GRAIN BOUNDARIES STRUCTURES AND WETTING IN DOPED SILICON, NICKEL AND COPPER

This thesis reports a series of fundamental investigations of grain boundary wetting, adsorption and structural (phases) transitions in doped Ni, Cu and Si with technological relevance to liquid metal embrittlement, liquid metal corrosion and device applications. First, intrinsically ductile metals are prone to catastrophic failure when exposed to certain liquid metals, but the atomic level mechanism for this effect is not fully understood. A nickel sample infused with bismuth atoms was characterized and a bilayer interfacial phase that is the underlying cause of embrittlement was observed. In a second related study, we showed that addition of minor impurities can significantly enhance the intergranular penetration of bismuth based liquids in polycrystalline nickel and copper, thereby increasing the liquid metal corrosion rates. Furthermore, we extended a concept that was initially proposed in the Rice-Wang model for grain boundary embrittlement to explain our observations of the impurity-enhanced intergranular penetration of liquid metals. Finally, a grain-boundary transition from a bilayer to an intrinsic is observed in the Si-Au system. This observation directly shows that a grain boundary can exhibit a first-order \u27phase\u27 transition, which often implies abrupt changes in properties

Structural and functional Alterations of FLT3 in Acute Myeloid Leukemia

Hematopoiesis is highly regulated through cytokine-induced stimulation of multiple signal transduction pathways in order to mediate appropriate differentiation and proliferation of specific progenitor populations. Ligand-induced stimulation of the FMS-like tyrosine kinase 3 (FLT3) leads to activation of multiple downstream effector pathways resulting in differentiation and proliferation of specific progenitor cell populations. Genomic alterations of the FLT3 gene leads to autonomous receptor activation, dysregulation of FLT3 signal transduction pathways, contributes to myeloid pathogenesis, and have been linked to response to therapy and clinical outcome. Exploring the mechanisms by which these FLT3 alterations lead to dysregulated proliferation would provide a better understanding of the molecular pathogenesis of AML and may provide insights into potential therapeutic interventions

QOS-Aware and Status-Aware Adaptive Resource Allocation Framework in SDN-Based IOT Middleware

