55 research outputs found
Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia
Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a buildâup of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapseâfree and overall survival. The CXCR4 ligand, CXCL12 (SDFâ1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a âmultiâhitâ therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in preâclinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a âmultiâhitâ therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM
Targeting the non-canonical NF-ÎșB pathway in chronic lymphocytic leukemia and multiple myeloma
In this study, we evaluated an NF-ÎșB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B-and T-lymphocytes. Basal NF-ÎșB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-ÎșB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-ÎșB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-ÎșB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-ÎșB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation
Characterizing the Cool KOIs III. KOI-961: A Small Star with Large Proper Motion and Three Small Planets
We present the characterization of the star KOI 961, an M dwarf with transit
signals indicative of three short-period exoplanets, originally discovered by
the Kepler Mission. We proceed by comparing KOI 961 to Barnard's Star, a
nearby, well-characterized mid-M dwarf. By comparing colors, optical and
near-infrared spectra, we find remarkable agreement between the two, implying
similar effective temperatures and metallicities. Both are metal-poor compared
to the Solar neighborhood, have low projected rotational velocity, high
absolute radial velocity, large proper motion and no quiescent H-alpha
emission--all of which is consistent with being old M dwarfs. We combine
empirical measurements of Barnard's Star and expectations from evolutionary
isochrones to estimate KOI 961's mass (0.13 +/- 0.05 Msun), radius (0.17 +/-
0.04 Rsun) and luminosity (2.40 x 10^(-3.0 +/- 0.3) Lsun). We calculate KOI
961's distance (38.7 +/- 6.3 pc) and space motions, which, like Barnard's Star,
are consistent with a high scale-height population in the Milky Way. We perform
an independent multi-transit fit to the public Kepler light curve and
significantly revise the transit parameters for the three planets. We calculate
the false-positive probability for each planet-candidate, and find a less than
1% chance that any one of the transiting signals is due to a background or
hierarchical eclipsing binary, validating the planetary nature of the transits.
The best-fitting radii for all three planets are less than 1 Rearth, with KOI
961.03 being Mars-sized (Rp = 0.57 +/- 0.18 Rearth), and they represent some of
the smallest exoplanets detected to date.Comment: Accepted to Ap
The Astropy Problem
The Astropy Project (http://astropy.org) is, in its own words, "a community
effort to develop a single core package for Astronomy in Python and foster
interoperability between Python astronomy packages." For five years this
project has been managed, written, and operated as a grassroots,
self-organized, almost entirely volunteer effort while the software is used by
the majority of the astronomical community. Despite this, the project has
always been and remains to this day effectively unfunded. Further, contributors
receive little or no formal recognition for creating and supporting what is now
critical software. This paper explores the problem in detail, outlines possible
solutions to correct this, and presents a few suggestions on how to address the
sustainability of general purpose astronomical software
The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey
The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic
data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data
release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median
z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar
spectra, along with the data presented in previous data releases. These spectra
were obtained with the new BOSS spectrograph and were taken between 2009
December and 2011 July. In addition, the stellar parameters pipeline, which
determines radial velocities, surface temperatures, surface gravities, and
metallicities of stars, has been updated and refined with improvements in
temperature estimates for stars with T_eff<5000 K and in metallicity estimates
for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars
presented in DR8, including stars from SDSS-I and II, as well as those observed
as part of the SDSS-III Sloan Extension for Galactic Understanding and
Exploration-2 (SEGUE-2).
