Pediatric High Risk Leukemia — Molecular Insights

Acute leukemia comprises of 31% of all cancers in children making it the most common childhood malignancy. Significant strides have been made in treatment, partly through risk stratification and intensified therapy. A number of subtypes remain at high risk for relapse and poor outcome, despite current therapies. Here we describe risk stratification and molecular diagnosis used to identify high risk leukemias and guide treatment. Specific cytogenetic alterations that contribute to high risk B and T cell acute lymphoblastic leukemia (ALL), as well as infant leukemia are discussed. Particular attention is given to genetic alterations in IKZF1, CRLF2, and JAK, that have been identified by whole genome sequencing and recently associated with Ph-like ALL. Ongoing studies of disease mechanisms and challenges in developing pre-clinical patient-derived xenograft models to evaluate therapies are discussed

Développement d’un concept combiné de production de biogaz et d’élimination de l’ammoniac appliqué aux affluents agricoles

Le traitement biologique de l’ammoniac par le procédé classique de nitrification / dénitrification se heurte à deux problèmes majeurs : le coût et la complexité. Ce projet a développé un concept intégré de production de biogaz et d’élimination biologique de l’ammoniac contenu dans le lisier en tirant parti des nouvelles recherches dans ce domaine afin de limiter les besoins d’aération, la consommation d’une source externe de carbone et de simplifier l’exploitation. Une étude expérimentale, menée sur l’effluent de l’installation de biogaz de la famille Martin à Puidoux, a été réalisée au Laboratoire de Biotechnologie Environnementale de l'EPFL et a montré que : (i) Le processus de nitritation est obtenu avec cet effluent dans un réacteur aérobie. (ii) Le processus de dénitritation est aussi obtenu dans le réacteur aérobie en utilisant un support mobile fixant la biomasse. Les rendements obtenus sont très élevés : 90% de l’ammonium est transformé et 80% est éliminé sous forme de N2. (iii) Le processus ANAMMOX peut également être obtenu, mais est instable et n’est donc pas recommandé. L’énorme avantage de cette nouvelle méthode est que l’ensemble des réactions se déroulent dans un seul réacteur, sans modifier le fonctionnement du digesteur. Le bilan d’azote montre que, si la totalité de l’effluent est traité dans le réacteur aérobie, l’élimination de l’azote total initial dans la configuration retenue est de 50%. L’élimination d’une partie seulement de l’azote peut être obtenue en ne traitant qu’une partie de l’effluent. Au niveau du bilan énergétique, le concept n’a pas d’incidence sur la production de biogaz. Un dimensionnement du réacteur aérobie a été proposé en fonction du débit journalier d’entrée et du temps de résidence hydraulique. Le volume utile du réacteur de nitritation / dénitritation devrait être de 30 m3 pour un digesteur de 400 m3. Le dimensionnement du système d’aération en vraie grandeur ne peut pas être défini précisément à partir de la présente étude, ni la consommation énergétique associée. La construction d’une installation pilote / démonstration permettrait de répondre à ces points

Red de medida contínua de irradiancia solar

Antecedentes. -- 1.1. Mapa Solar del Uruguay - versión 1 (MSUv1). -- 1.2. Estaciones de primera generación (G1). -- 1.2.1. Electrónica y telecomunicaciones. -- 1.3. Modelado de irradiancia solar en base a imágenes de satélite. -- 1.3.1. Base de Imágenes de la serie GOES. -- 1.3.2. Modelo BD-JPT para estimación de GHI. -- 1.3.3. Estimación de DNI e irradiancia en plano inclinado. -- 1.3.4. Validación del modelo satelital. -- 1.3.5. Segunda versión del Mapa Solar del Uruguay (MSUv2). -- 2 Estaciones de Medida de segunda generación. -- 2.1. Funcionalidad de las estaciones G2. -- 2.2. Distribución espacial y otras características. -- 2.3. Post-procesamiento y control de calidad. -- 2.3.1. Productos. -- 2.3.2. Control de calidad. -- 2.4. Calibración de Radiómetros y Termómetros. -- 2.4.1. Calibración de radiómetros. -- 2.4.2. Calibración de termómetros. -- 3 Perspectivas a corto y mediano plazo. -- 3.1. Líneas de trabajo en el LES. -- 3.2. Medidas complementarias. -- 3.3. Mejora continua en controles de calidad. -- 3.4. Accesibilidad de la información. -- 3.5. Año Meterológico Típico (AMT). -- Appendice A Certificados de calibración. -- Appendice B Equipo de trabajo del LES 50. -- Bibliografía

