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  • Articles  (74)
  • Disease Models, Animal  (74)
  • 2010-2014  (74)
  • 1980-1984
  • 1950-1954
  • 2014  (74)
  • 1953
  • Medicine  (74)
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  • Articles  (74)
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  • 2010-2014  (74)
  • 1980-1984
  • 1950-1954
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  • 1
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    Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington's disease (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-03-29
    Description: Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine gamma-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349202/" 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/PMC4349202/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paul, Bindu D -- Sbodio, Juan I -- Xu, Risheng -- Vandiver, M Scott -- Cha, Jiyoung Y -- Snowman, Adele M -- Snyder, Solomon H -- MH18501/MH/NIMH NIH HHS/ -- R01 MH018501/MH/NIMH NIH HHS/ -- T32 GM007309/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):96-100. doi: 10.1038/nature13136. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670645" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/enzymology ; Corpus Striatum/drug effects/enzymology/metabolism/pathology ; Cystathionine gamma-Lyase/*deficiency/genetics ; Cysteine/administration & dosage/biosynthesis/pharmacology/therapeutic use ; Dietary Supplements ; Disease Models, Animal ; Drinking Water/chemistry ; Gene Deletion ; Gene Expression Regulation, Enzymologic/genetics ; Huntington Disease/drug therapy/*enzymology/genetics/*pathology ; Male ; Mice ; Mutant Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; Neuroprotective Agents/administration & ; dosage/metabolism/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Sp1 Transcription Factor/antagonists & inhibitors/metabolism ; Transcription, Genetic/genetics
    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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    Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-09-23
    Description: The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arimura, Sumimasa -- Okada, Takashi -- Tezuka, Tohru -- Chiyo, Tomoko -- Kasahara, Yuko -- Yoshimura, Toshiro -- Motomura, Masakatsu -- Yoshida, Nobuaki -- Beeson, David -- Takeda, Shin'ichi -- Yamanashi, Yuji -- G0701521/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1505-8. doi: 10.1126/science.1250744.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. ; Department of Occupational Therapy, Nagasaki University School of Health Sciences, Nagasaki, Japan. ; Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan. ; Laboratory of Developmental Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. ; Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. yyamanas@ims.u-tokyo.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237101" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dependovirus ; Disease Models, Animal ; Female ; Genetic Therapy/*methods ; Genetic Vectors/administration & dosage ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Proteins/*genetics ; Muscle, Skeletal/*innervation/physiopathology ; Muscular Dystrophies, Limb-Girdle/genetics/*pathology/*therapy ; Neuromuscular Junction/*pathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Cancer. Cholesterol and cancer, in the balance (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-03-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silvente-Poirot, Sandrine -- Poirot, Marc -- New York, N.Y. -- Science. 2014 Mar 28;343(6178):1445-6. doi: 10.1126/science.1252787.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UMR 1037 INSERM-University Toulouse III, Cancer Research Center of Toulouse, and Institut Claudius Regaud, 31052 Toulouse, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24675946" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*metabolism/*pathology ; Cholesterol/*metabolism ; Cholesterol, Dietary/administration & dosage/metabolism ; Disease Models, Animal ; Female ; Humans ; Hypercholesterolemia/metabolism ; Metabolic Networks and Pathways ; Mice
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18 (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-15
    Description: Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Benyue -- Chassaing, Benoit -- Shi, Zhenda -- Uchiyama, Robin -- Zhang, Zhan -- Denning, Timothy L -- Crawford, Sue E -- Pruijssers, Andrea J -- Iskarpatyoti, Jason A -- Estes, Mary K -- Dermody, Terence S -- Ouyang, Wenjun -- Williams, Ifor R -- Vijay-Kumar, Matam -- Gewirtz, Andrew T -- AI038296/AI/NIAID NIH HHS/ -- AI080656/AI/NIAID NIH HHS/ -- AI107943/AI/NIAID NIH HHS/ -- DK061417/DK/NIDDK NIH HHS/ -- DK064730/DK/NIDDK NIH HHS/ -- DK56338/DK/NIDDK NIH HHS/ -- R01 AI038296/AI/NIAID NIH HHS/ -- R37 AI038296/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 14;346(6211):861-5. doi: 10.1126/science.1256999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. ; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. ; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. Departments of Pediatrics, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Department of Immunology, Genentech, South San Francisco, CA, USA. ; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ; Department of Nutritional Sciences and Medicine, Pennsylvania State University, University Park, PA 16802, USA. ; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. agewirtz@gsu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25395539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diarrhea/immunology/therapy/virology ; Disease Models, Animal ; Feces/virology ; Flagellin/*administration & dosage/immunology ; Homeodomain Proteins/genetics ; *Immunity, Innate ; Interleukin-18/administration & dosage/genetics/*immunology ; Interleukins/administration & dosage/genetics/*immunology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mutation ; Rotavirus Infections/immunology/*prevention & control/therapy ; Toll-Like Receptor 5/genetics/*physiology ; Virus Shedding
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Innate lymphoid cells regulate intestinal epithelial cell glycosylation (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-09-13
    Description: Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774895/" 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/PMC4774895/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goto, Yoshiyuki -- Obata, Takashi -- Kunisawa, Jun -- Sato, Shintaro -- Ivanov, Ivaylo I -- Lamichhane, Aayam -- Takeyama, Natsumi -- Kamioka, Mariko -- Sakamoto, Mitsuo -- Matsuki, Takahiro -- Setoyama, Hiromi -- Imaoka, Akemi -- Uematsu, Satoshi -- Akira, Shizuo -- Domino, Steven E -- Kulig, Paulina -- Becher, Burkhard -- Renauld, Jean-Christophe -- Sasakawa, Chihiro -- Umesaki, Yoshinori -- Benno, Yoshimi -- Kiyono, Hiroshi -- 1R01DK098378/DK/NIDDK NIH HHS/ -- R01 DK098378/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 12;345(6202):1254009. doi: 10.1126/science.1254009. Epub 2014 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. Microbe Division/Japan Collection of Microorganisms, RIKEN BioResource Center, Tsukuba 305-0074, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Microbe Division/Japan Collection of Microorganisms, RIKEN BioResource Center, Tsukuba 305-0074, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan. Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. ; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Nippon Institute for Biological Science, Tokyo 198-0024, Japan. ; Microbe Division/Japan Collection of Microorganisms, RIKEN BioResource Center, Tsukuba 305-0074, Japan. ; Yakult Central Institute, Tokyo 186-8650, Japan. ; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Department of Mucosal Immunology, School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan. ; Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. ; Department of Obstetrics and Gynecology, Cellular and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, MI 48109-5617, USA. ; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland. ; Ludwig Institute for Cancer Research and Universite Catholique de Louvain, Brussels B-1200, Belgium. ; Nippon Institute for Biological Science, Tokyo 198-0024, Japan. Division of Bacterial Infection, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan. ; Benno Laboratory, Innovation Center, RIKEN, Wako, Saitama 351-0198, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25214634" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Disease Models, Animal ; Fucose/*metabolism ; Fucosyltransferases/genetics/metabolism ; Germ-Free Life ; Glycosylation ; Goblet Cells/enzymology/immunology/microbiology ; Ileum/enzymology/immunology/microbiology ; *Immunity, Innate ; Interleukins/immunology ; Intestinal Mucosa/enzymology/*immunology/microbiology ; Lymphocytes/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microbiota/*immunology ; Molecular Sequence Data ; Paneth Cells/enzymology/immunology/microbiology ; Salmonella Infections/*immunology/microbiology ; *Salmonella typhimurium
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-30
    Description: Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues. The histone H3K9 demethylase KDM3B/JHDM2 associates with H3K9M-containing nucleosomes, and its misregulation in Drosophila results in changes of H3K9 methylation levels and heterochromatic silencing defects. We have established histone lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation pathways that also function as biochemical reagents for capturing site-specific histone-modifying enzymes, thus providing molecular insight into chromatin signaling pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508193/" 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/PMC4508193/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herz, Hans-Martin -- Morgan, Marc -- Gao, Xin -- Jackson, Jessica -- Rickels, Ryan -- Swanson, Selene K -- Florens, Laurence -- Washburn, Michael P -- Eissenberg, Joel C -- Shilatifard, Ali -- CA R01CA089455/CA/NCI NIH HHS/ -- R01 CA089455/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 29;345(6200):1065-70. doi: 10.1126/science.1255104.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. ; Saint Louis University School of Medicine, Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis, MO, USA. ; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. ; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. ash@northwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170156" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Animals ; Chromatin/*metabolism ; Disease Models, Animal ; Drosophila Proteins/genetics ; Drosophila melanogaster ; Gene Silencing ; Glioma/genetics/metabolism ; Heterochromatin/metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Histones/*genetics/metabolism ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Lysine/*genetics ; Methionine/*genetics ; Methylation ; Mutation ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-02-08
    Description: We report that the oxytocin-mediated neuroprotective gamma-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naive mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tyzio, Roman -- Nardou, Romain -- Ferrari, Diana C -- Tsintsadze, Timur -- Shahrokhi, Amene -- Eftekhari, Sanaz -- Khalilov, Ilgam -- Tsintsadze, Vera -- Brouchoud, Corinne -- Chazal, Genevieve -- Lemonnier, Eric -- Lozovaya, Natalia -- Burnashev, Nail -- Ben-Ari, Yehezkel -- New York, N.Y. -- Science. 2014 Feb 7;343(6171):675-9. doi: 10.1126/science.1247190.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24503856" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/*chemically induced/*genetics/metabolism ; Behavior, Animal ; Bumetanide/administration & dosage ; Chlorides/metabolism ; *Cytoprotection ; Disease Models, Animal ; Female ; Fragile X Mental Retardation Protein/genetics ; Maternal-Fetal Exchange ; Mice ; Oxytocin/*metabolism ; Parturition ; Pregnancy ; Rats ; Valproic Acid/pharmacology ; gamma-Aminobutyric Acid/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53 (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-06-12
    Description: Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112218/" 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/PMC4112218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viros, Amaya -- Sanchez-Laorden, Berta -- Pedersen, Malin -- Furney, Simon J -- Rae, Joel -- Hogan, Kate -- Ejiama, Sarah -- Girotti, Maria Romina -- Cook, Martin -- Dhomen, Nathalie -- Marais, Richard -- A12738/Cancer Research UK/United Kingdom -- A13540/Cancer Research UK/United Kingdom -- A17240/Cancer Research UK/United Kingdom -- A7091/Cancer Research UK/United Kingdom -- A7192/Cancer Research UK/United Kingdom -- C107/A10433/Cancer Research UK/United Kingdom -- C5759/A12328/Cancer Research UK/United Kingdom -- England -- Nature. 2014 Jul 24;511(7510):478-82. doi: 10.1038/nature13298. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2]. ; 1] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Histopathology, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919155" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Transformation, Neoplastic/*genetics/*radiation effects ; DNA Damage/genetics ; Disease Models, Animal ; Female ; Humans ; Melanocytes/metabolism/pathology/radiation effects ; Melanoma/etiology/*genetics/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mutagenesis/genetics/*radiation effects ; Mutation/genetics/radiation effects ; Nevus/etiology/genetics/metabolism/pathology ; Proto-Oncogene Proteins B-raf/*genetics/metabolism ; Skin Neoplasms/etiology/genetics/metabolism/pathology ; Sunburn/complications/etiology/genetics ; Sunscreening Agents/pharmacology ; Tumor Suppressor Protein p53/*genetics/metabolism ; Ultraviolet Rays/*adverse effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Copper is required for oncogenic BRAF signalling and tumorigenesis (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-04-11
    Description: The BRAF kinase is mutated, typically Val 600--〉Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAF(V600E) inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAF(V600E)-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138975/" 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/PMC4138975/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brady, Donita C -- Crowe, Matthew S -- Turski, Michelle L -- Hobbs, G Aaron -- Yao, Xiaojie -- Chaikuad, Apirat -- Knapp, Stefan -- Xiao, Kunhong -- Campbell, Sharon L -- Thiele, Dennis J -- Counter, Christopher M -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- CA094184/CA/NCI NIH HHS/ -- CA172104/CA/NCI NIH HHS/ -- CA178145/CA/NCI NIH HHS/ -- DK074192/DK/NIDDK NIH HHS/ -- HL075443/HL/NHLBI NIH HHS/ -- K01 CA178145/CA/NCI NIH HHS/ -- P01 HL075443/HL/NHLBI NIH HHS/ -- P30 CA014236/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R01 CA089614/CA/NCI NIH HHS/ -- R01 CA094184/CA/NCI NIH HHS/ -- R01 DK074192/DK/NIDDK NIH HHS/ -- R21 CA172104/CA/NCI NIH HHS/ -- T32 GM007184/GM/NIGMS NIH HHS/ -- T32 GM008570/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 22;509(7501):492-6. doi: 10.1038/nature13180. Epub 2014 Apr 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; 1] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717435" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cation Transport Proteins/deficiency/genetics ; Cell Line, Tumor ; *Cell Transformation, Neoplastic/drug effects ; Chelating Agents/pharmacology/therapeutic use ; Copper/*metabolism/pharmacology ; Disease Models, Animal ; Drug Repositioning ; Drug Resistance, Neoplasm/drug effects ; Female ; Hepatolenticular Degeneration/drug therapy ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/genetics/metabolism/pathology ; *MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase Kinases/antagonists & ; inhibitors/genetics/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/*metabolism ; Sulfonamides/pharmacology ; Survival Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-22
    Description: The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126858/" 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/PMC4126858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whitney, James B -- Hill, Alison L -- Sanisetty, Srisowmya -- Penaloza-MacMaster, Pablo -- Liu, Jinyan -- Shetty, Mayuri -- Parenteau, Lily -- Cabral, Crystal -- Shields, Jennifer -- Blackmore, Stephen -- Smith, Jeffrey Y -- Brinkman, Amanda L -- Peter, Lauren E -- Mathew, Sheeba I -- Smith, Kaitlin M -- Borducchi, Erica N -- Rosenbloom, Daniel I S -- Lewis, Mark G -- Hattersley, Jillian -- Li, Bei -- Hesselgesser, Joseph -- Geleziunas, Romas -- Robb, Merlin L -- Kim, Jerome H -- Michael, Nelson L -- Barouch, Dan H -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R56 AI091514/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):74-7. doi: 10.1038/nature13594. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA. ; Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Bioqual, Rockville, Maryland 20852, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25042999" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Retroviral Agents/administration & dosage/pharmacology/therapeutic use ; Carrier State/drug therapy/virology ; DNA, Viral/analysis/biosynthesis/blood ; Disease Models, Animal ; Female ; Kinetics ; Macaca mulatta/immunology/*virology ; Male ; Proviruses/genetics ; RNA, Viral/blood ; Rectum/virology ; Simian Acquired Immunodeficiency Syndrome/drug therapy/immunology/*virology ; Simian Immunodeficiency Virus/drug effects/*growth & ; development/immunology/physiology ; Time Factors ; Treatment Failure ; *Viral Load/drug effects ; Viremia/drug therapy/*virology ; Virus Replication/drug effects
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk (2014)
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    Publication Date: 2014-07-06
