No description available.

No description available.

No description available.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23684号 / 理博第4774号 / 新制||理||1684(附属図書館) / 京都大学大学院理学研究科数学・数理解析専攻 / (主査)教授 小野 薫, 教授 玉川 安騎男, 教授 望月 拓郎 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Cette thèse présente quelques propriétés des sous-variétés lagrangiennes monotones. On résoud d'abord une conjecture de Barraud et Cornea dans le cadre monotone en montrant que le rayon de Gromov relatif à deux lagrangiennes dans la même classe d'isotopie hamiltonienne donne une borne inférieure à la distance de Hofer entre ces deux mêmes lagrangiennes. Le cas non-monotone de cette conjecture reste ouvert encore. On définit toutes les structures nécessaires à l'énoncé et à la preuve de cette conjecture. Deuxièmement, on définit une nouvelle version d'un morphisme de Seidel relatif à l'aide des cobordismes lagrangiens de Biran et Cornea. On montre que cette version est chaîne-homotope aux différentes autres versions apparaissant dans la littérature. Que toutes ces définitions sont équivalentes fait partie du folklore mais n'apparaît pas dans la littérature. On conclut par une conjecture qui identifie un triangle exact obtenu par chirurgie lagrangienne et un autre dû à Seidel et faisant intervenir le twist de Dehn symplectique. / We present in this thesis a few properties of monotone Lagrangian submanifolds. We first solve a conjecture of Barraud and Cornea in the monotone setting by showing that the relative Gromov radius of two Hamiltonian-isotopic Lagrangians gives a lower bound on the Hofer distance between them. The general non-monotone case remains open to this day. We define all the structures relevant to state and prove the conjecture. We then define a new version of a Lagrangian Seidel morphism through the recently introduced Lagrangian cobordisms of Biran and Cornea. We show that this new version is chain-homotopic to various other versions appearing in the litterature. That all these previous versions are the same is folklore but did not appear in the litterature. We conclude with a conjecture claiming that an exact triangle obtained by Lagrangian surgery is isomorphic to an exact triangle of Seidel involving the symplectic Dehn twist.

L’existance de cellules souches leucémiques (CSL) dans la Leucémie Myéloïde Chronique (LMC) prédit que que seule la destruction des CSL conduirait à une guérison. Une proportion importante de patients atteints de LMC développe une résistance aux drogues, environ ~ 30% des cas, Les mécanismes de résistance aux inhibiteurs de tyrosine kinase (TKI) dans la leucémie myéloïde chronique (LMC) restent souvent obscures. Les cellules souches leucémiques de la LMC pourraient rester viables et en repos, malgré la présence de facteurs de croissance ou de médicaments qui semblent les protéger de l'apoptose. Nous avons montré dans la première parti de cette étude que certains transporteurs telles ABCG2, hOCT-1 pourraient jouer un rôle avec le micro environnement dans la résistance des lignées LMC en adhésion au stoma médullaire. De plus, dans deuxième parti nous avons montré que le gène TWIST-1 (est un acteur clé de l'embryogenèse) est déréglementé dans les cellules de LMC innée des résistants à l'imatinib, et que la sur-expression de l’oncogène TWIST-1 pourrait représenter un nouveau facteur clé de pronostiques potentiellement utiles pour améliorer la guérison de LMC aux TKI. De plus, nous avons pu également montrer que le gène TP73 est impliqué dans la résistance des CSL de LMC. Ce gène pourrait être un facteur prédictif pour identifier une résistance potentielle des patients de LMC au moment du diagnostic. Nous avons montré également que ce gène est régulé par le micro-environnement. Nous avons montrés une sur-expression des isoformes tronquées dans les lignées LMC avec l’adhésion au stroma. Les résultats suggèrent que les molécules intrinsèques comme TWIST-1, les transporteurs et les isoformes de p73 sont dérégulées dans les CSL par des mécanismes extrinsèques qui interviennent avec le micro environnement leucémique par le mécanisme d’adhésion dans le phénomène de résistance aux traitements. Ce mécanisme spécial de résistance due à la conservation de ces CSL dans l’état immature en adhésion avec son micro environnement. / The existence of Leukemia stem cells (CSL) in chronic myelogenous leukemia (CML) predicts that only the destruction of CSL lead to a cure. A significant proportion of