Targeting leukemic stem cells in chronic myeloid leukemia: Is it worth the effort?

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal transloca-tion, that converts it into a leukemic stem cell (LSC). The resulting BCR‐ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell‐intrinsic and ‐extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML

Systemic mastocytosis: Molecular landscape and implications for treatment

Over the past decade, we have witnessed significant advances in the molecular characterization of systemic mastocytosis (SM). This has provided important information for a better understanding of the pathogenesis of the disease but has also practically impacted the way we diagnose and manage it. Advances in molecular testing have run in parallel with advances in therapeutic targeting of constitutive active KIT, the major driver of the disease. Therefore, assessing the molecular landscape in each SM patient is essential for diagnosis, prognosis, treatment, and therapeutic efficacy monitoring. This is facilitated by the routine availability of novel technologies like digital PCR and NGS. This review aims to summarize the pathogenesis of the disease, discuss the value of molecular diagnostic testing and how it should be performed, and provide an overview of present and future therapeutic concepts based on fine molecular characterization of SM patients

Un método automático basado en el gradiente de la fase envuelta para la corrección de la aberración esférica de fase en microscopía holográfica digital

La mayoría de los montajes experimentales utilizados en microscopía holográfica digital introducen un objetivo de microscopio en el brazo objeto del miro-interferómetro con el objetivo de aumentar la resolución lateral; sin embargo, como consecuencia, aparece una aberración de fase esférica que debe corregirse para acceder al retardo de fase que experimenta es espécimen microscópico bajo estudio. En este trabajo se presenta un método rápido y simple para corregir numéricamente la curvatura de fase a partir del gradiente del mapa de fase envuelto del holograma reconstruido. Dado que no se requiere el empleo de métodos de desenvolvimiento de fase, los costos computacionales son notablemente reducidos. Adicionalmente, no se precisa del registro de hologramas adicionales, ni del conocimiento previo del objeto bajo estudio o del arreglo experimental. El método se demuestra experimentalmente a partir del holograma de una microalga del género Pediastrum.Most digital holographic microscopy architectures introduce a microscope objective in the object arm of the micro-interferometer in order to increase lateral resolution but, as a consequence, a spherical phase aberration arises. The phase distortion must be corrected to achieve reliable phase information linked to the microscopic object under study. In this work, we present a fast and simple numerical method for automatically compensate the phase curvature from the wrapped phase gradient of the reconstructed hologram. Since non-unwrapping methods are required, computational cost is significantly reduced. Furthermore, no additional holograms recording is needed and it does not require prior knowledge of the object or the setup. The method is experimentally demonstrated by a phase contrast imaging of a Pediastrum cell.Fil: Monaldi, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Investigaciones en Energía no Convencional. Universidad Nacional de Salta. Facultad de Ciencias Exactas. Departamento de Física. Instituto de Investigaciones en Energía no Convencional; ArgentinaFil: Romero, Gladis Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Investigaciones en Energía no Convencional. Universidad Nacional de Salta. Facultad de Ciencias Exactas. Departamento de Física. Instituto de Investigaciones en Energía no Convencional; ArgentinaFil: Blanc, Adriana Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Investigaciones en Energía no Convencional. Universidad Nacional de Salta. Facultad de Ciencias Exactas. Departamento de Física. Instituto de Investigaciones en Energía no Convencional; ArgentinaFil: Cabrera, C. M.. Universidad Nacional de Salta. Facultad de Ciencas Exactas. Departamento de Física. Grupo de Óptica Láser; Argentin

Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin

The Institutional Determinants of Political Transactions

Public policies are the outcome of the interaction among a variety of key political actors, each with its own preferences and incentives, who meet in different arenas and interact within the constraints of the institutions that frame their engagement. Therefore, to recognize the reasons behind the success or failure of any public policy it is necessary to understand the country's political institutions and the policymaking process they in turn help shape. This document looks at a number of those key actors, institutions, and arenas, with the aim of examining the roles, incentives, and capabilities of each of the actors in the policymaking process, by drawing from an extensive literature in political science and political economy. Each of the actors is looked at individually but connected to the other actors by linking the impact of political institutions on their incentives to the features of the policymaking game. Hopefully, this document will provide researchers with the tools necessary to embark in the fascinating analysis of policymaking processes not only for Latin American countries but also for other parts of the world

Correction of phase aberration induced by rolling shutter effect in digital holographic microscopy

Debido a la naturaleza de lectura secuencial de los sensores CMOS, cada fila del sensor se expone en diferentes tiempos, resultando en el denominado efecto persiana que introduce distorsiones geométricas en la imagen si la cámara o el objeto se mueven durante la adquisición. En particular, para el registro de hologramas digitales, y en general para la mayor parte de las condiciones experimentales, mientras el sensor captura barriendo progresivamente cada fila del holograma, las franjas producto de la interferencia entre el haz objeto y el haz de referencia oscilan debido a vibraciones y/o ruidos. El sensor captura cada fila del holograma en distintas instancias de estas perturbaciones; por ende, los desplazamientos entre las franjas se traducen en aberraciones de fase. Como efecto final se observan patrones de franjas espurias que distorsionan la calidad de los hologramas reconstruidos. En este trabajo se propone un método simple y eficiente para corregir este efecto mediante técnicas de procesamiento digital de imágenes. Se ejemplifica el método con hologramas de especímenes microscópicos estáticos. Los resultados alientan a la incorporación de sensores CMOS en lugar de sensores CCD en los montajes experimentales de Microscopía Holográfica Digital ya que estos ofrecen mejor resolución, además de ser menos costosos en el mercado.Due to the sequential-readout nature of CMOS sensors, each row of the sensor array is exposed at a different time, resulting in the so-called rolling shutter effect that induces images geometric distortion when whether the video camera or the object are moving during image acquisition. Particularly, in digital holograms recording for most experimental conditions, while sensor sweeps each row of the hologram, the fringes resulting from the superposition of the object beam and the reference one oscillate due to external vibrations and/or noises. Sensor captures each hologram row in different instants of these disturbances, therefore, the fringes shifting result in phase aberrations. As a final effect, a spurious pattern is observed that distorts the reconstructed holograms quality. In this work, a simple and efficient method for eliminating this effect by using image processing tools is proposed. The method is exemplified in holograms of microscopic statics biologic objects. Results encourage incorporating CMOS sensors over CCD in Digital Holographic Microscopy because of better resolution and less expensive benefits.Fil: Cabrera, C. M.. Universidad Nacional de Salta. Facultad de Ciencias Exactas; ArgentinaFil: Monaldi, Andrea Carolina. Universidad Nacional de Salta. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Romero, Gladis Graciela. Universidad Nacional de Salta. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin