Clinical and molecular characterization of HER2 amplified-pancreatic cancer

<p>Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.</p> <p>Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).</p> <p>Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.</p> <p>Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.</p&gt

ZFOURGE catalogue of AGN candidates: an enhancement of 160-μm-derived star formation rates in active galaxies to z = 3.2

We investigate active galactic nuclei (AGN) candidates within the FourStar Galaxy Evolution Survey (ZFOURGE) to determine the impact they have on star formation in their host galaxies. We first identify a population of radio, X-ray, and infrared-selected AGN by cross-matching the deep Ks-band imaging of ZFOURGE with overlapping multiwavelength data. From this, we construct a mass-complete (log(M∗/M⊙M∗/M⊙) ≥9.75), AGN luminosity limited sample of 235 AGN hosts over z = 0.2–3.2. We compare the rest-frame U − V versus V − J (UVJ) colours and specific star formation rates (sSFRs) of the AGN hosts to a mass-matched control sample of inactive (non-AGN) galaxies. UVJ diagnostics reveal AGN tend to be hosted in a lower fraction of quiescent galaxies and a higher fraction of dusty galaxies than the control sample. Using 160 μm Herschel PACS data, we find the mean specific star formation rate of AGN hosts to be elevated by 0.34 ± 0.07 dex with respect to the control sample across all redshifts. This offset is primarily driven by infrared-selected AGN, where the mean sSFR is found to be elevated by as much as a factor of ∼5. The remaining population, comprised predominantly of X-ray AGN hosts, is found mostly consistent with inactive galaxies, exhibiting only a marginal elevation. We discuss scenarios that may explain these findings and postulate that AGN are less likely to be a dominant mechanism for moderating galaxy growth via quenching than has previously been suggested

Schottky barrier heights at polar metal/semiconductor interfaces

Using a first-principle pseudopotential approach, we have investigated the Schottky barrier heights of abrupt Al/Ge, Al/GaAs, Al/AlAs, and Al/ZnSe (100) junctions, and their dependence on the semiconductor chemical composition and surface termination. A model based on linear-response theory is developed, which provides a simple, yet accurate description of the barrier-height variations with the chemical composition of the semiconductor. The larger barrier values found for the anion- than for the cation-terminated surfaces are explained in terms of the screened charge of the polar semiconductor surface and its image charge at the metal surface. Atomic scale computations show how the classical image charge concept, valid for charges placed at large distances from the metal, extends to distances shorter than the decay length of the metal-induced-gap states.Comment: REVTeX 4, 11 pages, 6 EPS figure

The SCUBA-2 Cosmology Legacy Survey: ALMA resolves the bright-end of the submillimeter number counts

We present high-resolution 870 μm Atacama Large Millimeter/sub-millimeter Array (ALMA) continuum maps of 30 bright sub-millimeter sources in the UKIDSS UDS field. These sources are selected from deep, 1 degree2 850 μm maps from the SCUBA-2 Cosmology Legacy Survey, and are representative of the brightest sources in the field (median = 8.7 ± 0.4 mJy). We detect 52 sub-millimeter galaxies (SMGs) at >4σ significance in our 30 ALMA maps. In of the ALMA maps the single-dish source comprises a blend of ≥2 SMGs, where the secondary SMGs are Ultra-luminous Infrared Galaxies (ULIRGs) with 1012 . The brightest SMG contributes on average of the single-dish flux density, and in the ALMA maps containing ≥2 SMGs the secondary SMG contributes of the integrated ALMA flux. We construct source counts and show that multiplicity boosts the apparent single-dish cumulative counts by 20% at S870 > 7.5 mJy, and by 60% at S870 > 12 mJy. We combine our sample with previous ALMA studies of fainter SMGs and show that the counts are well-described by a double power law with a break at 8.5 ± 0.6 mJy. The break corresponds to a luminosity of ~6 × 1012 or a star formation rate (SFR) of ~103 . For the typical sizes of these SMGs, which are resolved in our ALMA data with = 1.2 ± 0.1 kpc, this yields a limiting SFR density of ~100 yr−1 kpc−2 Finally, the number density of S870 2 mJy SMGs is 80 ± 30 times higher than that derived from blank-field counts. An over-abundance of faint SMGs is inconsistent with line-of-sight projections dominating multiplicity in the brightest SMGs, and indicates that a significant proportion of these high-redshift ULIRGs are likely to be physically associated

The G0 Experiment: Apparatus for Parity-Violating Electron Scattering Measurements at Forward and Backward Angles