    Description: Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mayer-Barber, Katrin D -- Andrade, Bruno B -- Oland, Sandra D -- Amaral, Eduardo P -- Barber, Daniel L -- Gonzales, Jacqueline -- Derrick, Steven C -- Shi, Ruiru -- Kumar, Nathella Pavan -- Wei, Wang -- Yuan, Xing -- Zhang, Guolong -- Cai, Ying -- Babu, Subash -- Catalfamo, Marta -- Salazar, Andres M -- Via, Laura E -- Barry, Clifton E 3rd -- Sher, Alan -- Intramural NIH HHS/ -- England -- Nature. 2014 Jul 3;511(7507):99-103. doi: 10.1038/nature13489. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; 1] Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA [2] Department of Immunology, Biomedical Sciences Institutes, University of Sao Paulo, 05508-900 Sao Paulo, Brazil. ; T Lymphocyte Biology Unit, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. ; Henan Chest Hospital, 450003 Zhengzhou, China. ; 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] National Institute for Research in Tuberculosis (NIRT), 600 031 Chennai, India. ; Sino-US International Research Center for Tuberculosis, and Henan Public Health Center, 450003 Zhengzhou, China. ; 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] Helminth Immunology Section, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Oncovir Inc., Washington, Washington DC 20008, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990750" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dinoprostone/antagonists & inhibitors/biosynthesis/metabolism ; Disease Models, Animal ; Female ; Humans ; Immunity, Innate/immunology ; *Immunotherapy ; Interferon Type I/antagonists & inhibitors/biosynthesis/*immunology ; Interleukin-1/*immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/*immunology ; Tuberculosis, Pulmonary/*immunology/microbiology/*therapy
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-23
    Description: Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122675/" 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/PMC4122675/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mazur, Pawel K -- Reynoird, Nicolas -- Khatri, Purvesh -- Jansen, Pascal W T C -- Wilkinson, Alex W -- Liu, Shichong -- Barbash, Olena -- Van Aller, Glenn S -- Huddleston, Michael -- Dhanak, Dashyant -- Tummino, Peter J -- Kruger, Ryan G -- Garcia, Benjamin A -- Butte, Atul J -- Vermeulen, Michiel -- Sage, Julien -- Gozani, Or -- DP2 OD007447/OD/NIH HHS/ -- R01 CA172560/CA/NCI NIH HHS/ -- T32 GM007276/GM/NIGMS NIH HHS/ -- U19 AI109662/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Jun 12;510(7504):283-7. doi: 10.1038/nature13320. Epub 2014 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA [3]. ; 1] Department of Biology, Stanford University, California 94305, USA [2]. ; Institute for Immunity, Transplantation and Infection, and Department of Medicine, Stanford University School of Medicine, California 94305, USA. ; Department of Molecular Cancer Research and Department of Medical Oncology, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands. ; Department of Biology, Stanford University, California 94305, USA. ; Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426 USA. ; 1] Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426 USA [2] Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA (D.D.); Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525GA Nijmegen, The Netherlands (M.V.). ; 1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA. ; 1] Department of Molecular Cancer Research and Department of Medical Oncology, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands [2] Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA (D.D.); Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525GA Nijmegen, The Netherlands (M.V.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847881" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/enzymology/genetics/metabolism/pathology ; Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; Disease Models, Animal ; Histone-Lysine N-Methyltransferase/*metabolism ; Humans ; Lung Neoplasms/enzymology/genetics/metabolism/pathology ; Lysine/*metabolism ; MAP Kinase Kinase Kinase 2/chemistry/*metabolism ; MAP Kinase Kinase Kinases/chemistry/*metabolism ; Methylation ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Oncogene Protein p21(ras)/genetics/*metabolism ; Pancreatic Neoplasms/enzymology/genetics/metabolism/pathology ; Protein Phosphatase 2/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins A-raf/metabolism ; Signal Transduction
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    Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer (2014)
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    Publication Date: 2014-04-25
    Description: Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075966/" 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/PMC4075966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asangani, Irfan A -- Dommeti, Vijaya L -- Wang, Xiaoju -- Malik, Rohit -- Cieslik, Marcin -- Yang, Rendong -- Escara-Wilke, June -- Wilder-Romans, Kari -- Dhanireddy, Sudheer -- Engelke, Carl -- Iyer, Mathew K -- Jing, Xiaojun -- Wu, Yi-Mi -- Cao, Xuhong -- Qin, Zhaohui S -- Wang, Shaomeng -- Feng, Felix Y -- Chinnaiyan, Arul M -- P50 CA069568/CA/NCI NIH HHS/ -- P50CA69568/CA/NCI NIH HHS/ -- T32 GM007863/GM/NIGMS NIH HHS/ -- U01 CA111275/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 12;510(7504):278-82. doi: 10.1038/nature13229. Epub 2014 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA. ; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [4] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [5] Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759320" target="_blank"〉PubMed〈/a〉
    Keywords: Androgen Antagonists/pharmacology ; Androgens/metabolism ; Animals ; Azepines/*pharmacology/therapeutic use ; Cell Line, Tumor ; Disease Models, Animal ; Epigenesis, Genetic ; Humans ; Male ; Mice ; Nuclear Proteins/*chemistry ; Oncogene Proteins, Fusion/genetics/metabolism ; Prostatic Neoplasms, Castration-Resistant/*drug therapy/genetics ; Protein Structure, Tertiary/drug effects ; Receptors, Androgen/chemistry/metabolism ; Signal Transduction/drug effects ; Transcription Factors/*chemistry ; Triazoles/*pharmacology/therapeutic use
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  • 14
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    Animal models: Dogged pursuit (2014)
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    Publication Date: 2014-11-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sohn, Emily -- England -- Nature. 2014 Nov 27;515(7528):S172-3. doi: 10.1038/515S172a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25427211" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Disease Models, Animal ; *Dogs ; Drug Evaluation, Preclinical/history ; Genetic Therapy ; Hemophilia A/*therapy ; Hemophilia B/*therapy ; History, 20th Century ; Research/trends
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  • 15
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    Selection and evaluation of clinically relevant AAV variants in a xenograft liver model (2014)
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    Publication Date: 2014-01-07
    Description: Recombinant adeno-associated viral (rAAV) vectors have shown early promise in clinical trials. The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of human outcome. Here, in an attempt to further our understanding of these discrepancies, we used a chimaeric human-murine liver model to compare directly the relative efficiency of rAAV transduction in human versus mouse hepatocytes in vivo. As predicted from preclinical and clinical studies, rAAV2 vectors functionally transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorly-approximately 20 times less efficiently than mouse hepatocytes. In light of the limitations of the rAAV vectors currently used in clinical studies, we used the same murine chimaeric liver model to perform serial selection using a human-specific replication-competent viral library composed of DNA-shuffled AAV capsids. One chimaeric capsid composed of five different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of human xenotransplants in mouse models of human diseases. More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939040/" 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/PMC3939040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lisowski, Leszek -- Dane, Allison P -- Chu, Kirk -- Zhang, Yue -- Cunningham, Sharon C -- Wilson, Elizabeth M -- Nygaard, Sean -- Grompe, Markus -- Alexander, Ian E -- Kay, Mark A -- DK048252/DK/NIDDK NIH HHS/ -- HL064274/HL/NHLBI NIH HHS/ -- HL092096/HL/NHLBI NIH HHS/ -- R01 DK048252/DK/NIDDK NIH HHS/ -- R01 HL064274/HL/NHLBI NIH HHS/ -- R01 HL092096/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):382-6. doi: 10.1038/nature12875. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Stanford University, School of Medicine, Departments of Pediatrics and Genetics, 269 Campus Drive, Stanford, California 94305, USA [2] Gene Transfer, Targeting and Therapeutics Core, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, San Diego, California 92037, USA (L.L.); Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK (A.P.D.). ; 1] Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Locked Bag 4001, Westmead, 2145 New South Wales, Australia [2] Gene Transfer, Targeting and Therapeutics Core, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, San Diego, California 92037, USA (L.L.); Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK (A.P.D.). ; Stanford University, School of Medicine, Departments of Pediatrics and Genetics, 269 Campus Drive, Stanford, California 94305, USA. ; Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Locked Bag 4001, Westmead, 2145 New South Wales, Australia. ; Yecuris Corporation, Portland, Oregon 97062, USA. ; Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA. ; 1] Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Locked Bag 4001, Westmead, 2145 New South Wales, Australia [2] Discipline of Paediatrics and Child Health, The University of Sydney, 2145 New South Wales, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390344" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capsid/metabolism ; Capsid Proteins/genetics/metabolism ; Carcinoma, Hepatocellular/genetics/pathology ; Cell Line, Tumor ; Cells, Cultured ; Chimera/genetics/metabolism ; Clinical Trials as Topic ; Dependovirus/*genetics/isolation & purification ; Disease Models, Animal ; Female ; Genetic Therapy/*methods ; Genetic Vectors/*genetics ; Hepatocytes/cytology/metabolism/pathology/transplantation ; Heterografts/*metabolism ; Humans ; Liver/cytology/*metabolism/pathology ; Male ; Mice ; Species Specificity ; Transduction, Genetic/*methods ; Transgenes/*genetics
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  • 16
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    Statin treatment rescues FGFR3 skeletal dysplasia phenotypes (2014)
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    Publication Date: 2014-09-19
    Description: Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in skeletal dysplasias, such as thanatophoric dysplasia and achondroplasia (ACH). The lack of disease models using human cells has hampered the identification of a clinically effective treatment for these diseases. Here we show that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. We converted fibroblasts from thanatophoric dysplasia type I (TD1) and ACH patients into iPSCs. The chondrogenic differentiation of TD1 iPSCs and ACH iPSCs resulted in the formation of degraded cartilage. We found that statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with TD1 and ACH.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamashita, Akihiro -- Morioka, Miho -- Kishi, Hiromi -- Kimura, Takeshi -- Yahara, Yasuhito -- Okada, Minoru -- Fujita, Kaori -- Sawai, Hideaki -- Ikegawa, Shiro -- Tsumaki, Noriyuki -- England -- Nature. 2014 Sep 25;513(7519):507-11. doi: 10.1038/nature13775. Epub 2014 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan. ; 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. ; Department of Obstetrics and Gynecology, Hyogo College of Medicine, Hyogo 663-8501, Japan. ; Laboratory of Bone and Joint Diseases, Center for Integrated Medical Sciences, RIKEN, Tokyo 108-8639, Japan. ; 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25231866" target="_blank"〉PubMed〈/a〉
    Keywords: Achondroplasia/*drug therapy/genetics/*pathology ; Animals ; Bone Development/drug effects ; Cartilage/cytology/drug effects/pathology ; Cell Differentiation ; Chondrocytes/cytology/pathology ; Disease Models, Animal ; Female ; Fluorobenzenes/administration & dosage/pharmacology/therapeutic use ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & ; dosage/pharmacology/*therapeutic use ; Induced Pluripotent Stem Cells/cytology/pathology ; Lovastatin/pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; Pyrimidines/administration & dosage/pharmacology/therapeutic use ; Receptor, Fibroblast Growth Factor, Type 3/*deficiency/*genetics ; Rosuvastatin Calcium ; Sulfonamides/administration & dosage/pharmacology/therapeutic use ; Thanatophoric Dysplasia/*drug therapy/genetics/*pathology
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  • 17
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    Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy (2014)
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    Publication Date: 2014-04-04
    Description: Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" 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/PMC4150021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huber, Kilian V M -- Salah, Eidarus -- Radic, Branka -- Gridling, Manuela -- Elkins, Jonathan M -- Stukalov, Alexey -- Jemth, Ann-Sofie -- Gokturk, Camilla -- Sanjiv, Kumar -- Stromberg, Kia -- Pham, Therese -- Berglund, Ulrika Warpman -- Colinge, Jacques -- Bennett, Keiryn L -- Loizou, Joanna I -- Helleday, Thomas -- Knapp, Stefan -- Superti-Furga, Giulio -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- F 4711/Austrian Science Fund FWF/Austria -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Apr 10;508(7495):222-7. doi: 10.1038/nature13194. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. ; Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17121 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695225" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoquinolines/pharmacology ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Colonic Neoplasms/drug therapy/genetics/pathology ; Crystallization ; DNA Breaks, Single-Stranded/drug effects ; DNA Repair ; DNA Repair Enzymes/*antagonists & inhibitors/biosynthesis/chemistry/*metabolism ; Disease Models, Animal ; Female ; Homeostasis/drug effects ; Humans ; Mice ; Mice, SCID ; Models, Molecular ; Nucleotides/metabolism ; Phosphoric Monoester Hydrolases/*antagonists & ; inhibitors/biosynthesis/chemistry/*metabolism ; Protein Conformation ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Proteomics ; Proto-Oncogene Proteins/genetics ; Pyrazoles/chemistry/*pharmacology ; Pyridines/chemistry/*pharmacology ; Substrate Specificity ; Xenograft Model Antitumor Assays ; ras Proteins/genetics
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  • 18
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    Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers (2014)
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    Publication Date: 2014-04-04
    Description: Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones. As carcinogenesis involves a breakdown in the cell-cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wnt1 generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somatic Hras mutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basal Hras mutant and luminal Hras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050741/" 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/PMC4050741/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cleary, Allison S -- Leonard, Travis L -- Gestl, Shelley A -- Gunther, Edward J -- R01 CA152222/CA/NCI NIH HHS/ -- England -- Nature. 2014 Apr 3;508(7494):113-7. doi: 10.1038/nature13187.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA [2] Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Hershey, Pennsylvania 17033, USA. ; 1] Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA [2] Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Hershey, Pennsylvania 17033, USA [3] Department of Medicine (Hematology/Oncology), Pennsylvania State University College of Medicine, Hershey, Hershey, Pennsylvania 17033, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695311" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Breast Neoplasms/genetics/*metabolism/*pathology ; Cell Lineage ; Cell Proliferation ; Clone Cells/metabolism/pathology ; Disease Models, Animal ; Female ; Mice ; Mosaicism ; Mutation ; Neoplasm Recurrence, Local/genetics/metabolism/pathology ; Neoplastic Stem Cells/metabolism/pathology ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Wnt Signaling Pathway ; Wnt1 Protein/deficiency/*metabolism
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    Rapid modelling of cooperating genetic events in cancer through somatic genome editing (2014)
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    Publication Date: 2014-10-23
    Description: Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of cancer. Using a Kras(G12D)-driven lung cancer model, we performed functional characterization of a panel of tumour suppressor genes with known loss-of-function alterations in human lung cancer. Cre-dependent somatic activation of oncogenic Kras(G12D) combined with CRISPR/Cas9-mediated genome editing of tumour suppressor genes resulted in lung adenocarcinomas with distinct histopathological and molecular features. This rapid somatic genome engineering approach enables functional characterization of putative cancer genes in the lung and other tissues using autochthonous mouse models. We anticipate that this approach can be used to systematically dissect the complex catalogue of mutations identified in cancer genome sequencing studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292871/" 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/PMC4292871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanchez-Rivera, Francisco J -- Papagiannakopoulos, Thales -- Romero, Rodrigo -- Tammela, Tuomas -- Bauer, Matthew R -- Bhutkar, Arjun -- Joshi, Nikhil S -- Subbaraj, Lakshmipriya -- Bronson, Roderick T -- Xue, Wen -- Jacks, Tyler -- K99 CA169512/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 CA169512/CA/NCI NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 18;516(7531):428-31. doi: 10.1038/nature13906. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Tufts University, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337879" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/*genetics/pathology ; Animals ; *Caspase 9 ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Disease Models, Animal ; Genes, Tumor Suppressor ; *Genetic Engineering ; Genome/*genetics ; Humans ; Lentivirus/genetics ; Lung Neoplasms/*genetics/pathology ; Mice ; Mice, Inbred C57BL ; Models, Genetic ; Mutation/genetics