The astrometry error introduced in the DR8 imaging catalogs has been
corrected in the DR9 data products. The next data release for SDSS-III will be
in Summer 2013, which will present the first data from the Apache Point
Observatory Galactic Evolution Experiment (APOGEE) along with another year of
data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at
http://www.sdss3.org/dr
KELT-25 b and KELT-26 b: A Hot Jupiter and a Substellar Companion Transiting Young A Stars Observed by TESS
We present the discoveries of KELT-25 b (TIC 65412605, TOI-626.01) and KELT-26 b (TIC 160708862, TOI-1337.01), two transiting companions orbiting relatively bright, early A stars. The transit signals were initially detected by the KELT survey and subsequently confirmed by Transiting Exoplanet Survey Satellite (TESS) photometry. KELT-25 b is on a 4.40 day orbit around the V = 9.66 star CD-24 5016 (Teff=8280-180+440 K, M â = 2.18-0.11+0.12 M oË), while KELT-26 b is on a 3.34 day orbit around the V = 9.95 star HD 134004 (Teff = 8640-240+500 K, M â = 1.93-0.16+0.14 M oË), which is likely an Am star. We have confirmed the substellar nature of both companions through detailed characterization of each system using ground-based and TESS photometry, radial velocity measurements, Doppler tomography, and high-resolution imaging. For KELT-25, we determine a companion radius of R P = 1.64-0.043+0.039 R J and a 3Ï upper limit on the companion\u27s mass of âŒ64 M J. For KELT-26 b, we infer a planetary mass and radius of M P = 1.41-0.51+0.43MJ and R P = 1.94-0.058+0.060 R J. From Doppler tomographic observations, we find KELT-26 b to reside in a highly misaligned orbit. This conclusion is weakly corroborated by a subtle asymmetry in the transit light curve from the TESS data. KELT-25 b appears to be in a well-aligned, prograde orbit, and the system is likely a member of the cluster Theia 449
LSST Science Book, Version 2.0
A survey that can cover the sky in optical bands over wide fields to faint
magnitudes with a fast cadence will enable many of the exciting science
opportunities of the next decade. The Large Synoptic Survey Telescope (LSST)
will have an effective aperture of 6.7 meters and an imaging camera with field
of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over
20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with
fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a
total point-source depth of r~27.5. The LSST Science Book describes the basic
parameters of the LSST hardware, software, and observing plans. The book
discusses educational and outreach opportunities, then goes on to describe a
broad range of science that LSST will revolutionize: mapping the inner and
outer Solar System, stellar populations in the Milky Way and nearby galaxies,
the structure of the Milky Way disk and halo and other objects in the Local
Volume, transient and variable objects both at low and high redshift, and the
properties of normal and active galaxies at low and high redshift. It then
turns to far-field cosmological topics, exploring properties of supernovae to
z~1, strong and weak lensing, the large-scale distribution of galaxies and
baryon oscillations, and how these different probes may be combined to
constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at
http://www.lsst.org/lsst/sciboo
TESS delivers its first Earth-sized planet and a warm sub-Neptune
The future of exoplanet science is bright, as TESS once again demonstrates
with the discovery of its longest-period confirmed planet to date. We hereby
present HD 21749b (TOI 186.01), a sub-Neptune in a 36-day orbit around a bright
(V = 8.1) nearby (16 pc) K4.5 dwarf. TESS measures HD21749b to be
2.61 , and combined archival and follow-up
precision radial velocity data put the mass of the planet at
. HD 21749b contributes to the TESS Level 1
Science Requirement of providing 50 transiting planets smaller than 4
with measured masses. Furthermore, we report the discovery of HD
21749c (TOI 186.02), the first Earth-sized () planet from TESS. The HD21749 system is a prime target for
comparative studies of planetary composition and architecture in multi-planet
systems.Comment: Published in ApJ Letters; 5 figures, 1 tabl
Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 Ă 10â13), 1q42.13 (rs41271473, P=1.06 Ă 10â10), 4q24 (rs71597109, P=1.37 Ă 10â10), 4q35.1 (rs57214277, P=3.69 Ă 10â8), 6p21.31 (rs3800461, P=1.97 Ă 10â8), 11q23.2 (rs61904987, P=2.64 Ă 10â11), 18q21.1 (rs1036935, P=3.27 Ă 10â8), 19p13.3 (rs7254272, P=4.67 Ă 10â8) and 22q13.33 (rs140522, P=2.70 Ă 10â9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response
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