Piecing Together the X-ray Background: Bolometric Corrections for Active Galactic Nuclei

(Abridged) The X-ray background can be used to constrain the accretion history of Supermassive Black Holes (SMBHs) in Active Galactic Nuclei (AGN). A knowledge of the hard X-ray bolometric correction, \kappa_{2-10keV} is a vital input into these studies. Variations in the disk emission in the UV have not previously been taken into account in calculating \kappa_{2-10keV}; we show that such variations are important by constructing optical--to--X-ray SEDs for 54 AGN. In particular, we use FUSE UV and X-ray data from the literature to constrain the disk emission as well as possible. Previous work has suggested a dependence of \kappa_{2-10keV} on AGN luminosity, but we find significant spread in \kappa_{2-10keV} with no simple dependence on luminosity. Populations such as Narrow-Line Seyfert 1 nuclei (NLS1s), Radio Loud and X-ray Weak AGN may have values of \kappa_{2-10keV} differing systematically from the rest of the AGN population. Other sources of uncertainty include intrinsic extinction in the optical--UV, X-ray and UV variability and uncertainties in SMBH mass estimates. Our results suggest a more well-defined relationship between \kappa_{2-10keV} and Eddington ratio in AGN, with a transitional region at an Eddington ratio of ~0.1, below which the bolometric correction is typically 15 - 25, and above which it is typically 40 - 70. We consider the potential implied parallels with the low/hard and high/soft states in Galactic Black Hole (GBH) accretion, and present bolometric corrections for the GBH binary GX 339-4 for comparison. Our findings reinforce previous studies proposing a multi-state description of AGN accretion analogous to that for GBH binaries. Future calculations of the SMBH mass density may need to account for the possible dependence of \kappa_{2-10keV} on Eddington ratio.Comment: 19 pages, 16 figures, 3 tables. Accepted for publication in MNRA

Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL

Genomic classification has improved risk assignment of pediatric but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (NCT00002514) trial accrued 1229 BCR-ABL1-negative adolescent/adult B-ALL patients (aged 14-65 years). While 93% of patients achieved remission, 41% relapsed at a median of 13 months (range 28 days to 12 years). Five-year overall survival (5yr-OS) was 42% (95% CI, 39, 44). Transcriptome sequencing (n=238), gene expression profiling (n=210), cytogenetics (n=197) and fusion PCR (n=274) enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients in the outcome analysis, 29.5% of cases had favorable outcomes with 5yr-OS of 65-80% and were deemed standard-risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5yr-OS of 0-27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); and 20.3% had intermediate-risk genotypes with 5yr-OS of 33-45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like and TP53 mutations occurred in low-hypodiploid (54%) and BCL2/MYC-rearranged patients (33%), but were not independently associated with outcome. Of patients considered high-risk for relapse based on presenting age and WBC count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses which may translate into future therapeutic benefits

The nature of X-ray absorbed QSOs

There exists a significant population of broad line, z~2 QSOs which have heavily absorbed X-ray spectra. Follow up observations in the submillimetre show that these QSOs are embedded in ultraluminous starburst galaxies, unlike most unabsorbed QSOs at the same redshifts and luminosities. Here we present X-ray spectra from XMM-Newton for a sample of 5 such X-ray absorbed QSOs that have been detected at submillimetre wavelengths. We also present spectra in the restframe ultraviolet from ground based telescopes. All 5 QSOs are found to exhibit strong C IV absorption lines in their ultraviolet spectra with equivalent width > 5 Angstroms. The X-ray spectra are inconsistent with the hypothesis that these objects show normal QSO continua absorbed by low-ionization gas. Instead, the spectra can be modelled successfully with ionized absorbers, or with cold absorbers if they posess unusually flat X-ray continuum shapes and unusual optical to X-ray spectral energy distributions. We show that the ionized absorber model provides the simplest, most self-consistent explanation for their observed properties. We estimate that the fraction of radiated power that is converted into kinetic luminosity of the outflowing winds is typically ~4 per cent, in agreement with recent estimates for the kinetic feedback from QSOs required to produce the M - sigma relation, and consistent with the hypothesis that the X-ray absorbed QSOs represent the transition phase between obscured accretion and the luminous QSO phase in the evolution of massive galaxies.Comment: Accepted for publication in MNRA

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL

High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL

Statistical Significance Threshold Criteria For Analysis of Microarray Gene Expression Data

The methodological advancement in microarray data analysis on the basis of false discovery rate (FDR) control, such as the q-value plots, allows the investigator to examine the FDR from several perspectives. However, when FDR control at the ``customary" levels 0.01, 0.05, or 0.1 does not provide fruitful findings, there is little guidance for making the trade off between the significance threshold and the FDR level by sound statistical or biological considerations. Thus, meaningful statistical significance criteria that complement the existing FDR methods for large-scale multiple tests are desirable. Three statistical significance criteria, the profile information criterion, the total error proportion, and the guide-gene driven selection, are developed in this research. The first two are general significance threshold criteria for large-scale multiple tests; the profile information criterion is related to the recent theoretical studies of the connection between FDR control and minimax estimation, and the total error proportion is closely related to the asymptotic properties of FDR control in terms of the total error risk. The guide-gene driven selection is an approach to combining statistical significance and the existing biological knowledge of the study at hand. Error properties of these criteria are investigated theoretically and by simulation. The proposed methods are illustrated and compared using an example of genomic screening for novel Arf gene targets. Operating characteristics of q-value and the proposed significance threshold criteria are investigated and compared in a simulation study that employs a model mimicking a gene regulatory pathway. A guideline for using these criteria is provided. Splus/R code is available from the corresponding author upon request.

Searching for the signature of radiative line driving: on the absence of Lyα-N v line-locking features in a large sample of BALQSOs

We have searched the hybrid BALQSO catalogue of Scaringi et al. derived from DR5 of the SDSS in order to compile the largest sample of objects displaying spectral signatures which may be indicative of radiative line driving. The feature in question is the "ghost of Ly-alpha", a line-locking feature previously identified in the broad C IV and Si IV absorption lines of a small fraction of BALQSOs, and formed via the interaction of Ly-alpha photons with N V ions. We test, where possible the criteria required to produce an observable ghost feature and find that these criteria are not met significantly more often in ghost-candidates than in a comparison sample chosen to exhibit relatively featureless broad absorption troughs. Indeed, the only significant differences we find between our ghost-candidate and comparison samples, is that on average, our ghost-candidate sample displays (i) significantly stronger N V absorption, and (ii) the onset of absorption occurs at lower velocities in our ghost-candidate objects. Significantly, we find no evidence for an excess of objects whose absorption troughs bracket the location of the Ly-alpha-N V line-locking region, rather the location of ghost-like features appears to be independent of any systematic velocity. Thus, the majority of objects identified here as strong ghost-candidates are likely multi-trough interlopers whose absorption feature simply bracket the region of interest.Comment: 23 pages and 21 figures. Accepted for publication in MNRAS