois a resposta molecular positiva (RM maior ou RM completa) passou de 81,5% para 86,1%. Em relação `a dosagem sérica do MI, com doses diárias entre 400-800 mg de MI, as amostras pré-filme apresentaram média superior `as do pósfilme (2.473,16 ± 1.049,55 ng/ml versus 1.414,72 ± 715,73 ng/ml), com coeficientes de variação interpaciente de 43,4% e 50,6%, respectivamente. Este elevado índice de dispersão encontrado tem sido relatado por outros autores. Pela análise multivariada, os pacientes foram separados em três grupos. O primeiro, reuniu os pacientes aderentes antes e após o filme e com boa resposta terapêutica (RM maior) após a intervenção. Foram eles: os doentes com mais de 53 anos, do gênero feminino, com doenças associadas antes e após o tratamento da LMC e que usam mais de dois medicamentos além do imatinibe. O segundo grupo foi marcado pela mudança de não adesão pré para adesão pós-filme. Suas características foram idade menor ou igual a 53, ausência de outra doença antes da LMC, uso de menos de dois medicamentos e resposta molecular completa pós-filme. No terceiro grupo, observou-se pacientes sem resposta molecular antes e depois da intervenção educativa, bem como não adesão medicamentosa após o filme. Eles tinham em comum a idade, menor ou igual a 53 anos, e suspensão do medicamento por reação adversa. Estes últimos representam o conjunto de pacientes resistentes ao filme educacional, chamando atenção para o fato de que somente um método pró-adesão pode ser insuficiente para todos os indivíduos. Conclui-se que a adesão medicamentosa foi maior entre os pacientes maiores de 53 anos, que o filme educativo é uma intervenção pró-adesão eficaz e que a educação continuada, aliada a outro método, poderia ajudar a manter ou ampliar os benefícios conquistados neste trabalho.

In this work the model ASAM is enriched with new eddy viscosity based dynamic Smagorinsky subgrid-scale models. Therefore the model is more physically based to study atmospheric flow configurations at several atmospheric scales with main focus to urban scale flow with building-resolved resolution. The implemented dynamic procedures work well and showed good agreement to literature data. In a convective atmospheric boundary layer (ABL) the dynamic Smagorinsky coefficient reaches maximum values of 0.15 and decreases towards the surface or in stable stratified flow regimes. Vertical profiles of the Smagorinsky coefficient in a diurnal cycle of ABL depict typical behaviour of the dynamic Smagorinsky coefficient in near surface flow, free-stream, or stable stratified flow. Furthermore a modified inflow generation approach is proposed to produce fully turbulent flow fields. To modify a mean flow turbulent fluctuations are generated by superposition of sinusoidal and cosinesoidal modes. Due to the implementation of this inflow method the model ASAM has the ability to reproduce a given wind field with information from its mean wind speed and their fluctuation energy spectrum. The model configuration developed in this work is able to reproduce flow structure in a complex urban geometry. The Mock Urban Setting Test (MUST) experiment represent an urban roughness geometry by placing 120 shipping containers ordinary arranged in an array. The used building-resolved resolution is able to capture dynamic flow structures like specific wake flow, recirculation regions or eddy detachment. The dynamic fluctuating behaviour of the wind velocity components is reproduced by the model with regard to peak magnitudes and their temporal occurrence. Satisfying agreement is found between tracer gas dispersion field measurements and the model results by capturing the fluctuating concentration magnitude and in some extend the mean values.:1 Introduction 1 2 Fundamentals of Large-Eddy Simulation in atmospheric boundary layers 7 2.1 The atmospheric boundary layer . . . . . . . . . . . . . . . . . . . . . 7 2.2 Atmospheric turbulence . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.3 Basic equations of LES . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3 Subgrid-scale modelling 15 3.1 Eddy viscosity subgrid-scale models . . . . . . . . . . . . . . . . . . . 15 3.1.1 Smagorinsky subgrid-scale model . . . . . . . . . . . . . . . . 16 3.1.2 Dynamic Smagorinsky subgrid-scale model . . . . . . . . . . . 18 3.1.3 Scale-dependent dynamic Smagorinsky subgrid-scale model . . 23 3.2 Implementation in the All Scale Atmospheric Model (ASAM) . . . . . 26 3.2.1 General description of ASAM . . . . . . . . . . . . . . . . . . 26 3.2.2 Subgrid-scale modelling in ASAM . . . . . . . . . . . . . . . . 27 3.3 Applications to meteorological situations . . . . . . . . . . . . . . . . 37 3.3.1 Stable and unstable stratified atmospheric boundary layers . . 37 3.3.2 Flow over periodic sinusoidal hill . . . . . . . . . . . . . . . . 49 4 Generation of turbulent inflow conditions 51 4.1 The necessity of turbulent inflow . . . . . . . . . . . . . . . . . . . . 51 4.2 Synthetic turbulent inflow generation method . . . . . . . . . . . . . 53 4.3 Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.4 2D simulation results . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5 Mock Urban Setting Test Experiment (MUST) 65 5.1 Micro-scale urban simulation . . . . . . . . . . . . . . . . . . . . . . . 65 5.2 Description of the experiment . . . . . . . . . . . . . . . . . . . . . . 68 5.3 Wind tunnel measurenments of MUST . . . . . . . . . . . . . . . . . 70 5.4 Numerical MUST simulation with ASAM . . . . . . . . . . . . . . . . 72 5.4.1 Choice of initial condition . . . . . . . . . . . . . . . . . . . . 75 5.4.2 Results of simulating case 2682353 . . . . . . . . . . . . . . . 81 5.4.3 Results of simulating case 2681829 . . . . . . . . . . . . . . . 98 5.4.4 Case resume . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 6 Summary and outlook 111 6.1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 6.2 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 7 Bibliography 117 List of Figures 127 List of Tables 135 Acronyms 137 Nomenclature 139 Acknowledgement 143 List of Publications 145