CML patients develop resistance to drugs, ~ 30% cases, mechanisms of resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) often remain obscure. Leukemic stem cells of CML could remain viable and quiet, despite the presence of growth factors or drugs that seem to protect them from apoptosis. We have shown in the first part of this study that some carriers such as ABCG2, hOCT could to be play a role with the microenvironment in the resistance among CML adhesion of stoma Bone marrow. Furthermore, in the second part we showed that the gene TWIST-1 (is a key player of the embryogenesis) is deregulated in cells of CML innately resistant to imatinib, and that overexpression of the oncogene TWIST-1 could represent a new prognostic factor key potentially useful for improving the querison CML to TKI. In addition, we also could show that the TP73 gene is involved in the resistance of CSL CML. This gene could be a predictor to identify potential resistance of CML patients at diagnosis. We have also shown that this gene is regulated by the microenvironment. We have shown an overexpression of truncated isoforms in CML cell lines with the accession to the stroma. The results suggest that intrinsic molecules such as TWIST-1 carriers and p73 isoforms are deregulated in CSL by extrinsic mechanisms involved with the leukemia microenvironment by the mechanism for participation in the phenomenon of drug resistance. This mechanism with its microenvironment.

Introdução: A doença falciforme (DF) é a afecção hematológica hereditária de maior prevalência no mundo, sendo que a anemia falciforme (AF) é a forma mais grave com elevada morbidade e mortalidade. Alterações cardíacas são reconhecidamente associadas à AF, como aumento cavitário, hipertensão arterial pulmonar e disfunção diastólica do ventrículo esquerdo. No entanto, ainda não existe consenso quanto à função sistólica ventricular nesses pacientes. O objetivo deste estudo foi o de investigar a função ventricular de pacientes com anemia falciforme utilizando o strain e o twist ventricular obtidos pelo speckle tracking bidimensional, e reconhecer os indivíduos sob maior risco cardiovascular, em que a instituição precoce de tratamento específico poderá beneficiar essa população. Métodos: Foram recrutados 40 pacientes com anemia falciforme (23,5 ± 9,3 anos; 24 homens) e 40 controles saudáveis pareados por sexo e idade, submetidos à entrevista estruturada, ecocardiograma transtorácico, cintilografia pulmonar ventilação perfusão e coleta de amostras de sangue. Todos os indivíduos foram submetidos à avaliação ecocardiográfica convencional padrão e subsequente avaliação offline do strain sistólico biventricular e estudo rotacional do ventrículo esquerdo utilizando speckle-tracking ecocardiográfico. Resultados: Os pacientes com AF apresentaram volume do VE indexado, massa do VE indexado, pressão arterial pulmonar e E/E\' médio superiores aos controles. As medidas de FE do VE, excursão sistólica do plano da tricúspide (TAPSE), Strain Global do VE (longitudinal, circunferencial, radial) e Strain Global do VD (longitudinal) não evidenciaram diferenças entre os grupos. Twist VE se mostrou reduzido em comparação aos controles (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) e Tempo de pico de rotação apical prolongado (366,7 ± 26,1ms vs 344,6 ± 11,7ms , P <0,0001 ). Algumas variáveis se mostraram fortemente relacionadas ao twist VE, como índice de gravidade clínico (Rho= - 0,97, Z value= - 6,05, P < 0,0001), relação E/E\' médio (r = 0,94, F valor= 156.9, p<0,0001), IVDFVE (índice do volume diastólico final do ventrículo esquerdo)(r = 0,81 e p<0,0001) e pressão sistólica arterial pulmonar (r = 0,72 e p<0,0001). Conclusões: Os resultados deste trabalho indicam que o twist ventricular esquerdo derivado do speckle tracking bidimensional encontra-se alterado em pacientes com anemia falciforme e função sistólica ventricular preservada, avaliada pela metodologia convencional, e existe forte correlação entre o twist ventricular esquerdo e o índice clínico de gravidade, relação E/E\', índice do volume diastólico final do ventrículo esquerdo e pressão sistólica arterial pulmonar. / Background: Sickle cell disease (SCD) is the most prevalent hematological condition in the world, with sickle cell anemia (SCA) being its most serious form, displaying a high level of morbidity and mortality. Cardiac changes are known to be associated with SCA, including an increase in cardiac chamber size, pulmonary hypertension and left ventricle diastolic dysfunction. However, there is still no consensus regarding the ventricular systolic function in these patients. The purpose of this study is to investigate the ventricular function of patients with sickle cell anemia utilizing the strain and ventricular twist, obtained by two-dimensional speckle tracking, as well as to identify individuals with higher cardiovascular risk, in which early application of specific treatment could benefit this group of people. Methods: 40 patients were recruited with sickle cell anemia (ages 23.5 ± 9.3 years; 24 males) and 40 healthy control individuals paired by gender and age, submitted to structured interviews, transthoracic echocardiogram, pulmonary scintigraphy and collection of blood samples. All individuals were submitted to a standard echocardiographic evaluation and subsequent off line evaluation of the biventricular systolic strain and rotational study of the left ventricle using echocardiographic speckle-tracking. Results: Patients with SCA presented LV volume indices, LV mass Indices, pulmonary arterial pressure and E/ E\' ratios statistically higher than the control individuals. Measurements of Ejection Fraction (EF) of the left ventricle, tricuspid annular plane systolic excursion (TAPSE), Overall LV Strain (Longitudinal, Circumferential, and Radial) and Overall RV Strain (Longitudinal) did not present differences between the groups. LV twist was significantly lower in relation to the control group (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) and prolonged time to peak apical rotation (366.7 ± 26.1ms vs 344.6 ± 11.7ms , P <0.0001 ). In addition, some variables showed themselves to be strongly related to LV twist such as the clinical severity index ( Rho= - 0.97, Z value= - 6.05, P < 0.0001), E/E\' Ratio (r = 0.94, F value=156.9 e p<0.0001) ), left ventricle end diastolic volume index (LVEDV index) (r = 0,81, p<0,0001) and pulmonary systolic arterial pressure (r = 0.72 e p<0.0001). Conclusions: The results of this study indicate that the left ventricular twist derived from two-dimensional speckle tracking is altered in patients with sickle cell anemia and a preserved ventricular systolic function, evaluated using conventional methodology and that there is a strong correlation between left ventricular twist and the clinical severity index, E/E\' ratio, left ventricle end diastolic volume index and the pulmonary systolic arterial pressure.

Cette thèse présente quelques propriétés des sous-variétés lagrangiennes monotones. On résoud d'abord une conjecture de Barraud et Cornea dans le cadre monotone en montrant que le rayon de Gromov relatif à deux lagrangiennes dans la même classe d'isotopie hamiltonienne donne une borne inférieure à la distance de Hofer entre ces deux mêmes lagrangiennes. Le cas non-monotone de cette conjecture reste ouvert encore. On définit toutes les structures nécessaires à l'énoncé et à la preuve de cette conjecture. Deuxièmement, on définit une nouvelle version d'un morphisme de Seidel relatif à l'aide des cobordismes lagrangiens de Biran et Cornea. On montre que cette version est chaîne-homotope aux différentes autres versions apparaissant dans la littérature. Que toutes ces définitions sont équivalentes fait partie du folklore mais n'apparaît pas dans la littérature. On conclut par une conjecture qui identifie un triangle exact obtenu par chirurgie lagrangienne et un autre dû à Seidel et faisant intervenir le twist de Dehn symplectique. / We present in this thesis a few properties of monotone Lagrangian submanifolds. We first solve a conjecture of Barraud and Cornea in the monotone setting by showing that the relative Gromov radius of two Hamiltonian-isotopic Lagrangians gives a lower bound on the Hofer distance between them. The general non-monotone case remains open to this day. We define all the structures relevant to state and prove the conjecture. We then define a new version of a Lagrangian Seidel morphism through the recently introduced Lagrangian cobordisms of Biran and Cornea. We show that this new version is chain-homotopic to various other versions appearing in the litterature. That all these previous versions are the same is folklore but did not appear in the litterature. We conclude with a conjecture claiming that an exact triangle obtained by Lagrangian surgery is isomorphic to an exact triangle of Seidel involving the symplectic Dehn twist.

