1,030 research outputs found
What clonal hematopoiesis can teach us about MDS
Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of CH, the environmental stressors that influence CH, and the implications of CH on health outcomes including MDS. Since MNs have shared risk factors and underlying biology, most of our discussion regarding the implications of CH surrounds MN in general rather than focusing specifically on MDS. We conclude with future directions and areas of investigation including how intervention studies of CH might inform future therapeutic approaches to MN including MDS
Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes
PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.
EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.
RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.
CONCLUSIONS: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838
The Sloan Lens ACS Survey. X. Stellar, Dynamical, and Total Mass Correlations of Massive Early-type Galaxies
We use stellar masses, photometry, lensing, and velocity dispersions to
investigate empirical correlations for the final sample of 73 early-type lens
galaxies (ETGs) from the SLACS survey. The traditional correlations
(Fundamental Plane [FP] and its projections) are consistent with those found
for non-lens galaxies, supporting the thesis that SLACS lens galaxies are
representative of massive ETGs. The addition of strong lensing estimates of the
total mass allows us to gain further insights into their internal structure: i)
the mean slope of the total mass density profile is = 2.078+/-0.027
with an intrinsic scatter of 0.16+/-0.02; ii) gamma' correlates with effective
radius and central mass density, in the sense that denser galaxies have steeper
profiles; iii) the dark matter fraction within reff/2 is a monotonically
increasing function of galaxy mass and size; iv) the dimensional mass M_dim is
proportional to the total mass, and both increase more rapidly than stellar
mass M*; v) the Mass Plane (MP), obtained by replacing surface brightness with
surface mass density in the FP, is found to be tighter and closer to the virial
relation than the FP and the M*P, indicating that the scatter of those
relations is dominated by stellar population effects; vi) we construct the
Fundamental Hyper-Plane by adding stellar masses to the MP and find the M*
coefficient to be consistent with zero and no residual intrinsic scatter. Our
results demonstrate that the dynamical structure of ETGs is not scale invariant
and that it is fully specified by the total mass, r_eff, and sigma. Although
the basic trends can be explained qualitatively in terms of varying star
formation efficiency as a function of halo mass and as the result of dry and
wet mergers, reproducing quantitatively the observed correlations and their
tightness may be a significant challenge for galaxy formation models.Comment: 16 pages, 9 figures; submitted to ApJ after responding to the referee
comment
Semi-numeric simulations of helium reionization and the fluctuating radiation background
Recent He II Lyman-alpha forest observations from 2.0 2.7. These results point to a fluctuating He-ionizing background, which may be due to the end of helium reionization of this era. We present a fast, semi-numeric procedure to approximate detailed cosmological simulations. We compute the distribution of dark matter halos, ionization state of helium, and density field at z = 3 in broad agreement with recent simulations. Given our speed and flexibility, we investigate a range of ionizing source and active quasar prescriptions. Spanning a large area of parameter space, we find order-of-magnitude fluctuations in the He II ionization rate in the post-reionization regime. During reionization, the fluctuations are even stronger and develop a bimodal distribution, in contrast to semi-analytic models and the hydrogen equivalent. These distributions indicate a low-level ionizing background even at significant He II fractions
Assessing the perceived value of Reflexive Groups for supporting Clergy in the Church of England
This is an Accepted Manuscript of an article published by Taylor & Francis in Mental Health, Religion and Culture on 18-7-16, available online: http://dx.doi.org/10.1080/13674676.2016.1197194Little research has been conducted to assess the effectiveness of reflexive groups in supporting clergy. For this research, eight Church of England Bishops’ Advisors for Pastoral Care and Counselling were interviewed to ascertain the value of reflexive groups. These data were analysed using a thematic analysis. Two superordinate themes emerged: Contextual issues and Benefits, along with 20 subordinate themes. An online survey, consisting of questions that came from the Bishops’ Advisors data, was then sent to reflexive group participants (n=64), to see if their experiences matched those benefits identified by the Bishops’ Advisors. The data from 37 participants was statistically analysed. The data from both sets of participants reveal that reflexive groups are psychologically beneficial to clergy. The research concludes that the implementation of reflexive groups as a way of developing self-awareness and enculturating attitudes towards resilience and self-care is important to foster psychologically and spiritually healthy practice
