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  • 1
    Publication Date: 2013-01-11
    Description: Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with 〉/=50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)--〉MEK--〉ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930354/" 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/PMC3930354/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das Thakur, Meghna -- Salangsang, Fernando -- Landman, Allison S -- Sellers, William R -- Pryer, Nancy K -- Levesque, Mitchell P -- Dummer, Reinhard -- McMahon, Martin -- Stuart, Darrin D -- R01 CA176839/CA/NCI NIH HHS/ -- R01-CA176839/CA/NCI NIH HHS/ -- T32 HL007185/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Feb 14;494(7436):251-5. doi: 10.1038/nature11814. Epub 2013 Jan 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23302800" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Administration Schedule ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Indoles/*administration & dosage/*adverse effects/pharmacology ; MAP Kinase Signaling System/drug effects ; Melanoma/*drug therapy/genetics/*pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mutation ; Neoplasm Transplantation ; Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism ; Subcutaneous Tissue ; Sulfonamides/*administration & dosage/*adverse effects/pharmacology ; Time Factors ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-09-06
    Description: Noble-metal nanoparticles have had a substantial impact across a diverse range of fields, including catalysis, sensing, photochemistry, optoelectronics, energy conversion and medicine. Although silver has very desirable physical properties, good relative abundance and low cost, gold nanoparticles have been widely favoured owing to their proved stability and ease of use. Unlike gold, silver is notorious for its susceptibility to oxidation (tarnishing), which has limited the development of important silver-based nanomaterials. Despite two decades of synthetic efforts, silver nanoparticles that are inert or have long-term stability remain unrealized. Here we report a simple synthetic protocol for producing ultrastable silver nanoparticles, yielding a single-sized molecular product in very large quantities with quantitative yield and without the need for size sorting. The stability, purity and yield are substantially better than those for other metal nanoparticles, including gold, owing to an effective stabilization mechanism. The particular size and stoichiometry of the product were found to be insensitive to variations in synthesis parameters. The chemical stability and structural, electronic and optical properties can be understood using first-principles electronic structure theory based on an experimental single-crystal X-ray structure. Although several structures have been determined for protected gold nanoclusters, none has been reported so far for silver nanoparticles. The total structure of a thiolate-protected silver nanocluster reported here uncovers the unique structure of the silver thiolate protecting layer, consisting of Ag2S5 capping structures. The outstanding stability of the nanoparticle is attributed to a closed-shell 18-electron configuration with a large energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, an ultrastable 32-silver-atom excavated-dodecahedral core consisting of a hollow 12-silver-atom icosahedron encapsulated by a 20-silver-atom dodecahedron, and the choice of protective coordinating ligands. The straightforward synthesis of large quantities of pure molecular product promises to make this class of materials widely available for further research and technology development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Desireddy, Anil -- Conn, Brian E -- Guo, Jingshu -- Yoon, Bokwon -- Barnett, Robert N -- Monahan, Bradley M -- Kirschbaum, Kristin -- Griffith, Wendell P -- Whetten, Robert L -- Landman, Uzi -- Bigioni, Terry P -- England -- Nature. 2013 Sep 19;501(7467):399-402. doi: 10.1038/nature12523. Epub 2013 Sep 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Toledo, Toledo, Ohio 43606, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24005327" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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