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  • Instrumentation and Photography  (10)
  • Gene Expression Profiling  (2)
  • 2010-2014  (12)
  • 1
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    The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-31
    Description: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320027/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320027/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barretina, Jordi -- Caponigro, Giordano -- Stransky, Nicolas -- Venkatesan, Kavitha -- Margolin, Adam A -- Kim, Sungjoon -- Wilson, Christopher J -- Lehar, Joseph -- Kryukov, Gregory V -- Sonkin, Dmitriy -- Reddy, Anupama -- Liu, Manway -- Murray, Lauren -- Berger, Michael F -- Monahan, John E -- Morais, Paula -- Meltzer, Jodi -- Korejwa, Adam -- Jane-Valbuena, Judit -- Mapa, Felipa A -- Thibault, Joseph -- Bric-Furlong, Eva -- Raman, Pichai -- Shipway, Aaron -- Engels, Ingo H -- Cheng, Jill -- Yu, Guoying K -- Yu, Jianjun -- Aspesi, Peter Jr -- de Silva, Melanie -- Jagtap, Kalpana -- Jones, Michael D -- Wang, Li -- Hatton, Charles -- Palescandolo, Emanuele -- Gupta, Supriya -- Mahan, Scott -- Sougnez, Carrie -- Onofrio, Robert C -- Liefeld, Ted -- MacConaill, Laura -- Winckler, Wendy -- Reich, Michael -- Li, Nanxin -- Mesirov, Jill P -- Gabriel, Stacey B -- Getz, Gad -- Ardlie, Kristin -- Chan, Vivien -- Myer, Vic E -- Weber, Barbara L -- Porter, Jeff -- Warmuth, Markus -- Finan, Peter -- Harris, Jennifer L -- Meyerson, Matthew -- Golub, Todd R -- Morrissey, Michael P -- Sellers, William R -- Schlegel, Robert -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-04/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- R33 CA155554-02/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 28;483(7391):603-7. doi: 10.1038/nature11003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460905" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Lineage ; Chromosomes, Human/genetics ; Clinical Trials as Topic/methods ; *Databases, Factual ; Drug Screening Assays, Antitumor/*methods ; *Encyclopedias as Topic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, ras/genetics ; Genome, Human/genetics ; Genomics ; Humans ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; *Models, Biological ; Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Pharmacogenetics ; Plasma Cells/cytology/drug effects/metabolism ; Precision Medicine/methods ; Receptor, IGF Type 1/antagonists & inhibitors/metabolism ; Receptors, Aryl Hydrocarbon/genetics/metabolism ; Sequence Analysis, DNA ; Topoisomerase Inhibitors/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-01-24
    Description: Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boyden, Lynn M -- Choi, Murim -- Choate, Keith A -- Nelson-Williams, Carol J -- Farhi, Anita -- Toka, Hakan R -- Tikhonova, Irina R -- Bjornson, Robert -- Mane, Shrikant M -- Colussi, Giacomo -- Lebel, Marcel -- Gordon, Richard D -- Semmekrot, Ben A -- Poujol, Alain -- Valimaki, Matti J -- De Ferrari, Maria E -- Sanjad, Sami A -- Gutkin, Michael -- Karet, Fiona E -- Tucci, Joseph R -- Stockigt, Jim R -- Keppler-Noreuil, Kim M -- Porter, Craig C -- Anand, Sudhir K -- Whiteford, Margo L -- Davis, Ira D -- Dewar, Stephanie B -- Bettinelli, Alberto -- Fadrowski, Jeffrey J -- Belsha, Craig W -- Hunley, Tracy E -- Nelson, Raoul D -- Trachtman, Howard -- Cole, Trevor R P -- Pinsk, Maury -- Bockenhauer, Detlef -- Shenoy, Mohan -- Vaidyanathan, Priya -- Foreman, John W -- Rasoulpour, Majid -- Thameem, Farook -- Al-Shahrouri, Hania Z -- Radhakrishnan, Jai -- Gharavi, Ali G -- Goilav, Beatrice -- Lifton, Richard P -- KL2 RR024138/RR/NCRR NIH HHS/ -- KL2 RR024138-07/RR/NCRR NIH HHS/ -- P30 DK079310/DK/NIDDK NIH HHS/ -- P30 DK079310-04S1/DK/NIDDK NIH HHS/ -- P30-DK079310/DK/NIDDK NIH HHS/ -- UL1-RR024139/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 22;482(7383):98-102. doi: 10.1038/nature10814.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22266938" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Blood Pressure/genetics ; Carrier Proteins/chemistry/*genetics ; Cohort Studies ; Cullin Proteins/chemistry/*genetics ; Electrolytes ; Exons/genetics ; Female ; Gene Expression Profiling ; Genes, Dominant/genetics ; Genes, Recessive/genetics ; Genotype ; Homeostasis/genetics ; Humans ; Hydrogen-Ion Concentration ; Hypertension/complications/*genetics/physiopathology ; Male ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutation/*genetics ; Phenotype ; Potassium/metabolism ; Pseudohypoaldosteronism/complications/*genetics/physiopathology ; Sodium Chloride/metabolism ; Water-Electrolyte Imbalance/complications/*genetics/physiopathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Implications of Weak Link Effects on Thermal Characteristics of Transition-Edge Sensors (2012)
    In:  Other Sources
    Details
    Publication Date: 2019-07-13
