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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Expression et optimisation des réorganisations de données dans du parallélisme de flots

De Oliveira Castro Herrero, Pablo 14 December 2010 (has links) (PDF)
Pour permettre une plus grande capacité de calcul les concepteurs de systèmes embarqués se tournent aujourd'hui vers les MPSoC. Malheureusement, ces systèmes sont difficiles à programmer. Un des problèmes durs est l'expression et l'optimisation des réorganisations de données au sein d'un programme. Dans cette thèse nous souhaitons proposer une chaîne de compilation qui : 1) propose une syntaxe simple et haut-niveau pour exprimer le découpage et la réorganisation des données d'un programme parallèle ; 2) définisse une exécution déterministe du programme (critique dans le cadre des systèmes embarqués) ; 3) optimise et adapte les programmes aux contraintes de l'architecture. Pour répondre au point 1) nous proposons un langage haut-niveau, SLICES, qui permet de décrire les réorganisation de données à travers des découpages multidimensionnels. Pour répondre au point 2) nous montrons qu'il est possible de compiler SLICES vers un langage de flots de données, SJD, qui s'inscrit dans le modèle des Cyclostatic Data-Flow et donc admet une exécution déterministe. Pour répondre au point 3) nous définissons un ensemble de transformations qui préservent la sémantique des programmes SJD. Nous montrons qu'il existe un sous-ensemble de ces transformations qui génère un espace de programmes équivalents fini. Nous proposons une heuristique pour explorer cet espace de manière à choisir la variante la plus adaptée à notre architecture. Enfin nous évaluons cette méthode sur deux problèmes classiques : la réduction de la mémoire consommée et la réduction des communications d'une application parallèle.
12

Role of STAT3 and SDF-1/CXCL 12 in mitochondrial function in hematopoietic stem and progenitor cells

Messina-Graham, Steven V. 10 August 2016 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Mitochondria are the major ATP producing source within cells. There is increasing data supporting a direct involvement of mitochondria and mitochondrial function in regulating stem cell pluripotency. Mitochondria have also been shown to be important for hematopoietic stem and progenitor cell function. Hematopoietic stem cells have lower numbers of mitochondria (mass), lower mitochondrial membrane potential, and lower ATP levels as compared to other blood cell types. Mitochondria play an important role in hematopoietic stem and progenitor cells, thus we investigated the role of the chemokine, SDF-1/CXCL12, in mitochondrial function in hematopoietic stem and progenitor cells using an SDF-1/CXCL12 transgenic mouse model. We found increased mitochondrial mass is linked to CD34 surface expression in hematopoietic stem and progenitor cells, suggesting that mitochondrial biogenesis is linked to loss of pluripotency. Interestingly these hematopoietic progenitor cells have low mitochondrial membrane potential and these mitochondrial become active prior to leaving the progenitor cell compartment. We also tested the ability of SDF-1/CXL12 to modulate mitochondrial function in vitro by treating the human leukemia cell line, HL-60, and primary mouse lineage- bone marrow cells with SDF-1/CXCL12. We found significantly reduced mitochondrial function at two hours while mitochondrial function was significantly increased at 24 hours. This suggests that SDF1/CXCL12 regulates mitochondrial function in a biphasic manner in a model of hematopoietic progenitors and immature blood cells. This suggests SDF1/CXCL12 may play a role in regulating mitochondrial function in hematopoiesis. We also investigated STAT3 in hematopoietic stem and progenitor cells. Mitochondrial STAT3 plays an essential role in regulating mitochondrial function. By using a knockout (Stat3-/-) mouse model we found that Stat3-/- hematopoietic progenitor cells had reduced colony forming ability, slower cell cycling status, and loss of proliferation in response to multi-cytokine synergy. We also found mitochondrial dysfunction in Stat3-/- hematopoietic stem and progenitor cells. Our results suggest an essential role for mitochondria in HSC function and a novel role for SDF-1/CXCL12 and STAT3 in regulating mitochondrial function in hematopoietic stem and progenitor cells.
13

NMR Dynamic Characterization of a Disordered Peptide Derived From the V3 Loop of HIV-1 Both Free and Conjugated With Bovine Pancreatic Trypsin Inhibitor

