Development of siRNA-loaded lipid nanoparticles targeting long non-coding RNA LINC01257 as a novel and safe therapeutic approach for t(8;21) pediatric acute myeloid leukemia

Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly attractive therapeutic target in the treatment of cancer due to their oncogenic functions and selective expression in cancer cells. However, lncRNAs have historically been considered ‘undruggable’ targets because they do not encode for a protein product. Here, we describe the development of a new siRNA-loaded lipid nanoparticle for the therapeutic silencing of the novel oncogenic lncRNA LINC01257. Transcriptomic analysis of children with AML identified LINC01257 as specifically expressed in t(8;21) AML and absent in healthy patients. Using NxGen microfluidic technology, we efficiently and reproducibly packaged anti-LINC01257 siRNA (LNP-si-LINC01257) into lipid nanoparticles based on the FDA-approved Patisiran (Onpattro®) formulation. LNP-si-LINC01257 size and ζ-potential were determined by dynamic light scattering using a Malvern Zetasizer Ultra. LNP-si-LINC01257 internalization and siRNA delivery were verified by fluorescence microscopy and flow cytometry analysis. lncRNA knockdown was determined by RT-qPCR and cell viability was characterized by flow cytometry-based apoptosis assay. LNP-siRNA production yielded a mean LNP size of ~65 nm with PDI ≤ 0.22 along with a >85% siRNA encapsulation rate. LNP-siRNAs were efficiently taken up by Kasumi-1 cells (>95% of cells) and LNP-si-LINC01257 treatment was able to successfully ablate LINC01257 expression which was accompanied by a significant 55% reduction in total cell count following 48 h of treatment. In contrast, healthy peripheral blood mononuclear cells (PBMCs), which do not express LINC01257, were unaffected by LNP-si-LINC01257 treatment despite comparable levels of LNP-siRNA uptake. This is the first report demonstrating the use of LNP-assisted RNA interference modalities for the silencing of cancer-driving lncRNAs as a therapeutically viable and non-toxic approach in the management of AML

Whole slide image registration for the study of tumor heterogeneity

Consecutive thin sections of tissue samples make it possible to study local variation in e.g. protein expression and tumor heterogeneity by staining for a new protein in each section. In order to compare and correlate patterns of different proteins, the images have to be registered with high accuracy. The problem we want to solve is registration of gigapixel whole slide images (WSI). This presents 3 challenges: (i) Images are very large; (ii) Thin sections result in artifacts that make global affine registration prone to very large local errors; (iii) Local affine registration is required to preserve correct tissue morphology (local size, shape and texture). In our approach we compare WSI registration based on automatic and manual feature selection on either the full image or natural sub-regions (as opposed to square tiles). Working with natural sub-regions, in an interactive tool makes it possible to exclude regions containing scientifically irrelevant information. We also present a new way to visualize local registration quality by a Registration Confidence Map (RCM). With this method, intra-tumor heterogeneity and charateristics of the tumor microenvironment can be observed and quantified.Comment: MICCAI2018 - Computational Pathology and Ophthalmic Medical Image Analysis - COMPA

Medication education program for Indian children with asthma: A feasibility study