    Description: Weak link behavior in transition-edge sensor (TES) microcalorimeters creates the need for a more careful characterization of a device's thermal characteristics through its transition. This is particularly true for small TESs where a small change in the bias current results in large changes in effective transition temperature. To correctly interpret measurements, especially complex impedance, it is crucial to know the temperature-dependent thermal conductance, G(T), and heat capacity, C(T), at each point through the transition. We present data illustrating these effects and discuss how we overcome the challenges that are present in accurately determining G and T from I-V curves. We also show how these weak link effects vary wi.th TES size. Additionally, we use this improVed understanding of G(T) to determine that, for these TES microcalorimeters. Kaptiza boundary resistance dominates the G of devices with absorbers while the electron-phonon coupling also needs to be considered when determining G for devices without absorbers
    Keywords: Instrumentation and Photography
    Type: GSFC.JA.7030.2012 , Journal of Low Temperature Physics; 167; 4-Mar; 121-128
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  • 4
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    Solar Wind Charge Exchange and Local Hot Bubble X-Ray Emission with the DXL Sounding Rocket Experiment (2012)
    In:  Other Sources
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    Publication Date: 2019-07-13
    Description: The Diffuse X-ray emission from the Local Galaxy (DXL) sounding rocket is a NASA approved mission with a scheduled first launch in December 2012. Its goal is to identify and separate the X-ray emission of the SWCX from that of the Local Hot Bubble (LHB) to improve our understanding of both. To separate the SWCX contribution from the LHB. DXL will use the SWCX signature due to the helium focusing cone at 1=185 deg, b=-18 deg, DXL uses large area propostionai counters, with an area of 1.000 sq cm and grasp of about 10 sq cm sr both in the 1/4 and 3/4 keY bands. Thanks to the large grasp, DXL will achieve in a 5 minule flight what cannot be achieved by current and future X-ray satellites.
    Keywords: Instrumentation and Photography
    Type: GSFC.JA.01144.2012 , Astronomical Notes; 333; 4; 383-387
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  • 5
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    AXIOM: Advanced X-Ray Imaging of the Magnetosphere (2011)
    In:  CASI
    Details
    Publication Date: 2019-07-12
    Description: Planetary plasma and magnetic field environments can be studied in two complementary ways by in situ measurements, or by remote sensing. While the former provide precise information about plasma behaviour, instabilities and dynamics on local scales, the latter offers the global view necessary to understand the overall interaction of the magnetospheric plasma with the solar wind. Some parts of the Earth's magnetosphere have been remotely sensed, but the majority remains unexplored by this type of measurements. Here we propose a novel and more elegant approach employing remote X-ray imaging techniques, which are now possible thanks to the relatively recent discovery of solar wind charge exchange X-ray emissions in the vicinity of the Earth's magnetosphere. In this article we describe how an appropriately designed and located X-ray telescope, supported by simultaneous in situ measurements of the solar wind, can be used to image the dayside magnetosphere, magnetosheath and bow shock, with a temporal and spatial resolution sufficient to address several key outstanding questions concerning how the solar wind interacts with the Earth's magnetosphere on a global level. Global images of the dayside magnetospheric boundaries require vantage points well outside the magnetosphere. Our studies have led us to propose AXIOM: Advanced X-ray Imaging Of the Magnetosphere, a concept mission using a Vega launcher with a LISA Pathfinder-type Propulsion Module to place the spacecraft in a Lissajous orbit around the Earth Moon L1 point. The model payload consists of an X-ray Wide Field Imager, capable of both imaging and spectroscopy, and an in situ plasma and magnetic field measurement package. This package comprises a Proton-Alpha Sensor, designed to measure the bulk properties of the solar wind, an Ion Composition Analyser, to characterize the minor ion populations in the solar wind that cause charge exchange emission, and a Magnetometer, designed to measure the strength and direction of the solar wind magnetic field. We also show simulations that demonstrate how the proposed X-ray telescope design is capable of imaging the predicted emission from the dayside magnetosphere with the sensitivity and cadence required to achieve the science goals of the mission.