No description available.

In this thesis, we have evaluated a stochastic Lagrangian model for computing particle deposition rates with prospects to use for atmospheric deposition applications.  The model is one-dimensional and models the particle dynamics in the boundary layers near walls and obstacles by simulating the coherent turbulent structures and Brownian motion governing the wall-normal transport. The deposition model is used with a hybrid deterministic/stochastic particle dispersion model governing the dynamics in the turbulent bulk flow. We used a steady-state RANS k-ϵ turbulence model to simulate the turbulent fluid flow in a neutral atmospheric boundary layer (ABL) using the with inflow boundary conditions by Richards & Hoxey (1993). The turbulence model is solved with the SIMPLE algorithm using the OpenFOAM software. The mean-field characteristic of the turbulent flow in the computational domain is exported and used for the particle model. The particle model is a Lagrangian Langevin-type model, consisting of a system of stochastic differential equations. The particle model was solved using a weakly first order a-stable scheme. We evaluated the deposition model by computing the deposition rate for a range of particle sizes and compared our results with collected experimental wind tunnel data. The numerical experiment was done in a computational domain based on the ABL model by Hargreaves & Wright (2007), a rectangular domain with a logarithmic wind profile. We used a particle source near the inflow boundary with an instantaneously release at the initial time. Results showed disagreement with the experimental data and was only valid for medium sized particles. However, time restrictions led to the analysis being cut short and only a single simulation was conducted. A definite conclusion on the suitability of the method could not be made based solely on this single results. Some uncertainties were identified and discussed for further potential work on the evaluation of the method. However, one conclusion was drawn on the performance of the method. The computational cost was concluded to be too high with the first order particle scheme used and higher order schemes is required for any practical use of the method for atmospheric deposition applications.

The stock market has proven to offer satisfactory means of raising capital for public companies. One behaviour that rather frequently can be observed is that companies on the stock market are becoming the subject of so-called takeover-offers. Immediately upon the commencement of a takeover-process the board of directors of a target-company is responsible for certain obligations stipulated in the legal framework for the stock market. An obligation of quite substantial significance for the shareholders in the target-company is the board of directors’ duty to make a statement on the takeover-offer. Since the said statement is of such significance for the shareholders, the question arises whether the board of directors can be held liable for irresponsible statements with regards to an imminent takeover-offer. This thesis aims to answer this question whilst examining closely related questions such as which obligations the board of directors has when making a statement on a takeover-offer as well as what basis of liability is applicable to the board of directors. Due to the nature of the Swedish capital market regulation the thesis also aims to illustrate and problematize the relationship between legislation and what is commonly referred to as self-regulation. By the means of a legal dogmatic method the thesis concludes that the boards of directors in some cases are liable for their statements on a takeover-offer. The conditions for which a basis of liability is applicable differs depending upon which ground of liability is chosen to establish said liability, this circumstance turns out to be of critical importance in a procedural sense. Although the basis of liability differs from one another the thesis displays that legitimate reasons speak for basing a claim for damages on the rule regarding tortious liability that the Swedish Supreme Court (Högsta domstolen) has developed. In addition to how the board of directors can be held liable the research has also demonstrated the importance of the statements the board of directors make on a takeover-offer. This provides support to the belief that the board of directors should be able to be held responsible for careless statements with regards to an impending takeover-offer. Furthermore, the research shows that a lack of distinct conjunction between self-regulation and legislation could generate an inconsistent construction of what the content of the current law is at any given time.

