<p>The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL).</p><p>Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up.</p><p>The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level.</p><p>Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and >6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters.</p><p>In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.</p>

<p>Despite major advances in the understanding of the biology of chronic lymphocytic leukaemia (CLL), progress in improving its treatment has been limited and it still remains an incurable disorder. In the present research, we have performed <i>in vitro</i> drug sensitivity testing of primary CLL cells for preclinical evaluation of cytotoxic drugs, using the fluorometric microculture cytotoxicity assay (FMCA).</p><p>The tumour type-specific activities of 14 standard drugs, evaluated <i>in vitro</i> on tumour cells from patients with CLL and acute leukaemias, were in good agreement with their known clinical activities. A correlation between drug treatment and development of cellular drug resistance was demonstrated in CLL, but not in the acute leukaemias. Moreover, the nucleoside analogues fludarabine, cladribine, cytarabine and gemcitabine, as well as the anthracycline idarubicin, were highly active in CLL cells.</p><p>A new cytotoxic drug candidate, CHS 828, was evaluated in primary cell cultures from a broad spectrum of tumours. CHS 828 was highly active against haematological malignancies <i>in vitro</i>, especially CLL, but also against some solid tumours. The drug appeared to be non cross-resistant with standard drugs.</p><p>In addition, the relationship between drug sensitivity <i>in vitro</i> and a recently described prognostic factor in CLL, the mutational status of the immunoglobulin variable heavy chain (IgV_H) gene, was evaluated. Interestingly, cells with unmutated IgV_H genes were more chemosensitive than the mutated cells. </p><p>In summary, our results indicate that <i>in vitro</i> studies on tumour cellsfrom leukaemia patients may yield considerable information regarding the activity, mechanisms of action and cross-resistance of cytotoxic drugs, as well as concerning the relationship between drug sensitivity and prognostic factors, which can be useful in the preclinical evaluation of new cytotoxic drugs. Furthermore, the results suggest that the pyrimidine analogues cytarabine and gemcitabine, as well as the anthracycline idarubicin, may have a role in the treatment of CLL. The new cyanoguanidine CHS 828 is highly active in CLL cells and appears to be non cross-resistant with standard drugs. The poorer prognosis in patients with CLL cells with unmutated IgV_H genes can not be explained by increased chemoresistance.</p>

The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL). Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up. The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level. Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and &gt;6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters. In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.

Despite major advances in the understanding of the biology of chronic lymphocytic leukaemia (CLL), progress in improving its treatment has been limited and it still remains an incurable disorder. In the present research, we have performed in vitro drug sensitivity testing of primary CLL cells for preclinical evaluation of cytotoxic drugs, using the fluorometric microculture cytotoxicity assay (FMCA). The tumour type-specific activities of 14 standard drugs, evaluated in vitro on tumour cells from patients with CLL and acute leukaemias, were in good agreement with their known clinical activities. A correlation between drug treatment and development of cellular drug resistance was demonstrated in CLL, but not in the acute leukaemias. Moreover, the nucleoside analogues fludarabine, cladribine, cytarabine and gemcitabine, as well as the anthracycline idarubicin, were highly active in CLL cells. A new cytotoxic drug candidate, CHS 828, was evaluated in primary cell cultures from a broad spectrum of tumours. CHS 828 was highly active against haematological malignancies in vitro, especially CLL, but also against some solid tumours. The drug appeared to be non cross-resistant with standard drugs. In addition, the relationship between drug sensitivity in vitro and a recently described prognostic factor in CLL, the mutational status of the immunoglobulin variable heavy chain (IgVH) gene, was evaluated. Interestingly, cells with unmutated IgVH genes were more chemosensitive than the mutated cells. In summary, our results indicate that in vitro studies on tumour cellsfrom leukaemia patients may yield considerable information regarding the activity, mechanisms of action and cross-resistance of cytotoxic drugs, as well as concerning the relationship between drug sensitivity and prognostic factors, which can be useful in the preclinical evaluation of new cytotoxic drugs. Furthermore, the results suggest that the pyrimidine analogues cytarabine and gemcitabine, as well as the anthracycline idarubicin, may have a role in the treatment of CLL. The new cyanoguanidine CHS 828 is highly active in CLL cells and appears to be non cross-resistant with standard drugs. The poorer prognosis in patients with CLL cells with unmutated IgVH genes can not be explained by increased chemoresistance.