«L’Internet des objets (IdO) est une infrastructure mondiale pour la société de l’information, qui permet de disposer de services évolués en interconnectant des objets (physiques ou virtuels) grâce aux technologies de l’information et de la communication interopérables existantes ou en évolution. »[1] La vision de l’Internet des Objets est d’étendre l’Internet dans nos vies quotidiennes afin d’améliorer la qualité de vie des personnes, de sorte que le nombre d’appareils connectés et d’applications innovantes augmente très rapidement pour amener l’intelligence dans différents secteurs comme la ville, le transport ou la santé. En 2020, les études affirment que les appareils connectés à Internet devraient compter entre 26 milliards et 50 milliards d’unités. [2, 3] La qualité de service d’application IoT dépend non seulement du réseau Internet et de l’infrastructure de communication, mais aussi du fonctionnement et des performances des appareils IoT. Par conséquent, les nouveaux paramètres de QoS tels que la précision des données et la disponibilité des appareils deviennent importants pour les applications IoT par rapport aux applications Internet. Le grand nombre de dispositifs et d’applications IoT connectés à Internet, et le flux de trafic spontané entre eux rendent la gestion de la qualité de service complexe à travers l’infrastructure Internet. D’un autre côté, les dispositifs non-IP et leurs capacités limitées en termes d’énergie et de transmission créent l’environnement dynamique et contraint. De plus, l’interconnexion de bout en bout entre les dispositifs et les applications n’est pas possible. Aussi, les applications sont intéressées par les données collectées, pas à la source spécifique qui les produit. Le Software Defined Networking (SDN) est un nouveau paradigme pour les réseaux informatiques apparu récemment pour cacher la complexité de l’architecture de réseau traditionnelle (par exemple de l’Internet) et briser la fermeture des systèmes de réseau dans les fonctions de contrôle et de données. Il permet aux propriétaires et aux administrateurs de réseau de contrôler et de gérer le comportement du réseau par programme, en découplant le plan de contrôle du plan de données. SDN a le potentiel de révolutionner les réseaux informatiques classiques existants, en offrant plusieurs avantages tels que la gestion centralisée, la programmabilité du réseau, l’efficacité des coûts d’exploitation, et les innovations. Dans cette thèse, nous étudions la gestion de ressources sur l’infrastructure IoT, y compris les réseaux de transport/Internet et de détection. Nous profitons de la technologie SDN comme le futur d’Internet pour offrir un système de support QoS flexible et adaptatif pour les services IoT. Nous présentons un intergiciel basé sur SDN pour définir un cadre de gestion de QoS pour gérer les besoins spécifiques de chaque application à travers l’infrastructure IoT. De plus, nous proposons un nouveau modèle QoS qui prend en compte les préférences de QoS des applications et l’état des éléments de réseau pour allouer efficacement les ressources sur le réseau transport/Internet basé sur SDN tout en maximisant les performances du réseau.----------ABSTRACT: The Internet of Things (IoT) is an integration of various kinds of technologies, wherein heterogeneous objects with capabilities of sensing, actuation, communication, computation, networking, and storage are rapidly developed to collect the data for the users and applications. The IoT vision is to extend the Internet into our everyday lives, so the number of connected devices and innovative applications are growing very fast to bring intelligence into as many domains as possible. The QoS for IoT application not only depends on the Internet network and communication infrastructure, it is also impacted by the operation and performance of IoT sensing infrastructure. Therefore, the new QoS parameters such as data accuracy, sampling rate, and device availability become important for the IoT applications compared to the Internet applications. The huge number of the Internet-connected IoT devices and application, and the spontaneous traffic flow among them make the management of the quality of service complex across the Internet infrastructure. On the other hand, the non-IP devices and their limited capabilities in terms of energy and transmission create the dynamic environment and hinder the direct interaction between devices and applications. The quality of service is becoming one of the critical non-functional IoT element which needs research and studies. A flexible and scalable QoS management mechanism must be implemented in IoT system to keep up with the growth rate of the Internet-connected IoT devices and applications as well as their heterogeneity and diversity. The solution should address the IoT application requirements and user satisfaction while considering the system dynamism, limitations, and characteristics. Software-Defined Networking (SDN) is an emerging paradigm in computer networking which separates the control plane and the data plane of the network elements. It makes the network elements programmable via the centralized control plane. This approach enables more agile management and control over the network behavior. In this thesis, we take advantage of SDN technology as the future of the Internet to offer a flexible and adaptive QoS support scheme for the IoT services. We present an SDN-based middleware to define a QoS management framework to manage the application specific QoS needs across the IoT infrastructure including transport and sensing network. Also, we propose a new QoS model that takes into account the application QoS preferences and the network elements status to allocate effectively the resources for the applications across SDN network while maximizing network performance

High Transcript Level of FLT3 Associated with High Risk of Relapse in Pediatric Acute Myeloid Leukemia

Identification of prognostic factors and risk-based post-remission therapy was proposed to improve the outcomes of acute myeloid leukemia (AML) and a mutation of FLT3 has been reported to be a risk factor, especially for pediatric patients. Recently, FLT3 expression level was implicated to have prognostic significance in adults, but little is known for childhood AML. To define the prognostic significance, transcript level of FLT3 was analyzed in 52 pediatric AML patients. The median copy number of FLT3 was 4.6×103 (40-5.9×107 copies)/1.0×106 GAPDH copy, and the relapse free survival of patients with high transcript level of FLT3 (>106 copy number) (0%) was significantly lower than that of the others (53.2%). High transcript level of FLT3 was associated with a markedly high risk of relapse. The development of new therapeutic scheme such as a frontline allogeneic stem cell transplantation or administration of FLT3 inhibitor is needed to improve outcomes

Ordered Assembly of the Adhesive and Electrochemical Connections within Newly Formed Intercalated Disks in Primary Cultures of Adult Rat Cardiomyocytes

