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  • 1
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    The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-06-16
    Description: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376394/" 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/PMC3376394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez-Mancera, Pedro A -- Rust, Alistair G -- van der Weyden, Louise -- Kristiansen, Glen -- Li, Allen -- Sarver, Aaron L -- Silverstein, Kevin A T -- Grutzmann, Robert -- Aust, Daniela -- Rummele, Petra -- Knosel, Thomas -- Herd, Colin -- Stemple, Derek L -- Kettleborough, Ross -- Brosnan, Jacqueline A -- Li, Ang -- Morgan, Richard -- Knight, Spencer -- Yu, Jun -- Stegeman, Shane -- Collier, Lara S -- ten Hoeve, Jelle J -- de Ridder, Jeroen -- Klein, Alison P -- Goggins, Michael -- Hruban, Ralph H -- Chang, David K -- Biankin, Andrew V -- Grimmond, Sean M -- Australian Pancreatic Cancer Genome Initiative -- Wessels, Lodewyk F A -- Wood, Stephen A -- Iacobuzio-Donahue, Christine A -- Pilarsky, Christian -- Largaespada, David A -- Adams, David J -- Tuveson, David A -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA122183/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- K01 CA122183/CA/NCI NIH HHS/ -- K01 CA122183-05/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50CA62924/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Apr 29;486(7402):266-70. doi: 10.1038/nature11114.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699621" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoikis/genetics ; Carcinoma, Pancreatic Ductal/*enzymology/genetics/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Endopeptidases ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Mice ; Mice, Inbred C57BL ; Pancreatic Neoplasms/*enzymology/genetics/pathology ; U937 Cells ; Ubiquitin Thiolesterase/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-03-31
    Description: Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324089/" 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/PMC3324089/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lamming, Dudley W -- Ye, Lan -- Katajisto, Pekka -- Goncalves, Marcus D -- Saitoh, Maki -- Stevens, Deanna M -- Davis, James G -- Salmon, Adam B -- Richardson, Arlan -- Ahima, Rexford S -- Guertin, David A -- Sabatini, David M -- Baur, Joseph A -- 1F32AG032833-01A1/AG/NIA NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- F32 AG032833/AG/NIA NIH HHS/ -- P30DK19525/DK/NIDDK NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Mar 30;335(6076):1638-43. doi: 10.1126/science.1215135.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22461615" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/metabolism ; Animals ; Carrier Proteins/genetics/metabolism ; Female ; Gluconeogenesis ; Glucose/metabolism ; Glucose Clamp Technique ; Homeostasis ; Insulin/administration & dosage/blood ; *Insulin Resistance ; Liver/metabolism ; *Longevity ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes ; Muscle, Skeletal/metabolism ; Phosphorylation ; Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/genetics/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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  • 3
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    Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-07-07
    Description: Obstruction of critical blood vessels due to thrombosis or embolism is a leading cause of death worldwide. Here, we describe a biomimetic strategy that uses high shear stress caused by vascular narrowing as a targeting mechanism--in the same way platelets do--to deliver drugs to obstructed blood vessels. Microscale aggregates of nanoparticles were fabricated to break up into nanoscale components when exposed to abnormally high fluid shear stress. When coated with tissue plasminogen activator and administered intravenously in mice, these shear-activated nanotherapeutics induce rapid clot dissolution in a mesenteric injury model, restore normal flow dynamics, and increase survival in an otherwise fatal mouse pulmonary embolism model. This biophysical strategy for drug targeting, which lowers required doses and minimizes side effects while maximizing drug efficacy, offers a potential new approach for treatment of life-threatening diseases that result from acute vascular occlusion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Korin, Netanel -- Kanapathipillai, Mathumai -- Matthews, Benjamin D -- Crescente, Marilena -- Brill, Alexander -- Mammoto, Tadanori -- Ghosh, Kaustabh -- Jurek, Samuel -- Bencherif, Sidi A -- Bhatta, Deen -- Coskun, Ahmet U -- Feldman, Charles L -- Wagner, Denisa D -- Ingber, Donald E -- New York, N.Y. -- Science. 