La dynamique des systèmes hyperboliques est considérée bien comprise du point de vue topologique aussi bien que du point de vue stochastique. S. Smale et R. Abraham ont donné un exemple montrant que, en général, les systèmes hyperboliques ne sont pas denses parmi tous les systèmes diffélrentiables. Dans les années 1970, M. Brin et Y. Pesin ont proposé une nouvelle notion: hyperbolicité partielle pour affaiblir la notion d’hyperbolicité. Un but de cette thèse est de comprendre la dynamique de certains systèmes partiellement hyperboliques du point de vue stochastique aussi bien que du point de vue topologique. Du point de vue stochastique, nous démontrons les résultats suivants: — Il existe un sous-ensemble U ouvert et dense de difféomorphismes non hyperboliques robustement transitifs loin de tangences homocliniques, tels que pour tout f ∈ U, il existe des mesures ergodiques non hyperboliques qui sont limite faible des mesures périodiques, avec un seul exposant de Lyapunov nul, et dont les supports sont la variété entière; — Il existe un sous-ensemble ouvert et dense de l’ensemble des difféomorphismes partiellement hyperboliques (mais non hyperboliques) de dimension centrale un dont les feuilletages forts sont robustement minimaux, de sorte que la fermeture de l’ensemble des mesures ergodiques est l’union de deux convexes qui sont la fermeture des ensembles de mesures ergodiques hyperboliques de deux s-indices différents respectivement; ces deux ensembles convexes se coupent le long de la fermeture de l’ensemble des mesures ergodiques non hyperboliques. Par conséquent, toute mesure ergodique non hyperbolique est approchée par des mesures périodiques. C’est le cas pour une perturbation robustement transitive du temps un d’un flot d’Anosov transitif, ou du produit fibré d’un difféomorphisme d’Anosov sur le tore par une rotation du cercle. Ces résultats sont basés sur des résultats locaux dont les démonstrations impliquent beaucoup de définitions techniques. Du point de vue topologique, pour tout flot d’Anosov non transitif sur des variétés de dimension 3 orientables, nous construisons de nouveaux difféomorphismes partiellement hyperboliques en composant le temps t des flots d’Anosov (pour t > 0 large) avec des twists de Dehn le long des tores transversaux. Ces nouveaux difféomorphismes partiellement hyperboliques sont robustement dynamiquement cohérents. Cela généralise dans un cas général le processus spécial dans [BPP] pour construire de nouveaux difféomorphismes partiellement hyperboliques. De plus, nous démontrons que pour les nouveaux difféomorphismes partiellement hyperboliques que nous avons construits, leurs feuilletages centraux sont topologiquement équivalentes aux flots d’Anosov utilisés pour les construire. En conséquence, la structure des feuilles centrales des nouveaux difféomorphismes partiellement hyperboliques est la même que la structure des orbites d’un flot d’Anosov. La présence de mesures ergodiques non hyperboliques montre la non hyperbolicité des systémes. Dans cette thése, nous cherchons également à comprendre: dans quelle mesure la présence de mesures ergodiques non hyperboliques peut-elle caractériser le degré de non-hyperbolicité des systèmes? Nous démontrons que, pour les difféomorphismes génériques, si une classe homoclinique contient des orbites périodiques d’indices différents et sans certaines dominations, il existe une mesure ergodique non hyperbolique avec plus d’un exposant de Lyapunov qui s’annule et dont le support est la classe homoclinique entière. Le nombre d’exposants de Lyapunov nuls montre combien d’hyperbolicité a été perdue dans un tel type de systèmes. / The dynamics of hyperbolic systems is considered well understood from topological point of view as well as from stochastic point of view. S. Smale and R. Abraham gave an example showing that, in general, the hyperbolic systems are not dense among all differentiable systems. In 1970s, M. Brin and Y. Pesin proposed a new notion: partial hyperbolicity to release the notion of hyperbolicity. One aim of this thesis is to understand the dynamics of certain partially hyperbolic systems