    Keywords: Instrumentation and Photography
    Type: GSFC.JA.5094.2011
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  • 6
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    High Performance Non-Dispersive X-Ray Spectrometers for Charge Exchange Measurements (2010)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: Currently, the only measurements of cosmological charge exchange have been made using low resolution, non-dispersive spectrometers like the PSPC on ROSAT and the CCD instruments on Chandra and XMM/Newton. However, upcoming cryogenic spectrometers on Astro-H and IXO will add vast new capabilities to investigate charge exchange in local objects such as comets and planetary atmospheres. They may also allow us to observe charge exchange in extra-solar objects such as galactic supernova remnants. With low spectral resolution instruments such as CCDs, x-ray emission due to charge exchange recombination really only provides information on the acceptor species, such as the solar wind. With the new breed of x-ray calorimeter instruments, emission from charge exchange becomes highly diagnostic allowing one to uniquely determine the acceptor species, ionization state, donor species and ionization state, and the relative velocity of the interaction. We will describe x-ray calorimeter instrumentation and its potential for charge exchange measurements in the near term. We will also touch on the instrumentation behind a decade of high resolution measurements of charge exchange using an x-ray calorimeter at the Lawrence Livermore National Laboratory.
    Keywords: Instrumentation and Photography
    Type: Charge Exchange Workshop; Sep 29, 2010 - Oct 01, 2010; Madrid; Spain
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  • 7
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    High Resolution, Non-Dispersive X-Ray Calorimeter Spectrometers on EBITs and Orbiting Observatories (2010)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: X-ray spectroscopy is the primary tool for performing atomic physics with Electron beam ion trap (EBITs). X-ray instruments have generally fallen into two general categories, 1) dispersive instruments with very high spectral resolving powers but limited spectral range, limited count rates, and require an entrance slit, generally, for EBITs, defined by the electron beam itself, and 2) non-dispersive solid-state detectors with much lower spectral resolving powers but that have a broad dynamic range, high count rate ability and do not require a slit. Both of these approaches have compromises that limit the type and efficiency of measurements that can be performed. In 1984 NASA initiated a program to produce a non-dispersive instrument with high spectral resolving power for x-ray astrophysics based on the cryogenic x-ray calorimeter. This program produced the XRS non-dispersive spectrometers on the Astro-E, Astro-E2 (Suzaku) orbiting observatories, the SXS instrument on the Astro-H observatory, and the planned XMS instrument on the International X-ray Observatory. Complimenting these spaceflight programs, a permanent high-resolution x-ray calorimeter spectrometer, the XRS/EBIT, was installed on the LLNL EBIT in 2000. This unique instrument was upgraded to a spectral resolving power of 1000 at 6 keV in 2003 and replaced by a nearly autonomous production-class spectrometer, the EBIT Calorimeter Spectrometer (ECS), in 2007. The ECS spectrometer has a simultaneous bandpass from 0.07 to over 100 keV with a spectral resolving power of 1300 at 6 keV with unit quantum efficiency, and 1900 at 60 keV with a quantum efficiency of 30%. X-ray calorimeters are event based, single photon spectrometers with event time tagging to better than 10 us. We are currently developing a follow-on instrument based on a newer generation of x-ray calorimeters with a spectral resolving power of 3000 at 6 keV, and improved timing and measurement cadence. The unique capabilities of the x-ray calorimeter spectrometer, coupled with higher spectral resolution dispersive spectrometers to resolve line blends, has enabled many science investigations, to date mostly in our x-ray laboratory astrophysics program. These include measurements of absolute cross sections for Land K shell emission from Fe and Ni, charge exchange measurements in many astrophysically abundant elements, lifetime measurements, line ratios, and wavelength measurements. In addition, we have performed many additional measurements in nuclear physics, and in support of diagnostics for laser fusion, for example. In this presentation we will give a detailed overview of x-ray calorimeter instruments in general and in our EBIT laboratory astrophysics program in particular. We will also discuss the science yield of our measurements at EBIT over the last decade) prospects for future science enabled by the current generation of spectrometers and that will be expanded in the near future by the next generation of spectrometers starting in 2611.