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    Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma (2014)
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    Publication Date: 2014-02-28
    Description: Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bald, Tobias -- Quast, Thomas -- Landsberg, Jennifer -- Rogava, Meri -- Glodde, Nicole -- Lopez-Ramos, Dorys -- Kohlmeyer, Judith -- Riesenberg, Stefanie -- van den Boorn-Konijnenberg, Debby -- Homig-Holzel, Cornelia -- Reuten, Raphael -- Schadow, Benjamin -- Weighardt, Heike -- Wenzel, Daniela -- Helfrich, Iris -- Schadendorf, Dirk -- Bloch, Wilhelm -- Bianchi, Marco E -- Lugassy, Claire -- Barnhill, Raymond L -- Koch, Manuel -- Fleischmann, Bernd K -- Forster, Irmgard -- Kastenmuller, Wolfgang -- Kolanus, Waldemar -- Holzel, Michael -- Gaffal, Evelyn -- Tuting, Thomas -- England -- Nature. 2014 Mar 6;507(7490):109-13. doi: 10.1038/nature13111. Epub 2014 Feb 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany. ; Molecular Immunology and Cell Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. ; Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany. ; Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Medical Faculty, University of Cologne, D-50931 Cologne, Germany. ; Immunology and Environment, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. ; Institute for Physiology I, Life & Brain Center, University of Bonn, 53105 Bonn, Germany. ; Department of Dermatology, University Hospital Essen, 45122 Essen, Germany. ; Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany. ; Division of Genetics and Cell Biology, San Raffaele University and Scientific Institute, 20132 Milan, Italy. ; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles (UCLA) Medical Center, Los Angeles, California 90095, USA. ; Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, 53105 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572365" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Movement/radiation effects ; Cell Transformation, Neoplastic/radiation effects ; Disease Models, Animal ; Disease Progression ; Female ; HMGB1 Protein/metabolism ; Immunity, Innate/radiation effects ; Inflammation/*etiology ; Keratinocytes/metabolism/pathology/radiation effects ; Lung Neoplasms/blood supply/etiology/*secondary ; Male ; Melanocytes/pathology/radiation effects ; Melanoma/*blood supply/etiology/*pathology ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/etiology ; Neutrophils/immunology/metabolism ; Skin Neoplasms/blood supply/etiology/*pathology ; Sunburn/complications/*etiology ; Toll-Like Receptor 4/metabolism ; *Ultraviolet Rays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 21
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    Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-08-15
    Description: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376130/" 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/PMC4376130/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viale, Andrea -- Pettazzoni, Piergiorgio -- Lyssiotis, Costas A -- Ying, Haoqiang -- Sanchez, Nora -- Marchesini, Matteo -- Carugo, Alessandro -- Green, Tessa -- Seth, Sahil -- Giuliani, Virginia -- Kost-Alimova, Maria -- Muller, Florian -- Colla, Simona -- Nezi, Luigi -- Genovese, Giannicola -- Deem, Angela K -- Kapoor, Avnish -- Yao, Wantong -- Brunetto, Emanuela -- Kang, Ya'an -- Yuan, Min -- Asara, John M -- Wang, Y Alan -- Heffernan, Timothy P -- Kimmelman, Alec C -- Wang, Huamin -- Fleming, Jason B -- Cantley, Lewis C -- DePinho, Ronald A -- Draetta, Giulio F -- CA016672/CA/NCI NIH HHS/ -- CA16672/CA/NCI NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01CA117969/CA/NCI NIH HHS/ -- P01CA120964/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA16672/CA/NCI NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- England -- Nature. 2014 Oct 30;514(7524):628-32. doi: 10.1038/nature13611. Epub 2014 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA. ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. ; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Pathology Unit, San Raffaele Scientific Institute, Milan 20132, Italy. ; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119024" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/*metabolism/*pathology ; Cell Respiration/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Female ; Gene Expression Regulation, Neoplastic ; Genes, p53/genetics ; Glycolysis ; Lysosomes/metabolism ; Mice ; Mitochondria/drug effects/*metabolism ; Mutation/genetics ; Neoplasm Recurrence, Local/prevention & control ; Neoplastic Stem Cells/drug effects/metabolism/pathology ; Oxidative Phosphorylation/drug effects ; Pancreatic Neoplasms/drug therapy/genetics/*metabolism/*pathology ; Proto-Oncogene Proteins p21(ras)/*genetics/metabolism ; Recurrence ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 22
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    Cloning comeback (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-01-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2014 Jan 23;505(7484):468-71. doi: 10.1038/505468a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24451524" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics/physiopathology ; Animals ; Animals, Genetically Modified ; Cattle ; *Cloning, Organism/economics/ethics/history ; Disease Models, Animal ; Dogs ; Embryo Research/ethics/history/legislation & jurisprudence ; Embryonic Stem Cells/cytology ; Epigenomics ; Female ; Heterografts/transplantation ; History, 21st Century ; Humans ; Interferons/biosynthesis/genetics ; Oocyte Donation/economics/ethics ; Parthenogenesis ; Pets ; Republic of Korea ; Research Personnel/economics/*ethics/standards ; Scientific Misconduct/history ; Swine
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 23
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    Protective mucosal immunity mediated by epithelial CD1d and IL-10 (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-04-11
    Description: The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression--as observed in inflammatory bowel disease--may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132962/" 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/PMC4132962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olszak, Torsten -- Neves, Joana F -- Dowds, C Marie -- Baker, Kristi -- Glickman, Jonathan -- Davidson, Nicholas O -- Lin, Chyuan-Sheng -- Jobin, Christian -- Brand, Stephan -- Sotlar, Karl -- Wada, Koichiro -- Katayama, Kazufumi -- Nakajima, Atsushi -- Mizuguchi, Hiroyuki -- Kawasaki, Kunito -- Nagata, Kazuhiro -- Muller, Werner -- Snapper, Scott B -- Schreiber, Stefan -- Kaser, Arthur -- Zeissig, Sebastian -- Blumberg, Richard S -- 260961/European Research Council/International -- AI50950/AI/NIAID NIH HHS/ -- DK0034854/DK/NIDDK NIH HHS/ -- DK034854/DK/NIDDK NIH HHS/ -- DK044319/DK/NIDDK NIH HHS/ -- DK051362/DK/NIDDK NIH HHS/ -- DK053056/DK/NIDDK NIH HHS/ -- DK088199/DK/NIDDK NIH HHS/ -- DK56260/DK/NIDDK NIH HHS/ -- HL38180/HL/NHLBI NIH HHS/ -- HL59561/HL/NHLBI NIH HHS/ -- P30 DK034854/DK/NIDDK NIH HHS/ -- P30 DK052574/DK/NIDDK NIH HHS/ -- P30CA013696/CA/NCI NIH HHS/ -- P30DK52574/DK/NIDDK NIH HHS/ -- R01 DK044319/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 May 22;509(7501):497-502. doi: 10.1038/nature13150. Epub 2014 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2]. ; 1] Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany [2]. ; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA. ; Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA. ; Department of Medicine, Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida 32611, USA. ; Department of Medicine II-Grosshadern, Ludwig Maximilians University, Munich 81377, Germany. ; Institute of Pathology, Ludwig Maximilians University, Munich 80337, Germany. ; Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan. ; Gastroenterology Division, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0027, Japan. ; Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan. ; Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan. ; Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK. ; 1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany. ; Division of Gastroenterology, Addenbrooke Hospital, University of Cambridge, Cambridge CB2 0QQ, UK. ; 1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717441" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD1d/*immunology ; Carrier Proteins/metabolism ; Colitis/immunology/pathology ; Disease Models, Animal ; Epithelial Cells/*immunology/metabolism ; Female ; HSP110 Heat-Shock Proteins/genetics/metabolism ; Humans ; Immunity, Mucosal/*immunology ; Inflammation/immunology/pathology ; Inflammatory Bowel Diseases/immunology/pathology ; Interleukin-10/genetics/*immunology ; Intestinal Mucosa/*cytology/*immunology ; Male ; Mice ; Natural Killer T-Cells/immunology/metabolism ; Oxazolone ; STAT3 Transcription Factor/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 24
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    Intranasal epidermal growth factor treatment rescues neonatal brain injury (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-01-07
    Description: There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106485/" 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/PMC4106485/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scafidi, Joseph -- Hammond, Timothy R -- Scafidi, Susanna -- Ritter, Jonathan -- Jablonska, Beata -- Roncal, Maria -- Szigeti-Buck, Klara -- Coman, Daniel -- Huang, Yuegao -- McCarter, Robert J Jr -- Hyder, Fahmeed -- Horvath, Tamas L -- Gallo, Vittorio -- DP1 OD006850/OD/NIH HHS/ -- K08 NS069815/NS/NINDS NIH HHS/ -- K08 NS073793/NS/NINDS NIH HHS/ -- K08NS069815/NS/NINDS NIH HHS/ -- K08NS073793/NS/NINDS NIH HHS/ -- K12NS052159/NS/NINDS NIH HHS/ -- P01 NS062686/NS/NINDS NIH HHS/ -- P30 HD040677/HD/NICHD NIH HHS/ -- P30 NS05219/NS/NINDS NIH HHS/ -- P30 NS052519/NS/NINDS NIH HHS/ -- P30HD040677/HD/NICHD NIH HHS/ -- R01 NS045702/NS/NINDS NIH HHS/ -- R01MH067528/MH/NIMH NIH HHS/ -- R01NS045702/NS/NINDS NIH HHS/ -- R01NS056427/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):230-4. doi: 10.1038/nature12880. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA [2] Department of Neurology, Children's National Medical Center, Washington DC 20010, USA. ; 1] Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA [2] Institute for Biomedical Sciences, The George Washington University, Washington DC 20052, USA. ; Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ; Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA. ; Department of Neurobiology, Yale University, New Haven, Connecticut 06520, USA. ; MRRC, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut 06520, USA. ; Center for Translational Science, Children's National Medical Center, Washington DC 20010, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390343" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Intranasal ; Animals ; Animals, Newborn ; Anoxia/genetics/metabolism/pathology/physiopathology ; Brain Injuries/*congenital/*drug therapy/pathology/prevention & control ; Cell Differentiation/drug effects ; Cell Division/drug effects ; Cell Lineage/drug effects ; Cell Survival/drug effects ; Demyelinating Diseases/congenital/metabolism/pathology/prevention & control ; Disease Models, Animal ; Epidermal Growth Factor/administration & dosage/*pharmacology/*therapeutic use ; Humans ; Infant, Premature, Diseases/drug therapy/metabolism/pathology ; Male ; Mice ; Molecular Targeted Therapy ; Oligodendroglia/cytology/*drug effects/metabolism/pathology ; Receptor, Epidermal Growth Factor/genetics/metabolism ; Regeneration/drug effects ; Signal Transduction/drug effects ; Stem Cells/cytology/drug effects/metabolism ; Time Factors
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    PVT1 dependence in cancer with MYC copy-number increase (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-22
    Description: 'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767149/" 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/PMC4767149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tseng, Yuen-Yi -- Moriarity, Branden S -- Gong, Wuming -- Akiyama, Ryutaro -- Tiwari, Ashutosh -- Kawakami, Hiroko -- Ronning, Peter -- Reuland, Brian -- Guenther, Kacey -- Beadnell, Thomas C -- Essig, Jaclyn -- Otto, George M -- O'Sullivan, M Gerard -- Largaespada, David A -- Schwertfeger, Kathryn L -- Marahrens, York -- Kawakami, Yasuhiko -- Bagchi, Anindya -- P30 CA077598/CA/NCI NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):82-6. doi: 10.1038/nature13311. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India. ; Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043044" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Transformation, Neoplastic ; Chromosomes, Human, Pair 8/genetics ; DNA Copy Number Variations/*genetics ; Disease Models, Animal ; Gene Amplification/*genetics ; Gene Dosage/*genetics ; Genes, myc/*genetics ; HCT116 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; Oncogene Protein p55(v-myc)/*genetics/metabolism ; Phenotype ; RNA, Long Noncoding/*genetics
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    In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-10-23
    Description: Chromosomal rearrangements have a central role in the pathogenesis of human cancers and often result in the expression of therapeutically actionable gene fusions. A recently discovered example is a fusion between the genes echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK), generated by an inversion on the short arm of chromosome 2: inv(2)(p21p23). The EML4-ALK oncogene is detected in a subset of human non-small cell lung cancers (NSCLC) and is clinically relevant because it confers sensitivity to ALK inhibitors. Despite their importance, modelling such genetic events in mice has proven challenging and requires complex manipulation of the germ line. Here we describe an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals. We apply it to generate a mouse model of Eml4-Alk-driven lung cancer. The resulting tumours invariably harbour the Eml4-Alk inversion, express the Eml4-Alk fusion gene, display histopathological and molecular features typical of ALK(+) human NSCLCs, and respond to treatment with ALK inhibitors. The general strategy described here substantially expands our ability to model human cancers in mice and potentially in other organisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270925/" 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/PMC4270925/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maddalo, Danilo -- Manchado, Eusebio -- Concepcion, Carla P -- Bonetti, Ciro -- Vidigal, Joana A -- Han, Yoon-Chi -- Ogrodowski, Paul -- Crippa, Alessandra -- Rekhtman, Natasha -- de Stanchina, Elisa -- Lowe, Scott W -- Ventura, Andrea -- P01 CA013106/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 18;516(7531):423-7. doi: 10.1038/nature13902. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program, 1275 York Avenue, New York, New York 10065, USA. ; 1] Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program, 1275 York Avenue, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Milano-Bicocca University, Department of Medical Oncology, San Gerardo Hospital, 20052, Via G B Pergolesi 33, Monza, Italy. ; Memorial Sloan Kettering Cancer Center, Thoracic Pathology and Cytopathology, 1275 York Avenue, New York, New York 10065, USA. ; Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, 1275 York Avenue, New York, New York 10065, USA. ; 1] Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program, 1275 York Avenue, New York, New York 10065, USA [2] Howard Hughes Medical Institute, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337876" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/therapeutic use ; *Caspase 9 ; Cells, Cultured ; Chromosome Inversion/genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Disease Models, Animal ; Genetic Engineering/*methods ; Lung Neoplasms/drug therapy/enzymology/pathology ; Mice ; NIH 3T3 Cells ; Protein Kinase Inhibitors/therapeutic use ; Pyrazoles/therapeutic use ; Pyridines/therapeutic use ; Receptor Protein-Tyrosine Kinases/metabolism ; Translocation, Genetic/*genetics
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Dichloroacetate prevents restenosis in preclinical animal models of vessel injury (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-04-22
    Description: Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (DeltaPsim) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented DeltaPsim hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal DeltaPsim and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323184/" 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/PMC4323184/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deuse, Tobias -- Hua, Xiaoqin -- Wang, Dong -- Maegdefessel, Lars -- Heeren, Joerg -- Scheja, Ludger -- Bolanos, Juan P -- Rakovic, Aleksandar -- Spin, Joshua M -- Stubbendorff, Mandy -- Ikeno, Fumiaki -- Langer, Florian -- Zeller, Tanja -- Schulte-Uentrop, Leonie -- Stoehr, Andrea -- Itagaki, Ryo -- Haddad, Francois -- Eschenhagen, Thomas -- Blankenberg, Stefan -- Kiefmann, Rainer -- Reichenspurner, Hermann -- Velden, Joachim -- Klein, Christine -- Yeung, Alan -- Robbins, Robert C -- Tsao, Philip S -- Schrepfer, Sonja -- 1R01HL105299/HL/NHLBI NIH HHS/ -- R01 HL105299/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 May 29;509(7502):641-4. doi: 10.1038/nature13232. Epub 2014 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] TSI-laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany [3] Cardiovascular Surgery, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. ; 1] TSI-laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, CMM L8:03, 17176 Stockholm, Sweden. ; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Zacarias Gonzalez 2, 37007 Salamanca, Spain. ; Institute of Neurogenetics, University of Lubeck, Maria-Goeppert-Strasse 1, 23562 Lubeck, Germany. ; Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA. ; Institute of Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. ; 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany [2] Department of General and Interventional Cardiology, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. ; 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany [2] Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany [2] Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany [2] Cardiovascular Surgery, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Krankenhausstrasse 8-10, 91054 Erlangen, Germany. ; Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA. ; 1] Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA [2] Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USA. ; 1] TSI-laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany [3] Cardiovascular Surgery, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany [4] Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24747400" target="_blank"〉PubMed〈/a〉