New constraints on the free-streaming of warm dark matter from intermediate and small scale Lyman-α forest data
We present new measurements of the free-streaming of warm dark matter (WDM) from Lyman-α flux-power spectra. We use data from the medium resolution, intermediate redshift XQ-100 sample observed with the X-shooter spectrograph (z=3–4.2) and the high-resolution, high-redshift sample used in Viel et al. (2013) obtained with the HIRES/MIKE spectrographs (z=4.2 – 5.4 ). Based on further improved modelling of the dependence of the Lyman- α flux-power spectrum on the free-streaming of dark matter, cosmological parameters, as well as the thermal history of the intergalactic medium (IGM) with hydrodynamical simulations, we obtain the following limits, expressed as the equivalent mass of thermal relic WDM particles. The XQ-100 flux power spectrum alone gives a lower limit of 1.4 keV, the re-analysis of the HIRES/MIKE sample gives 4.1 keV while the combined analysis gives our best and significantly strengthened lower limit of 5.3 keV (all 2 σ C.L.). The further improvement in the joint analysis is partly due to the fact that the two data sets have different degeneracies between astrophysical and cosmological parameters that are broken when the data sets are combined, and more importantly on chosen priors on the thermal evolution. These results all assume that the temperature evolution of the IGM can be modeled as a power law in redshift. Allowing for a nonsmooth evolution of the temperature of the IGM with sudden temperature changes of up to 5000 K reduces the lower limit for the combined analysis to 3.5 keV. A WDM with smaller thermal relic masses would require, however, a sudden temperature jump of 5000 K or more in the narrow redshift interval z = 4.6 – 4.8 , in disagreement with observations of the thermal history based on high-resolution resolution Lyman- α forest data and expectations for photo-heating and cooling in the low density IGM at these redshifts.V. I. is supported by U.S. NSF Grant No. AST-1514734. V. I. also thanks M. McQuinn for useful discussions, and IAS, Princeton, for hospitality during his stay where part of this work was completed. M. V. and T. S. K. are supported by ERC-StG “cosmoIGM”. S. L. has been supported by FONDECYT grant number 1140838 and partially by PFB-06 CATA. V. D., M. V., S. C. acknowledge support from the PRIN INAF 2012 “The X-Shooter sample of 100 quasar spectra at
z
∼
3.5
: Digging into cosmology and galaxy evolution with quasar absorption lines. G. B. is supported by the NSF under award AST-1615814. S. L. E. acknowledges the receipt of an NSERC Discovery Grant. M. H. acknowledges support by ERC ADVANCED GRANT 320596 “The Emergence of Structure during the epoch of Reionization”. L. C. is supported by YDUN DFF 4090-00079. K. D. D. is supported by an NSF AAPF fellowship awarded under NSF grant AST-1302093. J. S. B. acknowledges the support of a Royal Society University Research Fellowship. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programme 189.A-0424. This work made use of the DiRAC High Performance Computing System (HPCS) and the COSMOS shared memory service at the University of Cambridge. These are operated on behalf of the STFC DiRAC HPC facility. This equipment is funded by BIS National E-infrastructure capital grant ST/J005673/1 and STFC grants ST/H008586/1, ST/K00333X/1
A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival.
BACKGROUND: KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival. RESULTS: In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15 bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site. CONCLUSIONS: We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
The Baryon Oscillation Spectroscopic Survey of SDSS-III
The Baryon Oscillation Spectroscopic Survey (BOSS) is designed to measure the
scale of baryon acoustic oscillations (BAO) in the clustering of matter over a
larger volume than the combined efforts of all previous spectroscopic surveys
of large scale structure. BOSS uses 1.5 million luminous galaxies as faint as
i=19.9 over 10,000 square degrees to measure BAO to redshifts z<0.7.
Observations of neutral hydrogen in the Lyman alpha forest in more than 150,000
quasar spectra (g<22) will constrain BAO over the redshift range 2.15<z<3.5.
Early results from BOSS include the first detection of the large-scale
three-dimensional clustering of the Lyman alpha forest and a strong detection
from the Data Release 9 data set of the BAO in the clustering of massive
galaxies at an effective redshift z = 0.57. We project that BOSS will yield
measurements of the angular diameter distance D_A to an accuracy of 1.0% at
redshifts z=0.3 and z=0.57 and measurements of H(z) to 1.8% and 1.7% at the
same redshifts. Forecasts for Lyman alpha forest constraints predict a
measurement of an overall dilation factor that scales the highly degenerate
D_A(z) and H^{-1}(z) parameters to an accuracy of 1.9% at z~2.5 when the survey
is complete. Here, we provide an overview of the selection of spectroscopic
targets, planning of observations, and analysis of data and data quality of
BOSS.Comment: 49 pages, 16 figures, accepted by A
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