2012 Aug 10;337(6095):738-42. doi: 10.1126/science.1217815. Epub 2012 Jul 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22767894" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomimetic Materials ; Blood Circulation ; Drug Delivery Systems/*methods ; Fibrinolytic Agents/*administration & dosage ; Hemodynamics ; Hemorheology ; Lactic Acid ; Male ; Mesenteric Arteries ; Mesenteric Vascular Occlusion/*drug therapy ; Mice ; Mice, Inbred C57BL ; Microfluidic Analytical Techniques ; Models, Anatomic ; *Nanoparticles ; Polyglycolic Acid ; Pulmonary Embolism/*drug therapy ; Stress, Mechanical ; Thrombosis/*drug therapy/prevention & control ; Tissue Plasminogen Activator/*administration & dosage
    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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    Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-09-06
    Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" 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/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Animals ; Biphenyl Compounds/chemistry/pharmacology ; Body Fluids/drug effects ; COS Cells ; Cercopithecus aethiops ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors ; Dietary Fats/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hypoglycemic Agents/adverse effects/chemistry/*pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Models, Molecular ; Obesity/chemically induced/metabolism ; Osteogenesis/drug effects ; PPAR gamma/agonists/chemistry/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Thiazolidinediones/adverse effects/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Weight Gain/drug effects
    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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  • 5
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    CaMKII determines mitochondrial stress responses in heart (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-12
    Description: Myocardial cell death is initiated by excessive mitochondrial Ca(2+) entry causing Ca(2+) overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (DeltaPsim). However, the signalling pathways that control mitochondrial Ca(2+) entry through the inner membrane mitochondrial Ca(2+) uniporter (MCU) are not known. The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated in ischaemia reperfusion, myocardial infarction and neurohumoral injury, common causes of myocardial death and heart failure; these findings suggest that CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (I(MCU)). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia reperfusion injury, equivalently prevent mPTP opening, DeltaPsim deterioration and diminish mitochondrial disruption and programmed cell death in response to ischaemia reperfusion injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition have reduced I(MCU) and are resistant to ischaemia reperfusion injury, myocardial infarction and neurohumoral injury, suggesting that pathological actions of CaMKII are substantially mediated by increasing I(MCU). Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca(2+) entry in myocardial cell death, and indicate that mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure in response to common experimental forms of pathophysiological stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471377/" 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/PMC3471377/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joiner, Mei-Ling A -- Koval, Olha M -- Li, Jingdong -- He, B Julie -- Allamargot, Chantal -- Gao, Zhan -- Luczak, Elizabeth D -- Hall, Duane D -- Fink, Brian D -- Chen, Biyi -- Yang, Jinying -- Moore, Steven A -- Scholz, Thomas D -- Strack, Stefan -- Mohler, Peter J -- Sivitz, William I -- Song, Long-Sheng -- Anderson, Mark E -- R01 HL062494/HL/NHLBI NIH HHS/ -- R01 HL070250/HL/NHLBI NIH HHS/ -- R01 HL079031/HL/NHLBI NIH HHS/ -- R01 HL083422/HL/NHLBI NIH HHS/ -- R01 HL084583/HL/NHLBI NIH HHS/ -- R01 HL090905/HL/NHLBI NIH HHS/ -- R01 HL113001/HL/NHLBI NIH HHS/ -- R01 HL62494/HL/NHLBI NIH HHS/ -- R01 HL70250/HL/NHLBI NIH HHS/ -- R56 NS056244/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):269-73. doi: 10.1038/nature11444. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine and Cardiovascular Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. mei-ling-joiner@uiowa.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051746" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/drug effects ; Calcium/*metabolism/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & ; inhibitors/chemistry/*metabolism ; Cyclosporine/pharmacology ; Female ; Heart/drug effects/physiopathology ; Heart Failure/drug therapy/prevention & control ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria, Heart/enzymology/*metabolism/*pathology ; Mitochondrial Membrane Transport Proteins/metabolism ; Myocardial Infarction/drug therapy/prevention & control ; Myocardium/*enzymology/metabolism/*pathology ; Reperfusion Injury/enzymology/metabolism/pathology/prevention & control ; Serine/metabolism ; *Stress, Physiological/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-06-08
    Description: The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432565/" 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/PMC3432565/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iliev, Iliyan D -- Funari, Vincent A -- Taylor, Kent D -- Nguyen, Quoclinh -- Reyes, Christopher N -- Strom, Samuel P -- Brown, Jordan -- Becker, Courtney A -- Fleshner, Phillip R -- Dubinsky, Marla -- Rotter, Jerome I -- Wang, Hanlin L -- McGovern, Dermot P B -- Brown, Gordon D -- Underhill, David M -- 086558/Wellcome Trust/United Kingdom -- AI071116/AI/NIAID NIH HHS/ -- P01-DK046763/DK/NIDDK NIH HHS/ -- R01 DK093426/DK/NIDDK NIH HHS/ -- UL1 RR033176/RR/NCRR NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- UL1RR033176/RR/NCRR NIH HHS/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2012 Jun 8;336(6086):1314-7. doi: 10.1126/science.1221789. Epub 2012 Jun 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22674328" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Fungal/blood ; Candida tropicalis/immunology/isolation & purification/pathogenicity/physiology ; Colitis, Ulcerative/chemically induced/*immunology/*microbiology ; Colon/immunology/*microbiology ; Colony Count, Microbial ; Dextran Sulfate ; Disease Susceptibility ; Female ; Fungi/classification/*immunology/isolation & purification/*physiology ; Haplotypes ; Humans ; Immunity, Innate ; Immunity, Mucosal ; Intestinal Mucosa/immunology/*microbiology ; Intestines/immunology/microbiology ; Lectins, C-Type/deficiency/*genetics/*metabolism ; Metagenome ; Mice ; Mice, Inbred C57BL ; Polymorphism, Single Nucleotide
    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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    Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-02
    Description: Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241145/" 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/PMC4241145/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rasmussen, Angela L -- Okumura, Atsushi -- Ferris, Martin T -- Green, Richard -- Feldmann, Friederike -- Kelly, Sara M -- Scott, Dana P -- Safronetz, David -- Haddock, Elaine -- LaCasse, Rachel -- Thomas, Matthew J -- Sova, Pavel -- Carter, Victoria S -- Weiss, Jeffrey M -- Miller, Darla R -- Shaw, Ginger D -- Korth, Marcus J -- Heise, Mark T -- Baric, Ralph S -- de Villena, Fernando Pardo-Manuel -- Feldmann, Heinz -- Katze, Michael G -- P51 OD010425/OD/NIH HHS/ -- U19 AI100625/AI/NIAID NIH HHS/ -- U19 AI109761/AI/NIAID NIH HHS/ -- U54 AI081680/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):987-91. doi: 10.1126/science.1259595. Epub 2014 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, University of Washington, Seattle, WA, USA. ; Department of Microbiology, University of Washington, Seattle, WA, USA. Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA. ; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. ; Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA. ; Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA. ; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. ; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. ; Department of Microbiology, University of Washington, Seattle, WA, USA. Washington National Primate Research Center, Seattle, WA, USA. honey@uw.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25359852" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Blood Coagulation/genetics ; Capillary Permeability/genetics ; *Disease Models, Animal ; Endothelium, Vascular/physiopathology ; *Genetic Predisposition to Disease ; Hemorrhagic Fever, Ebola/blood/*genetics/*immunology ; Host-Pathogen Interactions/*genetics ; Liver/blood supply/metabolism/pathology ; Lymphocyte Activation/immunology ; *Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic/genetics ; Receptor, TIE-2/*genetics
