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  • 1
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    Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-09-04
    Description: The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor. Nf1 encodes neurofibromin, a GTPase-activating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38alpha. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119783/" 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/PMC4119783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lauchle, Jennifer O -- Kim, Doris -- Le, Doan T -- Akagi, Keiko -- Crone, Michael -- Krisman, Kimberly -- Warner, Kegan -- Bonifas, Jeannette M -- Li, Qing -- Coakley, Kristen M -- Diaz-Flores, Ernesto -- Gorman, Matthew -- Przybranowski, Sally -- Tran, Mary -- Kogan, Scott C -- Roose, Jeroen P -- Copeland, Neal G -- Jenkins, Nancy A -- Parada, Luis -- Wolff, Linda -- Sebolt-Leopold, Judith -- Shannon, Kevin -- K08 CA119105/CA/NCI NIH HHS/ -- K08 CA119105-01A1/CA/NCI NIH HHS/ -- K08 CA119105-02/CA/NCI NIH HHS/ -- K08 CA119105-03/CA/NCI NIH HHS/ -- K08 CA119105-04/CA/NCI NIH HHS/ -- R37 CA072614/CA/NCI NIH HHS/ -- R37 CA072614-11/CA/NCI NIH HHS/ -- R37 CA072614-12/CA/NCI NIH HHS/ -- R37 CA072614-13/CA/NCI NIH HHS/ -- R37 CA72614/CA/NCI NIH HHS/ -- T32 CA09043/CA/NCI NIH HHS/ -- T32HD044331/HD/NICHD NIH HHS/ -- U01 CA084221/CA/NCI NIH HHS/ -- U01 CA084221-06/CA/NCI NIH HHS/ -- U01 CA084221-07/CA/NCI NIH HHS/ -- U01 CA084221-08/CA/NCI NIH HHS/ -- U01 CA084221-09/CA/NCI NIH HHS/ -- U01 CA084221-10/CA/NCI NIH HHS/ -- U01 CA84221/CA/NCI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2009 Sep 17;461(7262):411-4. doi: 10.1038/nature08279. Epub 2009 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, University of California, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727076" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzamides/pharmacology ; *Drug Resistance, Neoplasm/drug effects/genetics ; Genes, ras ; Guanine Nucleotide Exchange Factors/genetics/metabolism ; Leukemia, Myeloid, Acute/*drug therapy/enzymology/genetics/*metabolism ; Mice ; Mitogen-Activated Protein Kinase 14/genetics/metabolism ; Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors/metabolism ; ras Proteins/genetics/*metabolism
    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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    PAPER CURRENT
  • 2
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    LDEF contaminants analysis data (1991)
    In:  Other Sources
    Details
    Publication Date: 2019-01-25
    Description: Modification of surface texture for Ram Facing FEP Teflon on the Long Duration Exposure Facility (LDEF) satellite is documented. Photos of changes in surface texture if thermal blanket material with position on tray C-08 are presented. Infrared spectra and photographic documentation of molecular film deposits on LDEF surfaces by location is reported. Results of a survey of the functional groups and elemental composition of the brown film found widely distributed on the surface of LDEF is shown. A partial photographic catalog of LDEF particulate contaminants is included. A set of photos of particles collected or photographed in place on the surface of LDEF is shown. Particle counts and surface obscuration data for the LDEF satellite are reported. The surface data in tables and charts is presented for the LDEF satellite by location.
    Keywords: SPACECRAFT DESIGN, TESTING AND PERFORMANCE
    Type: NASA, Langley Research Center, First LDEF Post-Retrieval Symposium Abstracts; p 8
    Format: text
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    NASA TECHNICAL REPORTS
  • 3
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    Migration and generation of contaminants from launch through recovery: LDEF case history (1991)
    In:  Other Sources
    Details
    Publication Date: 2019-01-25
    Description: The migration of contaminants to and between Long Duration Exposure Facility (LDEF) surfaces reveals new information relevant to all future space missions. The surface of the LDEF satellite closely paralleled over seven meters of the shuttle during one launch and one reentry. Transfer of contaminants from the shuttle bay to the payload were documented and partially quantified for both the launch and recovery separately. LDEF carried a load of volatile silicones and hydrocarbons into orbit which were then polymerized by UV radiation into tough, dark brown stains on exposed surfaces. The distribution of these stains is providing new information on deposition mechanisms that should be studied on future missions. Electrostatic effects, diffusional flow, and effects due to small surface temperature differences at the time of UV exposure are suggested. The types of functional groups present in the LDEF deposit it nearly identical to stains recovered from other spacecraft. These stains were remarkably stable in low Earth orbit even with atomic oxygen exposure if the amount of silicones present was sufficient to create a sealing layer of silicon dioxide over the dark brown stain beneath.
    Keywords: SPACECRAFT DESIGN, TESTING AND PERFORMANCE
    Type: NASA, Langley Research Center, First LDEF Post-Retrieval Symposium Abstracts; p 7
    Format: text
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    NASA TECHNICAL REPORTS
  • 4
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    Migration and generation of contaminants from launch through recovery: LDEF case history (1992)
    In:  CASI
    Details
    Publication Date: 2019-06-28
    Description: It is possible to recreate the contamination history of the Long Duration Exposure Facility (LDEF) through an analysis of its contaminants and selective samples that were collected from surfaces with better documented exposure histories. This data was then used to compare estimates based on monitoring methods that were selected for the purpose of tracking LDEF's exposure to contaminants. The LDEF experienced much more contamination than would have been assumed based on the monitors. Work is still in progress but much of what was learned so far is already being used in the selection of materials and in the design of systems for space. Now experiments are being prepared for flight to resolve questions created by the discoveries on the LDEF. A summary of what was learned about LDEF contaminants over the first year since recovery and deintegration is presented. Over 35 specific conclusions in 5 contamination related categories are listed.
    Keywords: SPACECRAFT DESIGN, TESTING AND PERFORMANCE
    Type: NASA. Langley Research Center, LDEF: 69 Months in Space. First Post-Retrieval Symposium, Part 1; p 121-140
    Format: application/pdf
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    NASA TECHNICAL REPORTS
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