from stochastic point of view as well as from topological point of view. From stochastic point of view, we prove the following results: — There exists an open and dense subset U of robustly transitive nonhyperbolic diffeomorphisms far from homoclinic tangency, such that forany f ∈ U, there exist non-hyperbolic ergodic measures as the weak*- limit of periodic measures, with only one vanishing Lyapunov exponent, and whose supports are the whole manifold; — There exists an open and dense subset of partially hyperbolic (but nonhyperbolic) diffeomorphisms with center dimension one whose strong foliations are robustly minimal, such that the closure of the set of ergodic measures is the union of two convex sets which are the closure of the sets of hyperbolic ergodic measures of two different s-indices respectively; these two convex sets intersect along the closure of the set of nonhyperbolic ergodic measures. As a consequence, every non-hyperbolic ergodic measure is approximated by periodic measures. That is the case for robustly transitive perturbation of the time one map of a transitive Anosov flow, or of the skew product of an Anosov torus diffeomorphism by a rotation of the circle. These results are based on some local results whose statements involve in lots of technical definitions. From topological point of view, for any non-transitive Anosov flow on orientable 3-manifolds, we build new partially hyperbolic diffeomorphisms by composing the time t-map of the Anosov flow (for t > 0 large) with Dehn twists along transverse tori. These new partially hyperbolic diffeomorphisms are robustly dynamically coherent. This generalizes the special process in [BPP] for constructing new partially hyperbolic diffeomorphisms to a general case. Furthermore, we prove that for the new partially hyperbolic diffeomorphisms we built, their center foliations are topologically equivalent to the Anosov flows used for building them. As a consequence, one has that the structure of the center leaves of the new partially hyperbolic diffeomorphisms is the same asthe structure of the orbits of an Anosov flow. The presence of non-hyperbolic ergodic measures shows the non-hyperbolicity of the systems. In this thesis, we also attempt to understand: to what extent, can the presence of non-hyperbolic ergodic measures character how far from hyperbolicity the systems are? We prove that, for generic diffeomorphisms, if a homoclinic class contains periodic orbits of different indices and without certain dominations, then there exists a non-hyperbolic ergodic measure with more than one vanishing Lyapunov exponents and whose support is the whole homoclinic class. The number of vanishing Lyapunov exponents shows how much hyperbolicity has been lost in such kind of systems.

Introdução: A doença falciforme (DF) é a afecção hematológica hereditária de maior prevalência no mundo, sendo que a anemia falciforme (AF) é a forma mais grave com elevada morbidade e mortalidade. Alterações cardíacas são reconhecidamente associadas à AF, como aumento cavitário, hipertensão arterial pulmonar e disfunção diastólica do ventrículo esquerdo. No entanto, ainda não existe consenso quanto à função sistólica ventricular nesses pacientes. O objetivo deste estudo foi o de investigar a função ventricular de pacientes com anemia falciforme utilizando o strain e o twist ventricular obtidos pelo speckle tracking bidimensional, e reconhecer os indivíduos sob maior risco cardiovascular, em que a instituição precoce de tratamento específico poderá beneficiar essa população. Métodos: Foram recrutados 40 pacientes com anemia falciforme (23,5 ± 9,3 anos; 24 homens) e 40 controles saudáveis pareados por sexo e idade, submetidos à entrevista estruturada, ecocardiograma transtorácico, cintilografia pulmonar ventilação perfusão e coleta de amostras de sangue. Todos os indivíduos foram submetidos à avaliação ecocardiográfica convencional padrão e subsequente avaliação offline do strain sistólico biventricular e estudo rotacional do ventrículo esquerdo utilizando speckle-tracking ecocardiográfico. Resultados: Os pacientes com AF apresentaram volume