    Keywords: Instrumentation and Photography
    Type: International Symposium on Electron Beam Ion Sources and Traps, EBIST2010/ITS-LEIF; Apr 07, 2010 - Apr 10, 2010; Stockholm; Sweden
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  • 8
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    Multi-Absorber Transition-Edge Sensors for X-Ray Astronomy Applications (2012)
    In:  CASI
    Details
    Publication Date: 2019-07-13
    Description: We are developing multi-absorber Transition-Edge Sensors (TESs) for applications in x-ray astronomy. These position-sensitive devices consist of multiple x-ray absorbers each with a different thermal coupling to a single readout TES. Heat diffusion between the absorbers and the TES gives rise to a characteristic pulse shape corresponding to each absorber element and enables position discrimination. The development of these detectors is motivated by a desire to maximize focal plane arrays with the fewest number of readout channels. In this contribution we report on the first results from devices consisting of nine) 65 X 65 sq. microns Au x-ray absorbers) 5 microns thick. These are coupled to a single 35 X 35 sq. microns Mo/Au bilayer TES. These devices have demonstrated full-width-half-maximum (FWHM) energy resolution of 2.1 eV at 1.5 keV) 2.5 eV at 5.9 keV and 3.3 eV at 8 keV. This is coupled with position discrimination from pulse shape over the same energy range. We use a finite-element model to reproduce the measured pulse shapes and investigate the detector non-linearity with energy) which impacts on the devices position sensitivity and energy resolution.
    Keywords: Instrumentation and Photography
    Type: GSFC.ABS.6329.2012 , Applied Superconductivity Conference; Oct 07, 2012 - Oct 11, 2012; Portland, OR; United States
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  • 9
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    IXO-XMS LVSID Anti-Coincidence Detector (2010)
    In:  CASI
    Details
    Publication Date: 2019-07-12
    Description: This document describes a high-TRL backup implementation of the anti-coincidence detector for the IXO/XMS instrument. The backup detector, hereafter referred to as the low-voltage silicon ionization detector (LVSID), has been successfully flown on Astro-E2 (Suzaku)/XRS and is currently being implemented, without significant changes, on the Astro-H/SXS instrument. The LVSID anti-coincidence detector on Astro-E2/XRS operated successfully for almost 2 years, and was not affected by the loss of liquid helium in that instrument. The LVSID continues to operate after almost 5 years on-orbit (LEO, 550 km) but with slightly increased noise following the expected depletion of solid Neon after 22 months. The noise of the device is increased after the loss of sNe due to thermally induced bias and readout noise. No radiation damage, or off-nominal affects have been observed with the LVSID on-orbit during the Astro-E2/XRS program. A detector die from the same fabrication run will be used on the Astro-H/SXS mission. The LVSID technology and cryogenic JFET readout system is thus TRL 9. The technology is described in detail in section 2. The IXO/XMS "backup-up" anti-coincidence detector is a small array of LVSID detectors that are almost identical to those employed for Astro -E2/XRS as described in this document. The readout system is identical and, infact would use the same design as the Astro -E2/XRS JFET amplifier module (19 channels) essentially without changes except for its mechanical mount. The changes required for the IXO/XMS LVSID array are limited to the mounting of the LVSID detectors, and the mechanical mounting of the JFET amplifier sub-assembly. There is no technical development needed for the IXO/XMS implementation and the technology is ready for detailed design-work leading to PDR. The TRL level is thus at least 6, and possibly higher. Characteristics of an IXO/XMS LVSID anti-co detector are given in Table 1 and described in detail in section 3.
    Keywords: Instrumentation and Photography
    Type: SRON-XMS-PL-2009-004
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  • 10
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    Advances in Small Pixel TES-Based X-Ray Microcalorimeter Arrays for Solar Physics and Astrophysics (2012)
    In:  CASI
    Details
    Publication Date: 2019-07-19
    Description: We are developing small-pixel transition-edge-sensor (TES) for solar physics and astrophysics applications. These large format close-packed arrays are fabricated on solid silicon substrates and are designed to accommodate count-rates of up to a few hundred counts/pixel/second at a FWHM energy resolution approximately 2 eV at 6 keV. We have fabricated versions that utilize narrow-line planar and stripline wiring. We present measurements of the performance and uniformity of kilo-pixel arrays, incorporating TESs with single 65-micron absorbers on a 7s-micron pitch, as well as versions with more than one absorber attached to the TES, 4-absorber and 9-absorber "Hydras". We have also fabricated a version of this detector optimized for lower energies and lower count-rate applications. These devices have a lower superconducting transition temperature and are operated just above the 40mK heat sink temperature. This results in a lower heat capacity and low thermal conductance to the heat sink. With individual single pixels of this type we have achieved a FWHM energy resolution of 0.9 eV with 1.5 keV Al K x-rays, to our knowledge the first x-ray microcalorimeter with sub-eV energy resolution. The 4-absorber and 9-absorber versions of this type achieved FWHM energy resolutions of 1.4 eV and 2.1 eV at 1.5 keV respectively. We will discuss the application of these devices for new astrophysics mission concepts.
    Keywords: Instrumentation and Photography
    Type: GSFC.ABS.01038.2012 , Applied Superconductivity Conference; Oct 07, 2012 - Oct 11, 2012; Portland, OR; United States
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