Sharma, Yugal K. January 2000 (has links)
No description available.
14

Mécanismes de progression des carcinomes de la prostate et recherche de nouveaux facteurs pronostiques / Progression Mechanisms of Prostate Cancer and New Prognostic Factors

Barry Delongchamps, Nicolas 29 March 2013 (has links)
Parallèlement au rôle central du récepteur aux androgènes, l’environnement tumoral immédiat exerce aussi une action majeure sur la progression du cancer de la prostate. L’hypoxie locale, par le biais de régulations multiples, serait impliquée dans la migration cellulaire et la dissémination tumorale. L’objectif de ma thèse a été d’identifier de nouvelles cibles thérapeutiques et de nouveaux marqueurs pronostiques pour ces cancers. J’ai tout d’abord participé à l’identification d’un partenaire du récepteur aux androgènes, la protéine CAD, enzyme clé de la synthèse des pyrimidines. Parallèlement, nous nous sommes intéressés au rôle d’un anti-angiogénique endogène dans la progression du cancer de la prostate, la thrombospondine-1 (TSP-1). Bien que l’activité anti angiogénique soit souvent considérée comme anti-tumorale, nous avons mis en évidence le caractère protumoral de la TSP-1, par son action promigratoire sur les cellules tumorales. Ces travaux m’ont conduits à étudier l’axe CXCR4/SDF-1, régulé en partie par l’hypoxie et stimulant la migration cellulaire. Nous avons montré sur tissu humain que CXCR4 était exprimé principalement au niveau du front tumoral des cancers localisés et localement avancés, et que son expression était associée à une transition épithélio-mésenchymateuse. SDF-1 était surexprimée selon un gradient croissant allant du centre des tumeurs vers le tissu péritumoral distant, exerçant possiblement un chimiotactisme sur les cellules du front tumoral. La surexpression de CXCR4 au front tumoral ainsi que le gradient de SDF1 étaient associés au pronostic. / In addition to the pivotal role of the androgen receptor, the immediate tumor microenvironment plays an essential role in prostate cancer progression. Local hypoxia, through multiple regulation mechanisms, may be implicated in the migration of tumor cells and dissemination. The aim of my thesis was to identify new therapeutic targets and prognostic markers for these cancers. I first participated in the identification of a new partner of the androgen receptor, the protein CAD that is a key enzyme of pyrimidine synthesis. We also studied the role of the endogenous anti-angiogenic thrombospondin-1 (TSP-1) in prostate cancer progression. Although anti-angiogenic activity is usually matched with tumor inhibition, we showed that TSP-1 exerted protumoral effects by stimulating cell migration. These observations led me to study the hypoxia-induced CXCR4/SDF-1 axis that is known to promote cell migration through the extra-cellular matrix. We showed on human tissue that CXCR4 was overexpressed in the tumor front of localized and locally advanced prostate cancers, and that its expression was associated with an epithelial mesenchymal transition. An increasing gradient of SDF-1 was observed from the tumor center to the distant peritumoral tissue, potentially attracting CXCR4-expressing tumor cells of the tumor front. CXCR4 overexpression in the tumor front, as well as SDF1 gradient, were associated with prognosis.
15

Die Rolle der Chemokinrezeptoren CXCR4 und CXCR7 bei der Entwicklung der Extremitätenmuskulatur der Maus

Hunger, Conny 18 March 2013 (has links) (PDF)
Das Chemokine SDF-1α und sein Rezeptor CXCR4 sind in eine Vielzahl biologischer Prozesse, wie der Organogenese, der Hämatopoese und der Immunantwort involviert. Die Entdeckung des alternativen SDF-1α-Rezeptors CXCR7 bewirkte eine erneute Untersuchung der Funktion des SDF-1-Systems in diesen Vorgängen. CXCR7 ist in der Lage, je nach Gewebe- oder Zelltyp, als \"Scavenger\"-Rezeptor, Modulator des CXCR4 oder selbstständig aktiver Rezeptor zu agieren. In dieser Arbeit wurde untersucht, inwiefern beide Rezeptoren im Verlauf der Entwicklung der Muskulatur exprimiert werden, welche Aufgabe sie dabei übernehmen und ob sich Rückschlüsse auf die Muskelregeneration daraus ableiten lassen. Hierfür erfolgten in vitro-Untersuchungen an C2C12-Zellen und die anschließende Analyse der Expression von CXCR4, CXCR7 und SDF-1α in der sich entwickelnden Gliedmaßenmuskulatur von Wildtyp- und mdx-Mäusen. Die Untersuchung von C2C12-Zellen zeigte in allen Differenzierungsstadien eine detektierbare Menge von CXCR4 und eine zunehmende Expression des CXCR7. Die Behandlung der Zellen mit SDF-1α führte zu einer Phosphorylierung von Erk1/2 und PKCζ/λ und hemmte gleichzeitig deren Differenzierung. Nach einer Blockierung des CXCR4 mit seinem pharmakologischen Antagonist AMD3100 oder nach Hemmung der Expression durch spezifische siRNA blieb die Aktivierung des Signalweges aus und der hemmende Einfluss des SDF-1α auf die Differenzierung verschwand vollständig. Im Gegensatz dazu blieben nach der pharmakologischen Blockierung oder durch siRNA vermittelten Expressionshemmung des CXCR7 alle SDF-1α induzierten Effekte vollständig erhalten. Eine Untersuchung des Signalweges am dritten Tag der Differenzierung zeigte keine Aktivierung von Erk1/2. Ebenso blieb Erk1/2 nach einer Hemmung der Expression des CXCR4 unphosphoryliert. Im Gegensatz dazu fand nach einer Hemmung der Expression des CXCR7 mit spezifischer siRNA erneut eine Aktivierung des Signalweges statt. Weiterhin konnte in vivo festgestellt werden, dass die Expression des CXCR4 in der Muskulatur während der embryonalen Entwicklung am höchsten ist und bereits kurz nach der Geburt stark abnimmt, wenn die sekundäre Muskelentwicklung abgeschlossen ist. Die Expression des CXCR7 hingegen steigt perinatal an und bleibt bis zum Erwachsenenalter bestehen. Zusammengefasst zeigen diese Ergebnisse, dass CXCR4 aktiv das Signalgeschehen von SDF-1α in der Myogenese vermittelt und somit zur Differenzierungshemmung von Myoblasten beiträgt. CXCR7 hingegen wirkt als passiver SDF-1α-Scavenger und induziert somit durch eine Modulierung der extrazellulären SDF-1α-Konzentration die Differenzierung. In Übereinstimmung mit der Rolle des SDF-1α-Systems bei der Muskelentwicklung, konnte eine kontinuierliche SDF-1α- Expression im Bindegewebe um pränatale und im Endomysium von postnatalen und adulten Muskelfasern festgestellt werden. Diese SDF-1α-Expression stieg ebenso wie die CXCR4-Expression bei der Analyse der Muskulatur von dystrophin-defizienten Mäusen an und zeigte somit, dass dieses System auch für die Proliferation von Muskelvorläuferzellen in der regenerativen Muskulatur eine wichtige Rolle spielt. Bemerkenswerter Weise hatte diese Muskeldystrophie keinen Einfluss auf die Expression des CXCR7 und beeinflusst vermutlich dessen Funktion über einen anderen Mechanismus. Durch die offensichtlich enge Kontrolle von Muskelentwicklung und Regeneration durch CXCR4, CXCR7 und deren Liganden SDF-1α, bilden diese ein vielversprechendes therapeutisches Ziel für bestimmte Muskelerkrankungen. / The chemokine, SDF-1α, and its receptor, CXCR4, are assumed to control a multitude of biological processes such as organogenesis, haematopoesis, and immune responses. The previous demonstration that SDF-1α additionally binds to the chemokine receptor, CXCR7, currently urges a re-evaluation of the function of the SDF-1 system in these processes. In fact, depending on the tissue and cell type, CXCR7 either acts as a scavenger receptor, a modulator of CXCR4 or an independent active receptor. This thesis is dedicated to answer the following questions: Are both SDF-1α receptors expressed during muscle development? What is the actual function of these receptors during myogenesis? Is there a role of the SDF-1 system in muscle regeneration? To adress these issues both in vitro studies with the myoblast cell line, C2C12, as well as in vivo analyses on the expression of CXCR4, CXCR7 and SDF-1α in developing and regenerating limb muscles have been performed. At all stages of differentiation, C2C12 cells exhibited measurable amounts of CXCR4. In addition, in the course of differentiation C2C12 cells showed increasing expression levels of CXCR7. Treatment of the cells with SDF-1α resulted in the phosphorylation of Erk1/2 and PKCζ/λ and subsequently blocked their myogenic differentiation. Following inactivation of CXCR4 either by its antagonist, AMD3100, or by specific siRNA, SDF-1α failed to activate both pathways and in addition no longer inhibited the myogenic differentiation of C2C12 cells. By contrast, inactivation of CXCR7 remained without effects on SDF-1α-induced cell signalling and resulting inhibitory effects on myogenic differentiation. Interestingly, SDF-1α also failed to activate Erk1/2 signalling in differentiated C2C12 cells. Cell signalling in differentiated C2C12 cells was, however, restored following inhibition of CXCR7 expression, but not following inhibition of CXCR4 expression. The in vivo analysis further revealed that in limb muscles expression of the CXCR4 is highest during embryonic development with a decrease in expression levels shortly after birth when secondary muscle development is completed. Vice versa, expression levels of CXCR7 increased perinatally and remained high into adulthood. In summary, these findings unravel that CXCR4 actively mediates SDF-1α-signalling during myogenesis. The findings further provide evidence that CXCR7 acts as a scavenger receptor during myogenesis which controls myogenic differentiation by modulating extracellular SDF-1α concentration. In further agreement with a major role of SDF-1α in muscle development, SDF-1α is continously expressed by the endomysium of postnatal and adult muscle fibers. Moreover, expression of SDF-1α as well as CXCR4 is massively increased in muscles of dystrophin-deficient mice further implying that the SDF-1 system plays an equally important role during muscle development and regeneration. The pivotal role of SDF-1α in muscle development and regeneration points to the SDF-1 system as a promising therapeutical target for certain muscle diseases.
16