do VE indexado, massa do VE indexado, pressão arterial pulmonar e E/E\' médio superiores aos controles. As medidas de FE do VE, excursão sistólica do plano da tricúspide (TAPSE), Strain Global do VE (longitudinal, circunferencial, radial) e Strain Global do VD (longitudinal) não evidenciaram diferenças entre os grupos. Twist VE se mostrou reduzido em comparação aos controles (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) e Tempo de pico de rotação apical prolongado (366,7 ± 26,1ms vs 344,6 ± 11,7ms , P <0,0001 ). Algumas variáveis se mostraram fortemente relacionadas ao twist VE, como índice de gravidade clínico (Rho= - 0,97, Z value= - 6,05, P < 0,0001), relação E/E\' médio (r = 0,94, F valor= 156.9, p<0,0001), IVDFVE (índice do volume diastólico final do ventrículo esquerdo)(r = 0,81 e p<0,0001) e pressão sistólica arterial pulmonar (r = 0,72 e p<0,0001). Conclusões: Os resultados deste trabalho indicam que o twist ventricular esquerdo derivado do speckle tracking bidimensional encontra-se alterado em pacientes com anemia falciforme e função sistólica ventricular preservada, avaliada pela metodologia convencional, e existe forte correlação entre o twist ventricular esquerdo e o índice clínico de gravidade, relação E/E\', índice do volume diastólico final do ventrículo esquerdo e pressão sistólica arterial pulmonar. / Background: Sickle cell disease (SCD) is the most prevalent hematological condition in the world, with sickle cell anemia (SCA) being its most serious form, displaying a high level of morbidity and mortality. Cardiac changes are known to be associated with SCA, including an increase in cardiac chamber size, pulmonary hypertension and left ventricle diastolic dysfunction. However, there is still no consensus regarding the ventricular systolic function in these patients. The purpose of this study is to investigate the ventricular function of patients with sickle cell anemia utilizing the strain and ventricular twist, obtained by two-dimensional speckle tracking, as well as to identify individuals with higher cardiovascular risk, in which early application of specific treatment could benefit this group of people. Methods: 40 patients were recruited with sickle cell anemia (ages 23.5 ± 9.3 years; 24 males) and 40 healthy control individuals paired by gender and age, submitted to structured interviews, transthoracic echocardiogram, pulmonary scintigraphy and collection of blood samples. All individuals were submitted to a standard echocardiographic evaluation and subsequent off line evaluation of the biventricular systolic strain and rotational study of the left ventricle using echocardiographic speckle-tracking. Results: Patients with SCA presented LV volume indices, LV mass Indices, pulmonary arterial pressure and E/ E\' ratios statistically higher than the control individuals. Measurements of Ejection Fraction (EF) of the left ventricle, tricuspid annular plane systolic excursion (TAPSE), Overall LV Strain (Longitudinal, Circumferential, and Radial) and Overall RV Strain (Longitudinal) did not present differences between the groups. LV twist was significantly lower in relation to the control group (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) and prolonged time to peak apical rotation (366.7 ± 26.1ms vs 344.6 ± 11.7ms , P <0.0001 ). In addition, some variables showed themselves to be strongly related to LV twist such as the clinical severity index ( Rho= - 0.97, Z value= - 6.05, P < 0.0001), E/E\' Ratio (r = 0.94, F value=156.9 e p<0.0001) ), left ventricle end diastolic volume index (LVEDV index) (r = 0,81, p<0,0001) and pulmonary systolic arterial pressure (r = 0.72 e p<0.0001). Conclusions: The results of this study indicate that the left ventricular twist derived from two-dimensional speckle tracking is altered in patients with sickle cell anemia and a preserved ventricular systolic function, evaluated using conventional methodology and that there is a strong correlation between left ventricular twist and the clinical severity index, E/E\' ratio, left ventricle end diastolic volume index and the pulmonary systolic arterial pressure.