Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies.
We used ...massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers.
We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 65%). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations.
Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).
Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the ...diagnosis of these neoplasms remains a challenge.
We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry.
Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients.
Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).
High-efficiency acceleration of charged particle beams at high gradients of energy gain per unit length is necessary to achieve an affordable and compact high-energy collider. The plasma wakefield ...accelerator is one concept being developed for this purpose. In plasma wakefield acceleration, a charge-density wake with high accelerating fields is driven by the passage of an ultra-relativistic bunch of charged particles (the drive bunch) through a plasma. If a second bunch of relativistic electrons (the trailing bunch) with sufficient charge follows in the wake of the drive bunch at an appropriate distance, it can be efficiently accelerated to high energy. Previous experiments using just a single 42-gigaelectronvolt drive bunch have accelerated electrons with a continuous energy spectrum and a maximum energy of up to 85 gigaelectronvolts from the tail of the same bunch in less than a metre of plasma. However, the total charge of these accelerated electrons was insufficient to extract a substantial amount of energy from the wake. Here we report high-efficiency acceleration of a discrete trailing bunch of electrons that contains sufficient charge to extract a substantial amount of energy from the high-gradient, nonlinear plasma wakefield accelerator. Specifically, we show the acceleration of about 74 picocoulombs of charge contained in the core of the trailing bunch in an accelerating gradient of about 4.4 gigavolts per metre. These core particles gain about 1.6 gigaelectronvolts of energy per particle, with a final energy spread as low as 0.7 per cent (2.0 per cent on average), and an energy-transfer efficiency from the wake to the bunch that can exceed 30 per cent (17.7 per cent on average). This acceleration of a distinct bunch of electrons containing a substantial charge and having a small energy spread with both a high accelerating gradient and a high energy-transfer efficiency represents a milestone in the development of plasma wakefield acceleration into a compact and affordable accelerator technology.
Haematopoietic stem cells drive blood production, but their population size and lifetime dynamics have not been quantified directly in humans. Here we identified 129,582 spontaneous, genome-wide ...somatic mutations in 140 single-cell-derived haematopoietic stem and progenitor colonies from a healthy 59-year-old man and applied population-genetics approaches to reconstruct clonal dynamics. Cell divisions from early embryogenesis were evident in the phylogenetic tree; all blood cells were derived from a common ancestor that preceded gastrulation. The size of the stem cell population grew steadily in early life, reaching a stable plateau by adolescence. We estimate the numbers of haematopoietic stem cells that are actively making white blood cells at any one time to be in the range of 50,000-200,000. We observed adult haematopoietic stem cell clones that generate multilineage outputs, including granulocytes and B lymphocytes. Harnessing naturally occurring mutations to report the clonal architecture of an organ enables the high-resolution reconstruction of somatic cell dynamics in humans.
The Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) is a hyperspectral imager on the Mars Reconnaissance Orbiter (MRO) spacecraft. CRISM consists of three subassemblies, a gimbaled ...Optical Sensor Unit (OSU), a Data Processing Unit (DPU), and the Gimbal Motor Electronics (GME). CRISM's objectives are (1) to map the entire surface using a subset of bands to characterize crustal mineralogy, (2) to map the mineralogy of key areas at high spectral and spatial resolution, and (3) to measure spatial and seasonal variations in the atmosphere. These objectives are addressed using three major types of observations. In multispectral mapping mode, with the OSU pointed at planet nadir, data are collected at a subset of 72 wavelengths covering key mineralogic absorptions and binned to pixel footprints of 100 or 200 m/pixel. Nearly the entire planet can be mapped in this fashion. In targeted mode the OSU is scanned to remove most along‐track motion, and a region of interest is mapped at full spatial and spectral resolution (15–19 m/pixel, 362–3920 nm at 6.55 nm/channel). Ten additional abbreviated, spatially binned images are taken before and after the main image, providing an emission phase function (EPF) of the site for atmospheric study and correction of surface spectra for atmospheric effects. In atmospheric mode, only the EPF is acquired. Global grids of the resulting lower data volume observations are taken repeatedly throughout the Martian year to measure seasonal variations in atmospheric properties. Raw, calibrated, and map‐projected data are delivered to the community with a spectral library to aid in interpretation.
An effective vaginal microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among microbicide candidates in clinical development is Maraviroc (MVC), a ...small-molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected individuals, but its ability to prevent transmission is untested. We have now evaluated MVC as a vaginal microbicide with use of a stringent model that involves challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/mL). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (half life of ∼4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated postinfection viremia. These findings validate MVC development as a vaginal microbicide for women and should guide clinical programs.
The identification of an acquired mutation of JAK2 in patients with myeloproliferative disorders has raised questions about the relationship between mutation-positive and mutation-negative subtypes, ...timing of the JAK2 mutation, and molecular mechanisms of disease progression. Here we demonstrate that patients with V617F- essential thrombocythemia do not commonly progress to become V617F+. Consistent with the concept of distinct pathogenetic mechanisms, we show that patients with and without the JAK2 mutation have different patterns of cytogenetic abnormality, with virtually all patients carrying the 20q deletion or trisomy 9 being V617F+. We also investigated the existence of a “pre-JAK2” phase by comparing the proportion of clonally derived granulocytes, estimated from X-chromosome inactivation patterns (XCIPs), with the proportion of V617F+ granulocytes. Our results demonstrate that inherent XCIP variability between granulocytes and T cells produces a systematically biased pattern of results that may be misinterpreted as evidence for an excess of clonally derived granulocytes, an observation that limits the utility of XCIP analysis in this context. Lastly, we studied 4 patients with V617F+ myeloproliferative disorders who subsequently developed acute myeloid leukemia. In 3 patients the leukemic cells were V617F-, suggesting that in these patients the leukemia arose in a V617F- cell.
We have conducted a Galactic plane survey of methanol masers at 6668 MHz using a seven-beam receiver on the Parkes telescope. Here we present results from the first part, which provides sensitive ...unbiased coverage of a large region around the Galactic Centre. Details are given for 183 methanol maser sites in the longitude range 345° through the Galactic Centre to 6°. Within 6° of the Galactic Centre, we found 88 maser sites, of which more than half (48) are new discoveries. The masers are confined to a narrow Galactic latitude range, indicative of many sources at the Galactic Centre distance and beyond, and confined to a thin disc population; there is no high-latitude population that might be ascribed to the Galactic bulge. Within 2° of the Galactic Centre the maser velocities all lie between −60 and +77 km s−1, a range much smaller than the 540 km s−1 range observed in CO. Elsewhere, the maser with highest positive velocity (+107 km s−1) occurs, surprisingly, near longitude 355° and is probably attributable to the Galactic bar. The maser with the most negative velocity (−127 km s−1) is near longitude 346°, within the longitude–velocity locus of the near side of the ‘3-kpc arm’. It has the most extreme velocity of a clear population of masers associated with the near and far sides of the 3-kpc arm. Closer to the Galactic Centre the maser space density is generally low, except within 0.25 kpc of the Galactic Centre itself, the ‘Galactic Centre zone’, where it is 50 times higher, which is hinted at by the longitude distribution, and confirmed by the unusual velocities.
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