    Keywords: Angioplasty, Balloon/adverse effects ; Animals ; Aorta/drug effects/*injuries/pathology ; Apoptosis/drug effects ; Arteries/drug effects/*injuries/pathology ; Cell Proliferation/drug effects ; Constriction, Pathologic/pathology/*prevention & control ; Coronary Vessels/drug effects/injuries/pathology ; Dichloroacetic Acid/*pharmacology/*therapeutic use ; Disease Models, Animal ; Enzyme Activation/drug effects ; Gene Knockdown Techniques ; Humans ; Hyperplasia/drug therapy/pathology ; Iliac Artery/drug effects/injuries/pathology ; Mammary Arteries/drug effects/injuries/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Heart/drug effects/metabolism ; Myocytes, Smooth Muscle/drug effects/pathology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/deficiency/genetics ; Rabbits ; Rats ; Secondary Prevention ; Stents/adverse effects ; Swine ; Tunica Intima/*drug effects/injuries/*pathology
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Comparative biology: Naked ambition (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deweerdt, Sarah -- England -- Nature. 2014 May 29;509(7502):S60-1. doi: 10.1038/509S60a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870823" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoxia/metabolism ; Carcinogens/pharmacology/toxicity ; Cell Death ; Contact Inhibition/drug effects ; Culture Media, Conditioned/chemistry/pharmacology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; DNA Damage ; Disease Models, Animal ; *Disease Susceptibility ; Drug Resistance/drug effects ; Humans ; Hyaluronic Acid/biosynthesis/chemistry ; Mice ; *Models, Animal ; Mole Rats/*physiology ; NF-E2-Related Factor 2/metabolism ; Neoplasms/chemically induced/genetics/pathology/*prevention & control ; Rats ; Selection, Genetic ; Spalax/physiology ; Tumor Suppressor Protein p53/genetics/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430 (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-03-05
    Description: Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Travis K -- Wells, Jay -- Panchal, Rekha G -- Stuthman, Kelly S -- Garza, Nicole L -- Van Tongeren, Sean A -- Dong, Lian -- Retterer, Cary J -- Eaton, Brett P -- Pegoraro, Gianluca -- Honnold, Shelley -- Bantia, Shanta -- Kotian, Pravin -- Chen, Xilin -- Taubenheim, Brian R -- Welch, Lisa S -- Minning, Dena M -- Babu, Yarlagadda S -- Sheridan, William P -- Bavari, Sina -- HHSN272201100016I/PHS HHS/ -- HHSN272201100019I/PHS HHS/ -- HHSN27220110005I/PHS HHS/ -- England -- Nature. 2014 Apr 17;508(7496):402-5. doi: 10.1038/nature13027. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA. ; BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA. ; 1] BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA [2] Wilco Consulting, LLC, Durham, North Carolina 27712, USA. ; MedExpert Consulting, Inc., Indialantic, Florida 32903, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590073" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives ; Administration, Oral ; Animals ; Antiviral Agents/administration & dosage/chemistry/pharmacokinetics/*pharmacology ; DNA-Directed RNA Polymerases/antagonists & inhibitors/metabolism ; Disease Models, Animal ; Ebolavirus/drug effects ; Filoviridae/*drug effects/enzymology ; Filoviridae Infections/*prevention & control/*virology ; Hemorrhagic Fever, Ebola/prevention & control/virology ; Humans ; Injections, Intramuscular ; Macaca fascicularis/virology ; Marburg Virus Disease/prevention & control/virology ; Marburgvirus/drug effects ; Purine Nucleosides/administration & ; dosage/chemistry/pharmacokinetics/*pharmacology ; RNA/biosynthesis ; Time Factors
    Print ISSN: 0028-0836
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    SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-06-10
    Description: Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells, was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2-GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boumahdi, Soufiane -- Driessens, Gregory -- Lapouge, Gaelle -- Rorive, Sandrine -- Nassar, Dany -- Le Mercier, Marie -- Delatte, Benjamin -- Caauwe, Amelie -- Lenglez, Sandrine -- Nkusi, Erwin -- Brohee, Sylvain -- Salmon, Isabelle -- Dubois, Christine -- del Marmol, Veronique -- Fuks, Francois -- Beck, Benjamin -- Blanpain, Cedric -- England -- Nature. 2014 Jul 10;511(7508):246-50. doi: 10.1038/nature13305. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; 1] Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2]. ; 1] Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium [2] DIAPATH-Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; Laboratory of Cancer Epigenetics, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; Machine Learning Group, Computer Science Department, Faculte des Sciences, Universite Libre de Bruxelles, Brussels B-1050, Belgium. ; Department of Dermatology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; 1] Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2] WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Carcinoma, Squamous Cell/genetics/pathology ; Cell Adhesion/genetics ; Cell Proliferation ; Cell Transformation, Neoplastic/*genetics/metabolism ; Disease Models, Animal ; Gene Deletion ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Gene Regulatory Networks/genetics ; Mice ; Mice, Inbred Strains ; Neoplastic Stem Cells/*metabolism ; SOXB1 Transcription Factors/genetics/*metabolism ; *Skin Neoplasms/genetics/pathology
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2 (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-22
    Description: Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-beta-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149606/" 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/PMC4149606/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krzeszinski, Jing Y -- Wei, Wei -- Huynh, HoangDinh -- Jin, Zixue -- Wang, Xunde -- Chang, Tsung-Cheng -- Xie, Xian-Jin -- He, Lin -- Mangala, Lingegowda S -- Lopez-Berestein, Gabriel -- Sood, Anil K -- Mendell, Joshua T -- Wan, Yihong -- 1P30 CA142543/CA/NCI NIH HHS/ -- 1S10RR02564801/RR/NCRR NIH HHS/ -- P01 CA134292/CA/NCI NIH HHS/ -- P30 CA142543/CA/NCI NIH HHS/ -- R01 CA120185/CA/NCI NIH HHS/ -- R01 CA139067/CA/NCI NIH HHS/ -- R01 DK089113/DK/NIDDK NIH HHS/ -- S10 RR024757/RR/NCRR NIH HHS/ -- S10 RR025648/RR/NCRR NIH HHS/ -- U54 CA151668/CA/NCI NIH HHS/ -- UH2 TR000943/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Aug 28;512(7515):431-5. doi: 10.1038/nature13375. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA. ; 1] Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Cancer Center, The 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/25043055" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Bone Neoplasms/genetics/pathology/*prevention & control/*secondary ; Bone Resorption/drug therapy/genetics ; Cell Differentiation/drug effects/*genetics ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Gene Deletion ; Homeodomain Proteins/antagonists & inhibitors/genetics/metabolism ; Humans ; Male ; Mammary Neoplasms, Animal/pathology ; Mice ; Mice, Transgenic ; MicroRNAs/*genetics/pharmacology/therapeutic use ; Neoplasm Transplantation ; Organ Size/drug effects ; Osteoclasts/drug effects/*pathology ; Osteoporosis/genetics/pathology/*prevention & control ; Ovariectomy ; Repressor Proteins/antagonists & inhibitors/*deficiency/genetics/metabolism ; Skin Neoplasms/pathology ; Transgenes ; Xenograft Model Antitumor Assays
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    Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-04-30
    Description: Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154594/" 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/PMC4154594/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chong, James J H -- Yang, Xiulan -- Don, Creighton W -- Minami, Elina -- Liu, Yen-Wen -- Weyers, Jill J -- Mahoney, William M -- Van Biber, Benjamin -- Cook, Savannah M -- Palpant, Nathan J -- Gantz, Jay A -- Fugate, James A -- Muskheli, Veronica -- Gough, G Michael -- Vogel, Keith W -- Astley, Cliff A -- Hotchkiss, Charlotte E -- Baldessari, Audrey -- Pabon, Lil -- Reinecke, Hans -- Gill, Edward A -- Nelson, Veronica -- Kiem, Hans-Peter -- Laflamme, Michael A -- Murry, Charles E -- P01 GM081619/GM/NIGMS NIH HHS/ -- P01 HL094374/HL/NHLBI NIH HHS/ -- P01GM081619/GM/NIGMS NIH HHS/ -- P01HL094374/HL/NHLBI NIH HHS/ -- P51 OD010425/OD/NIH HHS/ -- R01 HL084642/HL/NHLBI NIH HHS/ -- R01 HL117991/HL/NHLBI NIH HHS/ -- R01HL084642/HL/NHLBI NIH HHS/ -- T32 GM007266/GM/NIGMS NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- U01HL100405/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Jun 12;510(7504):273-7. doi: 10.1038/nature13233. Epub 2014 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Cardiology Westmead Hospital, Westmead, New South Wales 2145, Australia [4] School of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia [5] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [6] University of Sydney School of Medicine, Sydney, New South Wales 2006, Australia and Westmead Millennium Institute and Westmead Hospital, Westmead, New South Wales 2145, Australia. ; 1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA. ; Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA. ; 1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [4] Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA. ; Department of Comparative Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA. ; 1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [4] Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA. ; Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [2] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [4] Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA [5] Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776797" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrhythmias, Cardiac/physiopathology ; Calcium/metabolism ; Cell Survival ; Coronary Vessels/physiology ; Cryopreservation ; Disease Models, Animal ; Electrocardiography ; Embryonic Stem Cells/*cytology ; *Heart ; Humans ; Macaca nemestrina ; Male ; Mice ; Myocardial Infarction/*pathology/*therapy ; Myocytes, Cardiac/*cytology ; *Regeneration ; Regenerative Medicine/methods
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS (2014)
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    Publication Date: 2014-11-11
    Description: Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255242/" 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/PMC4255242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Pell, Victoria R -- Gaude, Edoardo -- Aksentijevic, Dunja -- Sundier, Stephanie Y -- Robb, Ellen L -- Logan, Angela -- Nadtochiy, Sergiy M -- Ord, Emily N J -- Smith, Anthony C -- Eyassu, Filmon -- Shirley, Rachel -- Hu, Chou-Hui -- Dare, Anna J -- James, Andrew M -- Rogatti, Sebastian -- Hartley, Richard C -- Eaton, Simon -- Costa, Ana S H -- Brookes, Paul S -- Davidson, Sean M -- Duchen, Michael R -- Saeb-Parsy, Kourosh -- Shattock, Michael J -- Robinson, Alan J -- Work, Lorraine M -- Frezza, Christian -- Krieg, Thomas -- Murphy, Michael P -- G1100562/Medical Research Council/United Kingdom -- MC_U105663142/Medical Research Council/United Kingdom -- MC_U105674181/Medical Research Council/United Kingdom -- MC_UP_1101/3/Medical Research Council/United Kingdom -- MC_UU_12022/6/Medical Research Council/United Kingdom -- PG/07/126/24223/British Heart Foundation/United Kingdom -- PG/12/42/29655/British Heart Foundation/United Kingdom -- R01 HL071158/HL/NHLBI NIH HHS/ -- RG/12/4/29426/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Nov 20;515(7527):431-5. doi: 10.1038/nature13909. Epub 2014 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK [2] Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. ; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. ; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK. ; King's College London, British Heart Foundation Centre of Research Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. ; Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. ; Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA. ; Institute of Cardiovascular &Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. ; School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK. ; Unit of Paediatric Surgery, UCL Institute of Child Health, London WC1N 1EH, UK. ; Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK. ; University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383517" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/metabolism ; Animals ; Aspartic Acid/metabolism ; Citric Acid Cycle ; Disease Models, Animal ; Electron Transport ; Electron Transport Complex I/metabolism ; Fumarates/metabolism ; Ischemia/enzymology/*metabolism ; Malates/metabolism ; Male ; Metabolomics ; Mice ; Mitochondria/enzymology/*metabolism ; Myocardial Infarction/enzymology/metabolism ; Myocardium/cytology/enzymology/metabolism ; Myocytes, Cardiac/enzymology/metabolism ; NAD/metabolism ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/enzymology/*metabolism ; Stroke/enzymology/metabolism ; Succinate Dehydrogenase/metabolism ; Succinic Acid/*metabolism
    Print ISSN: 0028-0836
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    Medical research: if depression were cancer (2014)
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    Publication Date: 2014-11-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2014 Nov 13;515(7526):182-4. doi: 10.1038/515182a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25391943" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antidepressive Agents/pharmacology/therapeutic use ; Biomedical Research/economics/*statistics & numerical data/*trends ; Depression/*epidemiology/genetics/psychology/*therapy ; Depressive Disorder/epidemiology/genetics/psychology/therapy ; Disease Models, Animal ; Humans ; Mice ; *Neoplasms ; Neurosciences/*trends ; Stress, Psychological/epidemiology/etiology/therapy
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer (2014)
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    Publication Date: 2014-07-22
    Description: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alpha-ketoglutarate (alphaKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple alphaKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4alpha, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4alpha silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499230/" 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/PMC4499230/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saha, Supriya K -- Parachoniak, Christine A -- Ghanta, Krishna S -- Fitamant, Julien -- Ross, Kenneth N -- Najem, Mortada S -- Gurumurthy, Sushma -- Akbay, Esra A -- Sia, Daniela -- Cornella, Helena -- Miltiadous, Oriana -- Walesky, Chad -- Deshpande, Vikram -- Zhu, Andrew X -- Hezel, Aram F -- Yen, Katharine E -- Straley, Kimberly S -- Travins, Jeremy -- Popovici-Muller, Janeta -- Gliser, Camelia -- Ferrone, Cristina R -- Apte, Udayan -- Llovet, Josep M -- Wong, Kwok-Kin -- Ramaswamy, Sridhar -- Bardeesy, Nabeel -- P50 CA127003/CA/NCI NIH HHS/ -- P50CA1270003/CA/NCI NIH HHS/ -- R01 CA136567/CA/NCI NIH HHS/ -- R01 DK098414/DK/NIDDK NIH HHS/ -- R01CA136567-02/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Sep 4;513(7516):110-4. doi: 10.1038/nature13441. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2]. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, and Department of Experimental Oncology, Milan 20133, Italy. ; HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Catalonia 08036, Spain. ; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA. ; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. ; University of Rochester Medical Center, Rochester, New York 14642, USA. ; Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA. ; 1] HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Catalonia 08010, Spain [4] University of Barcelona, Catalonia 08036, Spain. ; 1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] 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/25043045" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Duct Neoplasms/enzymology/genetics/*pathology ; Bile Ducts, Intrahepatic/enzymology/pathology ; Cell Differentiation/*genetics ; Cell Division/genetics ; Cell Lineage/genetics ; Cholangiocarcinoma/enzymology/genetics/*pathology ; Disease Models, Animal ; Female ; Glutarates/metabolism ; Hepatocyte Nuclear Factor 4/*antagonists & ; inhibitors/biosynthesis/genetics/metabolism ; Hepatocytes/enzymology/metabolism/*pathology ; Humans ; Isocitrate Dehydrogenase/*genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Mutant Proteins/genetics/*metabolism ; Mutation/genetics ; Neoplasm Metastasis ; Proto-Oncogene Proteins/genetics/metabolism ; Stem Cells/pathology ; ras Proteins/genetics/metabolism
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    Policy: NIH to balance sex in cell and animal studies (2014)
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    Publication Date: 2014-05-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clayton, Janine A -- Collins, Francis S -- England -- Nature. 2014 May 15;509(7500):282-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24834516" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Experimentation/standards ; Animals ; Animals, Laboratory ; Biomedical Research/economics/*methods/standards ; Cell Line ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Female ; Financing, Organized/organization & administration ; Humans ; Male ; Multiple Sclerosis/drug therapy/pathology ; *National Institutes of Health (U.S.)/economics ; Neurons/cytology/drug effects/pathology ; Peer Review, Research/standards ; *Research Design/standards ; *Sex Characteristics ; *Sex Ratio ; Substance-Related Disorders/drug therapy/physiopathology ; United States