Objective: It is postulated that children with asthma who receive an interactive, comprehensive,  culturally relevant education program would improve their asthma knowledge (AK), asthma control, and adherence compared with children receiving usual care. The aim of this study was to develop, implement, and evaluate the efficacy of a culturally relevant asthma education intervention for children with asthma and their parents in India.Methods: Children with asthma (7.12 years) and their parents were recruited from an outpatient clinic in a Chest Diseases Hospital in New Delhi, and were randomly assigned to either an intervention or usual care group. At baseline, outcome data collected included pediatric asthma caregiver quality of life (PACQL, primary outcome), AK, asthma control, adherence, inhaler technique, action plan ownership, and goal achievement. These data were collected again at 1 and 6 months after baseline. Outcomes were compared within and between groups using ANOVA techniques.Results: Forty parent.child pairs were recruited. Of these, 24 pairs of children with asthma and their parents received the educational intervention. The PACQL significantly improved from baseline to 6 months in the intervention (5.87 } 0.94.7.00 } 0.03) versus the usual care group (5.90 } 0.52.6.34 } 0.56) (P < 0.001). Other outcomes such as the parentsf and childfs AK, childfs asthma control and inhaler technique were significantly improved in the intervention group across the study. All the participants possessed a written asthma action plan at the end of the intervention. Eighty.five goals were set by children with asthma across all the visits and were achieved by completion.Conclusion: An asthma educator delivered interactive program simultaneously involving children with asthma and their parents, improved quality of life, empowered and promoted better self.management skills.Key words: Asthma education, asthma knowledge, asthma usual care, caregiver quality of life, childhood asthma, hospital.based program, program evaluatio

The evolution of Balmer jump selected galaxies in the ALHAMBRA survey

We present a new color-selection technique, based on the Bruzual & Charlot models convolved with the bands of the ALHAMBRA survey, and the redshifted position of the Balmer jump to select star-forming galaxies in the redshift range 0.5 < z < 1.5. These galaxies are dubbed Balmer jump Galaxies BJGs. We apply the iSEDfit Bayesian approach to fit each detailed SED and determine star-formation rate (SFR), stellar mass, age and absolute magnitudes. The mass of the haloes where these samples reside are found via a clustering analysis. Five volume-limited BJG sub-samples with different mean redshifts are found to reside in haloes of median masses $\sim 10^{12.5 \pm 0.2} M_\odot$ slightly increasing toward z=0.5. This increment is similar to numerical simulations results which suggests that we are tracing the evolution of an evolving population of haloes as they grow to reach a mass of $\sim 10^{12.7 \pm 0.1} M_\odot$ at z=0.5. The likely progenitors of our samples at z$\sim$3 are Lyman Break Galaxies, which at z$\sim$2 would evolve into star-forming BzK galaxies, and their descendants in the local Universe are elliptical galaxies.Hence, this allows us to follow the putative evolution of the SFR, stellar mass and age of these galaxies. From z$\sim$1.0 to z$\sim$0.5, the stellar mass of the volume limited BJG samples nearly does not change with redshift, suggesting that major mergers play a minor role on the evolution of these galaxies. The SFR evolution accounts for the small variations of stellar mass, suggesting that star formation and possible minor mergers are the main channels of mass assembly.Comment: 14 pages, 10 figures. Submitted to A&A. It includes first referee's comments. Abstract abridged due to arXiv requirement

N-body simulation of the Stephan's Quintet

The evolution of compact groups of galaxies may represent one of the few places in the nearby universe in which massive galaxies are being forged through a complex set of processes involving tidal interaction, ram-pressure stripping, and perhaps finally "dry-mergers" of galaxies stripped of their cool gas. Using collisionless N-body simulations, we propose a possible scenario for the formation of one of the best studied compact groups: Stephan's Quintet. We define a serial approach which allows us to consider the history of the group as sequence of galaxy-galaxy interactions seen as relatively separate events in time, but chained together in such a way as to provide a plausible scenario that ends in the current configuration of the galaxies. By covering a large set of parameters, we claim that it is very unlikely that both major tidal tails of the group have been created by the interaction between the main galaxy and a single intruder. We propose instead a scenario based on two satellites orbiting the main disk, plus the recent involvement of an additional interloper, coming from the background at high speed. This purely N-body study of the quintet will provide a parameter-space exploration of the basic dynamics of the group that can be used as a basis for a more sophisticated N-body/hydrodynamic study of the group that is necessary to explain the giant shock structure and other purely gaseous phenomena observed in both the cold, warm and hot gas in the group.Comment: 13 pages, 13 figures. Accepted for publication in Ap