Estudo da microcirculação na hanseníase usando videomicroscopia (Microscan) e laser-Doppler associado à iontoforese: um modelo de disautonomia vascular por denervação / Leprosymicrocirculation study using video microscopy (MicroScan ) and laser-Doppler associated with iontophoresis: a model of vascular dysautonome by denervation

Livia Cristina de Melo Pino Machado 22 August 2013 (has links)
A hanseníase é uma doença infecciosa com características únicas, dentre elas o fato de atingir intensamente a inervação da pele e seus anexos. Entremeando estes anexos, está a microcirculação cutânea, que a principio também tem sua inervação comprometida. Vários artigos apontam para alterações de disautonomiamicrocirculatória. O presente estudo se propõe a avaliar a microcirculação cutânea na hanseníase tuberculóide. Utilizamos a videomicroscopia de campo escuro (Microscan), a análise de Fourier do sinal do laser Doppler para estudo da vasomotricidade e o laser Doppler fluxometria associado à iontoforese de substâncias vasoativas (acetilcolina e nitroprussiato de sódio) para avaliação da reatividade vascular. Sete pacientes portadores de hanseníase tuberculóide, sem outras co-morbidades que pudessem alterar os parâmetros microcirculatórios, foram avaliados pelos métodos descritos e seus resultados foram comparados, com controles realizados nos próprios pacientes em área contralateral com pele sã. Em relação à vasomotricidade foi observada alteração estatisticamente significativa entre os grupos, apenas no componente endotelial. Em relação à iontoforese de substâncias vasoativas não se constatou diferenças entre as manchas e os controles. No Microscan, observamos as maiores alterações. Os resultados apresentados sugerem que, provavelmente devido à alteração inervatória decorrente da hanseníase tuberculóide, estes pacientes apresentam uma alteração quantitativa de vasos e também da reatividade vascular da microcirculação cutânea. / Leprosy is an infectious disease with unique features, among them the fact that it compromises not only the cutaneous and anexial innervation, but also the innervation of the cutaneous microcirculation. Several articles indicate the impact of disautonomy on the microcirculatory level, citing the example of changes in vasomotor level. The present study proposes to evaluate the microvascular reactivity of the cutaneous microcirculation of tuberculoid leprosy. Methods employed in the study were: the sidestream dark field imaging (Microscan), the Fourier analysis of the laser Doppler signal to study vasomotion, and the laser Doppler flowmetry associated to iontophoresis of vasoactive substances (acetylcholine and sodium nitroprusside).Seven patients with tuberculoid leprosy, without any other comorbidity that could modify the microvascular parameters were evaluated and their results were compared with contralateral areas of healthy skin from the same patients.Regarding the vasomotion, statistical significant difference was noticed only in endothelial component, between groups. In the iontophoresis of vasoactive substances, it was not found differences between areas with and without lesions and controls. In the results obtained with the Microscan we have observed the greatest changes. The results suggest that, probably due to changes resulting from denervation of tuberculoid leprosy, these patients have significant quantitative change on vessels and also in the vascular reactivity of the cutaneous microcirculation.
17