    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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    Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-12-14
    Description: The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-alpha and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487691/" 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/PMC3487691/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fritz, Jorg H -- Rojas, Olga Lucia -- Simard, Nathalie -- McCarthy, Douglas D -- Hapfelmeier, Siegfried -- Rubino, Stephen -- Robertson, Susan J -- Larijani, Mani -- Gosselin, Jean -- Ivanov, Ivaylo I -- Martin, Alberto -- Casellas, Rafael -- Philpott, Dana J -- Girardin, Stephen E -- McCoy, Kathy D -- Macpherson, Andrew J -- Paige, Christopher J -- Gommerman, Jennifer L -- 67157-3/Canadian Institutes of Health Research/Canada -- 89783-2/Canadian Institutes of Health Research/Canada -- MOP 114972/Canadian Institutes of Health Research/Canada -- MOP 67157/Canadian Institutes of Health Research/Canada -- MOP 89783/Canadian Institutes of Health Research/Canada -- MOP 9862/Canadian Institutes of Health Research/Canada -- R00 DK085329/DK/NIDDK NIH HHS/ -- R00 DK085329-02/DK/NIDDK NIH HHS/ -- Z01 AR041148-03/Intramural NIH HHS/ -- ZIA AR041148-08/Intramural NIH HHS/ -- England -- Nature. 2011 Dec 11;481(7380):199-203. doi: 10.1038/nature10698.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158124" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Cell Lineage ; Cells, Cultured ; Chimera/immunology ; Citrobacter rodentium/immunology ; Coculture Techniques ; Female ; Germ-Free Life ; Granulocytes/cytology/metabolism ; Immunity, Innate/immunology ; Immunoglobulin A/biosynthesis/*immunology ; Intestinal Mucosa/cytology/immunology ; Intestine, Small/*cytology/*immunology/microbiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes/cytology/metabolism ; Nitric Oxide Synthase Type II/biosynthesis/deficiency/metabolism ; Phenotype ; Plasma Cells/*cytology/*immunology/metabolism ; Spleen/cytology ; Stromal Cells/cytology ; Tumor Necrosis Factor-alpha/biosynthesis/deficiency/immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma (2014)
    Nature Publishing Group (NPG)
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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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    In vivo genome editing restores haemostasis in a mouse model of haemophilia (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-06-28
    Description: Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152293/" 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/PMC3152293/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Hojun -- Haurigot, Virginia -- Doyon, Yannick -- Li, Tianjian -- Wong, Sunnie Y -- Bhagwat, Anand S -- Malani, Nirav -- Anguela, Xavier M -- Sharma, Rajiv -- Ivanciu, Lacramiora -- Murphy, Samuel L -- Finn, Jonathan D -- Khazi, Fayaz R -- Zhou, Shangzhen -- Paschon, David E -- Rebar, Edward J -- Bushman, Frederic D -- Gregory, Philip D -- Holmes, Michael C -- High, Katherine A -- P01 HL064190/HL/NHLBI NIH HHS/ -- P01 HL064190-11A1/HL/NHLBI NIH HHS/ -- T32 HL007150/HL/NHLBI NIH HHS/ -- T32 HL007150-35/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 26;475(7355):217-21. doi: 10.1038/nature10177.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology, CTRB 5000, Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21706032" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; *Disease Models, Animal ; Endonucleases/chemistry/genetics/metabolism ; Exons/genetics ; Factor IX/analysis/genetics ; Gene Targeting/*methods ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; Genome/*genetics ; HEK293 Cells ; Hemophilia B/*genetics/physiopathology ; *Hemostasis ; Humans ; Introns/genetics ; Liver/metabolism ; Liver Regeneration ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Phenotype ; Sequence Homology ; Zinc Fingers
    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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