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    Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis (2014)
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    Publication Date: 2014-10-23
    Description: Secretion of C-C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. Here we report a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin (IL)-6- and vascular endothelial growth factor (VEGF)-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target. However, our results call for caution when considering anti-CCL2 agents as monotherapy in metastatic disease and highlight the tumour microenvironment as a critical determinant of successful anti-metastatic therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonapace, Laura -- Coissieux, Marie-May -- Wyckoff, Jeffrey -- Mertz, Kirsten D -- Varga, Zsuzsanna -- Junt, Tobias -- Bentires-Alj, Mohamed -- England -- Nature. 2014 Nov 6;515(7525):130-3. doi: 10.1038/nature13862. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Friedrich Miescher Institute for Biomedical Research (FMI), Basel 4058, Switzerland [2] Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland. ; Friedrich Miescher Institute for Biomedical Research (FMI), Basel 4058, Switzerland. ; 1] Department of Pathology, University Hospital Zurich, 8006 Zurich, Switzerland [2] Institute of Pathology Liestal, Cantonal Hospital Baselland, 4410 Liestal, Switzerland. ; Department of Pathology, University Hospital Zurich, 8006 Zurich, Switzerland. ; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337873" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Vessels/cytology/drug effects/growth & development ; Breast Neoplasms/*drug therapy/*pathology ; Cell Proliferation/drug effects ; Chemokine CCL2/*antagonists & inhibitors/*metabolism/secretion ; Disease Models, Animal ; Female ; Interleukin-6/antagonists & inhibitors/metabolism ; Lung Neoplasms/blood supply/pathology/secondary ; Mice ; Monocytes/cytology/metabolism ; *Neoplasm Metastasis/drug therapy ; *Neovascularization, Pathologic/drug therapy ; Survival Analysis ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism
    Print ISSN: 0028-0836
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    Perspective: Revealing molecular secrets (2014)
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    Publication Date: 2014-04-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hyman, Steven E -- England -- Nature. 2014 Apr 3;508(7494):S20. doi: 10.1038/508S20a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stanley Center for Psychiatric Research at the Broad Institute of Harvard and Massachusetts Institute of Technology in Cambridge, Massachusetts. He is a former director of the US National Institute of Mental Health.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695333" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; DNA Copy Number Variations/genetics ; Disease Models, Animal ; Humans ; Models, Genetic ; Multifactorial Inheritance/genetics ; Schizophrenia/drug therapy/*genetics ; Translational Medical Research/methods/*trends
    Print ISSN: 0028-0836
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    IgG1 protects against renal disease in a mouse model of cryoglobulinaemia (2014)
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    Publication Date: 2014-11-05
    Description: Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial pathogens. Yet IgG1, the predominant murine serum Ig isotype, cannot activate complement by the classical pathway, binds more avidly to an inhibitory than to stimulatory FcRs, and has limited ability to aggregate pathogens. In these regards, it resembles human IgG4 (ref. 4). We hypothesized that limited ability to activate effector mechanisms might protect against immune complex immunopathology. Here we show that IgG1-deficient (gamma1(-)) mice, immunized with a potent antigen, develop lethal renal disease soon after they begin to produce antigen-specific antibody, whereas similarly immunized wild-type mice remain healthy. Surprisingly, renal disease in this model is complement and FcR independent and results from immune complex precipitation in glomerular capillaries, as in some cryoglobulinaemic humans. IgG3, which self-associates to form large immune complexes, accounts for more than 97% of the mouse Ig in this cryoglobulin; furthermore, glomerular disease develops when mice are injected with IgG3 anti-trinitrophenyl (TNP) monoclonal antibody followed by a TNP-labelled protein. Renal disease is prevented in both active and passive immunization models by antigen-specific IgG1; other isotypes are less potent at preventing disease. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms, reveal an immune-complex-dependent, complement- and FcR-independent nephrotoxic mechanism, and suggest that isotypes that poorly activate effector mechanisms may be useful for inhibiting immune complex immunopathology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342786/" 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/PMC4342786/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Strait, Richard T -- Posgai, Monica T -- Mahler, Ashley -- Barasa, Nathaniel -- Jacob, Chaim O -- Kohl, Jorg -- Ehlers, Marc -- Stringer, Keith -- Shanmukhappa, Shiva Kumar -- Witte, David -- Hossain, Md Monir -- Khodoun, Marat -- Herr, Andrew B -- Finkelman, Fred D -- R01 AI072040/AI/NIAID NIH HHS/ -- R01AI072040/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jan 22;517(7535):501-4. doi: 10.1038/nature13868. Epub 2014 Nov 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. ; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. ; Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; Department of Medicine, University of Southern California School of Medicine, Los Angeles, California 90033, USA. ; 1] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Institute for Systemic Inflammation Research, University of Lubeck, 23538 Lubeck, Germany. ; Institute for Systemic Inflammation Research, University of Lubeck, 23538 Lubeck, Germany. ; Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. ; 1] Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA [2] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; 1] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA [3] Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363774" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/immunology ; Antigen-Antibody Complex/chemistry/immunology ; Antigens/immunology ; Binding, Competitive ; Complement System Proteins ; Cryoglobulinemia/*complications/immunology/pathology ; Disease Models, Animal ; Female ; Glomerulonephritis/*etiology/immunology/pathology/*prevention & control ; Goats ; Immunoglobulin G/*immunology ; Male ; Mice ; Receptors, IgG ; Solubility ; Trinitrobenzenes/immunology
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    CEACAM1 regulates TIM-3-mediated tolerance and exhaustion (2014)
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    Publication Date: 2014-11-05
    Description: T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297519/" 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/PMC4297519/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Yu-Hwa -- Zhu, Chen -- Kondo, Yasuyuki -- Anderson, Ana C -- Gandhi, Amit -- Russell, Andrew -- Dougan, Stephanie K -- Petersen, Britt-Sabina -- Melum, Espen -- Pertel, Thomas -- Clayton, Kiera L -- Raab, Monika -- Chen, Qiang -- Beauchemin, Nicole -- Yazaki, Paul J -- Pyzik, Michal -- Ostrowski, Mario A -- Glickman, Jonathan N -- Rudd, Christopher E -- Ploegh, Hidde L -- Franke, Andre -- Petsko, Gregory A -- Kuchroo, Vijay K -- Blumberg, Richard S -- AI039671/AI/NIAID NIH HHS/ -- AI056299/AI/NIAID NIH HHS/ -- AI073748/AI/NIAID NIH HHS/ -- DK0034854/DK/NIDDK NIH HHS/ -- DK044319/DK/NIDDK NIH HHS/ -- DK051362/DK/NIDDK NIH HHS/ -- DK053056/DK/NIDDK NIH HHS/ -- DK088199/DK/NIDDK NIH HHS/ -- GM32415/GM/NIGMS NIH HHS/ -- MOP-93787/Canadian Institutes of Health Research/Canada -- NS045937/NS/NINDS NIH HHS/ -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI056299/AI/NIAID NIH HHS/ -- P01 AI073748/AI/NIAID NIH HHS/ -- P30 DK034854/DK/NIDDK NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- R01 DK051362/DK/NIDDK NIH HHS/ -- R01 GM026788/GM/NIGMS NIH HHS/ -- R01 NS045937/NS/NINDS NIH HHS/ -- T32 GM007122/GM/NIGMS NIH HHS/ -- UL1 TR001102/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):386-90. doi: 10.1038/nature13848. Epub 2014 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. ; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. ; Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA. ; Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany. ; 1] Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA [2] Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo 0424, Norway. ; Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada. ; Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. ; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; Goodman Cancer Research Centre, McGill University, Montreal H3G 1Y6, Canada. ; Beckman Institute, City of Hope, Duarte, California 91010, USA. ; 1] Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada [2] Keenan Research Centre of St. Michael's Hospital, Toronto, Ontario M5S1A8, Canada. ; GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363763" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/immunology/*metabolism ; Autoimmunity/immunology ; Cell Adhesion Molecules/chemistry/immunology/*metabolism ; Cell Line ; Colorectal Neoplasms/immunology ; Disease Models, Animal ; Female ; Humans ; Immune Tolerance/*immunology ; Inflammation/immunology/pathology ; Ligands ; Male ; Membrane Proteins/chemistry/immunology/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Molecular ; Mucous Membrane/immunology/pathology ; Protein Conformation ; Protein Multimerization ; Receptors, Virus/chemistry/immunology/*metabolism ; T-Lymphocytes/*immunology/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Neuroscience: Tuning the brain (2014)
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    Publication Date: 2014-03-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Helen -- England -- Nature. 2014 Mar 20;507(7492):290-2. doi: 10.1038/507290a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24646978" target="_blank"〉PubMed〈/a〉
    Keywords: Aged ; Animals ; *Deep Brain Stimulation/instrumentation/trends ; Disease Models, Animal ; Epilepsy/therapy ; Humans ; Male ; Mental Disorders/therapy ; Models, Neurological ; Neural Pathways ; Parkinson Disease/physiopathology/*therapy
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Still much to learn about mice (2014)
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    Publication Date: 2014-05-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 May 22;509(7501):399.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24860878" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Specimen Banks ; Disease ; Disease Models, Animal ; Drug Discovery/methods ; Genome/*genetics ; Mice/*genetics ; Mice, Knockout/*genetics ; Mice, Mutant Strains ; *Phenotype ; Reproducibility of Results
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Inhibition of miR-25 improves cardiac contractility in the failing heart (2014)
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    Publication Date: 2014-03-29
    Description: Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/" 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/PMC4131725/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wahlquist, Christine -- Jeong, Dongtak -- Rojas-Munoz, Agustin -- Kho, Changwon -- Lee, Ahyoung -- Mitsuyama, Shinichi -- van Mil, Alain -- Park, Woo Jin -- Sluijter, Joost P G -- Doevendans, Pieter A F -- Hajjar, Roger J -- Mercola, Mark -- HHSN268201000045C/HL/NHLBI NIH HHS/ -- HHSN26820100045C/PHS HHS/ -- P01 HL098053/HL/NHLBI NIH HHS/ -- P01HL098053/HL/NHLBI NIH HHS/ -- P20 HL100396/HL/NHLBI NIH HHS/ -- P20HL100396/HL/NHLBI NIH HHS/ -- P30 AR061303/AR/NIAMS NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P30AR061303/AR/NIAMS NIH HHS/ -- P30CA030199/CA/NCI NIH HHS/ -- P50 HL112324/HL/NHLBI NIH HHS/ -- P50HL112324/HL/NHLBI NIH HHS/ -- R01 HL088434/HL/NHLBI NIH HHS/ -- R01 HL093183/HL/NHLBI NIH HHS/ -- R01 HL108176/HL/NHLBI NIH HHS/ -- R01 HL113601/HL/NHLBI NIH HHS/ -- R01HL088434/HL/NHLBI NIH HHS/ -- R01HL093183/HL/NHLBI NIH HHS/ -- R01HL108176/HL/NHLBI NIH HHS/ -- R01HL113601/HL/NHLBI NIH HHS/ -- S10 RR021084/RR/NCRR NIH HHS/ -- England -- Nature. 2014 Apr 24;508(7497):531-5. doi: 10.1038/nature13073. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2]. ; 1] The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2]. ; Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands. ; Global Research Laboratory, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea. ; Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670661" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Dependovirus/genetics ; Disease Models, Animal ; HEK293 Cells ; Heart/drug effects/physiology/physiopathology ; Heart Failure/*genetics/*therapy ; Humans ; Kinetics ; Male ; Mice ; MicroRNAs/analysis/*antagonists & inhibitors/genetics/metabolism ; Myocardial Contraction/*drug effects ; Myocardium/metabolism ; Myocytes, Cardiac/metabolism ; Oligonucleotides, Antisense/genetics/metabolism/pharmacology ; RNA, Messenger/genetics/metabolism ; Sarcoplasmic Reticulum/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism ; Survival Analysis ; Up-Regulation/genetics
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    PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies (2014)
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    Publication Date: 2014-08-15
    Description: The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉De Raedt, Thomas -- Beert, Eline -- Pasmant, Eric -- Luscan, Armelle -- Brems, Hilde -- Ortonne, Nicolas -- Helin, Kristian -- Hornick, Jason L -- Mautner, Victor -- Kehrer-Sawatzki, Hildegard -- Clapp, Wade -- Bradner, James -- Vidaud, Michel -- Upadhyaya, Meena -- Legius, Eric -- Cichowski, Karen -- England -- Nature. 2014 Oct 9;514(7521):247-51. doi: 10.1038/nature13561. Epub 2014 Aug 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA [3] Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA. ; 1] Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium [2] [3] Laboratory of Aquatic Biology, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit, Leuven Afdeling Kortrijk, 8500 Kortrijk, Belgium. ; 1] INSERM UMR_S745 et EA7331, Universite Paris Descartes, Sorbonne Paris Cite, Faculte des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Genetique Moleculaire, Hopital Cochin, Assistance Publique-Hopitaux de Paris, 75014 Paris, France [3]. ; 1] INSERM UMR_S745 et EA7331, Universite Paris Descartes, Sorbonne Paris Cite, Faculte des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Genetique Moleculaire, Hopital Cochin, Assistance Publique-Hopitaux de Paris, 75014 Paris, France. ; Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium. ; 1] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark [2] Center for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark [3] The Danish Stem Cell Center (Danstem), University of Copenhagen, 2200 Copenhagen, Denmark. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Maxillofacial Surgery, University Medical Centre, Hamburg-Eppendorf, 20246 Hamburg, Germany. ; Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany. ; Herman Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 46202 Indianapolis, Indiana, USA. ; 1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Massachusetts 02115, USA. ; Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. ; 1] Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium [2] Center for Human Genetics, University Hospital Leuven, 3000 Leuven Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119042" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azepines/pharmacology/therapeutic use ; Cell Death/drug effects ; Chromatin/drug effects/genetics/metabolism ; Disease Models, Animal ; Epigenesis, Genetic/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/drug therapy/genetics/pathology ; Humans ; Melanoma/drug therapy/genetics/pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Neoplasms/*drug therapy/*genetics/pathology ; Nerve Sheath Neoplasms/drug therapy/genetics/pathology ; Neurofibromin 1/deficiency/genetics ; Nuclear Proteins/*antagonists & inhibitors/deficiency/genetics/metabolism ; Polycomb Repressive Complex 2/*deficiency/genetics/metabolism ; Transcription Factors/*antagonists & inhibitors/deficiency/genetics/metabolism ; *Transcription, Genetic/drug effects ; Triazoles/pharmacology/therapeutic use ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; ras Proteins/antagonists & inhibitors/*metabolism
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    Disease research: Rare insights (2014)
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    Publication Date: 2014-01-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2014 Jan 16;505(7483):443-5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24436966" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biomedical Research/economics/trends ; Biotechnology/economics ; Child, Preschool ; Disease Models, Animal ; Drug Industry/economics ; Fellowships and Scholarships/economics ; Female ; Financing, Organized/economics ; Foundations/economics ; Fund Raising/economics ; Giant Axonal Neuropathy/therapy ; Humans ; Patient Advocacy ; *Rare Diseases/therapy ; Research Support as Topic/economics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Schizophrenia (2014)
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    Publication Date: 2014-04-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brody, Herb -- England -- Nature. 2014 Apr 3;508(7494):S1. doi: 10.1038/508S1a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695326" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Disease Models, Animal ; Female ; Humans ; Language ; Neuroimaging ; Psychotic Disorders/complications/physiopathology/psychology ; Schizophrenia/complications/drug therapy/genetics/*physiopathology ; Schizophrenic Psychology ; Young Adult