Estudo da microcirculação na hanseníase usando videomicroscopia (Microscan) e laser-Doppler associado à iontoforese: um modelo de disautonomia vascular por denervação / Leprosymicrocirculation study using video microscopy (MicroScan ) and laser-Doppler associated with iontophoresis: a model of vascular dysautonome by denervation

Livia Cristina de Melo Pino Machado 22 August 2013 (has links)
A hanseníase é uma doença infecciosa com características únicas, dentre elas o fato de atingir intensamente a inervação da pele e seus anexos. Entremeando estes anexos, está a microcirculação cutânea, que a principio também tem sua inervação comprometida. Vários artigos apontam para alterações de disautonomiamicrocirculatória. O presente estudo se propõe a avaliar a microcirculação cutânea na hanseníase tuberculóide. Utilizamos a videomicroscopia de campo escuro (Microscan), a análise de Fourier do sinal do laser Doppler para estudo da vasomotricidade e o laser Doppler fluxometria associado à iontoforese de substâncias vasoativas (acetilcolina e nitroprussiato de sódio) para avaliação da reatividade vascular. Sete pacientes portadores de hanseníase tuberculóide, sem outras co-morbidades que pudessem alterar os parâmetros microcirculatórios, foram avaliados pelos métodos descritos e seus resultados foram comparados, com controles realizados nos próprios pacientes em área contralateral com pele sã. Em relação à vasomotricidade foi observada alteração estatisticamente significativa entre os grupos, apenas no componente endotelial. Em relação à iontoforese de substâncias vasoativas não se constatou diferenças entre as manchas e os controles. No Microscan, observamos as maiores alterações. Os resultados apresentados sugerem que, provavelmente devido à alteração inervatória decorrente da hanseníase tuberculóide, estes pacientes apresentam uma alteração quantitativa de vasos e também da reatividade vascular da microcirculação cutânea. / Leprosy is an infectious disease with unique features, among them the fact that it compromises not only the cutaneous and anexial innervation, but also the innervation of the cutaneous microcirculation. Several articles indicate the impact of disautonomy on the microcirculatory level, citing the example of changes in vasomotor level. The present study proposes to evaluate the microvascular reactivity of the cutaneous microcirculation of tuberculoid leprosy. Methods employed in the study were: the sidestream dark field imaging (Microscan), the Fourier analysis of the laser Doppler signal to study vasomotion, and the laser Doppler flowmetry associated to iontophoresis of vasoactive substances (acetylcholine and sodium nitroprusside).Seven patients with tuberculoid leprosy, without any other comorbidity that could modify the microvascular parameters were evaluated and their results were compared with contralateral areas of healthy skin from the same patients.Regarding the vasomotion, statistical significant difference was noticed only in endothelial component, between groups. In the iontophoresis of vasoactive substances, it was not found differences between areas with and without lesions and controls. In the results obtained with the Microscan we have observed the greatest changes. The results suggest that, probably due to changes resulting from denervation of tuberculoid leprosy, these patients have significant quantitative change on vessels and also in the vascular reactivity of the cutaneous microcirculation.
18

Expression und Funktion der Chemokinrezeptoren CXCR4 und CXCR7 in der Schwannzelllinie RN22

