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  • 1
    Keywords: GENE ; neuroblastoma ; ENHANCERS ; LANDSCAPE ; TERT REARRANGEMENTS
    Abstract: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
    Type of Publication: Journal article published
    PubMed ID: 26466568
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  • 2
    Publication Date: 2015-11-17
    Description: Haematopoietic stresses mobilize haematopoietic stem cells (HSCs) from the bone marrow to the spleen and induce extramedullary haematopoiesis (EMH). However, the cellular nature of the EMH niche is unknown. Here we assessed the sources of the key niche factors, SCF (also known as KITL) and CXCL12, in the mouse spleen after EMH induction by myeloablation, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21(+) stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21(+) stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21(+) stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells, or of Scf or Cxcl12 from Tcf21+ stromal cells, severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow haematopoiesis. Endothelial cells and Tcf21(+) stromal cells thus create a perisinusoidal EMH niche in the spleen, which is necessary for the physiological response to diverse haematopoietic stresses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Inra, Christopher N -- Zhou, Bo O -- Acar, Melih -- Murphy, Malea M -- Richardson, James -- Zhao, Zhiyu -- Morrison, Sean J -- HL097760/HL/NHLBI NIH HHS/ -- R01 HL097760/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 26;527(7579):466-71. doi: 10.1038/nature15530. Epub 2015 Nov 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26570997" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Blood Cell Count ; Chemokine CXCL12/deficiency/metabolism ; Endothelial Cells/metabolism ; Erythropoiesis ; Female ; *Hematopoiesis, Extramedullary ; Hematopoietic Stem Cells/*cytology ; Hemorrhage/physiopathology ; Male ; Mice ; Pregnancy ; Spleen/blood supply/*cytology/metabolism ; Stem Cell Factor/deficiency/metabolism ; *Stem Cell Niche ; Stromal Cells/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-10-16
    Description: Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644103/" 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/PMC4644103/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Piskounova, Elena -- Agathocleous, Michalis -- Murphy, Malea M -- Hu, Zeping -- Huddlestun, Sara E -- Zhao, Zhiyu -- Leitch, A Marilyn -- Johnson, Timothy M -- DeBerardinis, Ralph J -- Morrison, Sean J -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):186-91. doi: 10.1038/nature15726. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA. ; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466563" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antioxidants/metabolism ; Female ; Folic Acid/metabolism ; Gene Knockdown Techniques ; Humans ; Male ; Melanoma/blood/*metabolism/*pathology ; Methotrexate/pharmacology ; Methylenetetrahydrofolate Dehydrogenase (NADP)/deficiency/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; NADP/metabolism ; Neoplasm Metastasis/*prevention & control ; Neoplasm Transplantation ; *Oxidative Stress ; Oxidoreductases Acting on CH-NH Group Donors/deficiency/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-09-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Nai-Zhuo -- England -- Nature. 2011 Sep 21;477(7365):407. doi: 10.1038/477407b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21938056" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry/*standards ; Research Personnel/*standards/*statistics & numerical data
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-06-23
    Description: Surface plasmons are collective oscillations of electrons in metals or semiconductors that enable confinement and control of electromagnetic energy at subwavelength scales. Rapid progress in plasmonics has largely relied on advances in device nano-fabrication, whereas less attention has been paid to the tunable properties of plasmonic media. One such medium--graphene--is amenable to convenient tuning of its electronic and optical properties by varying the applied voltage. Here, using infrared nano-imaging, we show that common graphene/SiO(2)/Si back-gated structures support propagating surface plasmons. The wavelength of graphene plasmons is of the order of 200 nanometres at technologically relevant infrared frequencies, and they can propagate several times this distance. We have succeeded in altering both the amplitude and the wavelength of these plasmons by varying the gate voltage. Using plasmon interferometry, we investigated losses in graphene by exploring real-space profiles of plasmon standing waves formed between the tip of our nano-probe and the edges of the samples. Plasmon dissipation quantified through this analysis is linked to the exotic electrodynamics of graphene. Standard plasmonic figures of merit of our tunable graphene devices surpass those of common metal-based structures.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fei, Z -- Rodin, A S -- Andreev, G O -- Bao, W -- McLeod, A S -- Wagner, M -- Zhang, L M -- Zhao, Z -- Thiemens, M -- Dominguez, G -- Fogler, M M -- Castro Neto, A H -- Lau, C N -- Keilmann, F -- Basov, D N -- England -- Nature. 2012 Jul 5;487(7405):82-5. doi: 10.1038/nature11253.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722866" target="_blank"〉PubMed〈/a〉
    Keywords: *Electromagnetic Fields ; Graphite/*chemistry ; *Infrared Rays ; Microscopy, Atomic Force ; Nanotechnology/*methods ; Static Electricity ; Surface Properties
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2012-03-01