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    Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation (2014)
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    Publication Date: 2014-04-25
    Description: The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing gammadelta T (gammadeltaT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal gammadeltaT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127885/" 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/PMC4127885/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Riol-Blanco, Lorena -- Ordovas-Montanes, Jose -- Perro, Mario -- Naval, Elena -- Thiriot, Aude -- Alvarez, David -- Paust, Silke -- Wood, John N -- von Andrian, Ulrich H -- 101054/Wellcome Trust/United Kingdom -- 5F31AR063546-02/AR/NIAMS NIH HHS/ -- AI069259/AI/NIAID NIH HHS/ -- AI078897/AI/NIAID NIH HHS/ -- AI095261/AI/NIAID NIH HHS/ -- AI111595/AI/NIAID NIH HHS/ -- F31 AR063546/AR/NIAMS NIH HHS/ -- G0901905/Medical Research Council/United Kingdom -- P01 AI078897/AI/NIAID NIH HHS/ -- P01 AI112521/AI/NIAID NIH HHS/ -- R01 AI069259/AI/NIAID NIH HHS/ -- R01 AI111595/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Jun 5;510(7503):157-61. doi: 10.1038/nature13199. Epub 2014 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2]. ; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Institute for Biomedical Research, University College London, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759321" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoquinolines ; Animals ; Disease Models, Animal ; Female ; Inflammation/chemically induced/immunology/pathology ; Interleukin-17/biosynthesis/immunology ; Interleukin-23/biosynthesis/*immunology ; Interleukins/biosynthesis/immunology ; Langerhans Cells/immunology/metabolism ; Lymph Nodes/immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; NAV1.8 Voltage-Gated Sodium Channel/metabolism ; Nociceptors/drug effects/*metabolism ; Psoriasis/chemically induced/*immunology/*pathology ; Sensory Receptor Cells/drug effects/*metabolism ; Skin/cytology/immunology/*innervation/*pathology ; T-Lymphocytes/immunology/metabolism ; TRPV Cation Channels/metabolism
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    Depression: the best way forward (2014)
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    Publication Date: 2014-11-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Monteggia, Lisa M -- Malenka, Robert C -- Deisseroth, Karl -- England -- Nature. 2014 Nov 13;515(7526):200-1. doi: 10.1038/515200a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA. ; Departments of Psychiatry and Behavioral Sciences and of Bioengineering, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25391955" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research/*methods/*trends ; Depression/physiopathology/psychology/*therapy ; Depressive Disorder/physiopathology/psychology/*therapy ; Disease Models, Animal ; Drug Discovery/*trends ; Humans ; Mice ; Molecular Targeted Therapy/trends
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    Contrasting forms of cocaine-evoked plasticity control components of relapse (2014)
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    Publication Date: 2014-05-23
    Description: Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-D-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pascoli, Vincent -- Terrier, Jean -- Espallergues, Julie -- Valjent, Emmanuel -- O'Connor, Eoin Cornelius -- Luscher, Christian -- England -- Nature. 2014 May 22;509(7501):459-64. doi: 10.1038/nature13257.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland [2]. ; 1] INSERM, U661, Montpellier F-34094, France [2] CNRS, UMR-5203, Institut de Genomique Fonctionnelle, Montpellier F-34094, France [3] Universites de Montpellier 1 & 2, UMR-5203, Montpellier F-34094, France. ; Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland. ; 1] Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland [2] Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24848058" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cocaine/*pharmacology ; Cocaine-Related Disorders/pathology/*physiopathology/psychology ; Disease Models, Animal ; Dopaminergic Neurons/drug effects ; Drug-Seeking Behavior/drug effects ; Female ; Hippocampus/cytology/drug effects/pathology ; Male ; Mice ; N-Methylaspartate/metabolism ; Neural Pathways/drug effects ; Neuronal Plasticity/*drug effects ; Nucleus Accumbens/cytology/*drug effects/pathology ; Optogenetics ; Prefrontal Cortex/cytology/drug effects/pathology ; Receptors, AMPA/metabolism ; Receptors, Dopamine D1/metabolism ; Recurrence ; Synapses/drug effects/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
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    Dietary modulation of the microbiome affects autoinflammatory disease (2014)
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    Publication Date: 2014-10-03
    Description: The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1beta (IL-1beta) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1beta production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1beta-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1beta expression in distant neutrophils. Furthermore, pro-IL-1beta expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1beta-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1beta and osteomyelitis in Pstpip2(cmo) mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268032/" 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/PMC4268032/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lukens, John R -- Gurung, Prajwal -- Vogel, Peter -- Johnson, Gordon R -- Carter, Robert A -- McGoldrick, Daniel J -- Bandi, Srinivasa Rao -- Calabrese, Christopher R -- Vande Walle, Lieselotte -- Lamkanfi, Mohamed -- Kanneganti, Thirumala-Devi -- 281600/European Research Council/International -- AI101935/AI/NIAID NIH HHS/ -- AR056296/AR/NIAMS NIH HHS/ -- CA163507/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 AI101935/AI/NIAID NIH HHS/ -- R01 AR056296/AR/NIAMS NIH HHS/ -- R01 CA163507/CA/NCI NIH HHS/ -- England -- Nature. 2014 Dec 11;516(7530):246-9. doi: 10.1038/nature13788. Epub 2014 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Animal Resources Center and the Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Small Animal Imaging Core, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium [2] Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274309" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics ; Animals ; Body Weight/drug effects ; Caspase 1/deficiency/genetics ; Caspase 8/genetics/metabolism ; Cholesterol/pharmacology ; Cytoskeletal Proteins/deficiency/genetics ; *Diet, High-Fat ; Disease Models, Animal ; Female ; Inflammasomes/metabolism ; Inflammation/diet therapy/pathology ; Interleukin-1beta/blood/metabolism ; Intestines/*drug effects/immunology/*microbiology ; Male ; Mice ; Mice, Inbred BALB C ; Microbiota/*drug effects ; Myeloblastin/deficiency ; Neutrophils/drug effects/metabolism ; Osteomyelitis/*diet therapy/*pathology ; Pancreatic Elastase/deficiency ; Prevotella/growth & development/isolation & purification
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    Mouse liver repopulation with hepatocytes generated from human fibroblasts (2014)
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    Publication Date: 2014-02-28
    Description: Human induced pluripotent stem cells (iPSCs) have the capability of revolutionizing research and therapy of liver diseases by providing a source of hepatocytes for autologous cell therapy and disease modelling. However, despite progress in advancing the differentiation of iPSCs into hepatocytes (iPSC-Heps) in vitro, cells that replicate the ability of human primary adult hepatocytes (aHeps) to proliferate extensively in vivo have not been reported. This deficiency has hampered efforts to recreate human liver diseases in mice, and has cast doubt on the potential of iPSC-Heps for liver cell therapy. The reason is that extensive post-transplant expansion is needed to establish and sustain a therapeutically effective liver cell mass in patients, a lesson learned from clinical trials of aHep transplantation. Here, as a solution to this problem, we report the generation of human fibroblast-derived hepatocytes that can repopulate mouse livers. Unlike current protocols for deriving hepatocytes from human fibroblasts, ours did not generate iPSCs but cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) could be efficiently differentiated. For this purpose we identified small molecules that aided endoderm and hepatocyte differentiation without compromising proliferation. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of aHeps. Unfractionated iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state. Our results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161230/" 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/PMC4161230/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Saiyong -- Rezvani, Milad -- Harbell, Jack -- Mattis, Aras N -- Wolfe, Alan R -- Benet, Leslie Z -- Willenbring, Holger -- Ding, Sheng -- P30 DK026743/DK/NIDDK NIH HHS/ -- P30 DK26743/DK/NIDDK NIH HHS/ -- R01 HD064610/HD/NICHD NIH HHS/ -- UH2 TR000487/TR/NCATS NIH HHS/ -- UH3 TR000487/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Apr 3;508(7494):93-7. doi: 10.1038/nature13020. Epub 2014 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, California 94158, USA. ; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, 35 Medical Center Way, San Francisco, California 94143, USA. ; Department of Surgery, Division of Transplantation, University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA. ; 1] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, 35 Medical Center Way, San Francisco, California 94143, USA [2] Liver Center, University of California San Francisco, 1001 Potrero Avenue, San Francisco, California 94110, USA [3] Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA. ; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Avenue, San Francisco, California 94143, USA. ; 1] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, 35 Medical Center Way, San Francisco, California 94143, USA [2] Department of Surgery, Division of Transplantation, University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA [3] Liver Center, University of California San Francisco, 1001 Potrero Avenue, San Francisco, California 94110, USA. ; 1] Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, California 94158, USA [2] Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572354" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Proliferation ; Cellular Reprogramming ; Disease Models, Animal ; Endoderm/cytology ; Female ; Fibroblasts/*cytology ; Hepatocytes/*cytology/*transplantation ; Humans ; Liver/*cytology ; Liver Failure/pathology/therapy ; Male ; Mice ; Multipotent Stem Cells/cytology
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    The alarmin IL-33 promotes regulatory T-cell function in the intestine (2014)
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    Publication Date: 2014-07-22
    Description: FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-beta1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339042/" 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/PMC4339042/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schiering, Chris -- Krausgruber, Thomas -- Chomka, Agnieszka -- Frohlich, Anja -- Adelmann, Krista -- Wohlfert, Elizabeth A -- Pott, Johanna -- Griseri, Thibault -- Bollrath, Julia -- Hegazy, Ahmed N -- Harrison, Oliver J -- Owens, Benjamin M J -- Lohning, Max -- Belkaid, Yasmine -- Fallon, Padraic G -- Powrie, Fiona -- 086335/Wellcome Trust/United Kingdom -- 095688/Wellcome Trust/United Kingdom -- 097109/Wellcome Trust/United Kingdom -- 099814/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Sep 25;513(7519):564-8. doi: 10.1038/nature13577. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK [2] Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK (C.S.); Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York 14214-3000, USA (E.A.W.). [3]. ; 1] Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK [2]. ; Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK. ; Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charite - University Medicine Berlin, and German Rheumatism Research Center (DRFZ), D-10117 Berlin, Germany. ; 1] Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA [2] Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK (C.S.); Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York 14214-3000, USA (E.A.W.). ; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. ; Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043027" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Colitis/immunology/pathology ; Colon/cytology/immunology/pathology ; Disease Models, Animal ; Female ; Immunity, Mucosal ; Inflammation/immunology/metabolism/pathology ; Interleukin-23/immunology ; Interleukin-33 ; Interleukins/antagonists & inhibitors/*immunology/metabolism ; Intestines/*cytology/*immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Interleukin/metabolism ; Signal Transduction/immunology ; T-Lymphocytes, Regulatory/cytology/*immunology ; Thymus Gland/cytology ; Transforming Growth Factor beta/metabolism
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    WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis (2014)
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    Publication Date: 2014-07-18
    Description: The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non-transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610745/" 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/PMC4610745/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ouyang, Hong -- Xue, Yuanchao -- Lin, Ying -- Zhang, Xiaohui -- Xi, Lei -- Patel, Sherrina -- Cai, Huimin -- Luo, Jing -- Zhang, Meixia -- Zhang, Ming -- Yang, Yang -- Li, Gen -- Li, Hairi -- Jiang, Wei -- Yeh, Emily -- Lin, Jonathan -- Pei, Michelle -- Zhu, Jin -- Cao, Guiqun -- Zhang, Liangfang -- Yu, Benjamin -- Chen, Shaochen -- Fu, Xiang-Dong -- Liu, Yizhi -- Zhang, Kang -- GM049369/GM/NIGMS NIH HHS/ -- R01 EY020846/EY/NEI NIH HHS/ -- R01 EY021374/EY/NEI NIH HHS/ -- England -- Nature. 2014 Jul 17;511(7509):358-61. doi: 10.1038/nature13465. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing 100730, China (X.Z.); Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang 110004, China (Y.Y.). ; Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China. ; 1] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California San Diego, La Jolla, California 92093, USA. ; 1] Department of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA [3] Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [3] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China [4] Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25030175" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Lineage ; Corneal Diseases/*metabolism/*pathology ; Disease Models, Animal ; Epithelium, Corneal/*cytology/*metabolism/pathology ; Eye Proteins/genetics/*metabolism ; Homeodomain Proteins/genetics/*metabolism ; *Homeostasis ; Humans ; Limbus Corneae/cytology/metabolism ; Male ; Paired Box Transcription Factors/genetics/*metabolism ; Rabbits ; Repressor Proteins/genetics/*metabolism ; Signal Transduction ; Skin/cytology/metabolism/pathology ; Stem Cell Transplantation ; Stem Cells/cytology/metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; Wnt Proteins/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    MicroRNA silencing for cancer therapy targeted to the tumour microenvironment (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-11-20
    Description: MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367962/" 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/PMC4367962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Christopher J -- Bahal, Raman -- Babar, Imran A -- Pincus, Zachary -- Barrera, Francisco -- Liu, Connie -- Svoronos, Alexander -- Braddock, Demetrios T -- Glazer, Peter M -- Engelman, Donald M -- Saltzman, W Mark -- Slack, Frank J -- 2T32HL007974/HL/NHLBI NIH HHS/ -- F32 CA174247/CA/NCI NIH HHS/ -- F32CA174247/CA/NCI NIH HHS/ -- P30 CA016359/CA/NCI NIH HHS/ -- R00 AG042487/AG/NIA NIH HHS/ -- R01 CA131301/CA/NCI NIH HHS/ -- R01 CA148996/CA/NCI NIH HHS/ -- R01 CA149128/CA/NCI NIH HHS/ -- R01 EB000487/EB/NIBIB NIH HHS/ -- R01 ES005775/ES/NIEHS NIH HHS/ -- R01 GM073857/GM/NIGMS NIH HHS/ -- R01 HL085416/HL/NHLBI NIH HHS/ -- R01CA131301/CA/NCI NIH HHS/ -- R01CA148996/CA/NCI NIH HHS/ -- R01EB000487/EB/NIBIB NIH HHS/ -- R01ES005775/ES/NIEHS NIH HHS/ -- R01GM073857/GM/NIGMS NIH HHS/ -- R01HL085416/HL/NHLBI NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- T32 HL007974/HL/NHLBI NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Feb 5;518(7537):107-10. doi: 10.1038/nature13905. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA [3] Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA. ; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA. ; Department of Pathology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409146" target="_blank"〉PubMed〈/a〉
    Keywords: Acids ; Animals ; Cell Membrane/metabolism ; Cell Membrane Permeability ; Disease Models, Animal ; *Drug Delivery Systems ; Female ; *Gene Expression Regulation, Neoplastic ; *Gene Silencing ; Hydrogen-Ion Concentration ; Lymphoma/*genetics/pathology/*therapy ; Male ; Mice ; MicroRNAs/*antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Nanoparticles/administration & dosage/chemistry ; Oncogenes/genetics ; Peptide Nucleic Acids/administration & dosage/chemistry/therapeutic use ; *Tumor Microenvironment/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-05-23
