Molecular landscapes of human hematopoietic stem cells in health and leukemia.

Blood cells are organized as a hierarchy with hematopoietic stem cells (HSCs) at the root. The advent of genomic technologies has opened the way for global characterization of the molecular landscape of HSCs and their progeny, both in mouse and human models, at the genetic, transcriptomic, epigenetic, and proteomics levels. Here, we outline our current understanding of the molecular programs that govern human HSCs and how dynamic changes occurring during HSC differentiation are necessary for well-regulated blood formation under homeostasis and upon injury. A large body of evidence is accumulating on how the programs of normal hematopoiesis are modified in acute myeloid leukemia, an aggressive adult malignancy driven by leukemic stem cells. We summarize these findings and their clinical implications.The authors would like to thank Emily Calderbank for critical review of the manuscript. Research in EL laboratory is supported by a Wellcome Trust Sir Henry Dale Fellowship and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/nyas.1298

Long-Term Safety of Anti-TNF Adalimumab in HBc Antibody-Positive Psoriatic Arthritis Patients: A Retrospective Case Series of 8 Patients

Immunosuppressive drugs commonly used in the treatment of psoriatic arthritis make patients more susceptible to viral, bacterial, and fungal infections because of their mechanism of action. They not only increase the risk of new infections but also act altering the natural course of preexisting infections. While numerous data regarding the reactivation of tuberculosis infection are available in the literature, poor information about the risk of reactivation or exacerbation of hepatitis viruses B and C infections during treatment with biologics has been reported. Furthermore, reported series with biological therapy included short periods of followup, and therefore, they are not adequate to verify the risk of reactivation in the long-term treatment. Our study evaluated patients with a history of hepatitis B and psoriatic arthritis treated with adalimumab and monitored up to six years. During the observation period, treatment was effective and well tolerated in all patients, and liver function tests and viral load levels remained unchanged

The AMS-02 RICH Imager Prototype - In-Beam Tests with 20 GeV/c per Nucleon Ions -

A prototype of the AMS Cherenkov imager (RICH) has been tested at CERN by means of a low intensity 20 GeV/c per nucleon ion beam obtained by fragmentation of a primary beam of Pb ions. Data have been collected with a single beam setting, over the range of nuclear charges 2<Z<~45 in various beam conditions and using different radiators. The charge Z and velocity beta resolutions have been measured.Comment: 4 pages, contribution to the ICRC 200

The Ring Imaging Cherenkov detector (RICH) of the AMS experiment

The Alpha Magnetic Spectrometer (AMS) experiment to be installed on the International Space Station (ISS) will be equipped with a proximity focusing Ring Imaging Cherenkov (RICH) detector for measuring the electric charge and velocity of the charged cosmic particles. A RICH prototype consisting of 96 photomultiplier units, including a piece of the conical reflector, was built and its performance evaluated with ion beam data. Preliminary results of the in-beam tests performed with ion fragments resulting from collisions of a 158 GeV/c/nuc primary beam of Indium ions (CERN SPS) on a Pb target are reported. The collected data included tests to the final front-end electronics and to different aerogel radiators. Cherenkov rings for a large range of charged nuclei and with reflected photons were observed. The data analysis confirms the design goals. Charge separation up to Fe and velocity resolution of the order of 0.1% for singly charged particles are obtained.Comment: 29th International Conference on Cosmic Rays (Pune, India

The AMS-RICH velocity and charge reconstruction

The AMS detector, to be installed on the International Space Station, includes a Ring Imaging Cerenkov detector with two different radiators, silica aerogel (n=1.05) and sodium fluoride (n=1.334). This detector is designed to provide very precise measurements of velocity and electric charge in a wide range of cosmic nuclei energies and atomic numbers. The detector geometry, in particular the presence of a reflector for acceptance purposes, leads to complex Cerenkov patterns detected in a pixelized photomultiplier matrix. The results of different reconstruction methods applied to test beam data as well as to simulated samples are presented. To ensure nominal performances throughout the flight, several detector parameters have to be carefully monitored. The algorithms developed to fulfill these requirements are presented. The velocity and charge measurements provided by the RICH detector endow the AMS spectrometer with precise particle identification capabilities in a wide energy range. The expected performances on light isotope separation are discussed.Comment: Contribution to the ICRC07, Merida, Mexico (2007); Presenter: F. Bara

Distinct routes of lineage development reshape the human blood hierarchy across ontogeny

In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34+ cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult ‘two-tier’ hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.This work was supported by Postdoctoral Fellowship Awards from Canadian Institute of Health Research (CIHR) to FN and SZ. SZ is supported by (Aplastic Anemia). FN is a recipient of a scholar’s research award from the Ontario Institute of Cancer Research (OICR), through generous support from the Ontario Ministry of Research and Innovation. Research in EL laboratory is supported by a Wellcome Trust Sir Henry Dale Fellowship and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. Work in the Dick laboratory is supported by grants from the CIHR, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, OICR with funds from the province of Ontario, a Canada Research Chair and the Ontario Ministry of Health and Long Term Care (OMOHLTC).This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aab211

A KRAB/KAP1-miRNA Cascade Regulates Erythropoiesis Through Stage-Specific Control of Mitophagy

During hematopoiesis, lineage- and stage-specific transcription factors work in concert with chromatin modifiers to direct the differentiation of all blood cells. We explored the role of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor KAP1 in this process. In mice, hematopoietic-restricted deletion of Kap1 resulted in severe hypoproliferative anemia. Kap1-deleted erythroblasts failed to induce mitophagy-associated genes and retained mitochondria. This was due to persistent expression of microRNAs (miRNAs) targeting mitophagy transcripts, itself secondary to a lack of repression by stage-specific KRAB-ZFPs. The KRAB/KAP1-miRNA regulatory cascade is evolutionarily conserved, as it also controls mitophagy during human erythropoiesis. Thus, a multilayered transcription regulatory system is present, in which protein- and RNA-based repressors are superimposed in combinatorial fashion to govern the timely triggering of an important differentiation event

The RICH detector of the AMS-02 experiment: status and physics prospects

The Alpha Magnetic Spectrometer (AMS), whose final version AMS-02 is to be installed on the International Space Station (ISS) for at least 3 years, is a detector designed to measure charged cosmic ray spectra with energies up to the TeV region and with high energy photon detection capability up to a few hundred GeV. It is equipped with several subsystems, one of which is a proximity focusing RICH detector with a dual radiator (aerogel+NaF) that provides reliable measurements for particle velocity and charge. The assembly and testing of the AMS RICH is currently being finished and the full AMS detector is expected to be ready by the end of 2008. The RICH detector of AMS-02 is presented. Physics prospects are briefly discussed.Comment: 5 pages. Contribution to the 10th ICATPP Conference on Astroparticle, Particle, Space Physics, Detectors and Medical Physics Applications (Como 2007). Presenter: Rui Pereir

Search for antihelium in cosmic rays

The Alpha Magnetic Spectrometer (AMS) was flown on the space shuttle Discovery during flight STS-91 in a 51.7 degree orbit at altitudes between 320 and 390 km. A total of 2.86 * 10^6 helium nuclei were observed in the rigidity range 1 to 140 GV. No antihelium nuclei were detected at any rigidity. An upper limit on the flux ratio of antihelium to helium of < 1.1 * 10^-6 is obtained.Comment: 18 pages, Latex, 9 .eps figure