No description available.

No description available.

<h2><strong>Sammanfattning</strong></h2><p>Denna uppsats fokuserar på röstspärren i lag (1973:1150) om förvaltning av samfälligheter 12 och 49 §§ (SFL). Röstspärren liknar den 20%-regel som fanns i gamla ABL och som togs bort därifrån år 1999. Bägge reglerna stoppar någon med andelar högre än en femtedel vid en om-röstning. Denna likhet väcker frågetecken om en gemensam bakgrund trots skillnaden mellan aktiebolag och samfälligheter. Den väcker också frågor kring varför röstspärren anses befogad vid omröstning på delägarsammanträde/föreningsstämma men inte längre vid en bolagsstäm-ma. Detta arbete har därför gått bakåt i tiden och undersökt ett eventuellt släktskap mellan de båda reglerna. Uppsatsen har också försökt utröna om röstspärren har någon effekt för samfäl-ligheter i dagens Sverige. Det kan ju vara så att röstspärren utgör en ”blindtarm” i SFL, precis som den gjorde i ABL innan den togs bort. De områden där röstspärrens effekter undersökts är i storkvarter, tredimensionellt avgränsade fastigheter, ägarlägenhetsfastigheter samt enskil-da vägar.</p><p>I detta arbete har visats att röstspärren såsom den ser ut i dagens SFL, har sina källor i vat-tenlagen från år 1918. Därifrån har regeln tagits från 1910-års ABL som i sin tur bygger på bolagsordningar från 1800-talet. Röstspärren och 20%-regeln har alltså gemensamma rötter i 1800-talets bolagsordningar. I detta arbete finns också klara indikationer på att röstspärren används i väldigt liten omfattning idag. Några vittnesmål om att röstspärren skulle fungera som ett effektivt skydd har inte hittats. Däremot finns det många betänkligheter kring regelns eventuellt negativa effekter för samfälligheter där ägarlägenhetsfastigheter och/eller tredimen-sionella fastigheter ingår. Detta arbete har således fastställt en historisk koppling mellan två lagregler som ej längre tillämpas i någon högre grad. Den ena är upphävd, den andra lever kvar men börjar bli omdebatterad. Slutsatsen av detta arbete är därför att regeln bör ses om och förslagsvis, i ett första steg, göras dispositiv och i förlängningen avskaffas.</p>

Sammanfattning Denna uppsats fokuserar på röstspärren i lag (1973:1150) om förvaltning av samfälligheter 12 och 49 §§ (SFL). Röstspärren liknar den 20%-regel som fanns i gamla ABL och som togs bort därifrån år 1999. Bägge reglerna stoppar någon med andelar högre än en femtedel vid en om-röstning. Denna likhet väcker frågetecken om en gemensam bakgrund trots skillnaden mellan aktiebolag och samfälligheter. Den väcker också frågor kring varför röstspärren anses befogad vid omröstning på delägarsammanträde/föreningsstämma men inte längre vid en bolagsstäm-ma. Detta arbete har därför gått bakåt i tiden och undersökt ett eventuellt släktskap mellan de båda reglerna. Uppsatsen har också försökt utröna om röstspärren har någon effekt för samfäl-ligheter i dagens Sverige. Det kan ju vara så att röstspärren utgör en ”blindtarm” i SFL, precis som den gjorde i ABL innan den togs bort. De områden där röstspärrens effekter undersökts är i storkvarter, tredimensionellt avgränsade fastigheter, ägarlägenhetsfastigheter samt enskil-da vägar. I detta arbete har visats att röstspärren såsom den ser ut i dagens SFL, har sina källor i vat-tenlagen från år 1918. Därifrån har regeln tagits från 1910-års ABL som i sin tur bygger på bolagsordningar från 1800-talet. Röstspärren och 20%-regeln har alltså gemensamma rötter i 1800-talets bolagsordningar. I detta arbete finns också klara indikationer på att röstspärren används i väldigt liten omfattning idag. Några vittnesmål om att röstspärren skulle fungera som ett effektivt skydd har inte hittats. Däremot finns det många betänkligheter kring regelns eventuellt negativa effekter för samfälligheter där ägarlägenhetsfastigheter och/eller tredimen-sionella fastigheter ingår. Detta arbete har således fastställt en historisk koppling mellan två lagregler som ej längre tillämpas i någon högre grad. Den ena är upphävd, den andra lever kvar men börjar bli omdebatterad. Slutsatsen av detta arbete är därför att regeln bör ses om och förslagsvis, i ett första steg, göras dispositiv och i förlängningen avskaffas.