Schmidt, Michael 31 January 2013 (has links)
Schwannzellen sind die myelinisierenden Zellen des peripheren Nervensystems, die auch eine Rolle bei Entzündungs- und Regenerationsprozessen spielen. Diese Arbeit beschäftigt sich mit der Bedeutung der Chemokinrezeptoren CXCR4 und CXCR7 bei der SDF-1-abhängigen Signalübermittlung in der Schwannzelllinie RN22. Mittels PCR, Western-Blotting und FACS erfolgte zunächst ein Expressionsnachweis der Chemokinrezeptoren. Anschließend wurde mittels Western-Blotting festgestellt, dass eine Behandlung mit SDF-1 zu einer Aktivierung der intrazellulären Signalkinasen Erk1/2, p38 und Akt führt. Für PKC ζ/λ wurde kein Effekt beobachtet. Durch Einsatz der spezifischen Antagonisten für CXCR4 (AMD3100) und CXCR7 (CCX733) konnten diese Effekte blockiert werden. Die Ergebnisse legen nahe, dass beide Rezeptoren ihren Liganden binden müssen, damit ein intrazellulärer Effekt auftritt. Ähnliches gilt auch für die SDF-1-abhängige Migration von RN22-Zellen, die ebenfalls bereits durch einen der beiden Antagonisten unterbunden werden kann.
19

L’implication du Stromal Cell-derived Factor-1 alpha dans le remodelage cardiaque une semaine après un infarctus du myocarde

Proulx, Cindy 08 1900 (has links)
L’injection de cellules souches provenant de la moelle osseuse est reconnue pour améliorer la fonction ventriculaire ainsi que le remodelage cicatriciel après un infarctus du myocarde (IM). Le Stromal Cell-derived factor-1 alpha (SDF-1 alpha), une chimiokine induite par l’ischémie cardiaque, représente une grande importance en raison de son rôle dans le recrutement de cellules inflammatoires et de cellules souches de la moelle osseuse vers les sites endommagés. Quoique les recherches sur le rôle de la chimiokine SDF-1 alpha dans le remodelage ventriculaire se multiplient, son implication dans la phase aiguë du remodelage reste inexplorée. Le but de la présente étude est de déterminer l’effet du SDF-1 alpha sur la taille de la cicatrice, l’hypertrophie cardiaque ainsi que la fonction ventriculaire chez des rats et des souris une semaine après un IM. La stratégie utilisée implique l’administration de l’AMD3100 (1 mg/kg, 24 heures après l’IM, pendant 6 jours), l’antagoniste sélectif du récepteur du SDF-1 alpha, le CXCR4. Ce récepteur est couplé à une protéine G alpha i et induit la migration et la prolifération cellulaire. Chez les rats du groupe IM, l’expression de la chimiokine a été détectée surtout dans les cellules musculaires lisses et les cellules endothéliales des vaisseaux cicatriciels. Le profil d’expression de la chimiokine dans le cœur infarci indique un gradient de concentration vers la cicatrice. Une semaine après l’IM, le traitement avec l’AMD3100 a diminué la taille de la cicatrice, résultant en une amélioration de la fonction ventriculaire et une diminution de l’élévation de l’expression de l’ARNm de l’ANP dans le ventricule gauche non infarci (VGNI). Chez les souris, le traitement avec l’AMD3100 a engendré les mêmes effets, soit une diminution de la taille de la cicatrice ainsi qu’une amélioration de la fonction ventriculaire. La réduction de la taille de la région infarcie chez les souris traitées avec l’AMD3100 est associée avec une atténuation de l’infiltration des neutrophiles dans la région ischémique. Ces résultats suggèrent que le blocage pharmacologique de l’axe SDF-1 alpha/CXCR4 lors de la phase aiguë du remodelage ventriculaire après un IM diminue la taille de la cicatrice et améliore la fonction ventriculaire, en partie, par la diminution de la réaction inflammatoire. / The injection of bone marrow stem cells in the infarcted heart was shown to improve ventricular function and scar remodelling. The chemokine Stromal Cell-derived factor-1 alpha (SDF-1 alpha) is implicated in the migration of inflammatory and bone marrow derived stem cells to damaged region. Despite a local increase of SDF-1 alpha expression in the damaged myocardium, the biological impact of the chemokine during the acute phase of remodelling in the ischemic heart remains undefined. Therefore, the present study examined the role of SDF-1 alpha on scar expansion, cardiac hypertrophy and ventricular function in rats following myocardial infarction (MI) via administration of AMD3100 (1 mg/kg, 24 hours post-MI and continued for 6 days) a selective antagonist of the SDF-1 alpha receptor, CXCR4. This receptor is coupled to a G alpha i protein and induced migration and proliferation of cells. In 1-week post-MI rats, chemokine expression was detected in smooth muscle and endothelial cells of blood vessels residing in the infarcted region. An SDF-1 alpha gradient towards the infarcted region was detected in the post-MI rat heart. In 1-week post-MI rats, AMD3100 therapy reduced scar size, concomitantly improved left ventricular function and partially supressed the elevated expression of ANP mRNA in the non-infarcted left ventricule. Preliminary studies on mice showed that the reduced infarct size in AMD3100-treated post-MI mice was associated with an attenuation of neutrophil infiltration in the ischemic region. These data highlight the novel observation that pharmacological antagonism of the SDF-1 alpha/CXCR4 axis during the acute phase of repartive fibrosis post-MI attenuated scar expansion and improved ventricular function in part via attenuation of the inflammatory response.
20