Integral Field Spectroscopy of the Central Regions of 3C 120: Evidence of a Past Merging Event

IFS combined with HST WFPC imaging were used to characterize the central regions of the Seyfert 1 radio galaxy 3C 120. We carried out the analysis of the data, deriving intensity maps of different emission lines and the continua at different wavelengths from the observed spectra. Applying a 2D modeling to the HST images we decoupled the nucleus and the host galaxy, and analyzed the host morphology. The host is a highly distorted bulge dominated galaxy, rich in substructures. We developed a new technique to model the IFS data extending the 2D modeling. Using this technique we separated the Seyfert nucleus and the host galaxy spectra, and derived a residual data cube with spectral and spatial information of the different structures in 3C 120. Three continuum-dominated structures (named A, B, and C) and other three extended emission line regions (EELRs, named E1, E2 and E3) are found in 3C 120 which does not follow the general behavior of a bulge dominated galaxy. We also found shells in the central kpc that may be remnants of a past merging event in this galaxy. The origin of E1 is most probably due to the interaction of the radio-jet of 3C 120 with the intergalactic medium. Structures A, B, and the shell at the southeast of the nucleus seem to correspond to a larger morphological clumpy structure that may be a tidal tail, consequence of the past merging event. We found a bright EELR (E2) in the innermost part of this tidal tail, nearby the nucleus, which shows a high ionization level. The kinematics of the E2 region and its connection to the tidal tail suggest that the tail has channeled gas from the outer regions to the center.Comment: 55 pages, 18 figures and 5 tables Accepted by AP

The ALHAMBRA photometric system

This paper presents the characterization of the optical range of the ALHAMBRA photometric system, a 20 contiguous, equal-width, medium-band CCD system with wavelength coverage from 3500A to 9700A. The photometric description of the system is done by presenting the full response curve as a product of the filters, CCD and atmospheric transmission curves, and using some first and second order moments of this response function. We also introduce the set of standard stars that defines the system, formed by 31 classic spectrophotometric standard stars which have been used in the calibration of other known photometric systems, and 288 stars, flux calibrated homogeneously, from the Next Generation Spectral Library (NGSL). Based on the NGSL, we determine the transformation equations between Sloan Digital Sky Survey (SDSS) ugriz photometry and the ALHAMBRA photometric system, in order to establish some relations between both systems. Finally we develop and discuss a strategy to calculate the photometric zero points of the different pointings in the ALHAMBRA project.Comment: Astronomical Journal on the 14th of January 201

JPCam: A 1.2Gpixel camera for the J-PAS survey

JPCam is a 14-CCD mosaic camera, using the new e2v 9k-by-9k 10microm-pixel 16-channel detectors, to be deployed on a dedicated 2.55m wide-field telescope at the OAJ (Observatorio Astrofisico de Javalambre) in Aragon, Spain. The camera is designed to perform a Baryon Acoustic Oscillations (BAO) survey of the northern sky. The J-PAS survey strategy will use 54 relatively narrow-band (~13.8nm) filters equi-spaced between 370 and 920nm plus 3 broad-band filters to achieve unprecedented photometric red-shift accuracies for faint galaxies over ~8000 square degrees of sky. The cryostat, detector mosaic and read electronics is being supplied by e2v under contract to J-PAS while the mechanical structure, housing the shutter and filter assembly, is being designed and constructed by a Brazilian consortium led by INPE (Instituto Nacional de Pesquisas Espaciais). Four sets of 14 filters are placed in the ambient environment, just above the dewar window but directly in line with the detectors, leading to a mosaic having ~10mm gaps between each CCD. The massive 500mm aperture shutter is expected to be supplied by the Argelander-Institut fur Astronomie, Bonn. We will present an overview of JPCam, from the filter configuration through to the CCD mosaic camera. A brief outline of the main J-PAS science projects will be included.Comment: 11 pages and 9 figure