    Description: Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142213/" 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/PMC4142213/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maianti, Juan Pablo -- McFedries, Amanda -- Foda, Zachariah H -- Kleiner, Ralph E -- Du, Xiu Quan -- Leissring, Malcolm A -- Tang, Wei-Jen -- Charron, Maureen J -- Seeliger, Markus A -- Saghatelian, Alan -- Liu, David R -- DP2 OD002374/OD/NIH HHS/ -- F30 CA174152/CA/NCI NIH HHS/ -- P30 DK057521/DK/NIDDK NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- R00 GM080097/GM/NIGMS NIH HHS/ -- R01 GM065865/GM/NIGMS NIH HHS/ -- R01 GM081539/GM/NIGMS NIH HHS/ -- R01 GM81539/GM/NIGMS NIH HHS/ -- T32 GM007598/GM/NIGMS NIH HHS/ -- T32 GM008444/GM/NIGMS NIH HHS/ -- UL1 TR000430/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 3;511(7507):94-8. doi: 10.1038/nature13297. Epub 2014 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA. ; Department of Pharmacological Sciences, Stony Brook University, 1 Circle Road, Stony Brook, New York 11794, USA. ; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. ; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 3204 Biological Sciences III, Irvine, California 92697, USA. ; Ben-May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; 1] Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847884" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Blood Glucose/metabolism ; Catalytic Domain ; Diabetes Mellitus, Type 2/drug therapy/genetics ; Disease Models, Animal ; Gastric Emptying/drug effects ; Genetic Predisposition to Disease ; Glucagon/*metabolism ; Glucose Tolerance Test ; Hypoglycemic Agents/chemistry/*pharmacology/therapeutic use ; Insulin/*metabolism ; Insulysin/*antagonists & inhibitors/chemistry/genetics/metabolism ; Islet Amyloid Polypeptide/*metabolism ; Macrocyclic Compounds/chemistry/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Obesity/drug therapy/metabolism ; Signal Transduction/drug effects ; Thinness/drug therapy/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Promoterless gene targeting without nucleases ameliorates haemophilia B in mice (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-11-05
    Description: Site-specific gene addition can allow stable transgene expression for gene therapy. When possible, this is preferred over the use of promiscuously integrating vectors, which are sometimes associated with clonal expansion and oncogenesis. Site-specific endonucleases that can induce high rates of targeted genome editing are finding increasing applications in biological discovery and gene therapy. However, two safety concerns persist: endonuclease-associated adverse effects, both on-target and off-target; and oncogene activation caused by promoter integration, even without nucleases. Here we perform recombinant adeno-associated virus (rAAV)-mediated promoterless gene targeting without nucleases and demonstrate amelioration of the bleeding diathesis in haemophilia B mice. In particular, we target a promoterless human coagulation factor IX (F9) gene to the liver-expressed mouse albumin (Alb) locus. F9 is targeted, along with a preceding 2A-peptide coding sequence, to be integrated just upstream to the Alb stop codon. While F9 is fused to Alb at the DNA and RNA levels, two separate proteins are synthesized by way of ribosomal skipping. Thus, F9 expression is linked to robust hepatic albumin expression without disrupting it. We injected an AAV8-F9 vector into neonatal and adult mice and achieved on-target integration into approximately 0.5% of the albumin alleles in hepatocytes. We established that F9 was produced only from on-target integration, and ribosomal skipping was highly efficient. Stable F9 plasma levels at 7-20% of normal were obtained, and treated F9-deficient mice had normal coagulation times. In conclusion, transgene integration as a 2A-fusion to a highly expressed endogenous gene may obviate the requirement for nucleases and/or vector-borne promoters. This method may allow for safe and efficacious gene targeting in both infants and adults by greatly diminishing off-target effects while still providing therapeutic levels of expression from integration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297598/" 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/PMC4297598/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barzel, A -- Paulk, N K -- Shi, Y -- Huang, Y -- Chu, K -- Zhang, F -- Valdmanis, P N -- Spector, L P -- Porteus, M H -- Gaensler, K M -- Kay, M A -- F32 HL119059/HL/NHLBI NIH HHS/ -- F32-HL119059/HL/NHLBI NIH HHS/ -- R01 HL064274/HL/NHLBI NIH HHS/ -- R01-HL064274/HL/NHLBI NIH HHS/ -- UL1 TR001085/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):360-4. doi: 10.1038/nature13864. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Pediatrics and Genetics, 269 Campus Drive, CCSR Building, Room 2105, Stanford, California 94305-5164, USA. ; Department of Medicine, Box 1270, UCSF, San Francisco, California 94143-1270, USA. ; Department of Pediatrics, 269 Campus Drive, Lorry Lokey Stem Cell Research Building, Room G3045, Stanford, California 94305-5164, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363772" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Codon, Terminator/genetics ; Dependovirus/genetics/physiology ; Disease Models, Animal ; Endonucleases ; Factor IX/*genetics/*metabolism ; Female ; Gene Targeting/*methods ; Hemophilia B/*genetics ; Hepatocytes/metabolism ; Humans ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic ; Ribosomes/metabolism ; Serum Albumin/genetics ; Transgenes/genetics
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-16
    Description: Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. Advanced CF is characterized by a deficit in mucociliary transport (MCT), a process that traps and propels bacteria out of the lungs, but whether this deficit occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn piglets with CF. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, impaired MCT is a primary defect in CF, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346163/" 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/PMC4346163/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoegger, Mark J -- Fischer, Anthony J -- McMenimen, James D -- Ostedgaard, Lynda S -- Tucker, Alex J -- Awadalla, Maged A -- Moninger, Thomas O -- Michalski, Andrew S -- Hoffman, Eric A -- Zabner, Joseph -- Stoltz, David A -- Welsh, Michael J -- DK054759/DK/NIDDK NIH HHS/ -- DP2 HL117744/DP/NCCDPHP CDC HHS/ -- DP2 HL117744/HL/NHLBI NIH HHS/ -- HL051670/HL/NHLBI NIH HHS/ -- HL091842/HL/NHLBI NIH HHS/ -- P01 HL051670/HL/NHLBI NIH HHS/ -- P01 HL091842/HL/NHLBI NIH HHS/ -- P30 DK054759/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Aug 15;345(6198):818-22. doi: 10.1126/science.1255825.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. ; Department of Pediatrics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. ; Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. ; Central Microscopy Research Facility, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. ; Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Radiology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA. ; Department of Molecular Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA. david-stoltz@uiowa.edu michael-welsh@uiowa.edu. ; Department of Molecular Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Howard Hughes Medical Institute (HHMI), University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. david-stoltz@uiowa.edu michael-welsh@uiowa.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25124441" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Anions/metabolism ; Cilia/physiology ; Cystic Fibrosis/*physiopathology ; Cystic Fibrosis Transmembrane Conductance Regulator/physiology ; Disease Models, Animal ; Exocrine Glands/*secretion ; Lung/physiopathology ; Methacholine Chloride/pharmacology ; *Mucociliary Clearance ; Mucus/*secretion ; Respiratory Mucosa/*physiopathology ; Respiratory System/*physiopathology ; Swine ; Trachea/physiopathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-12
    Description: Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Delta7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naryshkin, Nikolai A -- Weetall, Marla -- Dakka, Amal -- Narasimhan, Jana -- Zhao, Xin -- Feng, Zhihua -- Ling, Karen K Y -- Karp, Gary M -- Qi, Hongyan -- Woll, Matthew G -- Chen, Guangming -- Zhang, Nanjing -- Gabbeta, Vijayalakshmi -- Vazirani, Priya -- Bhattacharyya, Anuradha -- Furia, Bansri -- Risher, Nicole -- Sheedy, Josephine -- Kong, Ronald -- Ma, Jiyuan -- Turpoff, Anthony -- Lee, Chang-Sun -- Zhang, Xiaoyan -- Moon, Young-Choon -- Trifillis, Panayiota -- Welch, Ellen M -- Colacino, Joseph M -- Babiak, John -- Almstead, Neil G -- Peltz, Stuart W -- Eng, Loren A -- Chen, Karen S -- Mull, Jesse L -- Lynes, Maureen S -- Rubin, Lee L -- Fontoura, Paulo -- Santarelli, Luca -- Haehnke, Daniel -- McCarthy, Kathleen D -- Schmucki, Roland -- Ebeling, Martin -- Sivaramakrishnan, Manaswini -- Ko, Chien-Ping -- Paushkin, Sergey V -- Ratni, Hasane -- Gerlach, Irene -- Ghosh, Anirvan -- Metzger, Friedrich -- New York, N.Y. -- Science. 2014 Aug 8;345(6197):688-93. doi: 10.1126/science.1250127.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. ; Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. ; PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. friedrich.metzger@roche.com speltz@ptcbio.com. ; SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA. ; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. ; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. ; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. friedrich.metzger@roche.com speltz@ptcbio.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25104390" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Oral ; Alternative Splicing/*drug effects ; Animals ; Cells, Cultured ; Coumarins/*administration & dosage/chemistry ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Isocoumarins/*administration & dosage/chemistry ; Longevity/*drug effects ; Mice ; Muscular Atrophy, Spinal/*drug therapy/genetics/metabolism ; Pyrimidinones/*administration & dosage/chemistry ; RNA, Messenger/genetics ; Sequence Deletion ; Small Molecule Libraries/*administration & dosage/chemistry ; Survival of Motor Neuron 2 Protein/*genetics/metabolism
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    Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-06-07
    Description: Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (Drd2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of Drd2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-Drd2-dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349506/" 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/PMC4349506/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chun, Sungkun -- Westmoreland, Joby J -- Bayazitov, Ildar T -- Eddins, Donnie -- Pani, Amar K -- Smeyne, Richard J -- Yu, Jing -- Blundon, Jay A -- Zakharenko, Stanislav S -- R01 DC012833/DC/NIDCD NIH HHS/ -- R01 MH095810/MH/NIMH NIH HHS/ -- R01 MH097742/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1178-82. doi: 10.1126/science.1253895.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. stanislav.zakharenko@stjude.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904170" target="_blank"〉PubMed〈/a〉
    Keywords: 22q11 Deletion Syndrome/drug therapy/*genetics ; Animals ; Antipsychotic Agents/therapeutic use ; Auditory Cortex/*metabolism ; Disease Models, Animal ; Drug Resistance/genetics ; *Haploinsufficiency ; Mice ; Mice, Mutant Strains ; MicroRNAs/metabolism ; RNA-Binding Proteins/*genetics ; Receptors, Dopamine D2/*biosynthesis/genetics ; Schizophrenia/drug therapy/*genetics ; Synaptic Transmission/genetics ; Thalamus/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-02-22
    Description: Growth factors (GFs) are critical in tissue repair, but their translation to clinical use has been modest. Physiologically, GF interactions with extracellular matrix (ECM) components facilitate localized and spatially regulated signaling; therefore, we reasoned that the lack of ECM binding in their clinically used forms could underlie the limited translation. We discovered that a domain in placenta growth factor-2 (PlGF-2(123-144)) binds exceptionally strongly and promiscuously to ECM proteins. By fusing this domain to the GFs vascular endothelial growth factor-A, platelet-derived growth factor-BB, and bone morphogenetic protein-2, we generated engineered GF variants with super-affinity to the ECM. These ECM super-affinity GFs induced repair in rodent models of chronic wounds and bone defects that was greatly enhanced as compared to treatment with the wild-type GFs, demonstrating that this approach may be useful in several regenerative medicine applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martino, Mikael M -- Briquez, Priscilla S -- Guc, Esra -- Tortelli, Federico -- Kilarski, Witold W -- Metzger, Stephanie -- Rice, Jeffrey J -- Kuhn, Gisela A -- Muller, Ralph -- Swartz, Melody A -- Hubbell, Jeffrey A -- New York, N.Y. -- Science. 2014 Feb 21;343(6173):885-8. doi: 10.1126/science.1247663.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24558160" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Morphogenetic Protein 2/chemistry/genetics/metabolism ; Disease Models, Animal ; Extracellular Matrix/*metabolism ; Extracellular Matrix Proteins/chemistry/metabolism ; Heparitin Sulfate/chemistry/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/chemistry/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Pregnancy Proteins/chemistry/genetics/metabolism ; Protein Engineering ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-sis/chemistry/genetics/metabolism ; Vascular Endothelial Growth Factor A/chemistry/genetics/metabolism ; *Wound Healing
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    C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-08-12
    Description: An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted "RNA-only" repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mizielinska, Sarah -- Gronke, Sebastian -- Niccoli, Teresa -- Ridler, Charlotte E -- Clayton, Emma L -- Devoy, Anny -- Moens, Thomas -- Norona, Frances E -- Woollacott, Ione O C -- Pietrzyk, Julian -- Cleverley, Karen -- Nicoll, Andrew J -- Pickering-Brown, Stuart -- Dols, Jacqueline -- Cabecinha, Melissa -- Hendrich, Oliver -- Fratta, Pietro -- Fisher, Elizabeth M C -- Partridge, Linda -- Isaacs, Adrian M -- 089701/Wellcome Trust/United Kingdom -- 098565/Wellcome Trust/United Kingdom -- G0701441/Medical Research Council/United Kingdom -- G1000287/Medical Research Council/United Kingdom -- MR/J004022/1/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 5;345(6201):1192-4. doi: 10.1126/science.1256800. Epub 2014 Aug 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. ; Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany. ; Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany. Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK. ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK. ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. MRC Prion Unit, UCL Institute of Neurology, London WC1N 3BG, UK. ; Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK. ; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK. ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London WC1N 3BG, UK. ; Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany. Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK. a.isaacs@prion.ucl.ac.uk l.partridge@ucl.ac.uk. ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. a.isaacs@prion.ucl.ac.uk l.partridge@ucl.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25103406" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Cell Line, Tumor ; DNA Repeat Expansion/*genetics ; Dipeptides/metabolism ; Disease Models, Animal ; Drosophila melanogaster/*genetics ; Escherichia coli ; Frontotemporal Dementia/*genetics/pathology ; Humans ; Neurons/metabolism/pathology ; Proteins/*genetics
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    Comparative behavior. Anxiety-like behavior in crayfish is controlled by serotonin (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-06-14
    Description: Anxiety, a behavioral consequence of stress, has been characterized in humans and some vertebrates, but not invertebrates. Here, we demonstrate that after exposure to stress, crayfish sustainably avoided the aversive illuminated arms of an aquatic plus-maze. This behavior was correlated with an increase in brain serotonin and was abolished by the injection of the benzodiazepine anxiolytic chlordiazepoxide. Serotonin injection into unstressed crayfish induced avoidance; again, this effect was reversed by injection with chlordiazepoxide. Our results demonstrate that crayfish exhibit a form of anxiety similar to that described in vertebrates, suggesting the conservation of several underlying mechanisms during evolution. Analyses of this ancestral behavior in a simple model reveal a new route to understanding anxiety and may alter our conceptions of the emotional status of invertebrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fossat, Pascal -- Bacque-Cazenave, Julien -- De Deurwaerdere, Philippe -- Delbecque, Jean-Paul -- Cattaert, Daniel -- New York, N.Y. -- Science. 2014 Jun 13;344(6189):1293-7. doi: 10.1126/science.1248811.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Science and Health, Universite de Bordeaux, 33 076 Bordeaux Cedex, France. Centre National de la Recherche Scientifique (CNRS), UMR 5287, Institut des Neurosciences Cognitives et Integratives d'Aquitaine, Avenue des Facultes, F-33405 Talence Cedex, France. ; Department of Life Science and Health, Universite de Bordeaux, 33 076 Bordeaux Cedex, France. CNRS, UMR 5293, Institut des Maladies Neurodegeneratives, Rue Leo Saignat, F-33076 Bordeaux, France. ; Department of Life Science and Health, Universite de Bordeaux, 33 076 Bordeaux Cedex, France. Centre National de la Recherche Scientifique (CNRS), UMR 5287, Institut des Neurosciences Cognitives et Integratives d'Aquitaine, Avenue des Facultes, F-33405 Talence Cedex, France. daniel.cattaert@u-bordeaux.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24926022" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anxiety/chemically induced/*metabolism ; Astacoidea/drug effects/*physiology ; Avoidance Learning ; *Behavior, Animal/drug effects ; Benzodiazepines/pharmacology ; Biological Evolution ; Disease Models, Animal ; Maze Learning ; Serotonin/*metabolism/pharmacology ; Stress, Psychological/chemically induced/*metabolism
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    Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-08-02