    Description: Pressure has an essential role in the production and control of superconductivity in iron-based superconductors. Substitution of a large cation by a smaller rare-earth ion to simulate the pressure effect has raised the superconducting transition temperature T(c) to a record high of 55 K in these materials. In the same way as T(c) exhibits a bell-shaped curve of dependence on chemical doping, pressure-tuned T(c) typically drops monotonically after passing the optimal pressure. Here we report that in the superconducting iron chalcogenides, a second superconducting phase suddenly re-emerges above 11.5 GPa, after the T(c) drops from the first maximum of 32 K at 1 GPa. The T(c) of the re-emerging superconducting phase is considerably higher than the first maximum, reaching 48.0-48.7 K for Tl(0.6)Rb(0.4)Fe(1.67)Se(2), K(0.8)Fe(1.7)Se(2) and K(0.8)Fe(1.78)Se(2).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Liling -- Chen, Xiao-Jia -- Guo, Jing -- Gao, Peiwen -- Huang, Qing-Zhen -- Wang, Hangdong -- Fang, Minghu -- Chen, Xiaolong -- Chen, Genfu -- Wu, Qi -- Zhang, Chao -- Gu, Dachun -- Dong, Xiaoli -- Wang, Lin -- Yang, Ke -- Li, Aiguo -- Dai, Xi -- Mao, Ho-kwang -- Zhao, Zhongxian -- England -- Nature. 2012 Feb 22;483(7387):67-9. doi: 10.1038/nature10813.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Physics and Beijing National Laboratory for Condensed Matter Physics, Chinese Academy of Sciences, Beijing 100190, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367543" 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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  • 7
    Publication Date: 2013-10-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tian, Yongjun -- Xu, Bo -- Yu, Dongli -- Ma, Yanming -- Wang, Yanbin -- Jiang, Yingbing -- Hu, Wentao -- Tang, Chengchun -- Gao, Yufei -- Luo, Kun -- Zhao, Zhisheng -- Wang, Li-Min -- Wen, Bin -- He, Julong -- Liu, Zhongyuan -- England -- Nature. 2013 Oct 24;502(7472):E2-3. doi: 10.1038/nature12621.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153312" 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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  • 8
    Publication Date: 2014-06-13
    Description: Although diamond is the hardest material for cutting tools, poor thermal stability has limited its applications, especially at high temperatures. Simultaneous improvement of the hardness and thermal stability of diamond has long been desirable. According to the Hall-Petch effect, the hardness of diamond can be enhanced by nanostructuring (by means of nanograined and nanotwinned microstructures), as shown in previous studies. However, for well-sintered nanograined diamonds, the grain sizes are technically limited to 10-30 nm (ref. 3), with degraded thermal stability compared with that of natural diamond. Recent success in synthesizing nanotwinned cubic boron nitride (nt-cBN) with a twin thickness down to approximately 3.8 nm makes it feasible to simultaneously achieve smaller nanosize, ultrahardness and superior thermal stability. At present, nanotwinned diamond (nt-diamond) has not been fabricated successfully through direct conversions of various carbon precursors (such as graphite, amorphous carbon, glassy carbon and C60). Here we report the direct synthesis of nt-diamond with an average twin thickness of approximately 5 nm, using a precursor of onion carbon nanoparticles at high pressure and high temperature, and the observation of a new monoclinic crystalline form of diamond coexisting with nt-diamond. The pure synthetic bulk nt-diamond material shows unprecedented hardness and thermal stability, with Vickers hardness up to approximately 200 GPa and an in-air oxidization temperature more than 200 degrees C higher than that of natural diamond. The creation of nanotwinned microstructures offers a general pathway for manufacturing new advanced carbon-based materials with exceptional thermal stability and mechanical properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Quan -- Yu, Dongli -- Xu, Bo -- Hu, Wentao -- Ma, Yanming -- Wang, Yanbin -- Zhao, Zhisheng -- Wen, Bin -- He, Julong -- Liu, Zhongyuan -- Tian, Yongjun -- England -- Nature. 2014 Jun 12;510(7504):250-3. doi: 10.1038/nature13381.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004, China [2]. ; State Key Laboratory for Superhard Materials, Jilin University, Changchun 130012, China. ; Center for Advanced Radiation Sources, University of Chicago, Chicago, Illinois 60439, USA. ; State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919919" 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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  • 9
    Publication Date: 2018-11-29
    Description: The morbidity and mortality of hepatocellular carcinoma, the most common cancer, are increasing continuously worldwide. Galangin (Ga) has been demonstrated to possess anti-cancer effect, but the efficacy of Ga was limited by its low permeability and poor solubility. To develop aqueous formulation and improve the anti-cancer activity of Ga, surface decoration of functionalized selenium nanoparticles with Ga (Se@Ga) was synthesized in the present study. The aim of this study was to evaluate the anti-cancer effect of Se@Ga and the mechanism on HepG2 cells. Se@Ga-induced HepG2 cell apoptosis was confirmed by depletion of mitochondrial membrane potential, translocation of phosphatidylserine and caspase-3 activation. Furthermore, Se@Ga enhanced the anti-cancer activity of HepG2 cells through ROS-mediated AKT and p38 signalling pathways. In summary, these results suggest that Se@Ga might be potential candidate chemotherapy for cancer.
    Keywords: inorganic chemistry, materials science, nanotechnology
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 10
    Publication Date: 2018-12-14
    Description: Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
    Keywords: Development, Genetics, Neuroscience, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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