The intercalated disk (ID) is a complex structure that electromechanically couples adjoining cardiac myocytes into a functional syncitium. The integrity of the disk is essential for normal cardiac function, but how the diverse elements are assembled into a fully integrated structure is not well understood. In this study, we examined the assembly of new IDs in primary cultures of adult rat cardiac myocytes. From 2 to 5 days after dissociation, the cells flatten and spread, establishing new cell-cell contacts in a manner that recapitulates the in vivo processes that occur during heart development and myocardial remodeling. As cells make contact with their neighbors, transmembrane adhesion proteins localize along the line of apposition, concentrating at the sites of membrane attachment of the terminal sarcomeres. Cx43 gap junctions and ankyrin-G, an essential cytoskeletal component of voltage gated sodium channel complexes, were secondarily recruited to membrane domains involved in cell-cell contacts. The consistent order of the assembly process suggests that there are specific scaffolding requirements for integration of the mechanical and electrochemical elements of the disk. Defining the relationships that are the foundation of disk assembly has important implications for understanding the mechanical dysfunction and cardiac arrhythmias that accompany alterations of ID architecture

Impact of FAB classification on predicting outcome in acute myeloid leukemia, not otherwise specified, patients undergoing allogeneic stem cell transplantation in CR1 : An analysis of 1690 patients from the acute leukemia working party of EBMT

The French, American, and British (FAB) classification system for acute myeloid leukemia (AML) is extensively used and is incorporated into the AML, not otherwise specified (NOS) category in the 2016 WHO edition of myeloid neoplasm classification. While recent data proposes that FAB classification does not provide additional prognostic information for patients for whom NPM1 status is available, it is unknown whether FAB still retains a current prognostic role in predicting outcome of AML patients undergoing allogeneic stem cell transplantation. Using the European Society of Blood and Bone Marrow Transplantation registry we analyzed outcome of 1690 patients transplanted in CR1 to determine if FAB classification provides additional prognostic value. Multivariate analysis revealed that M6/M7 patients had decreased leukemia free survival (hazard ratio (HR) of 1.41, 95% confidence interval (CI), 1.01-1.99; P = .046) in addition to increased nonrelapse mortality (NRM) rates (HR, 1.79; 95% CI, 1.06-3.01; P = .028) compared with other FAB types. In the NPM1(wt) AML, NOS cohort, FAB M6/M7 was also associated with increased NRM (HR, 2.17; 95% CI, 1.14-4.16; P = .019). Finally, in FLT3-ITD+ patients, multivariate analyses revealed that specific FAB types were tightly associated with adverse outcome. In conclusion, FAB classification may predict outcome following transplantation in AML, NOS patients.Peer reviewe

Prenatal origin of childhood AML occurs less frequently than in childhood ALL

Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

FLT3 mutations in canine acute lymphocytic leukemia

<p>Abstract</p> <p>Background</p> <p>FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit <it>FLT3 </it>ITD mutations.</p> <p>Methods</p> <p>We molecularly characterized <it>FLT3 </it>mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via <it>in vitro </it>proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting.</p> <p>Results</p> <p>The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have <it>FLT3 </it>ITD mutations and <it>FLT3 </it>mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the <it>FLT3 </it>mutation. Finally, western blots were used to confirm the conserved downstream mediators of <it>FLT3 </it>activating mutations.</p> <p>Conclusions</p> <p>These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias.</p

Heat Shock Factor 1 (HSF1-pSer326) Predicts Response to Bortezomib-Containing Chemotherapy in Pediatric AML:A COG Study

Bortezomib (BTZ) was recently evaluated in a randomized Phase 3 clinical trial which compared standard chemotherapy (cytarabine, daunorubicin, etoposide; ADE) to standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia. While the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefitting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. We measured total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer326) in leukemic cells from 483 pediatric patients using Reverse Phase Protein Arrays. HSF1-pSer326 phosphorylation was significantly lower in pediatric AML compared to CD34+ non-malignant cells. We identified a strong correlation between HSF1-pSer326 expression and BTZ sensitivity. BTZ significantly improved outcome of patients with low-HSF1-pSer326 with a 5-year event-free survival of 44% (ADE) vs. 67% for low-HSF1-pSer326 treated with ADEB (P=0.019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and non-phosphorylated (S326E) HSF1-pSer326 were examined. Those with increased HSF1 phosphorylation showed clear resistance to BTZ vs. those with wild type or reduced HSF1-phosphorylation. We hypothesize that HSF1-pSer326 expression could identify patients that benefit from BTZ-containing chemotherapy