Reaction Force/Torque Sensing in a Master-Slave Robot System without Mechanical Sensors

In human-robot cooperative control systems, force feedback is often necessary in order to achieve high precision and high stability. Usually, traditional robot assistant systems implement force feedback using force/torque sensors. However, it is difficult to directly mount a mechanical force sensor on some working terminals, such as in applications of minimally invasive robotic surgery, micromanipulation, or in working environments exposed to radiation or high temperature. We propose a novel force sensing mechanism for implementing force feedback in a master-slave robot system with no mechanical sensors. The system consists of two identical electro-motors with the master motor powering the slave motor to interact with the environment. A bimanual coordinated training platform using the new force sensing mechanism was developed and the system was verified in experiments. Results confirm that the proposed mechanism is capable of achieving bilateral force sensing and mirror-image movements of two terminals in two reverse control directions

High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement.

Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL

Structural basis of colchicine-site targeting acylhydrazones active against multidrug-resistant acute lymphoblastic leukemia

Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized the tubulin-binding activity, the mechanism of action, and the in vivo anti-leukemia efficacy of three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target the colchicine-binding site of tubulin and that none is a substrate of ABC transporters. The crystal structure of the tubulin-bound N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide (12) revealed steric hindrance on the T7 loop movement of β-tubulin, thereby rendering tubulin assembly incompetent. Using dose escalation and short-term repeated dose studies, we further report that this compound class is well tolerated to >100 mg/kg in mice. We finally observed that intraperitoneally administered compound 12 significantly prolonged the overall survival of mice transplanted with both sensitive and multidrug-resistant acute lymphoblastic leukemia (ALL) cells. Taken together, this work describes promising colchicine-site-targeting tubulin inhibitors featuring favorable therapeutic effects against ALL and multidrug-resistant cell2195109CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305896/2013-0; 301596/2017-414/08247-8; 17/14737-6We thank Ganadería Fernando Díaz for calf brains for tubulin purification. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery.” J.F.D. is a member of the CIB Intramural Program “Molecular Machines for Better Life” (MACBET). N.M.C. was supported by a fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 14/08247-8, and 17/14737-6). J.A.Y. received a Productivity fellowship from the Brazilian National Counsel of Technological and Scientific Development (CNPq 305896/2013-0 and 301596/2017-4). This work was supported in part by grants BFU2016-75319-R (AEI/FEDER, UE) (J.F.D.) from Ministerio de Economía y Competitividad. The crystal structure work was supported by grants from the Swiss National Science Foundation (31003A_166608, to M.O.S.) and by the COST action CM1407 (to M.O.S.). Part of the in vivo work was supported by R01CA209829 and R01CA213912, Hyundai Hope On Wheels Scholar Grant, Bear Necessities Pediatric Cancer Foundation, Alex’s Lemonade Stand Foundation, the Four Diamonds Fund of the Pennsylvania State University College of Medicine, and the John Wawrynovic Leukemia Research Scholar Endowment (to S.D.

Predicción a corto plazo de la irradiación solar a partir de imágenes de satélite con aplicación a la generación fotovoltaica

Informe técnico final (Agosto 2018) Proyecto ANII FSE_1_2015_1_10993