The principal goal of this thesis is to develop a systematic method for the design of composite heat sinks (CHSs) that serve as passive and transient cooling devices for microelectronics. This is accomplished by posing the CHS design problem as a topology optimization problem wherein a phase-change material and a high-conductivity material are to be optimally distributed. Two different types of formulations are proposed. The first one aims to maximize the time of operation before a tolerable temperature is reached at the interface between a heat source and the CHS. The second one aims to minimize the maximum temperature across the heating interface for a given time of operation. The two materials are interpolated in topology optimization using the usual mixture law with penalty. The phase-change is modeled using the apparent heat capacity method in which the specific heat is taken as a nonlinear function of the temperature so that the latent heat absorption is accounted for at the melting point. The ensuing new transient topology optimization problem involving an interpolated material property that depends on the state variable is solved using continuous optimization algorithm. The validity of the phase-change modeling is verified with a one dimensional model as well as experimentation. Analytical sensitivity analysis is derived and verified with the finite difference derivatives. Several examples are solved to illustrate the intricacies of the problem and the effectiveness and the limitations of the proposed design method. Prototypes of an intuitively conceived CHS and optimized one are made. An experimental setup is devised to test the two prototypes. Based on the insight gained from the experiments, an improved conduction model is studied to also incorporate convective heat transfer also into the model.

Several boom segments form the crane boom. These segments are often truss structures formed out of circular hollow sections, which are welded together forming the truss joints. A adequate modelling of these truss joints is very important for operational strength and life. Due to the large boom sizes, efficient models are used in the finite element method, generally built of beam elements. These models have problems capturing the proper bending moments working in the truss joints. This is caused by a insufficient portrayal of the joint stiffness. In the literature several modelling techniques with beam elements are proposed, which capture the joint stiffness better. These different modelling methods are implemented in a parametric boom section and compared with a shell element FE model. From this comparison the most appropriate modelling method is selected, which improve the portrayal of internal loads and nominal stresses. With these improved nominal stress values, it is investigated to implement a different fatigue assessment. The structural stress can be calculated from the nominal stress in combination with stress concentration factor (SCF) equations. To implement the structural stress method as fatigue assessment, several modelling and extrapolation methods have been compared. Which lead to a method for evaluating the structural stress in a efficient matter. This method is compared with existing SCF K truss joint equations, from which a new set of SCF equations is derived. These equations are constructed from a larger dataset, hold a wider validity range and fit better with the FE models. When applying these SCF equations with the improved beam modelling method in a boom section, the structural stress is not adequately captured. This is caused by unsymmetrical stressed braces in the K truss joints. Both the modelling methods and SCF equations account for uniformly stressed braces forming the truss joints. More research needs to be conducted to this uneven behaviour. If the structural stress method needs to be implemented with efficient FE models, submodels out of shell elements combined with beam elements are recommended. For fatigue evaluation with the nominal stress method, beam models which account for the local joint flexibility give sufficient realistic results. / Flera kranarmsegment bildar kranarmen. Dessa segment är ofta fackverk utformade av cirkulära ihåliga profiler, som är sammansvetsade och bildar fackverkslederna. En ordentlig modellering av dessa fackförband är mycket viktig för dess driftsstyrka och livslängd. På grund av storleken används finita elementmetoden, vanligtvis uppbyggt av balkelement. Dessa modeller har problem med att beräkna de korrekta böjmomenten som uppstår i fackverkslederna. Detta orsakas av en otillräcklig beskrivning av ledstyvheten. I litteraturen föreslås flera modelleringstekniker med balkelement som tar hänsyn till ledens styvhet bättre. Dessa olika modelleringsmetoder implementeras i en parametrisk kranarmsektion och jämförs med en FE-modell med skalelement. Med denna jämförelse väljs den mest lämpliga modelleringsmetoden, vilket bör förbättra skildringen av interna belastningar och nominella spänningar. Med dessa förbättrade nominella spänningsvärden, undersöks det att genomföra en annan utmattningsbedömning. Den strukturella spänningen kan beräknas utifrån den nominella spänningen i kombination med spänningskoncentrationsfaktor- (SCF) ekvationerna. För att implementera strukturella spänningsmetoden som utmattningsbedömning, har flera modellerings- och extrapoleringsmetoder jämförts. Detta leder till en metod för att utvärdera den strukturella spänningen effektivt. Denna metod jämförs med befintliga SCF-ekvationer, från vilka en ny uppsättning SCF-ekvationer härleds. Dessa ekvationer är konstruerade från en större datauppsättning, har ett bredare giltighetsområde och passar bättre med FE-modellerna. När man applicerar dessa SCF-ekvationer med den förbättrade balkmodelleringsmetoden i en kranarmsektion, uppsamlas strukturella spänningar inte tillräckligt, detta orsakas av ojämna spänningar i diagonalelementen i fackverkslederna. Både modelleringsmetoderna och SCF-ekvationerna tar hänsyn till jämnt spända diagonalelement som uppstår i fackverkslederna. Mer forskning bör göras över detta ojämna beteende. Om den strukturella spänningsmetoden måste implementeras med effektiva FE-modeller, rekommenderas undermodeller av skalelement kombinerade med balkelement. För utmattningsutvärdering med den nominella spänningsmetoden, ger balkmodeller som tar hänsyn till den lokala ledflexibiliteten tillräckligt realistiska resultat.