Expressão da quimiocina SDF-1, (CXCL12) e seu respectivo receptor CXCR4  em células de pacientes com mieloma múltiplo em linhagem de células mieloma múltiplo humano (RPMI-8226) após tratamento com talidomida / Expression of the chemokine SDF-1 and its receptor CXCR4 in the cells of patients with multiple myeloma and line cell of the multiple myeloma after treatment of thalidomide

Oliveira, Adriana Morgan de 27 August 2008 (has links)
Mieloma Múltiplo é a segunda doença com maior prevalência nas doenças malignidades hematológica, incurável com média de sobrevivência de 3-5 anos. MM é uma malignidade das células do plasma caracterizada pela destruição e reabsorção óssea e supressão da formação do osso. A quimiocina SDF-1 (CXCL12) e seu receptor CXCR4 têm um importante papel direcional na migração, homing das células do plasma em mieloma múltiplo e mobilização das células de MM para fora da medula óssea. A talidomida tem sido usada com êxito no tratamento de pacientes com mieloma múltiplo. Neste estudo verificamos o efeito da talidomida na expressão da quimiocina SDF-1 e seu receptor CXCR4 em pacientes com mieloma múltiplo e em linhagem de células de mieloma múltiplo humano (RPMI-8226) tratados e sem tratamento de talidomida. Nossos resultamos mostraram uma expressão heterogênea na expressão da quimiocina SDF-1 e seu receptor CXCR4 nos pacientes com mieloma múltiplo estudado (n= 79). Entretanto, pacientes com mieloma múltiplo tratados com talidomida mostraram uma baixa expressão da quimiocina SDF-1 e seu receptor CXC4 quando comparados com pacientes recém diagnosticados para mieloma múltiplo e pacientes com mieloma múltiplo tratados com outros medicamentos. Nossos resultados sugerem que o tratamento com talidomida induz uma baixa regulação na expressão no ligante SDF-1 e seu receptor CXCR4 em pacientes com mieloma múltiplo / Multiple Myeloma (MM) is a second most prevalent hematological malignancy and remains incurable with a median survival of 3-5 years. MM is a plasma cell malignancy characterized by devastating bone destruction due to the enhanced bone resorption and suppressed bone formation. The chemokine stromal-derived factor-1 (SDF-1) and its receptor CXCR4 play an important role in directional migration, homing of plasma cells in multiple myeloma (MM) and mobilization of MM cells out of the bone marrow. The drug thalidomide has been successfully used in the treatment of patients with MM. In this study, we assessed the effect of thalidomide on SDF-1 and CXCR4 expression in MM patients and human myeloma-derived cell line, RPMI 8226 treated with or without thalidomide. A heterogeneous expression pattern of chemokines SDF-1 and CXCR4 receptor were observed for all MM patients studied. However, patients treated with thalidomide showed a significantly decrease in expression of SDF-1 and CXCR4 as compared to newly diagnosed MM patients and MM patients treated with other drugs. RPMI 8226 cell line treated with 10, 20 and 100µM thalidomide also demonstrated decrease in SDF-1 and CXCR4 expression as compared with cell control (RPMI-8226 without thalidomide). Ours results indicate that thalidomide therapy induces down-regulation of CXCR4 and its ligand SDF-1 in multiple myeloma

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