In the G0 experiment, performed at Jefferson Lab, the parity-violating elastic scattering of electrons from protons and quasi-elastic scattering from deuterons is measured in order to determine the neutral weak currents of the nucleon. Asymmetries as small as 1 part per million in the scattering of a polarized electron beam are determined using a dedicated apparatus. It consists of specialized beam-monitoring and control systems, a cryogenic hydrogen (or deuterium) target, and a superconducting, toroidal magnetic spectrometer equipped with plastic scintillation and aerogel Cerenkov detectors, as well as fast readout electronics for the measurement of individual events. The overall design and performance of this experimental system is discussed.Comment: Submitted to Nuclear Instruments and Method

Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets

The spins of ten stellar black holes have been measured using the continuum-fitting method. These black holes are located in two distinct classes of X-ray binary systems, one that is persistently X-ray bright and another that is transient. Both the persistent and transient black holes remain for long periods in a state where their spectra are dominated by a thermal accretion disk component. The spin of a black hole of known mass and distance can be measured by fitting this thermal continuum spectrum to the thin-disk model of Novikov and Thorne; the key fit parameter is the radius of the inner edge of the black hole's accretion disk. Strong observational and theoretical evidence links the inner-disk radius to the radius of the innermost stable circular orbit, which is trivially related to the dimensionless spin parameter a_* of the black hole (|a_*| < 1). The ten spins that have so far been measured by this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95. The robustness of the method is demonstrated by the dozens or hundreds of independent and consistent measurements of spin that have been obtained for several black holes, and through careful consideration of many sources of systematic error. Among the results discussed is a dichotomy between the transient and persistent black holes; the latter have higher spins and larger masses. Also discussed is recently discovered evidence in the transient sources for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2, 6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405) who find no evidence for a correlation between the power of ballistic jets and black hole spi

Different types of disease-causing non-coding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability

The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that non-coding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different non-coding variants. We used comprehensive structural, single nucleotide and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, RT-PCRs, western blots and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic non-coding variants: a retrotransposon insertion, a novel intronic splice donor and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favour of a regulatory non-coding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic non-coding variant discovery.Michael J. Field, Raman Kumar, Anna Hackett, Sayaka Kayumi, Cheryl A. Shoubridge, Lisa J. Ewans, Atma M. Ivancevic, Tracy Dudding, Byth, Renée Carroll, Thessa Kroes, Alison E. Gardner, Patricia Sullivan, Thuong T. Ha, Charles E. Schwartz, Mark J. Cowley, Marcel E. Dinger, Elizabeth E. Palmer, Louise Christie, Marie Shaw, Tony Roscioli, Jozef Gecz, Mark A. Corbet

Developing a predictive modelling capacity for a climate change-vulnerable blanket bog habitat: Assessing 1961-1990 baseline relationships

Aim: Understanding the spatial distribution of high priority habitats and developing predictive models using climate and environmental variables to replicate these distributions are desirable conservation goals. The aim of this study was to model and elucidate the contributions of climate and topography to the distribution of a priority blanket bog habitat in Ireland, and to examine how this might inform the development of a climate change predictive capacity for peat-lands in Ireland. Methods: Ten climatic and two topographic variables were recorded for grid cells with a spatial resolution of 1010 km, covering 87% of the mainland land surface of Ireland. Presence-absence data were matched to these variables and generalised linear models (GLMs) fitted to identify the main climatic and terrain predictor variables for occurrence of the habitat. Candidate predictor variables were screened for collinearity, and the accuracy of the final fitted GLM was evaluated using fourfold cross-validation based on the area under the curve (AUC) derived from a receiver operating characteristic (ROC) plot. The GLM predicted habitat occurrence probability maps were mapped against the actual distributions using GIS techniques. Results: Despite the apparent parsimony of the initial GLM using only climatic variables, further testing indicated collinearity among temperature and precipitation variables for example. Subsequent elimination of the collinear variables and inclusion of elevation data produced an excellent performance based on the AUC scores of the final GLM. Mean annual temperature and total mean annual precipitation in combination with elevation range were the most powerful explanatory variable group among those explored for the presence of blanket bog habitat. Main conclusions: The results confirm that this habitat distribution in general can be modelled well using the non-collinear climatic and terrain variables tested at the grid resolution used. Mapping the GLM-predicted distribution to the observed distribution produced useful results in replicating the projected occurrence of the habitat distribution over an extensive area. The methods developed will usefully inform future climate change predictive modelling for Irelan