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2011-2012 / L'ACTION CRÉATRICE DE L'ACTEUR DANS LA PIÈCE C.H.S.¹ Étude sur l'effet de présence actoral dans un dispositif intermedial Par un aller et retour entre la théorie et la pratique, l'objectif de notre recherche-création est d'expliciter le répertoire de techniques qui a permis de varier les registres de présence de l'acteur dans le dispositif intermedial² de C.H.S. Dans un premier temps, nous nous sommes demandé si les recherches en biomécanique de Meyerhold, consistant en des variations des mises en rapport de l'acteur, pouvaient s'avérer adéquates pour construire une présence actorale dans l'immobilité. Ensuite, nous avons enrichi notre répertoire de placements scéniques, avec les travaux de Stanislavski et Grotowski. Afin d'étudier les qualités relationnelles de l'acteur, nous avons abordé une définition de la présence à soi, proposée par la Psychologie Corporelle Intégrée et le modèle constructiviste de Masciotra (2004). Puis, des réflexions sur les pratiques théâtrales actuelles nous ont permis de mettre de l'avant la notion « d'être-entre ». Par le biais de laboratoires artistiques, nous avons réfléchi et mis en pratique ces fondements théoriques pour préciser les procédures techniques permettant de varier la présence de l'acteur qui interprète le scientifique³. Le but de notre réflexion a été de rendre compte des diverses mises en relation qui permettent à l'acteur de C.H.S. de moduler adéquatement ses degrés de présence entre performativité et théâtralité. 1 Voir Annexe A 2 Voir Annexe B 3 À partir de maintenant, chaque fois que nous ferons mention du scientifique, il s'agira du personnage que nous avons interprété dans la pièce C.H.S. Ce travail actoral sert d'étude de cas, tout au long de cette réflexion théorique.

The work follows training and education in climbing. At first, the theoretic part introduce climbing like a unit and show its history and sections. Then follows education, climbing rules, ethics and nature protection. At last, there are present climbing informations, completed with theory, practise and methodology of climbing education. The practical part is focused on concrete dates gaining about training and education in clubs of Czech mountaineering association and confirming the truth of research hypotheses made according to the theoretic part. The work is generally aimed to introduce a process of training and education in climbing and give actual informations about it, prooved by research.