    Description: Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1-triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219555/" 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/PMC4219555/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwartz, Neil -- Temkin, Paul -- Jurado, Sandra -- Lim, Byung Kook -- Heifets, Boris D -- Polepalli, Jai S -- Malenka, Robert C -- P01 DA008227/DA/NIDA NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 1;345(6196):535-42. doi: 10.1126/science.1253994.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. ; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Department of Pharmacology, School of Medicine, University of Maryland, 655 West Baltimore Street, Baltimore, MD 21201, USA. ; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. ; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. malenka@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25082697" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chronic Pain/*physiopathology/*psychology ; Disease Models, Animal ; Gene Knockdown Techniques ; Long-Term Synaptic Depression/drug effects/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; *Motivation ; Nucleus Accumbens/*physiopathology ; Receptor, Galanin, Type 1/antagonists & inhibitors/genetics/*physiology
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    T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-08-30
    Description: CD8 tissue-resident memory T (T(RM)) cells provide efficient local control of viral infection, but the role of CD4 T(RM) is less clear. Here, by using parabiotic mice, we show that a preexisting pool of CD4 T(RM) cells in the genital mucosa was required for full protection from a lethal herpes simplex virus 2 (HSV-2) infection. Chemokines secreted by a local network of macrophages maintained vaginal CD4 T(RM) in memory lymphocyte clusters (MLCs), independently of circulating memory T cells. CD4 T(RM) cells within the MLCs were enriched in clones that expanded in response to HSV-2. Our results highlight the need for vaccine strategies that enable establishment of T(RM) cells for protection from a sexually transmitted virus and provide insights as to how such a pool might be established.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254703/" 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/PMC4254703/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iijima, Norifumi -- Iwasaki, Akiko -- AI054359/AI/NIAID NIH HHS/ -- AI062428/AI/NIAID NIH HHS/ -- P30 CA016359/CA/NCI NIH HHS/ -- R01 AI054359/AI/NIAID NIH HHS/ -- R01 AI062428/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):93-8. doi: 10.1126/science.1257530. Epub 2014 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. ; Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170048" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/*immunology ; Chemokine CCL5/immunology ; Chemokines/genetics/*immunology ; Disease Models, Animal ; Female ; Herpes Genitalis/*immunology ; *Herpesvirus 2, Human ; *Immunologic Memory ; Macrophages/*immunology ; Mice ; Mucous Membrane/immunology/virology ; Vagina/*immunology/virology
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    Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-22
    Description: Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274127/" 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/PMC4274127/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fowler, Benjamin J -- Gelfand, Bradley D -- Kim, Younghee -- Kerur, Nagaraj -- Tarallo, Valeria -- Hirano, Yoshio -- Amarnath, Shoba -- Fowler, Daniel H -- Radwan, Marta -- Young, Mark T -- Pittman, Keir -- Kubes, Paul -- Agarwal, Hitesh K -- Parang, Keykavous -- Hinton, David R -- Bastos-Carvalho, Ana -- Li, Shengjian -- Yasuma, Tetsuhiro -- Mizutani, Takeshi -- Yasuma, Reo -- Wright, Charles -- Ambati, Jayakrishna -- BB/J017345/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- DP1 GM114862/GM/NIGMS NIH HHS/ -- DP1GM114862/DP/NCCDPHP CDC HHS/ -- K99 EY024336/EY/NEI NIH HHS/ -- K99EY024336/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY022238/EY/NEI NIH HHS/ -- R01 EY024068/EY/NEI NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01EY022238/EY/NEI NIH HHS/ -- R01EY024068/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- TL1 RR033172/RR/NCRR NIH HHS/ -- TL1 TR000115/TR/NCATS NIH HHS/ -- UL1 RR033173/RR/NCRR NIH HHS/ -- UL1 TR000117/TR/NCATS NIH HHS/ -- UL1RR033173/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):1000-3. doi: 10.1126/science.1261754.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA. Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy. ; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. ; School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. ; Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada. ; Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA. ; Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. jamba2@email.uky.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25414314" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Carrier Proteins/metabolism ; Caspase 1/metabolism ; Choroidal Neovascularization/drug therapy ; Disease Models, Animal ; Geographic Atrophy/drug therapy ; Graft vs Host Disease/drug therapy ; Hepatitis/drug therapy ; Inflammasomes/*drug effects ; Liver/drug effects ; Mice ; Receptors, Purinergic P2X7/metabolism ; Retinal Pigment Epithelium/drug effects/metabolism/physiology ; Reverse Transcriptase Inhibitors/*pharmacology/therapeutic use
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Neuroscience. Jump-starting natural resilience reverses stress susceptibility (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Friedman, Allyson -- F32 MH096464/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 31;346(6209):555. doi: 10.1126/science.1260781.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25359955" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antidepressive Agents/chemistry/*pharmacology/therapeutic use ; Depressive Disorder, Major/*drug therapy/physiopathology ; Disease Models, Animal ; Disease Susceptibility ; Dopamine/physiology ; Dopamine Agents/chemistry/*pharmacology/therapeutic use ; Dopaminergic Neurons/*drug effects/physiology ; Drug Design ; Humans ; Mice ; Molecular Targeted Therapy ; Potassium Channels/metabolism ; *Resilience, Psychological ; Stress, Psychological/physiopathology/*psychology ; Ventral Tegmental Area/*drug effects/physiopathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-09-27
    Description: Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1alpha (hypoxia-inducible factor-1alpha) pathway. Inhibition of Akt, mTOR, or HIF-1alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1alpha pathway represents the metabolic basis of trained immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226238/" 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/PMC4226238/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Shih-Chin -- Quintin, Jessica -- Cramer, Robert A -- Shepardson, Kelly M -- Saeed, Sadia -- Kumar, Vinod -- Giamarellos-Bourboulis, Evangelos J -- Martens, Joost H A -- Rao, Nagesha Appukudige -- Aghajanirefah, Ali -- Manjeri, Ganesh R -- Li, Yang -- Ifrim, Daniela C -- Arts, Rob J W -- van der Veer, Brian M J W -- Deen, Peter M T -- Logie, Colin -- O'Neill, Luke A -- Willems, Peter -- van de Veerdonk, Frank L -- van der Meer, Jos W M -- Ng, Aylwin -- Joosten, Leo A B -- Wijmenga, Cisca -- Stunnenberg, Hendrik G -- Xavier, Ramnik J -- Netea, Mihai G -- 1P30GM106394-01/GM/NIGMS NIH HHS/ -- 5P30GM103415-03/GM/NIGMS NIH HHS/ -- DK097485/DK/NIDDK NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 GM103415/GM/NIGMS NIH HHS/ -- P30 GM106394/GM/NIGMS NIH HHS/ -- R01 AI081838/AI/NIAID NIH HHS/ -- R01 DK097485/DK/NIDDK NIH HHS/ -- R01AI81838/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1250684. doi: 10.1126/science.1250684.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. ; 4th Department of Internal Medicine, University of Athens Medical School, 12462 Athens, Greece. ; Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Physiology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. ; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. mihai.netea@radboudumc.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258083" target="_blank"〉PubMed〈/a〉
    Keywords: Aerobiosis/immunology ; Animals ; Candida albicans/immunology ; Candidiasis/immunology/metabolism ; Disease Models, Animal ; *Epigenesis, Genetic ; Female ; Glucose/metabolism ; Glycolysis/*immunology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Immunity, Innate/*genetics ; Immunologic Memory/*genetics ; Male ; Mice ; Mice, Inbred C57BL ; Monocytes/*immunology/metabolism ; Sepsis/genetics/immunology/metabolism ; Staphylococcal Infections/immunology/metabolism ; Staphylococcus aureus ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Transcriptome ; beta-Glucans/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Translational Medicine. A target for pharmacological intervention in an untreatable human disease (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-12-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, Simon C -- New York, N.Y. -- Science. 2014 Dec 5;346(6214):1192. doi: 10.1126/science.aaa1811.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Albert Einstein College of Medicine, 1301 Morris Park Avenue, Room 469, Bronx, NY 10462, USA. simon.johnson@einstein.yu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25477449" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caloric Restriction ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Electron Transport Complex I/genetics ; Humans ; Leigh Disease/*drug therapy/genetics/metabolism ; Mice ; *Molecular Targeted Therapy ; Saccharomyces cerevisiae/genetics ; Sirolimus/*administration & dosage ; TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-12-18
    Description: Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359082/" 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/PMC4359082/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNeil, Benjamin D -- Pundir, Priyanka -- Meeker, Sonya -- Han, Liang -- Undem, Bradley J -- Kulka, Marianna -- Dong, Xinzhong -- K99 NS087088/NS/NINDS NIH HHS/ -- R01 GM087369/GM/NIGMS NIH HHS/ -- R01 NS054791/NS/NINDS NIH HHS/ -- R01GM087369/GM/NIGMS NIH HHS/ -- R01NS054791/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 12;519(7542):237-41. doi: 10.1038/nature14022. Epub 2014 Dec 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Solomon H. Snyder Department of Neuroscience, Department of Neurosurgery, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada. ; Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada [2] National Institute for Nanotechnology, National Research Council Canada, Edmonton, Alberta T6G 2M9, Canada. ; 1] The Solomon H. Snyder Department of Neuroscience, Department of Neurosurgery, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA [2] Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517090" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Disease Models, Animal ; Drug Hypersensitivity/genetics/*immunology/prevention & control ; Female ; HEK293 Cells ; Histamine Release ; Humans ; Inflammation/immunology/metabolism ; Male ; Mast Cells/drug effects/*immunology/*metabolism ; Mice ; Mice, Knockout ; Nerve Tissue Proteins/antagonists & inhibitors/metabolism ; Receptors, G-Protein-Coupled/antagonists & ; inhibitors/deficiency/genetics/immunology/*metabolism ; Receptors, Neuropeptide/antagonists & inhibitors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Towards a therapy for Angelman syndrome by targeting a long non-coding RNA (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-12-04
    Description: Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351819/" 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/PMC4351819/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meng, Linyan -- Ward, Amanda J -- Chun, Seung -- Bennett, C Frank -- Beaudet, Arthur L -- Rigo, Frank -- P30HD024064/HD/NICHD NIH HHS/ -- R01 HD037283/HD/NICHD NIH HHS/ -- U54 HD083092/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):409-12. doi: 10.1038/nature13975. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Texas 77030, USA. ; Department of Core Antisense Research, Isis Pharmaceuticals, Carlsbad, California 92010, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470045" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Angelman Syndrome/complications/*genetics/*therapy ; Animals ; Brain/drug effects/metabolism ; Cells, Cultured ; Disease Models, Animal ; Fathers ; Female ; Gene Silencing/drug effects ; Genomic Imprinting/genetics ; Male ; Memory Disorders/complications/genetics/therapy ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Obesity/complications/genetics/therapy ; Oligonucleotides, Antisense/*genetics/pharmacology/*therapeutic use ; Phenotype ; RNA, Antisense/antagonists & inhibitors/deficiency/genetics ; RNA, Long Noncoding/*antagonists & inhibitors/*genetics ; Time Factors ; Ubiquitin-Protein Ligases/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Staff support (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-09-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 Sep 25;513(7519):459-60. doi: 10.1038/513459b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25254436" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Rights ; Animals ; *Animals, Laboratory ; Biomedical Research/*methods ; *Communication ; Disease Models, Animal ; Germany ; Haplorhini/*physiology ; Neurosciences/methods ; Public Opinion ; *Research Personnel
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-07-22
    Description: Rheumatoid arthritis is a chronic autoinflammatory disease that affects 1-2% of the world's population and is characterized by widespread joint inflammation. Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to production of interleukin-1beta in rheumatoid arthritis is limited by the absence of suitable mouse models of the disease in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients. Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2). Here we show, however, that it crucially relies on the Nlrp3 inflammasome and interleukin-1 receptor signalling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1beta. As a result, A20-deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and interleukin-1beta secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, because deletion of Nlrp3, caspase-1 and the interleukin-1 receptor markedly protects against rheumatoid-arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126806/" 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/PMC4126806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vande Walle, Lieselotte -- Van Opdenbosch, Nina -- Jacques, Peggy -- Fossoul, Amelie -- Verheugen, Eveline -- Vogel, Peter -- Beyaert, Rudi -- Elewaut, Dirk -- Kanneganti, Thirumala-Devi -- van Loo, Geert -- Lamkanfi, Mohamed -- 281600/European Research Council/International -- AI101935/AI/NIAID NIH HHS/ -- AR056296/AR/NIAMS NIH HHS/ -- CA163507/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):69-73. doi: 10.1038/nature13322. Epub 2014 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium. ; Department of Rheumatology, Ghent University, Ghent B-9000, Belgium. ; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Inflammation Research Center, VIB, Ghent B-9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium. ; 1] Inflammation Research Center, VIB, Ghent B-9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3]. ; 1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043000" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/metabolism ; Arthritis, Rheumatoid/immunology/*metabolism/pathology/prevention & control ; Calcium-Binding Proteins/metabolism ; Carrier Proteins/*metabolism ; Caspase 1/deficiency/metabolism ; Cysteine Endopeptidases/deficiency/*metabolism ; DNA-Binding Proteins ; Disease Models, Animal ; Female ; Inflammasomes/*metabolism ; Interleukin-1/metabolism ; Intracellular Signaling Peptides and Proteins/deficiency/*metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Knockout ; Nuclear Proteins/metabolism ; Phenotype ; Receptors, Interleukin-1/deficiency/metabolism ; Signal Transduction
    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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    Drug development: Illuminated targets (2014)
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    Publication Date: 2014-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cully, Megan -- England -- Nature. 2014 Jul 10;511(7508):S12-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25019129" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anticonvulsants/history/*therapeutic use ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Discovery/*trends ; Epilepsy/*drug therapy ; History, 20th Century ; History, 21st Century ; Humans
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Interception of host angiogenic signalling limits mycobacterial growth (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-12-04
    Description: Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis. Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis. Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations. Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312197/" 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/PMC4312197/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oehlers, Stefan H -- Cronan, Mark R -- Scott, Ninecia R -- Thomas, Monica I -- Okuda, Kazuhide S -- Walton, Eric M -- Beerman, Rebecca W -- Crosier, Philip S -- Tobin, David M -- 1DP2-OD008614/OD/NIH HHS/ -- 5P30 AI064518/AI/NIAID NIH HHS/ -- DP2 OD008614/OD/NIH HHS/ -- T32 GM007184/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jan 29;517(7536):612-5. doi: 10.1038/nature13967. Epub 2014 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1023, New Zealand.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470057" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/*pharmacology/therapeutic use ; Animals ; Anoxia/metabolism/microbiology/pathology ; Antibiotics, Antitubercular/pharmacology ; Bacterial Load/drug effects ; Disease Models, Animal ; Drug Synergism ; Granuloma/drug therapy/metabolism/microbiology/pathology ; Larva/drug effects/microbiology ; Macrophages/metabolism/microbiology/pathology ; Mycobacterium Infections, Nontuberculous/drug ; therapy/metabolism/*microbiology/pathology ; Mycobacterium marinum/*drug effects/*growth & development/pathogenicity ; Neovascularization, Pathologic/drug therapy/*microbiology ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors/metabolism ; Signal Transduction/*drug effects ; Tuberculosis/drug therapy/microbiology/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism ; Zebrafish/growth & development/*microbiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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